A mimetic peptide of ACE2 protects against SARS-CoV-2 infection and decreases pulmonary inflammation related to COVID-19.

Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22-46 of the ACE2 alpha-helix α1) implicated in the S1 receptor-binding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells in vitro. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix α1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S1 RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix α1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the in vitro viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against in vivo SARS-CoV-2 infection and is effective for the treatment of COVID-19.

SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology.

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.

Host Retromer Protein Sorting Nexin 2 Interacts with Human Respiratory Syncytial Virus Structural Proteins and is Required for Efficient Viral Production.

Human respiratory syncytial virus (HRSV) envelope glycoproteins traffic to assembly sites through the secretory pathway, while nonglycosylated proteins M and N are present in HRSV inclusion bodies but must reach the plasma membrane, where HRSV assembly happens. Little is known about how nonglycosylated HRSV proteins reach assembly sites. Here, we show that HRSV M and N proteins partially colocalize with the Golgi marker giantin, and the glycosylated F and nonglycosylated N proteins are closely located in the trans-Golgi, suggesting their interaction in that compartment. Brefeldin A compromised the trafficking of HRSV F and N proteins and inclusion body sizes, indicating that the Golgi is important for both glycosylated and nonglycosylated HRSV protein traffic. HRSV N and M proteins colocalized and interacted with sorting nexin 2 (SNX2), a retromer component that shapes endosomes in tubular structures. Glycosylated F and nonglycosylated N HRSV proteins are detected in SNX2-laden aggregates with intracellular filaments projecting from their outer surfaces, and VPS26, another retromer component, was also found in inclusion bodies and filament-shaped structures. Similar to SNX2, TGN46 also colocalized with HRSV M and N proteins in filamentous structures at the plasma membrane. Cell fractionation showed enrichment of SNX2 in fractions containing HRSV M and N proteins. Silencing of SNX1 and 2 was associated with reduction in viral proteins, HRSV inclusion body size, syncytium formation, and progeny production. The results indicate that HRSV structural proteins M and N are in the secretory pathway, and SNX2 plays an important role in the traffic of HRSV structural proteins toward assembly sites.IMPORTANCE The present study contributes new knowledge to understand HRSV assembly by providing evidence that nonglycosylated structural proteins M and N interact with elements of the secretory pathway, shedding light on their intracellular traffic. To the best of our knowledge, the present contribution is important given the scarcity of studies about the traffic of HRSV nonglycosylated proteins, especially by pointing to the involvement of SNX2, a retromer component, in the HRSV assembly process.

B lymphocyte-induced maturation protein 1 controls TH9 cell development, IL-9 production, and allergic inflammation.

BACKGROUND: The transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1) has a key role in terminal differentiation in various T-cell subtypes. However, whether Blimp-1 regulates TH9 differentiation and its role in allergic inflammation are unknown. OBJECTIVE: We aimed to investigate the role of Blimp-1 in TH9 differentiation and in the pathogenesis of allergic airway inflammation. METHODS: In vitro TH9 differentiation, flow cytometry, ELISA, and real-time PCR were used to investigate the effects of Blimp-1 on TH9 polarization. T cell-specific Blimp-1-deficient mice, a model of allergic airway inflammation, and T-cell adoptive transfer to recombination-activating gene 1 (Rag-1)-/- mice were used to address the role of Blimp-1 in the pathogenesis of allergic inflammation. RESULTS: We found that Blimp-1 regulates TH9 differentiation because deleting Blimp-1 increased IL-9 production in CD4+ T cells in vitro. In addition, we showed that in T cell-specific Blimp-1-deficient mice, deletion of Blimp-1 in T cells worsened airway disease, and this worsening was inhibited by IL-9 neutralization. In asthmatic patients CD4+ T cells in response to TGF-ß plus IL-4 increased IL-9 expression and downregulated Blimp-1 expression compared with expression in healthy control subjects. Blimp-1 overexpression in human TH9 cells inhibited IL-9 expression. CONCLUSION: Blimp-1 is a pivotal negative regulator of TH9 differentiation and controls allergic inflammation.

Distinguishability notion based on Wootters statistical distance: Application to discrete maps.

We study the distinguishability notion given by Wootters for states represented by probability density functions. This presents the particularity that it can also be used for defining a statistical distance in chaotic unidimensional maps. Based on that definition, we provide a metric d¯ for an arbitrary discrete map. Moreover, from d¯, we associate a metric space with each invariant density of a given map, which results to be the set of all distinguished points when the number of iterations of the map tends to infinity. Also, we give a characterization of the wandering set of a map in terms of the metric d¯, which allows us to identify the dissipative regions in the phase space. We illustrate the results in the case of the logistic and the circle maps numerically and analytically, and we obtain d¯ and the wandering set for some characteristic values of their parameters. Finally, an extension of the metric space associated for arbitrary probability distributions (not necessarily invariant densities) is given along with some consequences. The statistical properties of distributions given by histograms are characterized in terms of the cardinal of the associated metric space. For two conjugate variables, the uncertainty principle is expressed in terms of the diameters of the associated metric space with those variables.

Comment on "Quantum Kaniadakis entropy under projective measurement".

We comment on the main result given by Ourabah et al. [Phys. Rev. E 92, 032114 (2015)PLEEE81539-375510.1103/PhysRevE.92.032114], noting that it can be derived as a special case of the more general study that we have provided in [Quantum Inf Process 15, 3393 (2016)10.1007/s11128-016-1329-5]. Our proof of the nondecreasing character under projective measurements of so-called generalized (h,ϕ) entropies (that comprise the Kaniadakis family as a particular case) has been based on majorization and Schur-concavity arguments. As a consequence, we have obtained that this property is obviously satisfied by Kaniadakis entropy but at the same time is fulfilled by all entropies preserving majorization. In addition, we have seen that our result holds for any bistochastic map, being a projective measurement a particular case. We argue here that looking at these facts from the point of view given in [Quantum Inf Process 15, 3393 (2016)10.1007/s11128-016-1329-5] not only simplifies the demonstrations but allows for a deeper understanding of the entropic properties involved.

Effect of the microtubule-associated protein tau on dynamics of single-headed motor proteins KIF1A.

Intracellular transport based on molecular motors and its regulation are crucial to the functioning of cells. Filamentary tracks of the cells are abundantly decorated with nonmotile microtubule-associated proteins, such as tau. Motivated by experiments on kinesin-tau interactions [Dixit et al., Science 319, 1086 (2008)] we developed a stochastic model of interacting single-headed motor proteins KIF1A that also takes into account the interactions between motor proteins and tau molecules. Our model reproduces experimental observations and predicts significant effects of tau on bound time and run length which suggest an important role of tau in regulation of kinesin-based transport.

Shock detection in dynamics of single-headed motor proteins KIF1A via Jensen-Shannon divergence.

Information theoretic quantities are useful tools to characterize symbolic sequences. In this paper, we use the Jensen-Shannon divergence to study symbolic binary sequences that represent the stationary state of a lattice-gas model describing the traffic of monomeric kinesin KIF1A. More specifically, the constructed binary sequences represent the state of a microtubule protofilament at different adenosine triphosphate (ATP) and KIF1A motor concentrations in the cytosol. The model presents some stationary regimes with phase coexistence. By using the Jensen-Shannon divergence, we develop a method of analysis that allows us to identify cases in which phase coexistence occurs and, for these cases, to locate the position of the interphase that separates the regions with different phase.

Regularization of the displacement moments for asymmetric Lévy flights.

Although the second displacement moments for Lévy flights are not defined in their usual sense, a few years ago it was shown that nonextensive statistical mechanics can be used to define them for symmetric flights. Here it is shown that the displacement moments for long-jump asymmetric Lévy flights can also be regularized by calculating the averages in the form prescribed by nonextensive statistical mechanics. The dependence of the generalized diffusion coefficient on the asymmetry strength is investigated. It is also shown that no extremum q -entropy principle can be associated with the asymmetric Lévy attractors.

Epidemiology of progressive supranuclear palsy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms.

Progressive supranuclear palsy (PSP) is a rare form of parkinsonism. The incidence rates are about 0.3-1.1 cases per 100,000 persons. The only two case-control studies performed up to now show conflictual results as regards education and residence in rural areas. Recently, a cluster of PSP and atypical parkinsonism has been observed in French Antilles. The hypothesis is that a consumption of both tropical fruit and herbal tea may be associated with PSP onset. Some PSP families with a probably autosomal dominant transmission have been described. A high frequency of a tau haplotype (H1/H1) associated with PSP is reported by some authors. The significance of this association is still not clear. We have performed a case-control study on 58 PSP cases, 116 hospital controls and 58 population controls.

Observability of stochastic resonance in neutron scattering.

The observability of the stochastic resonance phenomenon in a neutron scattering experiment is investigated, considering that the scatterer can hop between two sites. Under stochastic resonance conditions scattered intensity is transferred from the quasielastic region to two inelastic peaks. The magnitude of the signal-to-noise ratio is shown to be similar to that arising in the corresponding power spectrum. Effects of potential asymmetry are discussed in detail. Asymmetry leads to a reduction of the signal-to-noise ratio by a factor of 1-xi(2), where xi is an asymmetry parameter which is zero for symmetric problems and equal to unity in a completely asymmetric case.