Coupled Reversible and Irreversible Bistable Switches Underlying TGF-\beta-induced Epithelial to Mesenchymal Transition

Epithelial to mesenchymal transition (EMT) plays important roles in embryonic development, tissue regeneration and cancer metastasis. While several feedback loops have been shown to regulate EMT, it remains elusive how they coordinately modulate EMT response to TGF-\beta treatment. We construct a mathematical model for the core regulatory network controlling TGF-\beta-induced EMT. Through deterministic analyses and stochastic simulations, we show that EMT is a sequential two-step program that an epithelial cell first transits to partial EMT then to the mesenchymal state, depending on the strength and duration of TGF-\beta stimulation. Mechanistically the system is governed by coupled reversible and irreversible bistable switches. The SNAIL1/miR-34 double negative feedback loop is responsible for the reversible switch and regulates the initiation of EMT, while the ZEB/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-\beta/miR-200 feedback loop makes the second switch irreversible, modulating the maintenance of EMT. Such coupled bistable switches are robust to parameter variation and molecular noise. We provide a mechanistic explanation on multiple experimental observations. The model makes several explicit predictions on hysteretic dynamic behaviors, system response to pulsed stimulation and various perturbations, which can be straightforwardly tested.Comment: 32 pages, 8 figures, accepted by Biophysical Journa

Sequential Wnt Agonist then Antagonist Treatment Accelerates Tissue Repair and Minimizes Fibrosis

Tissue fibrosis compromises organ function and occurs as a potential long-term outcome in response to acute tissue injuries. Currently, lack of mechanistic understanding prevents effective prevention and treatment of the progression from acute injury to fibrosis. Here, we combined quantitative experimental studies with a mouse kidney injury model and a computational approach to determine how the physiological consequences are determined by the severity of ischemia injury, and to identify how to manipulate Wnt signaling to accelerate repair of ischemic tissue damage while minimizing fibrosis. The study reveals that Wnt-mediated memory of prior injury contributes to fibrosis progression, and ischemic preconditioning reduces the risk of death but increases the risk of fibrosis. Furthermore, we validated the prediction that sequential combination therapy of initial treatment with a Wnt agonist followed by treatment with a Wnt antagonist can reduce both the risk of death and fibrosis in response to acute injuries

Classical-driving-assisted quantum synchronization in non-Markovian environments

We study the quantum phase synchronization of a driven two-level system (TLS) coupled to a structured environment and demonstrate that quantum synchronization can be enhanced by the classical driving field. We use the Husimi $Q$-function to characterize the phase preference and find the in-phase and anti-phase locking phenomenon in the phase diagram. Remarkably, we show that the classical driving enables a TLS to reach stable anti-phase locking in the Markovian regime. However, we find that the synergistic action of classical driving and non-Markovian effects significantly enhances the in-phase locking. By introducing the $S$-function and its maximal value to quantify the strength of synchronization and sketch the synchronization regions, we observe the typical signatures of the hollowed Arnold tongue in the parameter regions of synchronization. In the hollowed Arnold tongue, the synchronization regions exist both inside and outside the tongue while unsynchronized regions only lie on the boundary line. We also provide an intuitive interpretation of the above results by using the quasimode theory.Comment: 10 pages, 5 figures, revised versio

Phase evolution of Ce-based heavy-fermion superconductors under pressure: a combined DFT+DMFT and effective-model description

In typical Ce-based heavy-fermion superconductors, superconducting (SC) phases emerge or can be tuned in proximity to the antiferromagnetic (AF) quantum critical point (QCP), but so far the explicit phase-evolution process and the coexistence of superconductivity and AF order near the QCP remain lack of understanding. Here, by combing DFT+DMFT with effective-model calculations, we provide a theoretical description for Ce-based SC compounds under pressure. Firstly, DFT+DMFT calculations for the normal states reveal that the Kondo hybridizations are significantly enhanced, while the initially localized $f$ electrons eventually become fully itinerant via a localized-itinerant crossover. In this context, we construct an effective model with tunable parameters under pressure, and show that the interplay of magnetic correlation and Kondo hybridization can drive successive transitions, from AF phase to AF+SC coexisting phase, then to paramagnetic SC phase via an AF transition which corresponds to the QCP, and finally to Kondo paramagnetic phase through a SC transition driven by localized-itinerant crossover. Our study gives a proper explanation for the pressure-induced magnetic QCP and SC transition, and for the phase-evolution process under pressure in typical Ce-based superconductors, and may also help to understand the SC states emerging around the ferromagnetic quantum transition points in uranium-based superconductors.Comment: 13 pages, 11 figure

Global fitness profiling of fission yeast deletion strains by barcode sequencing

A genome-wide deletion library is a powerful tool for probing gene functions and one has recently become available for the fission yeast Schizosaccharomyces pombe. Here we use deep sequencing to accurately characterize the barcode sequences in the deletion library, thus enabling the quantitative measurement of the fitness of fission yeast deletion strains by barcode sequencing

Node-line Dirac semimetal manipulated by Kondo mechanism in nonsymmorphic CePt2_2Si2_2

Dirac node lines (DNLs) are characterized by Dirac-type linear crossings between valence and conduction bands along one-dimensional node lines in the Brillouin zone (BZ). Spin-orbit coupling (SOC) usually shifts the degeneracy at the crossings thus destroys DNLs, and so far the reported DNLs in a few materials are non-interacting type, making the search for robust interacting DNLs in real materials appealing. Here, via first-principle calculations, we reveal that Kondo interaction together with nonsymmorphic lattice symmetries can drive a robust interacting DNLs in a Kondo semimetal CePt_2Si_2, and the feature of DNLs can be significantly manipulated by Kondo behavior in different temperature regions. Based on the density function theory combining dynamical mean-field theory (DFT+DMFT), we predict a transition to Kondo-coherent state at coherent temperature T_coh= 80 K upon cooling, verified by temperature dependence of Ce-4f self-energy, Kondo resonance peak, magnetic susceptibility and momentum-resolved spectral. Below T_coh, well-resolved narrow heavy-fermion bands emerge near the Fermi level, constructing clearly visualized interacting DNLs locating at the BZ boundary, in which the Dirac fermions have strongly enhanced effective mass and reduced velocity. In contrast, above a crossover temperature T_KS =600 K, the destruction of local Kondo screening drives non-interacting DNLs which are comprised by light conduction electrons at the same location. These DNLs are protected by lattice nonsymmorphic symmetries thus robust under intrinsic strong SOC. Our proposal of DNLs which can be significantly manipulated according to Kondo behavior provides an unique realization of interacting Dirac semimetals in real strongly correlated materials, and serves as a convenient platform to investigate the effect of electronic correlations on topological materials.Comment: 9 pages, 9 figure

The multitasking Fasciola gigantica Cathepsin B interferes with various functions of goat peripheral blood mononuclear cells in vitro

Cathepsin B, a lysosomal cysteine protease, is thought to be involved in the pathogenesis of Fasciola gigantica infection, but its exact role remains unclear. In the present study, a recombinant F. gigantica cathepsin B (rFgCatB) protein was expressed in the methylotrophic yeast Pichia pastoris. Western blot analysis confirmed the reactivity of the purified rFgCatB protein to serum from F. gigantica-infected goats. The effects of serial concentrations (10, 20, 40, 80, and 160 μg/ml) of rFgCatB on various functions of goat peripheral blood mononuclear cells (PBMCs) were examined. We demonstrated that rFgCatB protein can specifically bind to the surface of PBMCs. In addition, rFgCatB increased the expression of cytokines (IL-2, IL-4, IL-10, IL-17, TGF-β, and IFN-γ), and increased nitric oxide production and cell apoptosis, but reduced cell viability. These data show that rFgCatB can influence cellular and immunological functions of goat PBMCs. Further characterization of the posttranslational modification and assessment of rFgCatB in immunogenicity studies is warranted