Quench dynamics of Fano-like resonances in the presence of the on-dot superconducting pairing.

We explore the electron dynamics of a system composed of double quantum dot embedded between metallic and superconducting leads in a "T-shape" geometry. In nanoscopic systems, where electron transfer between electrodes can be realized via different paths, interference effects play an important role. For double quantum dot system in the chosen geometry, interference of electrons transferred between electrodes via the interfacial quantum dot and electrons scattered on the side dot gives rise to Fano-like interference. If such a system is additionally coupled to a superconducting electrode, together with the well-understood Fano resonance an additional resonance appears on the opposite side of the Fermi level. In the recent work (Baranski et al. in Sci Rep 10:2881, 2020), we showed that this resonance occurs solely as a result of the local pairing of non-scattered electrons with scattered ones. In this work, considering the quench dynamics, we explore how much time is required for formation of each of these resonances. In particular, (i) we analyze the charge oscillations between subsystems; (ii) we estimate the time required for each resonance to achieve stable equilibrium upon an abrupt change of interdot connection; (iii) we discuss a typical energy and time scales for experiments on similar architectures.

Anomalous Fano Resonance in Double Quantum Dot System Coupled to Superconductor.

We analyze the influence of a local pairing on the quantum interference in nanoscopic systems. As a model system we choose the double quantum dot coupled to one metallic and one superconducting electrode in the T-shape geometry. The analysis is particularly valuable for systems containing coupled objects with considerably different broadening of energy levels. In such systems, the scattering of itinerant electrons on a discrete (or narrow) energy level gives rise to the Fano-type interference. Systems with induced superconducting order, along well understood Fano resonances, exhibit also another features on the opposite side of the Fermi level. The lineshape of these resonances differs significantly from their reflection on the opposite side of the Fermi level, and their origin was not fully understood. Here, considering the spin-polarized tunneling model, we explain a microscopic mechanism of a formation of these resonances and discuss the nature of their uncommon lineshapes. We show that the anomalous Fano profiles originate solely from the pairing of nonscattered electrons with scattered ones. We investigate also the interplay of each type of resonances with the Kondo physics and discuss the resonant features in differential conductivity.

Diversity of charge orderings in correlated systems.

The phenomenon associated with inhomogeneous distribution of electron density is known as a charge ordering. In this work, we study the zero-bandwidth limit of the extended Hubbard model, which can be considered as a simple effective model of charge ordered insulators. It consists of the on-site interaction U and the intersite density-density interactions W_{1} and W_{2} between nearest neighbors and next-nearest neighbors, respectively. We derived the exact ground state diagrams for different lattice dimensionalities and discuss effects of small finite temperatures in the limit of high dimensions. In particular, we estimated the critical interactions for which new ordered phases emerge (laminar or stripe and four-sublattice-type). Our analysis show that the ground state of the model is highly degenerated. One of the most intriguing finding is that the nonzero temperature removes these degenerations.

Aesthetic Surgery in Patients with Lung Cancer: A Paradigm Shift.

BACKGROUND: Lung cancer is the most common cancer worldwide and the leading cause of cancer death. With the development of targeted therapy against causative driver mutations, some patients have experienced dramatic responses that have converted their disease into a chronic, stable form. Shifting concerns away from survival and back to quality-of-life issues has led some of these patients to seek aesthetic surgery. METHODS: Three patient examples are presented to illustrate current lung cancer treatment modalities, disease responses, and subsequent experiences with aesthetic surgical procedures. Two patients presented for blepharoplasty and the third for revisional breast augmentation surgery. RESULTS: Two patients were treated for lung cancer with targeted therapy and a third with more traditional chemotherapy before undergoing aesthetic surgery. All 3 patients experienced a normal recovery from surgery without any untoward results. Two remain free of disease and one has chronic stable disease. All have returned to normal, active lives. CONCLUSIONS: Recent developments in lung cancer treatment are transforming this entity into a less formidable diagnosis for some patients, much like breast cancer and prostate cancer. Plastic surgeons should be aware of this paradigm shift. Successfully treated patients should be considered as reasonable candidates for aesthetic surgery, particularly when they have the full support of their oncologist. Beyond the typical psychological benefits that plastic surgery can produce, it also provides affirmation in this patient population of a return to normalcy, thereby imparting hope and optimism for the future.

Patterning vascular networks in vivo for tissue engineering applications.

The ultimate design of functionally therapeutic engineered tissues and organs will rely on our ability to engineer vasculature that can meet tissue-specific metabolic needs. We recently introduced an approach for patterning the formation of functional spatially organized vascular architectures within engineered tissues in vivo. Here, we now explore the design parameters of this approach and how they impact the vascularization of an engineered tissue construct after implantation. We used micropatterning techniques to organize endothelial cells (ECs) into geometrically defined "cords," which in turn acted as a template after implantation for the guided formation of patterned capillaries integrated with the host tissue. We demonstrated that the diameter of the cords before implantation impacts the location and density of the resultant capillary network. Inclusion of mural cells to the vascularization response appears primarily to impact the dynamics of vascularization. We established that clinically relevant endothelial sources such as induced pluripotent stem cell-derived ECs and human microvascular endothelial cells can drive vascularization within this system. Finally, we demonstrated the ability to control the juxtaposition of parenchyma with perfused vasculature by implanting cords containing a mixture of both a parenchymal cell type (hepatocytes) and ECs. These findings define important characteristics that will ultimately impact the design of vasculature structures that meet tissue-specific needs.

Geometric control of vascular networks to enhance engineered tissue integration and function.

Tissue vascularization and integration with host circulation remains a key barrier to the translation of engineered tissues into clinically relevant therapies. Here, we used a microtissue molding approach to demonstrate that constructs containing highly aligned "cords" of endothelial cells triggered the formation of new capillaries along the length of the patterned cords. These vessels became perfused with host blood as early as 3 d post implantation and became progressively more mature through 28 d. Immunohistochemical analysis showed that the neovessels were composed of human and mouse endothelial cells and exhibited a mature phenotype, as indicated by the presence of alpha-smooth muscle actin-positive pericytes. Implantation of cords with a prescribed geometry demonstrated that they provided a template that defined the neovascular architecture in vivo. To explore the utility of this geometric control, we implanted primary rat and human hepatocyte constructs containing randomly organized endothelial networks vs. ordered cords. We found substantially enhanced hepatic survival and function in the constructs containing ordered cords following transplantation in mice. These findings demonstrate the importance of multicellular architecture in tissue integration and function, and our approach provides a unique strategy to engineer vascular architecture.

Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner.

Angiogenesis is regulated by both soluble growth factors and cellular interactions with the extracellular matrix (ECM). While cell adhesion via integrins has been shown to be required for angiogenesis, the effects of quantitative changes in cell adhesion and spreading against the ECM remain less clear. Here, we show that angiogenic sprouting in natural and engineered three-dimensional matrices exhibited a biphasic response, with peak sprouting when adhesion to the matrix was limited to intermediate levels. Examining changes in global gene expression to determine a genetic basis for this response, we demonstrate a vascular endothelial growth factor (VEGF)-induced upregulation of genes associated with vascular invasion and remodeling when cell adhesion was limited, whereas cells on highly adhesive surfaces upregulated genes associated with proliferation. To explore a mechanistic basis for this effect, we turned to focal adhesion kinase (FAK), a central player in adhesion signaling previously implicated in angiogenesis, and its homologue, proline-rich tyrosine kinase 2 (Pyk2). While FAK signaling had some impact, our results suggested that Pyk2 can regulate both gene expression and endothelial sprouting through its enhanced activation by VEGF in limited adhesion contexts. We also demonstrate decreased sprouting of tissue explants from Pyk2-null mice as compared to wild type mice as further confirmation of the role of Pyk2 in angiogenic sprouting. These results suggest a surprising finding that limited cell adhesion can enhance endothelial responsiveness to VEGF and demonstrate a novel role for Pyk2 in the adhesive regulation of angiogenesis.

Bioactive hydrogels made from step-growth derived PEG-peptide macromers.

Synthetic hydrogels based on poly(ethylene glycol) (PEG) have been used as biomaterials for cell biology and tissue engineering investigations. Bioactive PEG-based gels have largely relied on heterobifunctional or multi-arm PEG precursors that can be difficult to synthesize and characterize or expensive to obtain. Here, we report an alternative strategy, which instead uses inexpensive and readily available PEG precursors to simplify reactant sourcing. This new approach provides a robust system in which to probe cellular interactions with the microenvironment. We used the step-growth polymerization of PEG diacrylate (PEGDA, 3400Da) with bis-cysteine matrix metalloproteinase (MMP)-sensitive peptides via Michael-type addition to form biodegradable photoactive macromers of the form acrylate-PEG-(peptide-PEG)(m)-acrylate. The molecular weight (MW) of these macromers is controlled by the stoichiometry of the reaction, with a high proportion of resultant macromer species greater than 500kDa. In addition, the polydispersity of these materials was nearly identical for three different MMP-sensitive peptide sequences subjected to the same reaction conditions. When photopolymerized into hydrogels, these high MW materials exhibit increased swelling and sensitivity to collagenase-mediated degradation as compared to previously published PEG hydrogel systems. Cell-adhesive acrylate-PEG-CGRGDS was synthesized similarly and its immobilization and stability in solid hydrogels was characterized with a modified Lowry assay. To illustrate the functional utility of this approach in a biological setting, we applied this system to develop materials that promote angiogenesis in an ex vivo aortic arch explant assay. We demonstrate the formation and invasion of new sprouts mediated by endothelial cells into the hydrogels from embedded embryonic chick aortic arches. Furthermore, we show that this capillary sprouting and three-dimensional migration of endothelial cells can be tuned by engineering the MMP-susceptibility of the hydrogels and the presence of functional immobilized adhesive ligands (CGRGDS vs. CGRGES peptide). The facile chemistry described and significant cellular responses observed suggest the usefulness of these materials in a variety of in vitro and ex vivo biologic investigations, and may aid in the design or refinement of material systems for a range of tissue engineering approaches.

Geometrically controlled endothelial tubulogenesis in micropatterned gels.

We present a novel approach to control endothelial tubulogenesis by spatially patterning cells within micromolded collagen gels. Endothelial cells cultured within microscale channels that were filled with collagen gel organized into tubes with lumens within 24-48 h of seeding. These tubes extended up to 1 cm in length, and exhibited cell-cell junction formation characteristic of early stage capillary vessels. Tube diameter could be controlled by varying collagen concentrations or channel width. The geometry of the microfabricated template also could be used to guide the development of branches during tube formation, allowing for the generation of more complex capillary architectures. Time-lapse imaging of tube formation revealed a highly dynamic process involving coalescence of endothelial cells, reorganization and alignment of collagen fibers into a central core, and arrangement of cells into cords. This platform may be of use to generate geometrically defined vascular networks for tissue engineering applications as well as a means to better understand the process of endothelial tubulogenesis.

Indirect involvement of allergen-captured mast cells in antigen presentation.

It is generally thought that mast cells influence T-cell activation nonspecifically through the release of inflammatory mediators. In this report, we provide evidence that mast cells may also affect antigen-specific T-cell responses by internalizing immunoglobulin E-bound antigens for presentation to antigen-specific T cells. Surprisingly, T-cell activation did not require that mast cells express major histocompatibility complex class II, indicating that mast cells were not involved in the direct presentation of the internalized antigens. Rather, the antigen captured by mast cells is presented by other major histocompatibility complex class II(+) antigen-presenting cells. To explore how this may occur, we investigated the fate of mast cells stimulated by antigen and found that FcepsilonRI crosslinking enhances mast cell apoptosis. Cell death by antigen-captured mast cells was required for efficient presentation because protection of mast cell death significantly decreased T-cell activation. These results suggest that mast cells may be involved in antigen presentation by acting as an antigen reservoir after antigen capture through specific immunoglobulin E molecules bound to their FcepsilonRI. This mechanism may contribute to how mast cells impact the development of T-cell responses.