The Hippo pathway and its downstream effectors, the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), regulate organ growth and ...cell plasticity during animal development and regeneration. Remarkably, experimental activation of YAP/TAZ in the mouse can promote regeneration in organs with poor or compromised regenerative capacity, such as the adult heart and the liver and intestine of old or diseased mice. However, therapeutic YAP/TAZ activation may cause serious side effects. Most notably, YAP/TAZ are hyperactivated in human cancers, and prolonged activation of YAP/TAZ triggers cancer development in mice. Thus, can the power of YAP/TAZ to promote regeneration be harnessed in a safe way? Here, we review the role of Hippo signalling in animal regeneration, examine the promises and risks of YAP/TAZ activation for regenerative medicine and discuss strategies to activate YAP/TAZ for regenerative therapy while minimizing adverse side effects.
In this work, we establish a relation between entanglement entropy and fractal dimension D of generic many-body wave functions, by generalizing the result of Page Phys. Rev. Lett. 71, 1291 (1993) to ...the case of sparse random pure states (SRPS). These SRPS living in a Hilbert space of size N are defined as normalized vectors with only ND (0≤D≤1) random nonzero elements. For D=1, these states used by Page represent ergodic states at an infinite temperature. However, for 0<D<1, the SRPS are nonergodic and fractal, as they are confined in a vanishing ratio ND/N of the full Hilbert space. Both analytically and numerically, we show that the mean entanglement entropy S1(A) of a subsystem A, with Hilbert space dimension NA, scales as S1¯(A)∼DlnN for small fractal dimensions D, ND<NA. Remarkably, S1¯(A) saturates at its thermal (Page) value at an infinite temperature, S1¯(A)∼lnNA at larger D. Consequently, we provide an example when the entanglement entropy takes an ergodic value even though the wave function is highly nonergodic. Finally, we generalize our results to Renyi entropies Sq(A) with q>1 and to genuine multifractal states and also show that their fluctuations have ergodic behavior in a narrower vicinity of the ergodic state D=1.
These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many ...cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.
Staining with Congo Red (CR) is a qualitative method used for the identification of amyloids
and in tissue sections. However, the drawbacks and artefacts obtained when using this dye can be found ...both
and
Analysis of scientific data from previous studies shows that CR staining alone is not sufficient for confirmation of the amyloid nature of protein aggregates
or for diagnosis of amyloidosis in tissue sections. In the present paper, we describe the characteristics and limitations of other methods used for amyloid studies. Our historical review on the use of CR staining for amyloid studies may provide insight into the pitfalls and caveats related to this technique for researchers considering using this dye.
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand ...(PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8
and T
1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.
The eigenstate thermalization hypothesis (ETH) is one of the cornerstones of contemporary quantum statistical mechanics. The extent to which ETH holds for nonlocal operators is an open question that ...we partially address in this Letter. We report on the construction of highly nonlocal operators, behemoths, that are building blocks for various kinds of local and nonlocal operators. The behemoths have a singular distribution and width w∼D^{-1} (D being the Hilbert space dimension). From there, one may construct local operators with the ordinary Gaussian distribution and w∼D^{-1/2} in agreement with ETH. Extrapolation to even larger widths predicts sub-ETH behavior of typical nonlocal operators with w∼D^{-δ}, 0<δ<1/2. This operator construction is based on a deep analogy with random matrix theory and shows striking agreement with numerical simulations of nonintegrable many-body systems.
Updated Clinical Classification of Pulmonary Hypertension Simonneau, Gerald, MD; Gatzoulis, Michael A., MD, PhD; Adatia, Ian, MD ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
25
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic ...approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension PAH) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4.
Duality defects in E 8 Ivan M. Burbano; Justin Kulp; Jonas Neuser
The journal of high energy physics,
10/2022, Letnik:
2022, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Abstract We classify all non-invertible Kramers-Wannier duality defects in the E 8 lattice Vertex Operator Algebra (i.e. the chiral (E 8)1 WZW model) coming from ℤ m symmetries. We illustrate how ...these defects are systematically obtainable as ℤ2 twists of invariant sub-VOAs, compute defect partition functions for small m, and verify our results against other techniques. Throughout, we focus on taking a physical perspective and highlight the important moving pieces involved in the calculations. Kac’s theorem for finite automorphisms of Lie algebras and contemporary results on holomorphic VOAs play a role. We also provide a perspective from the point of view of (2+1)d Topological Field Theory and provide a rigorous proof that all corresponding Tambara-Yamagami actions on holomorphic VOAs can be obtained in this manner. We include a list of directions for future studies.
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