Gravitation and Duality Symmetry

By generalizing the Hodge dual operator to the case of soldered bundles, and working in the context of the teleparallel equivalent of general relativity, an analysis of the duality symmetry in gravitation is performed. Although the basic conclusion is that, at least in the general case, gravitation is not dual symmetric, there is a particular theory in which this symmetry shows up. It is a self dual (or anti-self dual) teleparallel gravity in which, due to the fact that it does not contribute to the interaction of fermions with gravitation, the purely tensor part of torsion is assumed to vanish. The ensuing fermionic gravitational interaction is found to be chiral. Since duality is intimately related to renormalizability, this theory may eventually be more amenable to renormalization than teleparallel gravity or general relativity.Comment: 7 pages, no figures. Version 2: minor presentation changes, references added. Accepted for publication in Int. J. Mod. Phys.

Gauge field theory for Poincar\'{e}-Weyl group

On the basis of the general principles of a gauge field theory the gauge theory for the Poincar\'{e}-Weyl group is constructed. It is shown that tetrads are not true gauge fields, but represent functions from true gauge fields: Lorentzian, translational and dilatational ones. The equations of gauge fields which sources are an energy-momentum tensor, orbital and spin momemta, and also a dilatational current of an external field are obtained. A new direct interaction of the Lorentzian gauge field with the orbital momentum of an external field appears, which describes some new effects. Geometrical interpretation of the theory is developed and it is shown that as a result of localization of the Poincar\'{e}-Weyl group spacetime becomes a Weyl-Cartan space. Also the geometrical interpretation of a dilaton field as a component of the metric tensor of a tangent space in Weyl-Cartan geometry is proposed.Comment: LaTex, 27 pages, no figure

Metabolic gatekeeper function of B-lymphoid transcription factors.

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation

Torsion Gravity: a Reappraisal

The role played by torsion in gravitation is critically reviewed. After a description of the problems and controversies involving the physics of torsion, a comprehensive presentation of the teleparallel equivalent of general relativity is made. According to this theory, curvature and torsion are alternative ways of describing the gravitational field, and consequently related to the same degrees of freedom of gravity. However, more general gravity theories, like for example Einstein-Cartan and gauge theories for the Poincare and the affine groups, consider curvature and torsion as representing independent degrees of freedom. By using an active version of the strong equivalence principle, a possible solution to this conceptual question is reviewed. This solution favors ultimately the teleparallel point of view, and consequently the completeness of general relativity. A discussion of the consequences for gravitation is presented.Comment: RevTeX, 34 pages. Review article to be published by Int. J. Mod. Phys.

Invariant Correlations in Simplicial Gravity

Some first results are presented regarding the behavior of invariant correlations in simplicial gravity, with an action containing both a bare cosmological term and a lattice higher derivative term. The determination of invariant correlations as a function of geodesic distance by numerical methods is a difficult task, since the geodesic distance between any two points is a function of the fluctuating background geometry, and correlation effects become rather small for large distances. Still, a strikingly different behavior is found for the volume and curvature correlation functions. While the first one is found to be negative definite at large geodesic distances, the second one is always positive for large distances. For both correlations the results are consistent in the smooth phase with an exponential decay, turning into a power law close to the critical point at $G_c$. Such a behavior is not completely unexpected, if the model is to reproduce the classical Einstein theory at distances much larger than the ultraviolet cutoff scale.Comment: 27 pages, conforms to published versio

Fibre bundle formulation of nonrelativistic quantum mechanics: I. Introduction. The evolution transport

We propose a new systematic fibre bundle formulation of nonrelativistic quantum mechanics. The new form of the theory is equivalent to the usual one but it is in harmony with the modern trends in theoretical physics and potentially admits new generalizations in different directions. In it a pure state of some quantum system is described by a state section (along paths) of a (Hilbert) fibre bundle. Its evolution is determined through the bundle (analogue of the) Schr\"odinger equation. Now the dynamical variables and the density operator are described via bundle morphisms (along paths). The mentioned quantities are connected by a number of relations derived in this work. The present first part of this investigation is devoted to the introduction of basic concepts on which the fibre bundle approach to quantum mechanics rests. We show that the evolution of pure quantum-mechanical states can be described as a suitable linear transport along paths, called evolution transport, of the state sections in the Hilbert fibre bundle of states of a considered quantum system.Comment: 26 standard (11pt, A4) LaTeX 2e pages. The packages AMS-LaTeX and amsfonts are required. Revised: new material, references, and comments are added. Minor style chages. Continuation of quan-ph/9803083. For continuation of the this series see http://www.inrne.bas.bg/mathmod/bozhome

Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease

Background aims: Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3× 106 cells), and therefore novel methods of Treg expansion to generate clinically relevant numbers are needed. Methods: Several methodologies are currently being used for ex vivo Treg expansion. We report a new approach to expand Treg from CB and demonstrate their efficacy in vitro by blunting allogeneic mixed lymphocyte reactions and in vivo by preventing GvHD through the use of a xenogenic GvHD mouse model. Results: With the use of magnetic cell sorting, naturally occurring Treg were isolated from CB by the positive selection of CD25+ cells. These were expanded to clinically relevant numbers by use ofCD3/28 co-expressing Dynabeads and interleukin (IL)-2. Ex vivo-expanded Treg were CD4+25+FOXP3+127lo and expressed a polyclonal T-cell receptor, Vβ repertoire. When compared with conventional T-lymphocytes (CD4+25- cells), Treg consistently showed demethylation of the FOXP3 TSDR promoter region and suppression of allogeneic proliferation responses in vitro. Conclusions: In our NOD-SCID IL-2Rγnull xenogeneic model of GvHD, prophylactic injection of third-party, CB-derived, ex vivo-expanded Treg led to the prevention of GvHD that translated into improved GvHD score, decreased circulating inflammatory cytokines and significantly superior overall survival. This model of xenogenic GvHD can be used to study the mechanism of action of CB Treg as well as other therapeutic interventions

Predicting effective pro-apoptotic antileukaemic drug combinations using cooperative dynamic BH3 profiling

The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide. We found that a broad range of anti-leukaemic agents–notably MCL-1 inhibitors, DNA damaging agents and FLT3 inhibitors–sensitise leukaemia cells to BAD-BH3. We further analysed the BCL-2 inhibitors ABT-199 and JQ1, the MCL-1 inhibitors pladienolide B and torin1, the FLT3 inhibitor AC220 and the DNA double-strand break inducer etoposide to correlate priming responses with co-operative induction of apoptosis. ABT-199 in combination with pladienolide B, torin1, etoposide or AC220 strongly induced apoptosis within 4 hours, but the MCL-1 inhibitors did not co-operate with etoposide or AC220. In keeping with the long half-life of BCL-2, the BET domain inhibitor JQ1 was found to downregulate BCL-2 and to prime cells to respond to MS1-BH3 at 48, but not at 4 hours: prolonged priming with JQ1 was then shown to induce rapid cytochrome C release when pladienolide B, torin1, etoposide or AC220 were added. In conclusion, dynamic BH3 profiling is a useful mechanism-based tool for understanding and predicting co-operative lethality between drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism. A plethora of agents sensitised cells to BAD-BH3-mediated mitochondrial outer membrane permeabilisation in the dynamic BH3 profiling assay and this was associated with effective co-operation with the BCL-2 inhibitory compounds ABT-199 or JQ1

Genetic Ablation of Bcl-x Attenuates Invasiveness without Affecting Apoptosis or Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Cancer

Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro- and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-xL, demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic β-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-xL upon exogenous over-expression

The role of anthropogenic habitats in freshwater mussel conservation

Anthropogenic freshwater habitats may provide undervalued prospects for long-term conservation as part of species conservation planning. This fundamental, but overlooked, issue requires attention considering the pace that humans have been altering natural freshwater ecosystems and the accelerated levels of biodiversity decline in recent decades. We compiled 709 records of freshwater mussels (Bivalvia, Unionida) inhabiting a broad variety of anthropogenic habitat types (from small ponds to large reservoirs and canals) and reviewed their importance as refuges for this faunal group. Most records came from Europe and North America, with a clear dominance of canals and reservoirs. The dataset covered 228 species, including 34 threatened species on the IUCN Red List. We discuss the conservation importance and provide guidance on how these anthropogenic habitats could be managed to provide optimal conservation value to freshwater mussels. This review also shows that some of these habitats may function as ecological traps owing to conflicting management practices or because they act as a sink for some populations. Therefore, anthropogenic habitats should not be seen as a panacea to resolve conservation problems. More information is necessary to better understand the trade-offs between human use and the conservation of freshwater mussels (and other biota) within anthropogenic habitats, given the low number of quantitative studies and the strong biogeographic knowledge bias that persists.This publication is based upon work from COST Action CA18239, supported by COST (European Cooperation in Science and Technology). A.M.L. was financed by the Institute of Environmental Sciences Jagiellonian University (N18/DBS/000003) and K.N. by the Aragón Government. The authors acknowledge Jarosław Andrzejewski, Bartosz Czader, Anna Fica, Marcin Horbacz, Tomasz Jonderko, Steinar Kålås, Tomasz Kapela, Bjørn Mejdell Larsen, Maciej Pabijan, Katarzyna Pawlik, Ilona Popławska, Joanna Przybylska, Tomasz Przybył, Mateusz Rybak, Kjell Sandaas, Jarosław Słowikowski, Tomasz Szczasny, Michał Zawadzki and Paweł Zowada for providing detailed information on specific examples concerning freshwater mussels in anthropogenic habitats. We thank the editor and two anonymous referees for the valuable suggestions made, which increased the clarity of our manuscript.info:eu-repo/semantics/publishedVersio