The R.I. Pimenov unified gravitation and electromagnetism field theory as semi-Riemannian geometry

More then forty years ago R.I. Pimenov introduced a new geometry -- semi-Riemannian one -- as a set of geometrical objects consistent with a fibering $pr: M_n \to M_m.$ He suggested the heuristic principle according to which the physically different quantities (meter, second, coulomb etc.) are geometrically modelled as space coordinates that are not superposed by automorphisms. As there is only one type of coordinates in Riemannian geometry and only three types of coordinates in pseudo-Riemannian one, a multiple fibered semi-Riemannian geometry is the most appropriate one for the treatment of more then three different physical quantities as unified geometrical field theory. Semi-Euclidean geometry $^{3}R_5^4$ with 1-dimensional fiber $x^5$ and 4-dimensional Minkowski space-time as a base is naturally interpreted as classical electrodynamics. Semi-Riemannian geometry $^{3}V_5^4$ with the general relativity pseudo-Riemannian space-time $^{3}V^4,$ and 1-dimensional fiber $x^5,$ responsible for the electromagnetism, provides the unified field theory of gravitation and electromagnetism. Unlike Kaluza-Klein theories, where the 5-th coordinate appears in nondegenerate Riemannian or pseudo-Riemannian geometry, the theory based on semi-Riemannian geometry is free from defects of the former. In particular, scalar field does not arise. PACS: 04.50.Cd, 02.40.-k, 11.10.KkComment: 16 pages, 2 figures. Submited to Physics of Atomic Nucle

Indicators of hormonal status of the military servicemen in the modern type of military technogenesis

© 2016, International Journal of Pharmacy and Technology. All rights reserved.The paper presents the results of the evaluation of the testosterone level in the military servicemen. The work at the military enterprises is characterized by storage and disposal of chemical weapons and the presence of a number of harmful factors. The effect of carcinogens and reproductive hazards in the operation environment on the hormonal system changes the levels of hormones responsible for the reproductive function of the body. It is known that the reduction in the concentration of testosterone leads to male infertility, and its increase with age can trigger the development of prostate cancer. Testosterone indicators in our study were distributed subject to the contingent, age, length of service and a type of troops. Determination of hormone was conducted by enzyme-linked immunosorbent assay (ELISA) of blood. The study revealed hormonal disorders in all contingents examined. A high-risk group involves retired and former military servicemen (high levels of testosterone were found in 52.1% of the surveyed of this contingent), persons over 70 years old (high levels of testosterone were found in 61.5% of the surveyed in this age group), the workers with length of service of 30-39 years (high levels of testosterone were found in 55.2% of the surveyed with this length of service). Low levels of testosterone were found in private soldiers (3.6% of the surveyed of this contingent), in persons aged 18-29 years (3.3% of the surveyed in this age group), and in those with length of service of 1-2 years (3.6% of the surveyed with this length of service)

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

Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes

Myeloid cell leukemia sequence-1 (Mcl-1) is a critical anti-apoptotic factor in T lymphocytes. However, in spite of the many pro-apoptotic proteins with proposed binding to Mcl-1, the specific interactions by which Mcl-1 regulates primary T-cell survival under different conditions have not been fully explored. Further, how different trophic cytokines modulate the specific role(s) of Mcl-1 is unknown. Here, we use genetic mouse models to dissect the roles of Mcl-1 in primary T lymphocytes. Using the inducible Mcl-1-floxed estrogen receptor-Cre fusion protein (Mcl-1f/fERCre) deletion system in combination with genetic modification of other B-cell lymphoma 2 (Bcl-2) family members, we show that loss of pro-apoptotic Bcl-2 homologous antagonist/killer (Bak) rescues the survival of Mcl-1-deficient T cells in the presence of IL-7. Without IL-7, the survival of Mcl-1-deficient cells cannot be rescued by loss of Bak, but is partially rescued by overexpression of Bcl-2 or loss of Bcl-2-interacting mediator of cell death (Bim). Thus, Mcl-1 and Bcl-2 have a shared role, the inhibition of Bim, in promoting T-cell survival during cytokine withdrawal. Finally, we show that other common gamma-chain (γc) cytokines differentially modulate the roles of Mcl-1. IL-15 has effects similar to those of IL-7 in memory T cells and naïve CD8+ cells, but not naïve CD4+ cells. However, IL-4 maintains Mcl-1 and Bcl-2 but also upregulates Bim and Bcl-2-associated X protein (Bax), thus altering the cell's dependence on Mcl-1

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC50 in most cases of 165–320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg × 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation

RNA Silencing of Mcl-1 Enhances ABT-737-Mediated Apoptosis in Melanoma: Role for a Caspase-8-Dependent Pathway

BACKGROUND: Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma's striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that knockdown of Mcl-1 greatly reduces cell viability in combination with ABT-737 in six different melanoma cell lines. We demonstrate that the cytotoxic effect of this combination treatment is due to apoptotic cell death involving not only caspase-9 activation but also activation of caspase-8, caspase-10 and Bid, which are normally associated with the extrinsic pathway of apoptosis. Caspase-8 (and caspase-10) activation is abrogated by inhibition of caspase-9 but not by inhibitors of the death receptor pathways. Furthermore, while caspase-8/-10 activity is required for the full induction of cell death with treatment, the death receptor pathways are not. Finally, we demonstrate that basal levels of caspase-8 and Bid correlate with treatment sensitivity. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma. We also report a death receptor-independent role for extrinsic pathway proteins in treatment response and suggest that caspase-8 and Bid may represent potential markers of treatment sensitivity

Temporal Dissection of K-rasG12D Mutant In Vitro and In Vivo Using a Regulatable K-rasG12D Mouse Allele

Animal models which allow the temporal regulation of gene activities are valuable for dissecting gene function in tumorigenesis. Here we have constructed a conditional inducible estrogen receptor-K-rasG12D (ER-K-rasG12D) knock-in mice allele that allows us to temporally switch on or off the activity of K-ras oncogenic mutant through tamoxifen administration. In vitro studies using mice embryonic fibroblast (MEF) showed that a dose of tamoxifen at 0.05 µM works optimally for activation of ER-K-rasG12D independent of the gender status. Furthermore, tamoxifen-inducible activation of K-rasG12D promotes cell proliferation, anchor-independent growth, transformation as well as invasion, potentially via activation of downstream MAPK pathway and cell cycle progression. Continuous activation of K-rasG12D in vivo by tamoxifen treatment is sufficient to drive the neoplastic transformation of normal lung epithelial cells in mice. Tamoxifen withdrawal after the tumor formation results in apoptosis and tumor regression in mouse lungs. Taken together, these data have convincingly demonstrated that K-ras mutant is essential for neoplastic transformation and this animal model may provide an ideal platform for further detailed characterization of the role of K-ras oncogenic mutant during different stages of lung tumorigenesis

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