Position space versions of Magueijo-Smolin doubly special relativity proposal and the problem of total momentum

We present and discuss two different possibilities to construct position space version for Magueijo-Smolin (MS) doubly special relativity proposal. The first possibility is to start from ordinary special relativity and then to define conserved momentum in special way. It generates MS invariant as well as nonlinear MS transformations on the momentum space, leading to consistent picture for one-particle sector of the theory. The second possibility is based on the following observation. Besides the nonlinear MS transformations, the MS energy-momentum relation is invariant also under some inhomogeneous linear transformations. The latter are induced starting from linearly realized Lorentz group in five-dimensional position space. Particle dynamics and kinematics are formulated starting from the corresponding five-dimensional interval. There is no problem of total momentum in the theory. The formulation admits two observer independent scales, the speed of light, $c$, and $k$ with dimension of velocity. We speculate on different possibilities to relate $k$ with fundamental constants. In particular, expression of $k$ in terms of vacuum energy suggests emergence of (minimum) quantum of mass.Comment: Latex twice, 14 pages, revised in accordance with the version publishedin Phys. Rev.

On the connection between Lenz's law and relativity

In this work, we demonstrate explicitly the unified nature of electric and magnetic fields, from the principles of special relativity and Lorentz transformations of the electromagnetic field tensor. Using an operational approach we construct the tensor and its corresponding transformation law, based on the principle of relativity. Our work helps to elucidate concepts of advanced courses on electromagnetism for primary-level learners and shows an alternative path to derive the Lenz's law based solely on relativity arguments.Comment: 6 pages, 4 figure

New "Green" approaches to the synthesis of pyrazole derivatives.

A novel approach to the synthesis of pyrazole derivatives from tosylhydrazones of alpha,beta-unsaturated carbonyl compounds possessing a beta-hydrogen is proposed, exploiting microwave (MW) activation coupled with solvent free reaction conditions. The cycloaddition was studied on three ketones (trans-4-phenyl-3-buten-2-one, beta-ionone and trans-chalcone). The corresponding 3,5-disubstituted-1H-pyrazoles were obtained in high yields and after short reaction times. In order to simplify and point out the green chemistry features of the method, a further improvement was achieved under the same catalytic conditions with a "one pot" synthesis of these heterocyclic compounds, starting directly from their carbonyl precursors via tosylhydrazones generated in situ. For an exhaustive study, the dielectric properties of the solid reaction mixtures were also measured, in order to obtain input data for the numerical simulation of their heating behaviour in the single mode MW cavity which was used for experimental work. In order to supply a valid methodology and tool for measuring the environmental impact, a comparative study between the synthetic route proposed and the classical synthetic route has been carried out

Human enzyme PADI4 binds to the nuclear carrier Importin a3

PADI4 is a peptidyl-arginine deiminase (PADI) involved in the conversion of arginine to citrulline. PADI4 is present in macrophages, monocytes, granulocytes, and several cancer cells. It is the only PADI family member observed within both the nucleus and the cytoplasm. PADI4 has a predicted nuclear localization sequence (NLS) comprising residues Pro56 to Ser83, to allow for nuclear translocation. Recent predictors also suggest that the region Arg495 to Ile526 is a possible NLS. To understand how PADI4 is involved in cancer, we studied the ability of intact PADI4 to bind importin a3 (Impa3), a nuclear transport factor that plays tumor-promoting roles in several cancers, and its truncated species (¿Impa3) without the importin-binding domain (IBB), by using fluorescence, circular dichroism (CD), and isothermal titration calorimetry (ITC). Furthermore, the binding of two peptides, encompassing the first and the second NLS regions, was also studied using the same methods and molecular docking simulations. PADI4 interacted with both importin species, with affinity constants of ~1–5 µM. The isolated peptides also interacted with both importins. The molecular simulations predict that the anchoring of both peptides takes place in the major binding site of Impa3 for the NLS of cargo proteins. These findings suggest that both NLS regions were essentially responsible for the binding of PADI4 to the two importin species. Our data are discussed within the framework of a cell mechanism of nuclear transport that is crucial in cancer

Intrinsically disordered chromatin protein NUPR1 binds to the enzyme PADI4

The nuclear protein 1 (NUPR1) is an intrinsically disordered protein involved in stress-mediated cellular conditions. Its paralogue nuclear protein 1-like (NUPR1L) is p53-regulated, and its expression down-regulates that of the NUPR1 gene. Peptidyl-arginine deiminase 4 (PADI4) is an isoform of a family of enzymes catalyzing arginine to citrulline conversion; it is also involved in stress-mediated cellular conditions. We characterized the interaction between NUPR1 and PADI4 in vitro, in silico, and in cellulo. The interaction of NUPR1 and PADI4 occurred with a dissociation constant of 18 ± 6 μM. The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch surrounding the key residue Ala33, as pinpointed by: (i) computational results; and, (ii) site-directed mutagenesis of residues of NUPR1. The association between PADI4 and wild-type NUPR1 was also assessed in cellulo by using proximity ligation assays (PLAs) and immunofluorescence (IF), and it occurred mainly in the nucleus. Moreover, binding between NUPR1L and PADI4 also occurred in vitro with an affinity similar to that of NUPR1. Molecular modelling provided information on the binding hot spot for PADI4. This is an example of a disordered partner of PADI4, whereas its other known interacting proteins are well-folded. Altogether, our results suggest that the NUPR1/PADI4 complex could have crucial functions in modulating DNA-repair, favoring metastasis, or facilitating citrullination of other proteins

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ''fuzzy'' interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs

MicroRNA expression analysis identifies a subset of downregulated miRNAs in ALS motor neuron progenitors

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder that is characterized by a progressive degeneration of motor neurons (MNs). The pathomechanism underlying the disease is largely unknown, even though increasing evidence suggests that RNA metabolism, including microRNAs (miRNAs) may play an important role. In this study, human ALS induced pluripotent stem cells were differentiated into MN progenitors and their miRNA expression profiles were compared to those of healthy control cells. We identified 15 downregulated miRNAs in patients' cells. Gene ontology and molecular pathway enrichment analysis indicated that the predicted target genes of the differentially expressed miRNAs were involved in neurodegeneration-related pathways. Among the 15 examined miRNAs, miR-34a and miR504 appeared particularly relevant due to their involvement in the p53 pathway, synaptic vesicle regulation and general involvement in neurodegenerative diseases. Taken together our results demonstrate that the neurodegenerative phenotype in ALS can be associated with a dysregulation of miRNAs involved in the control of disease-relevant genetic pathways, suggesting that targeting entire gene networks can be a potential strategy to treat complex diseases such as ALS