Fractional Kinetics for Relaxation and Superdiffusion in Magnetic Field

We propose fractional Fokker-Planck equation for the kinetic description of relaxation and superdiffusion processes in constant magnetic and random electric fields. We assume that the random electric field acting on a test charged particle is isotropic and possesses non-Gaussian Levy stable statistics. These assumptions provide us with a straightforward possibility to consider formation of anomalous stationary states and superdiffusion processes, both properties are inherent to strongly non-equilibrium plasmas of solar systems and thermonuclear devices. We solve fractional kinetic equations, study the properties of the solution, and compare analytical results with those of numerical simulation based on the solution of the Langevin equations with the noise source having Levy stable probability density. We found, in particular, that the stationary states are essentially non-Maxwellian ones and, at the diffusion stage of relaxation, the characteristic displacement of a particle grows superdiffusively with time and is inversely proportional to the magnetic field.Comment: 15 pages, LaTeX, 5 figures PostScrip

The scaling attractor and ultimate dynamics for Smoluchowski's coagulation equations

We describe a basic framework for studying dynamic scaling that has roots in dynamical systems and probability theory. Within this framework, we study Smoluchowski's coagulation equation for the three simplest rate kernels $K(x,y)=2$, $x+y$ and $xy$. In another work, we classified all self-similar solutions and all universality classes (domains of attraction) for scaling limits under weak convergence (Comm. Pure Appl. Math 57 (2004)1197-1232). Here we add to this a complete description of the set of all limit points of solutions modulo scaling (the scaling attractor) and the dynamics on this limit set (the ultimate dynamics). The main tool is Bertoin's L\'{e}vy-Khintchine representation formula for eternal solutions of Smoluchowski's equation (Adv. Appl. Prob. 12 (2002) 547--64). This representation linearizes the dynamics on the scaling attractor, revealing these dynamics to be conjugate to a continuous dilation, and chaotic in a classical sense. Furthermore, our study of scaling limits explains how Smoluchowski dynamics ``compactifies'' in a natural way that accounts for clusters of zero and infinite size (dust and gel)

Smoking influences the yield of dendritic cells for cancer immunotherapy

Background: Dendritic cell (DC)-based vaccination is considered to be a potentially effective therapeutic strategy against advanced cancer. The aim of this study was to address the smoking history that might affect the preparation of DC vaccines in validated instructional manufacture. Materials and Methods: Data on mature DCs generated from 102 sessions of leukapheresis performed on 92 patients with advanced cancer or sarcoma were retrospectively evaluated and compared in relation to the data between their smoking history and the generation of DCs from these patients. 61 patients with adenocarcinoma, including 7 with lung, 10 with breast, 8 with stomach, 12 with colorectal, and 23 with pancreatic adenocarcinoma were enrolled. Results: The average yield of autologous DCs (15.5 ± 8.3x107) was thought to be dependent on the number of monocytes (124.2 ± 74.1x107) collected by leukapheresis. The average ratio of DCs/apheresed monocytes (DC/aM ratio) was lower in the smoker group (11.1 ± 7.2%) than that in the non-smoker group (17.2 ± 9.3%, p=0.001). The number of DCs and the DC/aM ratio were lower in the patients with gastric and pancreatic cancer than in those with adenocarcinoma of other sites. Conclusions: As cancer therapy moves forward into the field of personaArticlePharmaceutical Regulatory Affairs. 4(1):133 (2015)journal articl

Broad-band X-ray spectral evolution of GX 339-4 during a state transition

We report on X-ray and soft gamma-ray observations of the black-hole candidate GX 339-4 during its 2007 outburst, performed with the RXTE and INTEGRAL satellites. The hardness-intensity diagram of all RXTE/PCA data combined shows a q-shaped track similar to that observed in previous outbursts.The evolution in the diagram suggested that a transition from hard-intermediate state to soft-intermediate state occurred, simultaneously with INTEGRAL observations performed in March. The transition is confirmed by the timing analysis presented in this work, which reveals that a weak type-A quasi-periodic oscillation (QPO) replaces a strong type-C QPO. At the same time, spectral analysis shows that the flux of the high-energy component shows a significant decrease in its flux. However, we observe a delay (roughly one day) between variations of the spectral parameters of the high-energy component and changes in the flux and timing properties. The changes in the high-energy component can be explained either in terms the high-energy cut-off or in terms of a variations in the reflection component. We compare our results with those from a similar transition during the 2004 outburst of GX 339-4.Comment: 8 pages, 6 figures, accepted for publication in MNRAS Main Journa

Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive escherichia coli (AIEC) in immune cells

Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients

Endocannabinoids Generated by Ca2+ or by Metabotropic Glutamate Receptors Appear to Arise from Different Pools of Diacylglycerol Lipase

The identity and subcellular sources of endocannabinoids (eCBs) will shape their ability to affect synaptic transmission and, ultimately, behavior. Recent discoveries support the conclusion that 2-arachidonoyl glycerol, 2-AG, is the major signaling eCB, however, some important issues remain open. 2-AG can be synthesized by a mechanism that is strictly Ca2+-dependent, and another that is initiated by G-protein coupled receptors (GPCRs) and facilitated by Ca2+. An important question is whether or not the 2-AG in these cases is synthesized by the same pool of diacylglycerol lipase alpha (DAGLα). Using whole-cell voltage-clamp techniques in CA1 pyramidal cells in acute in vitro rat hippocampal slices, we investigated two mechanistically distinct eCB-mediated responses to address this issue. We now report that pharmacological inhibitors of DGLα have quantitatively different effects on eCB-mediated responses triggered by different stimuli, suggesting that functional, and perhaps physical, distinctions among pools of DAGLα exist

Tetrahydrobiopterin modulates ubiquitin conjugation to UBC13/UBE2N and proteasome activity by S-nitrosation

Nitric Oxide (NO) is an intracellular signalling mediator, which affects many biological processes via the posttranslational modification of proteins through S-nitrosation. The availability of NO and NOS-derived reactive oxygen species (ROS) from enzymatic uncoupling are determined by the NO synthase cofactor Tetrahydrobiopterin (BH4). Here, using a global proteomics “biotin-switch” approach, we identified components of the ubiquitin-proteasome system to be altered via BH4-dependent NO signalling by protein S-nitrosation. We show S-nitrosation of ubiquitin conjugating E2 enzymes, in particular the catalytic residue C87 of UBC13/UBE2N, leading to impaired polyubiquitylation by interfering with the formation of UBC13~Ub thioester intermediates. In addition, proteasome cleavage activity in cells also seems to be altered by S-nitrosation, correlating with the modification of cysteine residues within the 19S regulatory particle and catalytic subunits of the 20S complex. Our results highlight the widespread impact of BH4 on downstream cellular signalling as evidenced by the effect of a perturbed BH4-dependent NO-Redox balance on critical processes within the ubiquitin-proteasome system (UPS). These studies thereby uncover a novel aspect of NO associated modulation of cellular homeostasis

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms “mental retardation”. To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus