Knot Invariants for Intersecting Loops

We generalize the braid algebra to the case of loops with intersections. We introduce the Reidemeister moves for 4 and 6-valent vertices to have a theory of rigid vertex equivalence. By considering representations of the extended braid algebra, we derive skein relations for link polynomials, which allow us to generalize any link Polynomial to the intersecting case. We perturbatively show that the HOMFLY Polynomials for intersecting links correspond to the vacuum expectation value of the Wilson line operator of the Chern Simon's Theory. We make contact with quantum gravity by showing that these polynomials are simply related with some solutions of the complete set of constraints with cosmological constantComment: 22 page

O18O and C18O observations of rho Oph A

Observations of the (N_J=1_1-1_0) ground state transition of O_2 with the Odin satellite resulted in a about 5 sigma detection toward the dense core rho Oph A. At the frequency of the line, 119 GHz, the Odin telescope has a beam width of 10', larger than the size of the dense core, so that the precise nature of the emitting source and its exact location and extent are unknown. The current investigation is intended to remedy this. Telluric absorption makes ground based O_2 observations essentially impossible and observations had to be done from space. mm-wave telescopes on space platforms were necessarily small, which resulted in large, several arcminutes wide, beam patterns. Although the Earth's atmosphere is entirely opaque to low-lying O_2 transitions, it allows ground based observations of the much rarer O18O in favourable conditions and at much higher angular resolution with larger telescopes. In addition, rho Oph A exhibits both multiple radial velocity systems and considerable velocity gradients. Extensive mapping of the region in the proxy C18O (J=3-2) line can be expected to help identify the O_2 source on the basis of its line shape and Doppler velocity. Line opacities were determined from observations of optically thin 13C18O (J=3-2) at selected positions. During several observing periods, two C18O intensity maxima in rho Oph A were searched for in the 16O18O (2_1-0_1) line at 234 GHz with the 12m APEX telescope. Our observations resulted in an upper limit on the integrated O18O intensity of < 0.01 K km/s (3 sigma) into the 26.5" beam. We conclude that the source of observed O_2 emission is most likely confined to the central regions of the rho Oph A cloud. In this limited area, implied O_2 abundances could thus be higher than previously reported, by up to two orders of magnitude.Comment: 7 pages, 6 figures (5 colour), Astronomy & Astrophysic

Deuterated formaldehyde in rho Ophiuchi A

From mapping observations of H2CO, HDCO, and D2CO, we have determined how the degree of deuterium fractionation changes over the central 3'x3' region of rho Oph A. The multi-transition data of the various H2CO isotopologues, as well as from other molecules (e.g., CH3OH and N2D+) present in the observed bands, were analysed using both the standard type rotation diagram analysis and, in selected cases, a more elaborate method of solving the radiative transfer for optically thick emission. In addition to molecular column densities, the analysis also estimates the kinetic temperature and H2 density. Toward the SM1 core in rho Oph A, the H2CO deuterium fractionation is very high. In fact, the observed D2CO/HDCO ratio is 1.34+/-0.19, while the HDCO/H2CO ratio is 0.107+/-0.015. This is the first time, to our knowledge, that the D2CO/HDCO abundance ratio is observed to be greater than 1. The kinetic temperature is in the range 20-30 K in the cores of rho Oph A, and the H2 density is (6-10)x10^5 cm-3. We estimate that the total H2 column density toward the deuterium peak is (1-4)x10^23 cm-2. As depleted gas-phase chemistry is not adequate, we suggest that grain chemistry, possibly due to abstraction and exchange reactions along the reaction chain H2CO -> HDCO -> D2CO, is at work to produce the very high deuterium levels observed.Comment: 17 pages, 11 figures, accepted for publication in Astronomy & Astrophysic

Small molecule induced reactivation of mutant p53 in cancer cells

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53

LABOCA 870 micron dust continuum mapping of selected infrared-dark cloud regions in the Galactic plane

We have mapped four selected about 0.5 deg x 0.5 deg-sized fields containing Spitzer 8-micron dark regions with APEX/LABOCA at 870 micron. Selected positions in the fields were observed in C17O(2-1) to obtain kinematic information. The obtained LABOCA maps are used in conjunction with the Spitzer IR images. The total number of clumps identified in this survey is 91, out of which 40 (44%) appear dark at 8 and 24 micron. The remaining clumps are associated with mid-IR emission. Many of the identified clumps are massive enough to allow high-mass star formation, and some of them already show clear signposts of that. Seven clumps associated with extended-like 4.5 micron emission are candidate extended green objects (EGOs). Filamentary dust "ridges" were found towards the Spitzer bubbles N10/11 in one of our fields, which conforms to the triggered high-mass star formation in the system. The relative number of IR-dark and IR-bright clumps suggest that the duration of the former stage is about 1.6x10^5 yr. The mass distribution of the total sample of clumps, and that separately constructed for the IR-dark and IR-bright clumps, could be fitted at the high-mass end with the power-law function dN/dlogM ~ M^(-0.8...-0.7). The C17O observation positions appear to be dominated by non-thermal motions, and the data also revealed some potential sites of strong CO depletion. In G11.36+0.80, which is the best example of a filamentary IRDC in our sample, the clumps appear to be gravitationally bound. The fragmentation of the filament can be understood in terms of a "sausage"-type fluid instability, in agreement with the results for other IRDCs. The formation of filamentary IRDCs might be caused by converging turbulent flows, and the same process may play a role in exciting the fluid perturbations responsible for the fragmentation of the clouds into clumps.Comment: 23 pages, 14 figures, and 6 tables. Accepted for publication in Astronomy and Astrophysic

Disruption of the MDM2–p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway

Wild-type p53 has a major role in the response and execution of apoptosis after chemotherapy in many cancers. Although high levels of wild-type p53 and hardly any TP53 mutations are found in testicular cancer (TC), chemotherapy resistance is still observed in a significant subgroup of TC patients. In the present study, we demonstrate that p53 resides in a complex with MDM2 at higher cisplatin concentrations in cisplatin-resistant human TC cells compared with cisplatin-sensitive TC cells. Inhibition of the MDM2–p53 interaction using either Nutlin-3 or MDM2 RNA interference resulted in hyperactivation of the p53 pathway and a strong induction of apoptosis in cisplatin-sensitive and -resistant TC cells. Suppression of wild-type p53 induced resistance to Nutlin-3 in TC cells, demonstrating the key role of p53 for Nutlin-3 sensitivity. More specifically, our results indicate that p53-dependent induction of Fas membrane expression (∼threefold) and enhanced Fas/FasL interactions at the cell surface are important mechanisms of Nutlin-3-induced apoptosis in TC cells. Importantly, an analogous Fas-dependent mechanism of apoptosis upon Nutlin-3 treatment is executed in wild-type p53 expressing Hodgkin lymphoma and acute myeloid leukaemia cell lines. Finally, we demonstrate that Nutlin-3 strongly augmented cisplatin-induced apoptosis and cell kill via the Fas death receptor pathway. This effect is most pronounced in cisplatin-resistant TC cells

Histone H2A and H2B Are Monoubiquitinated at AID-Targeted Loci

Background: Somatic hypermutation introduces base substitutions into the rearranged and expressed immunoglobulin (Ig) variable regions to promote immunity. This pathway requires and is initiated by the Activation Induced Deaminase (AID) protein, which deaminates cytidine to produce uracils and UG mismatches at the Ig genes. Subsequent processing of uracil by mismatch repair and base excision repair factors contributes to mutagenesis. While selective for certain genomic targets, the chromatin modifications which distinguish hypermutating from non-hypermutating loci are not defined. Methodology/Principal Findings: Here, we show that AID-targeted loci in mammalian B cells contain ubiquitinated chromatin. Chromatin immunoprecipitation (ChIP) analysis of a constitutively hypermutating Burkitt\u27s B cell line, Ramos, revealed the presence of monoubiquitinated forms of both histone H2A and H2B at two AID-associated loci, but not at control loci which are expressed but not hypermutated. Similar analysis using LPS activated primary murine splenocytes showed enrichment of the expressed V(H) and S gamma 3 switch regions upon ChIP with antibody specific to AID and to monoubiquitinated H2A and H2B. In the mechanism of mammalian hypermutation, AID may interact with ubiquitinated chromatin because confocal immunofluorescence microscopy visualized AID colocalized with monoubiquitinated H2B within discrete nuclear foci. Conclusions/Significance: Our results indicate that monoubiquitinated histones accompany active somatic hypermutation, revealing part of the histone code marking AID-targeted loci. This expands the current view of the chromatin state during hypermutation by identifying a specific nucleosome architecture associated with somatic hypermutation

Kinase inhibitors for the treatment of inflammatory and autoimmune disorders

Drugs targeting inhibition of kinases for the treatment of inflammation and autoimmune disorders have become a major focus in the pharmaceutical and biotech industry. Multiple kinases from different pathways have been the targets of interest in this endeavor. This review describes some of the recent developments in the search for inhibitors of IKK2, Syk, Lck, and JAK3 kinases. It is anticipated that some of these compounds or newer inhibitors of these kinases will be approved for the treatment of rheumatoid arthritis, psoriasis, organ transplantation, and other autoimmune diseases