Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.270

Representations of Time Coordinates in FITS

In a series of three previous papers, formulation and specifics of the representation of World Coordinate Transformations in FITS data have been presented. This fourth paper deals with encoding time. Time on all scales and precisions known in astronomical datasets is to be described in an unambiguous, complete, and self-consistent manner. Employing the well--established World Coordinate System (WCS) framework, and maintaining compatibility with the FITS conventions that are currently in use to specify time, the standard is extended to describe rigorously the time coordinate. World coordinate functions are defined for temporal axes sampled linearly and as specified by a lookup table. The resulting standard is consistent with the existing FITS WCS standards and specifies a metadata set that achieves the aims enunciated above.Comment: FITS WCS Paper IV: Time. 27 pages, 11 table

Anomalous radio emission from dust in the Helix

A byproduct of experiments designed to map the CMB is the recent detection of a new component of foreground Galactic emission. The anomalous foreground at ~ 10--30 GHz, unexplained by traditional emission mechanisms, correlates with 100um dust emission. We report that in the Helix the emission at 31 GHz and 100um are well correlated, and exhibit similar features on sky images, which are absent in H\beta. Upper limits on the 250 GHz continuum emission in the Helix rule out cold grains as candidates for the 31 GHz emission, and provide spectroscopic evidence for an excess at 31 GHz over bremsstrahlung. We estimate that the 100um-correlated radio emission, presumably due to dust, accounts for at least 20% of the 31 GHz emission in the Helix. This result strengthens previous tentative interpretations of diffuse ISM spectra involving a new dust emission mechanism at radio frequencies. Very small grains have not been detected in the Helix, which hampers interpreting the new component in terms of spinning dust. The observed iron depletion in the Helix favors considering the identity of this new component to be magnetic dipole emission from hot ferromagnetic grains. The reduced level of free-free continuum we report also implies an electronic temperature of Te=4600\pm1200K for the free-free emitting material, which is significantly lower than the temperature of 9500\pm500K inferred from collisionally-excited lines (abridged).Comment: Accepted for publication in Ap

Fast and scalable optical packet switch architecture for computer communication networks

We present a novel low latency, high throughput and scalable optical packet switch (UPS) capable to optically interconnect hundreds of input/output ports. We focus on a strictly non-blocking Spanke architecture with contention resolution based on wavelength conversion. Highly distributed control of the UPS reduces the switching time to few nanoseconds regardless the amount of inputs/outputs. Queuing node analysis (mean values analysis) of input buffers in a computer communication network with windowflow control confirms that the new architecture, unlike rearrangeable nonblocking (i.e. Benes) architecture, can operate with low latency and high throughput with a very large amount of input/output ports

Fast and scalable optical packet switch architecture for computer communication networks

We present a novel low latency, high throughput and scalable optical packet switch (UPS) capable to optically interconnect hundreds of input/output ports. We focus on a strictly non-blocking Spanke architecture with contention resolution based on wavelength conversion. Highly distributed control of the UPS reduces the switching time to few nanoseconds regardless the amount of inputs/outputs. Queuing node analysis (mean values analysis) of input buffers in a computer communication network with windowflow control confirms that the new architecture, unlike rearrangeable nonblocking (i.e. Benes) architecture, can operate with low latency and high throughput with a very large amount of input/output ports

Representations of spectral coordinates in FITS

Greisen & Calabretta describe a generalized method for specifying the coordinates of FITS data samples. Following that general method, Calabretta & Greisen describe detailed conventions for defining celestial coordinates as they are projected onto a two-dimensional plane. The present paper extends the discussion to the spectral coordinates of wavelength, frequency, and velocity. World coordinate functions are defined for spectral axes sampled linearly in wavelength, frequency, or velocity, linearly in the logarithm of wavelength or frequency, as projected by ideal dispersing elements, and as specified by a lookup table.Comment: 25 pages, 5 figure

Optical switching and detection of 640 Gbits/s optical time-division multiplexed data packets transmitted over 50 km of fiber

We demonstrate 1×4 optical-packet switching with error-free transmission of 640¿Gbits/s single-wavelength optical time-division multiplexed data packets including clock distribution and short pulse generation for optical time demultiplexing based on a cavityless pulse source

CDKN2A-independent role of BMI1 in promoting growth and survival of Ph+ acute lymphoblastic leukemia

BMI1 is a key component of the PRC1 (polycomb repressive complex-1) complex required for maintenance of normal and cancer stem cells. Its aberrant expression is detected in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL), but no data exist on BMI1 requirement in ALL cells. We show here that BMI1 expression is important for proliferation and survival of Ph+ ALL cells and for leukemogenesis of Ph+ cells in vivo. Levels of BIM, interferon-α (IFNα)-regulated genes and E2F7 were upregulated in BMI1-silenced cells, suggesting that repressing their expression is important for BMI1 biological effects. Consistent with this hypothesis, we found that: (i) downregulation of BIM or E2F7 abrogated apoptosis or rescued, in part, the reduced proliferation and colony formation of BMI1 silenced BV173 cells; (ii) BIM/E2F7 double silencing further enhanced colony formation and in vivo leukemogenesis of BMI1-silenced cells; (iii) overexpression of BIM and E2F7 mimicked the effect of BMI1 silencing in BV173 and SUP-B15 cells; and (iv) treatment with IFNα suppressed proliferation and colony formation of Ph+ ALL cells. These studies indicate that the growth-promoting effects of BMI1 in Ph+ ALL cells depend on suppression of multiple pathways and support the use of IFNα in the therapy of Ph+ ALL

A New Look at the Large-Scale HI Structure of the LMC

We present a Parkes multibeam \HI survey of the Large Magellanic Cloud (LMC). This survey, which is sensitive to spatial structure in the range 200 pc to 10 kpc, complements the Australia Telescope Compact survey, which is sensitive to structure in the range 15 pc to 500 pc. With an rms column density sensitivity of 8 x 10^16/cm^2 for narrow lines and 4 x 10^17/cm^2 for typical linewidths of 40 km/s, emission is found to be extensive well beyond the main body of the LMC. Arm-like features extend from the LMC to join the Magellanic Bridge and the Leading Arm, a forward counterpart to the Magellanic Stream. These features, whilst not as dramatic as those in the SMC, appear to have a common origin in the Galactic tidal field, in agreement with recent 2MASS and DENIS results for the stellar population. The diffuse gas which surrounds the LMC, particularly at pa's 90 to 330 deg, appears to be loosely associated with tidal features, but loosening by the ram pressure of tenuous Galactic halo gas against the outer parts of the LMC cannot be discounted. High-velocity clouds, which lie between the Galaxy and the LMC in velocity and which appear in the UV spectra of some LMC stars, are found to be associated with the LMC if their heliocentric velocity exceeds about +100 km/s. They are possibly the product of energetic outflows from the LMC disk. The HI mass of the LMC is found to be (4.8+/-0.2) x 10^8 Msun (for an assumed distance of 50 kpc), substantially more than previous recent measurements.Comment: Accepted by MNRAS, 19 pages, 13 figurs, 21 eps files, full resolution paper (1.4 M) available at http://www.atnf.csiro.au/~lstavele/papers/lmc_mb_paper.ps.g