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

Attentive and Pre-Attentive Processes in Change Detection and Identification

In studies of change blindness, observers often have the phenomenological impression that the blindness is overcome all at once, so that change detection, localization and identification apparently occur together. Three experiments are described that explore dissociations between these processes using a discrete trial procedure in which 2 visual frames are presented sequentially with no intervening inter-frame-interval. The results reveal that change detection and localization are essentially perfect under these conditions regardless of the number of elements in the display, which is consistent with the idea that change detection and localization are mediated by pre-attentive parallel processes. In contrast, identification accuracy for an item before it changes is generally poor, and is heavily dependent on the number of items displayed. Identification accuracy after a change is substantially better, but depends on the new item’s duration. This suggests that the change captures attention, which substantially enhances the likelihood of correctly identifying the new item. However, the results also reveal a limited capacity to identify unattended items. Specifically, we provide evidence that strongly suggests that, at least under these conditions, observers were able to identify two items without focused attention. Our results further suggest that spatial pre-cues that attract attention to an item before the change occurs simply ensure that the cued item is one of the two whose identity is encoded

Critical Fluctuations and Disorder at the Vortex Liquid to Crystal Transition in Type-II Superconductors

We present a functional renormalization group (FRG) analysis of a Landau-Ginzburg model of type-II superconductors (generalized to $n/2$ complex fields) in a magnetic field, both for a pure system, and in the presence of quenched random impurities. Our analysis is based on a previous FRG treatment of the pure case [E.Br\'ezin et. al., Phys. Rev. B, {\bf 31}, 7124 (1985)] which is an expansion in $\epsilon = 6-d$. If the coupling functions are restricted to the space of functions with non-zero support only at reciprocal lattice vectors corresponding to the Abrikosov lattice, we find a stable FRG fixed point in the presence of disorder for $1<n<4$, identical to that of the disordered $O(n)$ model in $d-2$ dimensions. The pure system has a stable fixed point only for $n>4$ and so the physical case ($n = 2$) is likely to have a first order transition. We speculate that the recent experimental findings that disorder removes the apparent first order transition are consistent with these calculations.Comment: 4 pages, no figures, typeset using revtex (v3.0

Melting and Dimensionality of the Vortex Lattice in Underdoped YBa2Cu3O6.60

Muon spin rotation measurements of the magnetic field distribution in the vortex state of the oxygen deficient high-Tc superconductor YBa{2}Cu{3}O{6.60} reveal a vortex-lattice melting transition at much lower temperature than that in the fully oxygenated material. The transition is best described by a model in which adjacent layers of ``pancake'' vortices decouple in the liquid phase. Evidence is also found for a pinning-induced crossover from a solid 3D to quasi-2D vortex lattice, similar to that observed in the highly anisotropic superconductor Bi{2+x}Sr{2-x}CaCu{2}O{8+y}.Comment: 8 pages, 4 figures, 5 postscript file

Bidirectional control of saccadic eye movements by the disconnected cerebral hemispheres

The present investigation demonstrates that callosotomy patient J.W. can generate either leftward or rightward saccades in response to color cues presented unilaterally. When asked to name the colors, performance was at chance for left visual field presentations, demonstrating a disability in interhemispheric transfer of chromatic information. The successful control of saccadic direction based on discriminative color cues that appear confined to a single hemisphere may suggest a capacity for bidirectional control of saccadic eye movements in the disconnected cerebral hemispheres.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46564/1/221_2004_Article_BF00231667.pd

Effect of disorder on the vortex-lattice melting transition

We use a three dimensional stacked triangular network of Josephson junctions as a model for the study of vortex structure in the mixed state of high Tc superconductors. We show that the addition of disorder destroys the first order melting transition occurring for clean samples. The melting transition splits in two different (continuous) transitions, ocurring at temperatures Ti and Tp (>Ti). At Ti the perpendicular-to-field superconductivity is lost, and at Tp the parallel-to-field superconductivity is lost. These results agree well with recent experiments in YBaCuO.Comment: 4 pages + 2 figure

Longitudinal Current Dissipation in Bose-glass Superconductors

A scaling theory of vortex motion in Bose glass superconductors with currents parallel to the common direction of the magnetic field and columnar defects is presented. Above the Bose-glass transition the longitudinal DC resistivity $\rho_{||}(T)\sim (T-T_{BG})^{\nu' z'}$ vanishes much faster than the corresponding transverse resistivity $\rho_{\perp}(T)\sim (T-T_{BG})^{\nu' (z'-2)}$, thus {\it reversing} the usual anisotropy of electrical transport in the normal state of layered superconductors. In the presence of a current $\bf J$ at an angle $\theta_J$ with the common field and columnar defect axis, the electric field angle $\theta_E$ approaches $\pi/2$ as $T\rightarrow T_{BG}^+$. Scaling also predicts the behavior of penetration depths for the AC currents as $T\rightarrow T_{BG}^-$, and implies a {\it jump discontinuity} at $T_{BG}$ in the superfluid density describing transport parallel to the columns.Comment: 5 pages, revte

HIV, STI prevalence and risk behaviours among women selling sex in Lahore, Pakistan

<p>Abstract</p> <p>Background</p> <p>More than 340 million cases of curable sexually transmitted infections (STIs) were estimated to have occurred worldwide in 1995. Previous studies have shown that the presence of other concomitant STIs increases the likelihood of HIV transmission. The first national study of STIs conducted in Pakistan in 2004 revealed a high burden of STIs among women selling sex. The HIV epidemic in Pakistan has thus far followed the "Asian epidemic model". Earlier studies among women selling sex have shown a low prevalence of HIV coupled with a low level of knowledge about AIDS. The aim of our study was to estimate the prevalence of HIV and STIs, and assess knowledge and risk behaviours related to HIV/STI, among women selling sex in Lahore, Pakistan.</p> <p>Methods</p> <p>A total of 730 participants were recruited through respondent-driven sampling. The participants were women selling sex in three areas (referred to as "A", "B", and "C") of Lahore. A structured questionnaire addressing demographic information, sexual life history, sexual contacts, and knowledge and practices related to HIV/STI prevention was administered by face-to-face interview. Biological samples were obtained from all participants and tested for HIV, <it>Treponema pallidum</it>, <it>Neisseria gonorrhoeae</it>, <it>Chlamydia trachomatis </it>and <it>Trichomonas vaginalis</it>. Pearson's chi-square and multivariable logistic regression analysis were performed to test associations between potential risk factors and specified diagnosed infections.</p> <p>Results</p> <p>The prevalence of HIV infection was 0.7%, <it>T pallidum </it>4.5%, <it>N gonorrhoeae </it>7.5%, <it>C trachomatis </it>7.7% and <it>T vaginalis </it>5.1%. The participants had been selling sex for a median period of seven years and had a median of three clients per day. Sixty five percent of the participants reported that they "Always use condom". The median fee per sexual contact was Rs. 250 (3 Euro). Compared to Areas A and C, women selling sex in Area B had a significantly higher risk of chlamydial infection, gonorrhoea and trichomoniasis. Among the participants, 37% had correct knowledge about HIV/AIDS transmission and its prevention.</p> <p>Conclusions</p> <p>The prevalence of HIV was <1%, and of any other STI 18.5% among participating women selling sex in Lahore, Pakistan. A reasonably high condom use, a relatively low number of sexual partners, and a relatively low prevalence of STIs might have contributed to the low HIV prevalence.</p

Plasticity and memory effects in the vortex solid phase of twinned YBa2Cu3O7 single crystals

We report on marked memory effects in the vortex system of twinned YBa2Cu3O7 single crystals observed in ac susceptibility measurements. We show that the vortex system can be trapped in different metastable states with variable degree of order arising in response to different system histories. The pressure exerted by the oscillating ac field assists the vortex system in ordering, locally reducing the critical current density in the penetrated outer zone of the sample. The robustness of the ordered and disordered states together with the spatial profile of the critical current density lead to the observed memory effects

Is there a Phase Transition to the Flux Lattice State?

The sharp drops in the resistance and magnetization which are usually attributed to a phase transition from the vortex liquid state to a crystal state are explained instead as a crossover between three and two dimensional behavior, which occurs when the phase coherence length in the liquid becomes comparable to the sample thickness. Estimates of the width of the crossover region and the phase coherence length scales are in agreement with experiment.Comment: 4 pages, RevTe