Molecular dynamics simulation study of the high frequency sound waves in the fragile glass former ortho-terphenyl

Using a realistic flexible molecule model of the fragile glass former orthoterphenyl, we calculate via molecular dynamics simulation the collective dynamic structure factor, recently measured in this system by Inelastic X-ray Scattering. The comparison of the simulated and measured dynamic structure factor, and the study of its properties in an extended momentum, frequency and temperature range allows: i) to conclude that the utilized molecular model gives rise to a dynamic structure factor in agreement with the experimental data, for those thermodynamic states and momentum values where the latter are available; ii) to confirm the existence of a slope discontinuity on the T-dependence of the sound velocity that, at finite Q, takes place at a temperature T_x higher than the calorimetric glass transition temperature T_g; iii) to find that the values of T_x is Q-dependent and that its vanishing Q limit is consistent with T_g. The latter finding is interpreted within the framework of the current description of the dynamics of supercooled liquids in terms of exploration of the potential energy landscape.Comment: RevTex, 9 pages, 10 eps figure

Relaxation processes in harmonic glasses?

A relaxation process, with the associated phenomenology of sound attenuation and sound velocity dispersion, is found in a simulated harmonic Lennard-Jones glass. We propose to identify this process with the so called microscopic (or instantaneous) relaxation process observed in real glasses and supercooled liquids. A model based on the memory function approach accounts for the observation, and allows to relate to each others: 1) the characteristic time and strength of this process, 2) the low frequency limit of the dynamic structure factor of the glass, and 3) the high frequency sound attenuation coefficient, with its observed quadratic dependence on the momentum transfer.Comment: 11 pages, 3 figure

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

The RNA recognition motif protein RBM11 is a novel tissue-specific splicing regulator.

Mammalian tissues display a remarkable complexity of splicing patterns. Nevertheless, only few examples of tissue-specific splicing regulators are known. Herein, we characterize a novel splicing regulator named RBM11, which contains an RNA Recognition Motif (RRM) at the amino terminus and a region lacking known homology at the carboxyl terminus. RBM11 is selectively expressed in brain, cerebellum and testis, and to a lower extent in kidney. RBM11 mRNA levels fluctuate in a developmentally regulated manner, peaking perinatally in brain and cerebellum, and at puberty in testis, in concomitance with differentiation events occurring in neurons and germ cells. Deletion analysis indicated that the RRM of RBM11 is required for RNA binding, whereas the carboxyl terminal region permits nuclear localization and homodimerization. RBM11 is localized in the nucleoplasm and enriched in SRSF2-containing splicing speckles. Transcription inhibition/release experiments and exposure of cells to stress revealed a dynamic movement of RBM11 between nucleoplasm and speckles, suggesting that its localization is affected by the transcriptional status of the cell. Splicing assays revealed a role for RBM11 in the modulation of alternative splicing. In particular, RBM11 affected the choice of alternative 5' splice sites in BCL-X by binding to specific sequences in exon 2 and antagonizing the SR protein SRSF1. Thus, our findings identify RBM11 as a novel tissue-specific splicing factor with potential implication in the regulation of alternative splicing during neuron and germ cell differentiation

Evidence of anomalous dispersion of the generalized sound velocity in glasses

The dynamic structure factor, S(Q,w), of vitreous silica, has been measured by inelastic X-ray scattering in the exchanged wavevector (Q) region Q=4-16.5 nm-1 and up to energies hw=115 meV in the Stokes side. The unprecedented statistical accuracy in such an extended energy range allows to accurately determine the longitudinal current spectra, and the energies of the vibrational excitations. The simultaneous observation of two excitations in the acoustic region, and the persistence of propagating sound waves up to Q values comparable with the (pseudo-)Brillouin zone edge, allow to observe a positive dispersion in the generalized sound velocity that, around Q=5 nm-1, varies from 6500 to 9000 m/s: this phenomenon was never experimentally observed in a glass.Comment: 5 pages, 3 figures. To appear in Phys. Rev.

Role of c-kit in mammalian spermatogenesis

The tyrosine-kinase receptor c-kit and its ligand, stem cell factor (SCF), are essential for the maintenance of primordial germ cells (PGCs) in both sexes. However, c-kit and a post-meiotic-specific alternative c-kit gene product play important roles also during post-natal stages of spermatogenesis. In the adult testis, the c-kit receptor is re-expressed in differentiating spermatogonia, but not in spermatogonial stem cells, whereas SCF is expressed by Sertoli cells under FSH stimulation. SCF stimulates DNA synthesis in type A spermatogonia cultured in vitro, and injection of anti-c-kit antibodies blocks their proliferation in vivo. A point mutation in the c-kit gene, which impairs SCF-mediated activation of phosphatidylinositol 3-kinase, does not cause any significant reduction in PGCs number during embryonic development, nor in spermatogonial stem cell populations. However males are completely sterile due to a block in the initial stages of spermatogenesis, associated to abolishment of DNA-synthesis in differentiating A1-A4 spermatogonia. With the onset of meiosis c-kit expression ceases, but a truncated c-kit product, tr-kit, is specifically expressed in post-meiotic stages of spermatogenesis, and is accumulated in mature spermatozoa. Microinjection of tr-kit into mouse eggs causes their parthenogenetic activation, suggesting that it might play a role in the final function of the gametes, fertilization