mTORC2 signaling drives the development and progression of pancreatic cancer

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer

Accurate Liability Estimation Improves Power in Ascertained Case Control Studies

Linear mixed models (LMMs) have emerged as the method of choice for confounded genome-wide association studies. However, the performance of LMMs in non-randomly ascertained case-control studies deteriorates with increasing sample size. We propose a framework called LEAP (Liability Estimator As a Phenotype, https://github.com/omerwe/LEAP) that tests for association with estimated latent values corresponding to severity of phenotype, and demonstrate that this can lead to a substantial power increase

Normative Alethic Pluralism

Some philosophers have argued that truth is a norm of judgement and have provided a variety of formulations of this general thesis. In this paper, I shall side with these philosophers and assume that truth is a norm of judgement. What I am primarily interested in here are two core questions concerning the judgement-truth norm: (i) what are the normative relationships between truth and judgement? And (ii) do these relationships vary or are they constant? I argue for a pluralist picture—what I call Normative Alethic Pluralism (NAP)—according to which (i) there is more than one correct judgement-truth norm and (ii) the normative relationships between truth and judgement vary in relation to the subject matter of the judgement. By means of a comparative analysis of disagreement in three areas of the evaluative domain—refined aesthetics, basic taste and morality—I show that there is an important variability in the normative significance of disagreement—I call this the variability conjecture. By presenting a variation of Lynch’s scope problem for alethic monism, I argue that a monistic approach to the normative function of truth is unable to vindicate the conjecture. I then argue that normative alethic pluralism provides us with a promising model to account for it

Horizontal, Anomalous U(1) Symmetry for the More Minimal Supersymmetric Standard Model

We construct explicit examples with a horizontal, ``anomalous'' $U(1)$ gauge group, which, in a supersymmetric extension of the standard model, reproduce qualitative features of the fermion spectrum and CKM matrix, and suppress FCNC and proton decay rates without the imposition of global symmetries. We review the motivation for such ``more'' minimal supersymmetric standard models and their predictions for the sparticle spectrum. There is a mass hierarchy in the scalar sector which is the inverse of the fermion mass hierarchy. We show in detail why DeltaS = 2 FCNC are suppressed when compared with naive estimates for nondegenerate squarks.Comment: Revised version clarifies calculation of FCNC amplitudes and rules out one model considered previousl

Preliminary genetic evidence of two different populations of Opisthorchis viverrini in Lao PDR

Opisthorchis viverrini is a major public health concern in Southeast Asia. Various reports have suggested that this parasite may represent a species complex, with genetic structure in the region perhaps being dictated by geographical factors and different species of intermediate hosts. We used four microsatellite loci to analyze O. viverrini adult worms originating from six species of cyprinid fish in Thailand and Lao PDR. Two distinct O. viverrini populations were observed. In Ban Phai, Thailand, only one subgroup occurred, hosted by two different fish species. Both subgroups occurred in fish from That Luang, Lao PDR, but were represented to very different degrees among the fish hosts there. Our data suggest that, although geographical separation is more important than fish host specificity in influencing genetic structure, it is possible that two species of Opisthorchis, with little interbreeding, are present near Vientiane in Lao PDR

Evolutionary dynamics of the most populated genotype on rugged fitness landscapes

We consider an asexual population evolving on rugged fitness landscapes which are defined on the multi-dimensional genotypic space and have many local optima. We track the most populated genotype as it changes when the population jumps from a fitness peak to a better one during the process of adaptation. This is done using the dynamics of the shell model which is a simplified version of the quasispecies model for infinite populations and standard Wright-Fisher dynamics for large finite populations. We show that the population fraction of a genotype obtained within the quasispecies model and the shell model match for fit genotypes and at short times, but the dynamics of the two models are identical for questions related to the most populated genotype. We calculate exactly several properties of the jumps in infinite populations some of which were obtained numerically in previous works. We also present our preliminary simulation results for finite populations. In particular, we measure the jump distribution in time and find that it decays as $t^{-2}$ as in the quasispecies problem.Comment: Minor changes. To appear in Phys Rev

High resolution AMI Large Array imaging of spinning dust sources: spatially correlated 8 micron emission and evidence of a stellar wind in L675

We present 25 arcsecond resolution radio images of five Lynds Dark Nebulae (L675, L944, L1103, L1111 & L1246) at 16 GHz made with the Arcminute Microkelvin Imager (AMI) Large Array. These objects were previously observed with the AMI Small Array to have an excess of emission at microwave frequencies relative to lower frequency radio data. In L675 we find a flat spectrum compact radio counterpart to the 850 micron emission seen with SCUBA and suggest that it is cm-wave emission from a previously unknown deeply embedded young protostar. In the case of L1246 the cm-wave emission is spatially correlated with 8 micron emission seen with Spitzer. Since the MIR emission is present only in Spitzer band 4 we suggest that it arises from a population of PAH molecules, which also give rise to the cm-wave emission through spinning dust emission.Comment: accepted MNRA

Cation Ordering and Exsolution in Copper-Containing Forms of the Flexible Zeolite Rho (Cu,M-Rho; M=H, Na) and Their Consequences for CO₂ Adsorption

Funding: UK Engineering and Physical Sciences Research Council. Grant Numbers: EP/N024613/1, EP/N032942/1, EP/L017008/1.The flexibility of the zeolite Rho framework offers great potential for tunable molecular sieving. The fully copper-exchanged form of Rho and mixed Cu,H- and Cu,Na-forms have been prepared. EPR spectroscopy reveals that Cu2+ ions are present in the dehydrated forms and Rietveld refinement shows these prefer S6R sites, away from the d8r windows that control diffusion. Fully exchanged Cu-Rho remains in an open form upon dehydration, the d8r windows remain nearly circular and the occupancy of window sites is low, so that it adsorbs CO2 rapidly at room temperature. Breakthrough tests with 10 % CO2/40 % CH4 mixtures show that Cu4.9-Rho is able to produce pure methane, albeit with a relatively low capacity at this pCO2 due to the weak interaction of CO2 with Cu cations. This is in strong contrast to Na-Rho, where cations in narrow elliptical window sites enable CO2 to be adsorbed with high selectivity and uptake but too slowly to enable the production of pure methane in similar breakthrough experiments. A series of Cu,Na-Rho materials was prepared to improve uptake and selectivity compared to Cu-Rho, and kinetics compared to Na-Rho. Remarkably, Cu,Na-Rho with >2 Cu cations per unit cell exhibited exsolution, due to the preference of Na cations for narrow S8R sites in distorted Rho and of Cu cations for S6R sites in the centric, open form of Rho. The exsolved Cu,Na-Rho showed improved performance in CO2/CH4 breakthrough tests, producing pure CH4 with improved uptake and CO2/CH4 selectivity compared to that of Cu4.9-Rho.Publisher PDFPeer reviewe

Dynamically Driven Evolution of the Interstellar Medium in M51

Massive star formation occurs in giant molecular clouds (GMCs); an understanding of the evolution of GMCs is a prerequisite to develop theories of star formation and galaxy evolution. We report the highest-fidelity observations of the grand-design spiral galaxy M51 in carbon monoxide (CO) emission, revealing the evolution of GMCs vis-a-vis the large-scale galactic structure and dynamics. The most massive GMCs (giant molecular associations (GMAs)) are first assembled and then broken up as the gas flow through the spiral arms. The GMAs and their H_2 molecules are not fully dissociated into atomic gas as predicted in stellar feedback scenarios, but are fragmented into smaller GMCs upon leaving the spiral arms. The remnants of GMAs are detected as the chains of GMCs that emerge from the spiral arms into interarm regions. The kinematic shear within the spiral arms is sufficient to unbind the GMAs against self-gravity. We conclude that the evolution of GMCs is driven by large-scale galactic dynamics—their coagulation into GMAs is due to spiral arm streaming motions upon entering the arms, followed by fragmentation due to shear as they leave the arms on the downstream side. In M51, the majority of the gas remains molecular from arm entry through the interarm region and into the next spiral arm passage

The HD 192263 system: planetary orbital period and stellar variability disentangled

As part of the Transit Ephemeris Refinement and Monitoring Survey (TERMS), we present new radial velocities and photometry of the HD 192263 system. Our analysis of the already available Keck-HIRES and CORALIE radial velocity measurements together with the five new Keck measurements we report in this paper results in improved orbital parameters for the system. We derive constraints on the size and phase location of the transit window for HD 192263b, a Jupiter-mass planet with a period of 24.3587 \pm 0.0022 days. We use 10 years of Automated Photoelectric Telescope (APT) photometry to analyze the stellar variability and search for planetary transits. We find continuing evidence of spot activity with periods near 23.4 days. The shape of the corresponding photometric variations changes over time, giving rise to not one but several Fourier peaks near this value. However, none of these frequencies coincides with the planet's orbital period and thus we find no evidence of star-planet interactions in the system. We attribute the ~23-day variability to stellar rotation. There are also indications of spot variations on longer (8 years) timescales. Finally, we use the photometric data to exclude transits for a planet with the predicted radius of 1.09 RJ, and as small as 0.79 RJ.Comment: 9 pages, 6 tables, 6 figures; accepted to Ap