Cosmological Hydrodynamics with Multi-Species Chemistry and Nonequilibrium Ionization and Cooling

We have developed a method of solving for multi-species chemical reaction flows in non--equilibrium and self--consistently with the hydrodynamic equations in an expanding FLRW universe. The method is based on a backward differencing scheme for the required stability when solving stiff sets of equations and is designed to be efficient for three-dimensional calculations without sacrificing accuracy. In all, 28 kinetic reactions are solved including both collisional and radiative processes for the following nine separate species: H, H+, He, He+, He++, H-, H2+, H2, and e-. The method identifies those reactions (involving H- and H2+) ocurring on the shortest time scales, decoupling them from the rest of the network and imposing equilibrium concentrations to good accuracy over typical cosmological dynamical times. Several tests of our code are presented, including radiative shock waves, cosmological sheets, conservation constraints, and fully three-dimensional simulations of CDM cosmological evolutions in which we compare our method to results obtained when the packaged routine LSODAR is substituted for our algorithms.Comment: Latex and postscript, 24 pages, with 6 figures. The paper is also available at http://zeus.ncsa.uiuc.edu:8080/~abel/PGas/bib.html Submitted to New Astronom

Optical Imaging with a Cathepsin B Activated Probe for the Enhanced Detection of Esophageal Adenocarcinoma by Dual Channel Fluorescent Upper GI Endoscopy

Despite significant advances in diagnosis and treatment, the prognosis of esophageal adenocarcinoma remains poor highlighting the importance of early detection. Although white light (WL) upper endoscopy can be used for screening of the esophagus, it has limited sensitivity for early stage disease. Thus, development of new imaging technology to improve the diagnostic capabilities of upper GI endoscopy for early detection of esophageal adenocarcinoma is an important unmet need. The goal of this study was to develop a method for the detection of malignant lesions in the esophagus using WL upper endoscopy combined with near infrared (NIR) imaging with a protease activatable probe (Prosense750) selective for cathepsin B (CTSB). An orthotopic murine model for distal esophageal adenocarcinoma was generated through the implantation of OE-33 and OE-19 human esophageal adenocarcinoma lines in immunocompromised mice. The mice were imaged simultaneously for WL and NIR signal using a custom-built dual channel upper GI endoscope. The presence of tumor was confirmed by histology and target to background ratios (TBR) were compared for both WL and NIR imaging. NIR imaging with ProSense750 significantly improved upon the TBRs of esophageal tumor foci, with a TBR of 3.64$\pm$0.14 and 4.50$\pm$0.11 for the OE-33 and OE-19 tumors respectively, compared to 0.88$\pm$0.04 and 0.81$\pm$0.02 TBR for WL imaging. The combination of protease probes with novel imaging devices has the potential to improve esophageal tumor detection by fluorescently highlighting neoplastic regions

Integrable lattice spin models from supersymmetric dualities

Recently, there has been observed an interesting correspondence between supersymmetric quiver gauge theories with four supercharges and integrable lattice models of statistical mechanics such that the two-dimensional spin lattice is the quiver diagram, the partition function of the lattice model is the partition function of the gauge theory and the Yang-Baxter equation expresses the identity of partition functions for dual pairs. This correspondence is a powerful tool which enables us to generate new integrable models. The aim of the present paper is to give a short account on a progress in integrable lattice models which has been made due to the relationship with supersymmetric gauge theories.Comment: 35 pages, preliminary versio

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies

Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review

Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear. Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI. Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation]. Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae. VI: The Sixth Year (2013-2014)

Continuing the project described by Kato et al. (2009, PASJ, 61, S395, arXiv:0905.1757), we collected times of superhump maxima for 56 SU UMa-type dwarf novae mainly observed during the 2013-2014 season and characterized these objects. We detected negative superhumps in VW Hyi and indicated that the low number of normal outbursts in some supercycle can be interpreted as a result of the disk tilt. This finding, combined with the Kepler observation of V1504 Cyg and V344 Lyr, suggests that the disk tilt is responsible for modulating the outburst pattern in SU UMa-type dwarf novae. We also studied the deeply eclipsing WZ Sge-type dwarf nova MASTER OT J005740.99+443101.5 and found evidence of a sharp eclipse during the phase of early superhumps. The profile can be reproduced by a combination of the eclipse of the axisymmetric disk and the uneclipsed light source of early superhumps. This finding confirms the lack of evince of a greatly enhanced hot spot during the early stage of WZ Sge-type outburst. We detected growing (stage A) superhumps in MN Dra and give a suggestion that some of SU UMa-type dwarf novae situated near the critical condition of tidal instability may show long-lasting stage A superhumps. The large negative period derivatives reported in such systems can be understood a result of the combination of stage A and B superhumps. The WZ Sge-type dwarf novae AL Com and ASASSN-13ck showed a long-lasting (plateau-type) rebrightening. In the early phase of the rebrightening, both objects showed a precursor-like outburst, suggesting that the long-lasting rebrightening is triggered by a precursor outburst.Comment: 73 pages, 88 figures, accepted for publication in PAS

Multisite-binding turn-on fluorescent probe for monitoring mitochondrial ATP levels fluctuation in live cells

10.1002/anie.201510003Angewandte Chemie International Edition5551773-177

Theoretical Aspects of Charge Ordering in Molecular Conductors

Theoretical studies on charge ordering phenomena in quarter-filled molecular (organic) conductors are reviewed. Extended Hubbard models including not only the on-site but also the inter-site Coulomb repulsion are constructed in a straightforward way from the crystal structures, which serve for individual study on each material as well as for their systematic understandings. In general the inter-site Coulomb interaction stabilizes Wigner crystal-type charge ordered states, where the charge localizes in an arranged manner avoiding each other, and can drive the system insulating. The variety in the lattice structures, represented by anisotropic networks in not only the electron hopping but also in the inter-site Coulomb repulsion, brings about diverse problems in low-dimensional strongly correlated systems. Competitions and/or co-existences between the charge ordered state and other states are discussed, such as metal, superconductor, and the dimer-type Mott insulating state which is another typical insulating state in molecular conductors. Interplay with magnetism, e.g., antiferromagnetic state and spin gapped state for example due to the spin-Peierls transition, is considered as well. Distinct situations are pointed out: influences of the coupling to the lattice degree of freedom and effects of geometrical frustration which exists in many molecular crystals. Some related topics, such as charge order in transition metal oxides and its role in new molecular conductors, are briefly remarked.Comment: 21 pages, 19 figures, to be published in J. Phys. Soc. Jpn. special issue on "Organic Conductors"; figs. 4 and 11 replaced with smaller sized fil

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae

We systematically surveyed period variations of superhumps in SU UMa-type dwarf novae based on newly obtained data and past publications. In many systems, the evolution of superhump period are found to be composed of three distinct stages: early evolutionary stage with a longer superhump period, middle stage with systematically varying periods, final stage with a shorter, stable superhump period. During the middle stage, many systems with superhump periods less than 0.08 d show positive period derivatives. Contrary to the earlier claim, we found no clear evidence for variation of period derivatives between superoutburst of the same object. We present an interpretation that the lengthening of the superhump period is a result of outward propagation of the eccentricity wave and is limited by the radius near the tidal truncation. We interpret that late stage superhumps are rejuvenized excitation of 3:1 resonance when the superhumps in the outer disk is effectively quenched. Many of WZ Sge-type dwarf novae showed long-enduring superhumps during the post-superoutburst stage having periods longer than those during the main superoutburst. The period derivatives in WZ Sge-type dwarf novae are found to be strongly correlated with the fractional superhump excess, or consequently, mass ratio. WZ Sge-type dwarf novae with a long-lasting rebrightening or with multiple rebrightenings tend to have smaller period derivatives and are excellent candidate for the systems around or after the period minimum of evolution of cataclysmic variables (abridged).Comment: 239 pages, 225 figures, PASJ accepte