Spatiotemporally Complete Condensation in a Non-Poissonian Exclusion Process

We investigate a non-Poissonian version of the asymmetric simple exclusion process, motivated by the observation that coarse-graining the interactions between particles in complex systems generically leads to a stochastic process with a non-Markovian (history-dependent) character. We characterize a large family of one-dimensional hopping processes using a waiting-time distribution for individual particle hops. We find that when its variance is infinite, a real-space condensate forms that is complete in space (involves all particles) and time (exists at almost any given instant) in the thermodynamic limit. The mechanism for the onset and stability of the condensate are both rather subtle, and depends on the microscopic dynamics subsequent to a failed particle hop attempts.Comment: 5 pages, 5 figures. Version 2 to appear in PR

Combining Targeted DNA Repair Inhibition and Immune-Oncology Approaches for Enhanced Tumor Control

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations

Product Distributions In The CO2-NH3-H2O System From Liquid Conductivity Measurements

The objective of this work was to illustrate how liquid conductivity measurements could be used to provide information about the extent of ionization and the amounts of the various ionic products that are formed in the liquid phase in the CO2-NH3-H2O system. To accomplish this, pressures and liquid-phase conductivities for the CO2-NH3-H2O system were measured at 25 °C and over a range of pressures and concentrations. In order to acquire the desired information from bulk conductivity measurements, calibration curves were established from measurements with several potassium salts. These curves, in conjunction with the experimental conductivity, allowed the (approximate) determination of both the concentration of the NH4+ ion and the distribution of CO2 between singly and doubly charged ions. Comparison to the predictions of two existing models for the CO2-NH3-H2O system showed that these models underpredicted the concentration of the ammonium ion. This suggests that correct predictions of the vapor-phase compositions and pressures by a solution model do not guarantee that the description of the liquid phase is correct. © 1992, American Chemical Society. All rights reserved

Enzymatic Characterization of ER Stress-Dependent Kinase, PERK, and Development of a High-Throughput Assay for Identification of PERK Inhibitors

PERK is serine/threonine kinase localized to the endoplasmic reticulum (ER) membrane. PERK is activated and contributes to cell survival in response to a variety of physiological stresses that affect protein quality control in the ER, such as hypoxia, glucose depravation, increased lipid biosynthesis, and increased protein translation. Pro-survival functions of PERK are triggered by such stresses, suggesting that development of small-molecule inhibitors of PERK may be efficacious in a variety of disease scenarios. Hence, we have conducted a detailed enzymatic characterization of the PERK kinase to develop a high-throughput-screening assay (HTS) that will permit the identification of small-molecule PERK inhibitors. In addition to establishing the Km of PERK for both its primary substrate, eIF2?, and for adenosine triphosphate, further mechanistic studies revealed that PERK targets its substrate via either a random/steady-state ordered mechanism. For HTS, we developed a time-resolved fluorescence resonance energy transfer–based assay that yielded a robust Z? factor and percent coefficient of variation value, enabling the successful screening of 79,552 compounds. This approach yielded one compound that exhibited good in vitro and cellular activity. These results demonstrate the validity of this screen and represent starting points for drug discovery efforts

Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-? precursor protein dimerization

The amyloid ? precursor protein (APP) is a single-pass transmembrane glycoprotein that is ubiquitously expressed in many cell types, including neurons. Amyloidogenic processing of APP by ?- and ?-secretases leads to the production of amyloid-? (A?) peptides that can oligomerize and aggregate into amyloid plaques, a characteristic hallmark of Alzheimer’s disease (AD) brains. Multiple reports suggest that dimerization of APP may play a role in A? production; however, it is not yet clear whether APP dimers increase or decrease A? and the mechanism is not fully understood. To better understand the relationship between APP dimerization and production of A?, a high throughput screen for small molecule modulators of APP dimerization was conducted using APP-Firefly luciferase enzyme complementation to detect APP dimerization. Selected modulators identified from a compound library of 77,440 compounds were tested for their effects on A? generation. Two molecules that inhibited APP dimerization produced a reduction in A? levels as measured by ELISA. The inhibitors did not change sAPP? or ?-CTF levels, but lowered sAPP? levels, suggesting that blocking the dimerization is preventing the cleavage by ?-secretase in the amyloidogenic processing of APP. To our knowledge, this is the first High Throughput Screen (HTS) effort to identify small molecule modulators of APP dimerization. Inhibition of APP dimerization has previously been suggested as a therapeutic target in AD. The findings reported here further support that modulation of APP dimerization may be a viable means of reducing the production of A?

Perinatal Exposure to Low Levels of the Environmental Antiandrogen Vinclozolin Alters Sex-Differentiated Social Play and Sexual Behaviors in the Rat

In this study we examined the effects of exposure to the antiandrogenic fungicide vinclozolin (Vz) on the development of two sex-differentiated behaviors that are organized by the perinatal actions of androgens. Pregnant Long-Evans rats were administered a daily oral dose of 0, 1.5, 3, 6, or 12 mg/kg Vz from the 14th day of gestation through postnatal day (PND)3. The social play behavior of juvenile offspring was examined on PND22 and again on PND34 during play sessions with a same-sex littermate. After they reached adulthood, the male offspring were examined with the ex copula penile reflex procedure to assess erectile function. Vz did not produce any gross maternal or neonatal toxicity, nor did it reduce the anogenital distance in male pups. We observed no effects of Vz on play behavior on PND22. However, the 12-mg/kg Vz dose significantly increased play behavior in the male offspring on PND34 compared with controls. The most dramatic increases were seen with the nape contact and pounce behavior components of play. The Vz effect was more pronounced in male than in female offspring. As adults, male offspring showed a significant reduction of erections at all dose levels during the ex copula penile reflex tests. The 12-mg/kg dose was also associated with an increase in seminal emissions. These effects demonstrate that perinatal Vz disrupts the development of androgen-mediated behavioral functions at exposure levels that do not produce obvious structural changes or weight reductions in androgen-sensitive reproductive organs

Search for the lepton-family-number nonconserving decay \mu -> e + \gamma

The MEGA experiment, which searched for the muon- and electron-number violating decay \mu -> e + \gamma, is described. The spectrometer system, the calibrations, the data taking procedures, the data analysis, and the sensitivity of the experiment are discussed. The most stringent upper limit on the branching ratio of \mu -> e + \gamma) < 1.2 x 10^{-11} was obtained

Optical Spectroscopy of Type Ia Supernovae

We present 432 low-dispersion optical spectra of 32 Type Ia supernovae (SNe Ia) that also have well-calibrated light curves. The coverage ranges from 6 epochs to 36 epochs of spectroscopy. Most of the data were obtained with the 1.5m Tillinghast telescope at the F. L. Whipple Observatory with typical wavelength coverage of 3700-7400A and a resolution of ~7A. The earliest spectra are thirteen days before B-band maximum; two-thirds of the SNe were observed before maximum brightness. Coverage for some SNe continues almost to the nebular phase. The consistency of the method of observation and the technique of reduction makes this an ideal data set for studying the spectroscopic diversity of SNe Ia.Comment: Accepted for publication in the Astronomical Journal, 109 pages (including data table), 44 figures, full resolution figures at http://www.noao.edu/noao/staff/matheson/Iaspec.ps.g

UBVRI Light Curves of 44 Type Ia Supernovae

We present UBVRI photometry of 44 type-Ia supernovae (SN Ia) observed from 1997 to 2001 as part of a continuing monitoring campaign at the Fred Lawrence Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics. The data set comprises 2190 observations and is the largest homogeneously observed and reduced sample of SN Ia to date, nearly doubling the number of well-observed, nearby SN Ia with published multicolor CCD light curves. The large sample of U-band photometry is a unique addition, with important connections to SN Ia observed at high redshift. The decline rate of SN Ia U-band light curves correlates well with the decline rate in other bands, as does the U-B color at maximum light. However, the U-band peak magnitudes show an increased dispersion relative to other bands even after accounting for extinction and decline rate, amounting to an additional ~40% intrinsic scatter compared to B-band.Comment: 84 authors, 71 pages, 51 tables, 10 figures. Accepted for publication in the Astronomical Journal. Version with high-res figures and electronic data at http://astron.berkeley.edu/~saurabh/cfa2snIa