Covalency-enabled Drug Discovery is Redefining Druggability

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Cognitive biases to healthy and unhealthy food words predict change in BMI

The current study explored the predictive value of cognitive biases to food cues (assessed by emotional Stroop and dot probe tasks) on weight change over a 1-year period. This was a longitudinal study with undergraduate students (N = 102) living in shared student accommodation. After controlling for the effects of variables associated with weight (e.g., physical activity, stress, restrained eating, external eating, and emotional eating), no effects of cognitive bias were found with the dot probe. However, for the emotional Stroop, cognitive bias to unhealthy foods predicted an increase in BMI whereas cognitive bias to healthy foods was associated with a decrease in BMI. Results parallel findings in substance abuse research; cognitive biases appear to predict behavior change. Accordingly, future research should consider strategies for attentional retraining, encouraging individuals to reorient attention away from unhealthy eating cues

Evidence for an FU Orionis-like Outburst from a Classical T Tauri Star

We present pre- and post-outburst observations of the new FU Orionis-like young stellar object PTF 10qpf (also known as LkHa 188-G4 and HBC 722). Prior to this outburst, LkHa 188-G4 was classified as a classical T Tauri star on the basis of its optical emission-line spectrum superposed on a K8-type photosphere, and its photometric variability. The mid-infrared spectral index of LkHa 188-G4 indicates a Class II-type object. LkHa 188-G4 exhibited a steady rise by ~1 mag over ~11 months starting in Aug. 2009, before a subsequent more abrupt rise of > 3 mag on a time scale of ~2 months. Observations taken during the eruption exhibit the defining characteristics of FU Orionis variables: (i) an increase in brightness by > 4 mag, (ii) a bright optical/near-infrared reflection nebula appeared, (iii) optical spectra are consistent with a G supergiant and dominated by absorption lines, the only exception being Halpha which is characterized by a P Cygni profile, (iv) near-infrared spectra resemble those of late K--M giants/supergiants with enhanced absorption seen in the molecular bands of CO and H_2O, and (v) outflow signatures in H and He are seen in the form of blueshifted absorption profiles. LkHa 188-G4 is the first member of the FU Orionis-like class with a well-sampled optical to mid-infrared spectral energy distribution in the pre-outburst phase. The association of the PTF 10qpf outburst with the previously identified classical T Tauri star LkHa 188-G4 (HBC 722) provides strong evidence that FU Orionis-like eruptions represent periods of enhanced disk accretion and outflow, likely triggered by instabilities in the disk. The early identification of PTF 10qpf as an FU Orionis-like variable will enable detailed photometric and spectroscopic observations during its post-outburst evolution for comparison with other known outbursting objects.Comment: 14 pages, 11 figures, ApJ accepte

ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene.

OBJECTIVES: We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients. BACKGROUND: CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction. METHODS: In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP. CONCLUSIONS: ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling

Reimagining large river management using the Resist–Accept–Direct (RAD) framework in the Upper Mississippi River

Background: Large-river decision-makers are charged with maintaining diverse ecosystem services through unprecedented social-ecological transformations as climate change and other global stressors intensify. The interconnected, dendritic habitats of rivers, which often demarcate jurisdictional boundaries, generate complex management challenges. Here, we explore how the Resist–Accept–Direct (RAD) framework may enhance large-river management by promoting coordinated and deliberate responses to social-ecological trajectories of change. The RAD framework identifies the full decision space of potential management approaches, wherein managers may resist change to maintain historical conditions, accept change toward different conditions, or direct change to a specified future with novel conditions. In the Upper Mississippi River System, managers are facing social-ecological transformations from more frequent and extreme high-water events. We illustrate how RAD-informed basin-, reach-, and site-scale decisions could: (1) provide cross-spatial scale framing; (2) open the entire decision space of potential management approaches; and (3) enhance coordinated inter-jurisdictional management in response to the trajectory of the Upper Mississippi River hydrograph. Results: The RAD framework helps identify plausible long-term trajectories in different reaches (or subbasins) of the river and how the associated social-ecological transformations could be managed by altering site-scale conditions. Strategic reach-scale objectives may reprioritize how, where, and when site conditions could be altered to contribute to the basin goal, given the basin’s plausible trajectories of change (e.g., by coordinating action across sites to alter habitat connectivity, diversity, and redundancy in the river mosaic). Conclusions: When faced with long-term systemic transformations (e.g., \u3e 50 years), the RAD framework helps explicitly consider whether or when the basin vision or goals may no longer be achievable, and direct options may open yet unconsidered potential for the basin. Embedding the RAD framework in hierarchical decision-making clarifies that the selection of actions in space and time should be derived from basin-wide goals and reach-scale objectives to ensure that site-scale actions contribute effectively to the larger river habitat mosaic. Embedding the RAD framework in large-river decisions can provide the necessary conduit to link flexibility and innovation at the site scale with stability at larger scales for adaptive governance of changing social-ecological systems

Estradiol-independent restoration of T-cell function in post-reproductive females

Aging leads to a general decline in protective immunity. The most common age-associated effects are in seen T-cell mediated immune function. Adult mice whose immune systems show only moderate changes in T-cell subsets tend to live longer than age-matched siblings that display extensive T-cell subset aging. Importantly, at the time of reproductive decline, the increase in disease risks in women significantly outpace those of men. In female mice, there is a significant decline in central and peripheral naïve T-cell subsets at the time of reproductive failure. Available evidence indicates that this naïve T-cell decline is sensitive to ovarian function and can be reversed in post-reproductive females by transplantation of young ovaries. The restoration of naïve T-cell subsets due to ovarian transplantation was impressive compared with post-reproductive control mice, but represented only a partial recovery of what was lost from 6 months of age. Apparently, the influence of ovarian function on immune function may be an indirect effect, likely moderated by other physiological functions. Estradiol is significantly reduced in post-reproductive females, but was not increased in post-reproductive females that received new ovaries, suggesting an estradiol-independent, but ovarian-dependent influence on immune function. Further evidence for an estradiol-independent influence includes the restoration of immune function through the transplantation of young ovaries depleted of follicles and through the injection of isolated ovarian somatic cells into the senescent ovaries of old mice. While the restoration of naïve T-cell populations represents only a small part of the immune system, the ability to reverse this important functional parameter independent of estradiol may hold promise for the improvement of post-reproductive female immune health. Further studies of the non-reproductive influence of the ovary will be needed to elucidate the mechanisms of the relationship between the ovary and health

PTF10nvg: An Outbursting Class I Protostar in the Pelican/North American Nebula

During a synoptic survey of the North American Nebula region, the Palomar Transient Factory (PTF) detected an optical outburst (dubbed PTF10nvg) associated with the previously unstudied flat or rising spectrum infrared source IRAS 20496+4354. The PTF R-band light curve reveals that PTF10nvg brightened by more than 5 mag during the current outburst, rising to a peak magnitude of R~13.5 in 2010 Sep. Follow-up observations indicate PTF10nvg has undergone a similar ~5 mag brightening in the K band, and possesses a rich emission-line spectrum, including numerous lines commonly assumed to trace mass accretion and outflows. Many of these lines are blueshifted by ~175 km/s from the North American Nebula's rest velocity, suggesting that PTF10nvg is driving an outflow. Optical spectra of PTF10nvg show several TiO/VO bandheads fully in emission, indicating the presence of an unusual amount of dense (> 10^10 cm^-3), warm (1500-4000 K) circumstellar material. Near-infrared spectra of PTF10nvg appear quite similar to a spectrum of McNeil's Nebula/V1647 Ori, a young star which has undergone several brightenings in recent decades, and 06297+1021W, a Class I protostar with a similarly rich near--infrared emission line spectrum. While further monitoring is required to fully understand this event, we conclude that the brightening of PTF10nvg is indicative of enhanced accretion and outflow in this Class-I-type protostellar object, similar to the behavior of V1647 Ori in 2004-2005.Comment: Accepted to the Astronomical Journal; 21 pages, 11 figures, 6 tables in emulateapj format; v2 fixes typo in abstract; v3 updates status to accepted, adjusts affiliations, adds acknowledgmen

The Community Climate System Model version 3 (CCSM3)

Author Posting. © American Meteorological Society 2006. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 19 (2006): 2122–2143, doi:10.1175/JCLI3761.1.The Community Climate System Model version 3 (CCSM3) has recently been developed and released to the climate community. CCSM3 is a coupled climate model with components representing the atmosphere, ocean, sea ice, and land surface connected by a flux coupler. CCSM3 is designed to produce realistic simulations over a wide range of spatial resolutions, enabling inexpensive simulations lasting several millennia or detailed studies of continental-scale dynamics, variability, and climate change. This paper will show results from the configuration used for climate-change simulations with a T85 grid for the atmosphere and land and a grid with approximately 1° resolution for the ocean and sea ice. The new system incorporates several significant improvements in the physical parameterizations. The enhancements in the model physics are designed to reduce or eliminate several systematic biases in the mean climate produced by previous editions of CCSM. These include new treatments of cloud processes, aerosol radiative forcing, land–atmosphere fluxes, ocean mixed layer processes, and sea ice dynamics. There are significant improvements in the sea ice thickness, polar radiation budgets, tropical sea surface temperatures, and cloud radiative effects. CCSM3 can produce stable climate simulations of millennial duration without ad hoc adjustments to the fluxes exchanged among the component models. Nonetheless, there are still systematic biases in the ocean–atmosphere fluxes in coastal regions west of continents, the spectrum of ENSO variability, the spatial distribution of precipitation in the tropical oceans, and continental precipitation and surface air temperatures. Work is under way to extend CCSM to a more accurate and comprehensive model of the earth's climate system.We would like to acknowledge the substantial contributions to and support for the CCSM project from the National Science Foundation (NSF), the Department of Energy (DOE), the National Oceanic and Atmospheric Administration, and the National Aeronautics and Space Administration