Amygdala circuitry mediating reversible and bidirectional control of anxiety

Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.     

Two aberrant karyotypes in the sagebrush lizard ( Sceloporus graciosus ): triploidy and a "supernumerary" oddity

Widespread karyotypic sampling in the lizard Sceloporus graciosus Baird & Girard has confirmed previous reports of chromosomal monotypy. Most individuals throughout the range have a diploid karyotype of 2N = 30 consisting of 12 biarmed macrochromosomes and 18 microchromosomes. A single female karyotyped from the vicinity of Riverside, California, was unmistakably triploid, showing 3N = 45 with 18 macrochromosomes and 27 microchromosomes. This female appeared phenotypically normal but appeared reproductively incompetent. A male from Zion National Park, Utah, showed an extra bivalent in some diakinesis arrays, which apparently represents a supernumerary chromosome.     

A large discontinuity in the mid-twentieth century in observed global-mean surface temperature

Data sets used to monitor the Earth's climate indicate that the surface of the Earth warmed from approximately 1910 to 1940, cooled slightly from approximately 1940 to 1970, and then warmed markedly from approximately 1970 onward. The weak cooling apparent in the middle part of the century has been interpreted in the context of a variety of physical factors, such as atmosphere-ocean interactions and anthropogenic emissions of sulphate aerosols. Here we call attention to a previously overlooked discontinuity in the record at 1945, which is a prominent feature of the cooling trend in the mid-twentieth century. The discontinuity is evident in published versions of the global-mean temperature time series, but stands out more clearly after the data are filtered for the effects of internal climate variability. We argue that the abrupt temperature drop of approximately 0.3 degrees C in 1945 is the apparent result of uncorrected instrumental biases in the sea surface temperature record. Corrections for the discontinuity are expected to alter the character of mid-twentieth century temperature variability but not estimates of the century-long trend in global-mean temperatures.     

Novel recursive inference algorithm for discrete dynamic Bayesian networks

Dynamic Bayesian networks (DBNs) can effectively perform modeling and qualitative reasoning for many dynamic systems. However, most of its inference algorithms involve complicated graphical transformations that are hard to program and time-consuming to compute. This article proposes a new recursive inference algorithm, which is a purely numerical method derived from probability theory and the characteristics of Bayesian networks to do both on-line and off-line inferences in discrete DBNs. The most prominent advantages of this novel approach include: (1) it is an exact inference algorithm, thus its accuracy and stability can be guaranteed, (2) it avoids the complex graphical transformation so as to remarkably improve the inference speed, and (3) its concise recursive formulae facilitate programming of both forwards and backwards pass. All of these issues are verified by accurate mathematical derivation as well as a couple of application examples with comparison between the new algorithm and the two most prevailing inference approaches of discrete DBNs – the interface algorithm and the forwards–backwards algorithm.     

RR-Lyrae-type pulsations from a 0.26-solar-mass star in a binary system

RR Lyrae pulsating stars have been extensively used as tracers of old stellar populations for the purpose of determining the ages of galaxies, and as tools to measure distances to nearby galaxies. There was accordingly considerable interest when the RR Lyrae star OGLE-BLG-RRLYR-02792 (referred to here as RRLYR-02792) was found to be a member of an eclipsing binary system, because the mass of the pulsator (hitherto constrained only by models) could be unambiguously determined. Here we report that RRLYR-02792 has a mass of 0.26 solar masses M[symbol see text] and therefore cannot be a classical RR Lyrae star. Using models, we find that its properties are best explained by the evolution of a close binary system that started with M[symbol see text] and 0.8M[symbol see text]stars orbiting each other with an initial period of 2.9 days. Mass exchange over 5.4 billion years produced the observed system, which is now in a very short-lived phase where the physical properties of the pulsator happen to place it in the same instability strip of the Hertzsprung-Russell diagram as that occupied by RR Lyrae stars. We estimate that only 0.2 per cent of RR Lyrae stars may be contaminated by systems similar to this one, which implies that distances measured with RR Lyrae stars should not be significantly affected by these binary interlopers.     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.