Heightened cocaine-seeking in male rats associates with a distinct transcriptomic profile in the medial prefrontal cortex

Drug overdose deaths involving cocaine have skyrocketed, an outcome attributable in part to the lack of FDA-approved medications for the treatment of cocaine use disorder (CUD), highlighting the need to identify new pharmacotherapeutic targets. Vulnerability to cocaine-associated environmental contexts and stimuli serves as a risk factor for relapse in CUD recovery, with individual differences evident in the motivational aspects of these cues. The medial prefrontal cortex (mPFC) provides top-down control of striatal circuitry to regulate the incentive-motivational properties of cocaine-associated stimuli. Clinical and preclinical studies have identified genetic variations that impact the degree of executive restraint over drug-motivated behaviors, and we designed the present study to employ next-generation sequencing to identify specific genes associated with heightened cue-evoked cocaine-seeking in the mPFC of male, outbred rats. Rats were trained to stably self-administer cocaine, and baseline cue-reinforced cocaine-seeking was established. Rats were phenotyped as either high cue (HC) or low cue (LC) responders based upon lever pressing for previously associated cocaine cues and allowed 10 days of abstinence in their home cages prior to mPFC collection for RNA-sequencing. The expression of 309 genes in the mPFC was significantly different in HC vs. LC rats. Functional gene enrichment analyses identified ten biological processes that were overrepresented in the mPFC of HC vs. LC rats. The present study identifies distinctions in mPFC mRNA transcripts that characterizes individual differences in relapse-like behavior and provides prioritized candidates for future pharmacotherapeutics aimed to help maintain abstinence in CUD. In particular the Htr2c gene, which encodes the serotonin 5-HT2C receptor (5-HT2CR), is expressed to a lower extent in HC rats, relative to LC rats. These findings build on a plethora of previous studies that also point to the 5-HT2CR as an attractive target for the treatment of CUD

An ATP-binding cassette-type cysteine transporter in Campylobacter jejuni inferred from the structure of an extracytoplasmic solute receptor protein

Campylobacter jejuni is a Gram-negative food-borne pathogen associated with gastroenteritis in humans as well as cases of the autoimmune disease Guillain Barre syndrome. C. jejuni is asaccharolytic because it lacks an active glycolytic pathway for the use of sugars as a carbon source. This suggests an increased reliance on amino acids as nutrients and indeed the genome sequence of this organism indicates the presence of a number of amino acid uptake systems. Cj0982, also known as CjaA, is a putative extracytoplasmic solute receptor for one such uptake system as well as a major surface antigen and vaccine candidate. The crystal structure of Cj0982 reveals a two-domain protein with density in the enclosed cavity between the domains that clearly defines the presence of a bound cysteine ligand. Fluorescence titration experiments were used to demonstrate that Cj0982 binds cysteine tightly and specifically with a K-d of similar to 10(-7) M consistent with a role as a receptor for a high- affinity transporter. These data imply that Cj0982 is the binding protein component of an ABC-type cysteine transporter system and that cysteine uptake is important in the physiology of C. jejuni

Simulating the influences of groundwater on regional geomorphology using a distributed, dynamic, landscape evolution modelling platform

A dynamic landscape evolution modelling platform (CLiDE) is presented that allows a variety of Earth system interactions to be explored under differing environmental forcing factors. Representation of distributed surface and subsurface hydrology within CLiDE is suited to simulation at sub-annual to centennial time-scales. In this study the hydrological components of CLiDE are evaluated against analytical solutions and recorded datasets. The impact of differing groundwater regimes on sediment discharge is examined for a simple, idealised catchment, Sediment discharge is found to be a function of the evolving catchment morphology. Application of CLiDE to the upper Eden Valley catchment, UK, suggests the addition of baseflow-return from groundwater into the fluvial system modifies the total catchment sediment discharge and the spatio-temporal distribution of sediment fluxes during storm events. The occurrence of a storm following a period of appreciable antecedent rainfall is found to increase simulated sediment fluxes

Glyconanoparticles for colorimetric bioassays

Carbohydrate molecules are involved in many of the cellular processes that are important for life. By combining the specific analyte targeting of carbohydrates with the multivalent structure and change of solution colour as a consequence of plasmonic interactions with the aggregation of metal nanoparticles, glyconanoparticles have been used extensively for the development of bioanalytical assays. The noble metals used to create the nanocore, the methodologies used to assemble the carbohydrates on the nanoparticle surface, the carbohydrate chosen for each specific target, the length of the tether that separates the carbohydrate from the nanocore and the density of carbohydrates on the surface all impact on the structural formation of metal based glyconanoparticles. This tutorial review highlights these key components, which directly impact on the selectivity and sensitivity of the developed bioassay, for the colorimetric detection of lectins, toxins and viruses

Are moving punctures equivalent to moving black holes?

When simulating the inspiral and coalescence of a binary black-hole system, special care needs to be taken in handling the singularities. Two main techniques are used in numerical-relativity simulations: A first and more traditional one ``excises'' a spatial neighbourhood of the singularity from the numerical grid on each spacelike hypersurface. A second and more recent one, instead, begins with a ``puncture'' solution and then evolves the full 3-metric, including the singular point. In the continuum limit, excision is justified by the light-cone structure of the Einstein equations and, in practice, can give accurate numerical solutions when suitable discretizations are used. However, because the field variables are non-differentiable at the puncture, there is no proof that the moving-punctures technique is correct, particularly in the discrete case. To investigate this question we use both techniques to evolve a binary system of equal-mass non-spinning black holes. We compare the evolution of two curvature 4-scalars with proper time along the invariantly-defined worldline midway between the two black holes, using Richardson extrapolation to reduce the influence of finite-difference truncation errors. We find that the excision and moving-punctures evolutions produce the same invariants along that worldline, and thus the same spacetimes throughout that worldline's causal past. This provides convincing evidence that moving-punctures are indeed equivalent to moving black holes.Comment: 4 pages, 3 eps color figures; v2 = major revisions to introduction & conclusions based on referee comments, but no change in analysis or result

Black Hole Mass Estimates Based on CIV are Consistent with Those Based on the Balmer Lines

Using a sample of high-redshift lensed quasars from the CASTLES project with observed-frame ultraviolet or optical and near-infrared spectra, we have searched for possible biases between supermassive black hole (BH) mass estimates based on the CIV, Halpha and Hbeta broad emission lines. Our sample is based upon that of Greene, Peng & Ludwig, expanded with new near-IR spectroscopic observations, consistently analyzed high S/N optical spectra, and consistent continuum luminosity estimates at 5100A. We find that BH mass estimates based on the FWHM of CIV show a systematic offset with respect to those obtained from the line dispersion, sigma_l, of the same emission line, but not with those obtained from the FWHM of Halpha and Hbeta. The magnitude of the offset depends on the treatment of the HeII and FeII emission blended with CIV, but there is little scatter for any fixed measurement prescription. While we otherwise find no systematic offsets between CIV and Balmer line mass estimates, we do find that the residuals between them are strongly correlated with the ratio of the UV and optical continuum luminosities. Removing this dependency reduces the scatter between the UV- and optical-based BH mass estimates by a factor of approximately 2, from roughly 0.35 to 0.18 dex. The dispersion is smallest when comparing the CIV sigma_l mass estimate, after removing the offset from the FWHM estimates, and either Balmer line mass estimate. The correlation with the continuum slope is likely due to a combination of reddening, host contamination and object-dependent SED shapes. When we add additional heterogeneous measurements from the literature, the results are unchanged.Comment: Accepted for publication in The Astrophysical Journal. 37 text pages + 8 tables + 23 figures. Updated with comments by the referee and with a expanded discussion on literature data including new observation

Intermediate and extreme mass-ratio inspirals — astrophysics, science applications and detection using LISA

Black hole binaries with extreme (gtrsim104:1) or intermediate (~102–104:1) mass ratios are among the most interesting gravitational wave sources that are expected to be detected by the proposed laser interferometer space antenna (LISA). These sources have the potential to tell us much about astrophysics, but are also of unique importance for testing aspects of the general theory of relativity in the strong field regime. Here we discuss these sources from the perspectives of astrophysics, data analysis and applications to testing general relativity, providing both a description of the current state of knowledge and an outline of some of the outstanding questions that still need to be addressed. This review grew out of discussions at a workshop in September 2006 hosted by the Albert Einstein Institute in Golm, Germany

The Current Status of Binary Black Hole Simulations in Numerical Relativity

Since the breakthroughs in 2005 which have led to long term stable solutions of the binary black hole problem in numerical relativity, much progress has been made. I present here a short summary of the state of the field, including the capabilities of numerical relativity codes, recent physical results obtained from simulations, and improvements to the methods used to evolve and analyse binary black hole spacetimes.Comment: 14 pages; minor changes and corrections in response to referee

Black Holes in the Early Universe

The existence of massive black holes was postulated in the sixties, when the first quasars were discovered. In the late nineties their reality was proven beyond doubt, in the Milky way and a handful nearby galaxies. Since then, enormous theoretical and observational efforts have been made to understand the astrophysics of massive black holes. We have discovered that some of the most massive black holes known, weighing billions of solar masses, powered luminous quasars within the first billion years of the Universe. The first massive black holes must therefore have formed around the time the first stars and galaxies formed. Dynamical evidence also indicates that black holes with masses of millions to billions of solar masses ordinarily dwell in the centers of today's galaxies. Massive black holes populate galaxy centers today, and shone as quasars in the past; the quiescent black holes that we detect now in nearby bulges are the dormant remnants of this fiery past. In this review we report on basic, but critical, questions regarding the cosmological significance of massive black holes. What physical mechanisms lead to the formation of the first massive black holes? How massive were the initial massive black hole seeds? When and where did they form? How is the growth of black holes linked to that of their host galaxy? Answers to most of these questions are work in progress, in the spirit of these Reports on Progress in Physics.Comment: Reports on Progress in Physics, in pres

Broad geographic sampling reveals the shared basis and environmental correlates of seasonal adaptation in Drosophila.

To advance our understanding of adaptation to temporally varying selection pressures, we identified signatures of seasonal adaptation occurring in parallel among Drosophila melanogaster populations. Specifically, we estimated allele frequencies genome-wide from flies sampled early and late in the growing season from 20 widely dispersed populations. We identified parallel seasonal allele frequency shifts across North America and Europe, demonstrating that seasonal adaptation is a general phenomenon of temperate fly populations. Seasonally fluctuating polymorphisms are enriched in large chromosomal inversions, and we find a broad concordance between seasonal and spatial allele frequency change. The direction of allele frequency change at seasonally variable polymorphisms can be predicted by weather conditions in the weeks prior to sampling, linking the environment and the genomic response to selection. Our results suggest that fluctuating selection is an important evolutionary force affecting patterns of genetic variation in Drosophila