Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2) deficient mice: Do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms?

Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner's 'two-headed' model indicates that antipsychotics not only reverse LI disruption, 'disrupted LI', but also potentiate LI when low/absent in controls, 'persistent' LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1 -/- and wild-type mice, indicating no such moderation in Drd1 -/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis

Extended Lyman-Alpha Emission around Star-forming Galaxies

Lyman-alpha (Lya) photons that escape the interstellar medium of star-forming galaxies may be resonantly scattered by neutral hydrogen atoms in the circumgalactic and intergalactic media, thereby increasing the angular extent of the galaxy's Lya emission. We present predictions of this extended, low surface brightness Lya emission based on radiative transfer modeling in a cosmological reionization simulation. The extended emission can be detected from stacked narrowband images of Lya emitters (LAEs) or of Lyman break galaxies (LBGs). Its average surface brightness profile has a central cusp, then flattens to an approximate plateau beginning at an inner characteristic scale below ~0.2 Mpc (comoving), then steepens again beyond an outer characteristic scale of ~1 Mpc. The inner scale marks the transition from scattered light of the central source to emission from clustered sources, while the outer scale marks the spatial extent of scattered emission from these clustered sources. Both scales tend to increase with halo mass, UV luminosity, and observed Lya luminosity. The extended emission predicted by our simulation is already within reach of deep narrowband photometry using large ground-based telescopes. Such observations would test radiative transfer models of emission from LAEs and LBGs, and they would open a new window on the circumgalactic environment of high-redshift star-forming galaxies.Comment: 14 pages, 10 figures, accepted for publication in ApJ, revised according to the referee's comments, more discussions and test

Bit-precise procedure-modular termination analysis

Non-termination is the root cause of a variety of program bugs, such as hanging programs and denial-of-service vulnerabilities. This makes an automated analysis that can prove the absence of such bugs highly desirable. To scale termination checks to large systems, an interprocedural termination analysis seems essential. This is a largely unexplored area of research in termination analysis, where most effort has focussed on small but difficult single-procedure problems. We present a modular termination analysis for C programs using template-based interprocedural summarisation. Our analysis combines a context-sensitive, over-approximating forward analysis with the inference of under-approximating preconditions for termination. Bit-precise termination arguments are synthesised over lexicographic linear ranking function templates. Our experimental results show the advantage of interprocedural reasoning over monolithic analysis in terms of efficiency, while retaining comparable precision.</jats:p

Precision Epoch of Reionization studies with next-generation CMB experiments

Future arcminute resolution polarization data from ground-based Cosmic Microwave Background (CMB) observations can be used to estimate the contribution to the temperature power spectrum from the primary anisotropies and to uncover the signature of reionization near $\ell=1500$ in the small angular-scale temperature measurements. Our projections are based on combining expected small-scale E-mode polarization measurements from Advanced ACTPol in the range $300<\ell<3000$ with simulated temperature data from the full Planck mission in the low and intermediate $\ell$ region, $2<\ell<2000$. We show that the six basic cosmological parameters determined from this combination of data will predict the underlying primordial temperature spectrum at high multipoles to better than $1\%$ accuracy. Assuming an efficient cleaning from multi-frequency channels of most foregrounds in the temperature data, we investigate the sensitivity to the only residual secondary component, the kinematic Sunyaev-Zel'dovich (kSZ) term. The CMB polarization is used to break degeneracies between primordial and secondary terms present in temperature and, in effect, to remove from the temperature data all but the residual kSZ term. We estimate a $15 \sigma$ detection of the diffuse homogeneous kSZ signal from expected AdvACT temperature data at $\ell>1500$, leading to a measurement of the amplitude of matter density fluctuations, $\sigma_8$, at $1\%$ precision. Alternatively, by exploring the reionization signal encoded in the patchy kSZ measurements, we bound the time and duration of the reionization with $\sigma(z_{\rm re})=1.1$ and $\sigma(\Delta z_{\rm re})=0.2$. We find that these constraints degrade rapidly with large beam sizes, which highlights the importance of arcminute-scale resolution for future CMB surveys.Comment: 10 pages, 10 figure

Amyloid β 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks

Alzheimer's disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide. Brain hypometabolism is a major feature of AD, appearing decades before cognitive decline and pathologic lesions. To date, the majority of studies on hypometabolism in AD have used transgenic animal models or imaging studies of the human brain. As it is almost impossible to validate these findings using human tissue, alternative models are required. In this study, we show that human stem cell-derived neuron and astrocyte cultures treated with oligomers of amyloid beta 1-42 (Aβ1-42) also display a clear hypometabolism, particularly with regard to utilization of substrates such as glucose, pyruvate, lactate, and glutamate. In addition, a significant increase in the glycogen content of cells was also observed. These changes were accompanied by changes in NAD+ /NADH, ATP, and glutathione levels, suggesting a disruption in the energy-redox axis within these cultures. The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aβ-induced hypometabolism. Further research using this model may elucidate the mechanisms associated with Aβ-induced hypometabolism

Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System

Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations

A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection.

A genome-scale CRISPR knockout library screen of THP-1 human macrophages was performed to identify loss-of-function mutations conferring resistance to Salmonella uptake. The screen identified 183 candidate genes, from which 14 representative genes involved in actin dynamics (ACTR3, ARPC4, CAPZB, TOR3A, CYFIP2, CTTN, and NHLRC2), glycosaminoglycan metabolism (B3GNT1), receptor signaling (PDGFB and CD27), lipid raft formation (CLTCL1), calcium transport (ATP2A2 and ITPR3), and cholesterol metabolism (HMGCR) were analyzed further. For some of these pathways, known chemical inhibitors could replicate the Salmonella resistance phenotype, indicating their potential as targets for host-directed therapy. The screen indicated a role for the relatively uncharacterized gene NHLRC2 in both Salmonella invasion and macrophage differentiation. Upon differentiation, NHLRC2 mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles. Immunoprecipitation confirmed an interaction of NHLRC2 with FRYL, EIF2AK2, and KLHL13.IMPORTANCESalmonella exploits macrophages to gain access to the lymphatic system and bloodstream to lead to local and potentially systemic infections. With an increasing number of antibiotic-resistant isolates identified in humans, Salmonella infections have become major threats to public health. Therefore, there is an urgent need to identify alternative approaches to anti-infective therapy, including host-directed therapies. In this study, we used a simple genome-wide screen to identify 183 candidate host factors in macrophages that can confer resistance to Salmonella infection. These factors may be potential therapeutic targets against Salmonella infections