T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXR

AbstractThe liver X receptors (LXRα and β) are nuclear receptors that coordinate carbohydrate and lipid metabolism. Insight into the physiologic roles of the LXRs has been greatly facilitated by the discovery of potent synthetic agonists. Here we show that one of these compounds, T0901317, is also a high-affinity ligand for the xenobiotic receptor pregnane X receptor (PXR). T0901317 binds and activates PXR with the same nanomolar potency with which it stimulates LXR activity. T0901317 induces expression not only of LXR target genes, but also of PXR target genes in cells and animals, including the scavenger receptor CD36, a property not shared by more specific LXR ligands, such as GW3965. Activation of PXR targets may explain why T0901317 induces dramatic liver steatosis, while GW3965 has a milder effect. These results suggest that many of the biological activities heretofore associated with LXR activation may be mediated by PXR, not LXR. Since T0901317 has been widely used in animals to study LXR function, the in vivo effects of this compound ascribed to LXR activation should be re-examined

Role of RNA-binding proteins Rbfox1l and Rbfox2 in neuronal development and behavior in zebrafish

Rbfox proteins are RNA-binding proteins that play a significant role in the alternative splicing of neuronal transcripts in the central nervous system (CNS). Rbfox proteins are required for proper brain development and function. In humans, RBFOX1 has been implicated in a variety of neurological disorders, including autism, anxiety, epilepsy, and schizophrenia. Rbfox2 is involved in cerebellar development in mammals. The zebrafish is used as a model system for studies in neurobiology given their neuroanatomical conservation with mammals, and remarkable capability to regenerate parts of their CNS. Rbfox1l (Rbfox1-like) and Rbfox2 have been identified in neurons of the adult zebrafish brain. Rbfox1l was found in a restricted population of dorsal telencephalic neurons, and Rbfox2 was found broadly throughout the brain. Both genes have been found in Purkinje cells of the cerebellum. Utilizing antibody staining on zebrafish brain tissue sections, we will analyze expression of Rbfox1l and Rbfox2 at larval stages and stages leading up to adulthood. Furthermore, we will use rbfox1l and rbfox2 mutant zebrafish (in collaboration with Ohio State University) to better understand the role of rbfox1l in behavior and determine whether rbfox2 is necessary for the regeneration of the cerebellum. Understanding the role of the Rbfox proteins in neural development, regeneration, and behavior may lead to a substantial advancement in the research field and health care

Role of RNA-binding proteins Rbfox1l and Rbfox2 in neuronal development and behavior in zebrafish

Rbfox proteins are RNA-binding proteins that play a significant role in the alternative splicing of neuronal transcripts in the central nervous system (CNS). Rbfox proteins are required for proper brain development and function. In humans, RBFOX1 has been implicated in a variety of neurological disorders, including autism, anxiety, epilepsy, and schizophrenia. Rbfox2 is involved in cerebellar development in mammals. The zebrafish is used as a model system for studies in neurobiology given their neuroanatomical conservation with mammals, and remarkable capability to regenerate parts of their CNS. Rbfox1l (Rbfox1-like) and Rbfox2 have been identified in neurons of the adult zebrafish brain. Rbfox1l was found in a restricted population of dorsal telencephalic neurons, and Rbfox2 was found broadly throughout the brain. Both genes have been found in Purkinje cells of the cerebellum. Utilizing antibody staining on zebrafish brain tissue sections, we will analyze expression of Rbfox1l and Rbfox2 at larval stages and stages leading up to adulthood. Furthermore, we will use rbfox1l and rbfox2 mutant zebrafish (in collaboration with Ohio State University) to better understand the role of rbfox1l in behavior and determine whether rbfox2 is necessary for the regeneration of the cerebellum. Understanding the role of the Rbfox proteins in neural development, regeneration, and behavior may lead to a substantial advancement in the research field and health care

Enhancing offspring hypothalamic-pituitary-adrenal (HPA) regulation via systematic novelty exposure: The influence of maternal HPA function

In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother's ability to mount a rapid corticosterone (CORT) response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring hypothalamic-pituitary-adrenal (HPA) regulation. Using a 2 × 2 within-litter design, one half of each litter were exposed to a relatively novel non-home environment for 3-min (Neo_Novel) daily during infancy (PND 1-21) and the other half of the litter remained in the home cage (Neo_Home); we further exposed half of these two groups to early adulthood (PND 54-63) novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting CORT (CORTB) and the ability to mount a large rapid CORT response (CORTE) to the onset of an acute stressor. Assessment of adult offspring's ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring's ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent upon the context of maternal HPA regulation. © 2014 Dinces, Romeo, McEwen and Tang.Link_to_subscribed_fulltex

Temperature and abundance profiles of hot gas in galaxy groups - I. Results and statistical analysis

The distribution of metals in groups of galaxies holds important information about the chemical enrichment history of the Universe. Here we present radial profiles of temperature and the abundance of iron and silicon of the hot intragroup medium for a sample of 15 nearby groups of galaxies observed by Chandra, selected for their regular X-ray morphology. All but one group display a cool core, the size of which is found to correlate with the mean temperature of the group derived outside this core. When scaled to this mean temperature, the temperature profiles are remarkably similar, being analogous to those of more massive clusters at large radii but significantly flatter inwards of the temperature peak. The Fe abundance generally shows a central excess followed by a radial decline, reaching a typical value of 0.1 solar within r_500, a factor of two lower than corresponding results for clusters. Si shows less systematic radial variation, on average displaying a less pronounced decline than Fe and showing evidence for a flattening at large radii. Off-centre abundance peaks are seen both for Fe and Si in a number of groups with well-resolved cores. Derived abundance ratios indicate that supernovae type Ia are responsible for 80 per cent of the Fe in the group core, but the type II contribution increases with radius and completely dominates at r_500. We present fitting formulae for the radial dependence of temperature and abundances, to facilitate comparison to results of numerical simulations of group formation and evolution. In a companion paper, we discuss the implications of these results for feedback and enrichment in galaxy groups.Comment: 21 pages, 11 figures, accepted for publication in MNRA

In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial.

Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16-53 nM), matched with a high potency against P. vivax field isolates (Mean IC50 29 nM). Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P.berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent

Targeted Amplicon Sequencing (TAS): A Scalable Next-Gen Approach to Multilocus, Multitaxa Phylogenetics

Next-gen sequencing technologies have revolutionized data collection in genetic studies and advanced genome biology to novel frontiers. However, to date, next-gen technologies have been used principally for whole genome sequencing and transcriptome sequencing. Yet many questions in population genetics and systematics rely on sequencing specific genes of known function or diversity levels. Here, we describe a targeted amplicon sequencing (TAS) approach capitalizing on next-gen capacity to sequence large numbers of targeted gene regions from a large number of samples. Our TAS approach is easily scalable, simple in execution, neither time-nor labor-intensive, relatively inexpensive, and can be applied to a broad diversity of organisms and/or genes. Our TAS approach includes a bioinformatic application, BarcodeCrucher, to take raw next-gen sequence reads and perform quality control checks and convert the data into FASTA format organized by gene and sample, ready for phylogenetic analyses. We demonstrate our approach by sequencing targeted genes of known phylogenetic utility to estimate a phylogeny for the Pancrustacea. We generated data from 44 taxa using 68 different 10-bp multiplexing identifiers. The overall quality of data produced was robust and was informative for phylogeny estimation. The potential for this method to produce copious amounts of data from a single 454 plate (e.g., 325 taxa for 24 loci) significantly reduces sequencing expenses incurred from traditional Sanger sequencing. We further discuss the advantages and disadvantages of this method, while offering suggestions to enhance the approach

Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent In Vitro and In Vivo Activities

The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3, now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate