243 research outputs found
A Machine Checked Model of Idempotent MGU Axioms For Lists of Equational Constraints
We present formalized proofs verifying that the first-order unification
algorithm defined over lists of satisfiable constraints generates a most
general unifier (MGU), which also happens to be idempotent. All of our proofs
have been formalized in the Coq theorem prover. Our proofs show that finite
maps produced by the unification algorithm provide a model of the axioms
characterizing idempotent MGUs of lists of constraints. The axioms that serve
as the basis for our verification are derived from a standard set by extending
them to lists of constraints. For us, constraints are equalities between terms
in the language of simple types. Substitutions are formally modeled as finite
maps using the Coq library Coq.FSets.FMapInterface. Coq's method of functional
induction is the main proof technique used in proving many of the axioms.Comment: In Proceedings UNIF 2010, arXiv:1012.455
Genome stability of bovine in vivo-conceived cleavage-stage embryos is higher compared to in vitro-produced embryos.
STUDY QUESTION
Is the rate and nature of chromosome instability (CIN) similar between bovine in vivo-derived and in vitro-cultured cleavage-stage embryos?
SUMMARY ANSWER
There is a major difference regarding chromosome stability of in vivo-derived and in vitro-cultured embryos, as CIN is significantly lower in in vivo-derived cleavage-stage embryos compared to in vitro-cultured embryos.
WHAT IS KNOWN ALREADY
CIN is common during in vitro embryogenesis and is associated with early embryonic loss in humans, but the stability of in vivo-conceived cleavage-stage embryos remains largely unknown.
STUDY DESIGN, SIZE, DURATION
Because human in vivo preimplantation embryos are not accessible, bovine (Bos taurus) embryos were used to study CIN in vivo. Five young, healthy, cycling Holstein Friesian heifers were used to analyze single blastomeres of in vivo embryos, in vitro embryos produced by ovum pick up with ovarian stimulation (OPU-IVF), and in vitro embryos produced from in vitro matured oocytes retrieved without ovarian stimulation (IVM-IVF).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Single blastomeres were isolated from embryos, whole-genome amplified and hybridized on Illumina BovineHD BeadChip arrays together with the bulk DNA from the donor cows (mothers) and the bull (father). DNA was also obtained from the parents of the bull and from the parents of the cows (paternal and maternal grandparents, respectively). Subsequently, genome-wide haplotyping and copy-number profiling was applied to investigate the genomic architecture of 171 single bovine blastomeres of 16 in vivo, 13 OPU-IVF and 13 IVM-IVF embryos.
MAIN RESULTS AND THE ROLE OF CHANCE
The genomic stability of single blastomeres in both of the in vitro-cultured embryo cohorts was severely compromised (P < 0.0001), and the frequency of whole chromosome or segmental aberrations was higher in embryos produced in vitro than in embryos derived in vivo. Only 18.8% of in vivo-derived embryos contained at least one blastomere with chromosomal anomalies, compared to 69.2% of OPU-IVF embryos (P < 0.01) and 84.6% of IVM-IVF embryos (P < 0.001).
LARGE SCALE DATA
Genotyping data obtained in this study has been submitted to NCBI Gene Expression Omnibus (GEO; accession number GSE95358)
LIMITATIONS REASONS FOR CAUTION
There were two main limitations of the study. First, animal models may not always reflect the nature of human embryogenesis, although the use of an animal model to investigate CIN was unavoidable in our study. Second, a limited number of embryos were obtained, therefore more studies are warranted to corroborate the findings.
WIDER IMPLICATIONS OF THE FINDINGS
Although CIN is also present in in vivo-developed embryos, in vitro procedures exacerbate chromosomal abnormalities during early embryo development. Hence, the present study highlights that IVF treatment compromises embryo viability and should be applied with care. Additionally, our results encourage to refine and improve in vitro culture conditions and assisted reproduction technologies.
STUDY FUNDING/COMPETING INTEREST(S)
The study was funded by the Agency for Innovation by Science and Technology (IWT) (TBM-090878 to J.R.V. and T.V.), the Research Foundation Flanders (FWO; G.A093.11 N to T.V. and J.R.V. and G.0392.14 N to A.V.S. and J.R.V.), the European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, EU324509 to J.R.V., T.V., O.T, A.D., A.S. and A.K.) and Horizon 2020 innovation programme (WIDENLIFE, 692065 to J.R.V., O.T., T.V., A.K. and A.S.). M.Z.E., J.R.V. and T.V. are co-inventors on a patent application ZL913096-PCT/EP2014/068315-WO/2015/028576 (âHaplotyping and copy-number typing using polymorphic variant allelic frequenciesâ), licensed to Cartagenia (Agilent Technologies
The Novel Atypical Dopamine Uptake Inhibitor (S)-CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding
Animal studies of effort-based choice behavior are being used to model effort-related
motivational dysfunctions in humans. With these procedures, animals are offered a choice
between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/
low reward options. Several previous studies have shown that dopamine (DA) uptake
inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040,
can reverse the effort-related effects of the vesicular monoamine transport blocker
tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport
act as major stimulants that also release DA, and produce a number of undesirable
side effects, there is a need to develop and characterize novel atypical DA transport
inhibitors. (S)-CE-123 ((S)-5-((benzhydrylsulfnyl) methyl)thiazole) is a recently developed
analog of modafnil with the biochemical characteristics of an atypical DA transport
blocker. The present paper describes the enantioselective synthesis and initial chemical
characterization of (S)-CE-123, as well as behavioral experiments involving effort-based
choice and microdialysis studies of extracellular DA. Rats were assessed using the fxed
ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior,
decreasing lever pressing and increasing chow intake. (S)-CE-123 was coadministered
at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but signifcantly
reversed the effects of tetrabenazine, although this dose had no effect on fxed ratio
responding when administered alone. Additional experiments showed that (S)-CE-123
signifcantly increased lever pressing on a progressive ratio/chow feeding choice task and
that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core.
In summary, (S)-CE-123 has the behavioral and neurochemical profle of a compound
that can block DA transport, reverse the effort-related effects of tetrabenazine, and
increase selection of high-effort progressive ratio responding. This suggests that (S)-CE-
123 or a similar compound could be useful as a treatment for effort-related motivational
dysfunction in humans
Low-Affinity/High-Selectivity Dopamine Transport Inhibition Sufficient to Rescue Cognitive Functions in the Aging Rat
The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory. Following binding studies to DAT, NET and SERT, GPCR and kinome screening, pharmacokinetics and a basic neurotoxic screen, S-CE-123 was tested for its potential to enhance and/or rescue cognitive functions in young and in aged rats in the non-invasive reward-motivated paradigm of a hole-board test for spatial learning. In addition, an open field study with young rats was carried out. We demonstrated that S-CE-123 is a low-affinity but highly selective dopamine reuptake inhibitor with good bioavailability. S-CE-123 did not induce hyperlocomotion or anxiogenic or stereotypic behaviour in young rats. Our compound improved the performance of aged but not young rats in a reward-motivated task. The well-described impairment of the dopaminergic system in aging may underlie the age-specific effect. We propose S-CE-123 as a possible candidate for developing a tentative therapeutic strategy for age-related cognitive decline and cognitive dysfunction in psychiatric disorders
A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions
Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson's and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders
Carbon sources of Antarctic nematodes as revealed by natural carbon isotope ratios and a pulse-chase experiment
ÎŽ13C of nematode communities in 27 sites was analyzed, spanning a large depth range (from 130 to 2,021 m) in five Antarctic regions, and compared to isotopic signatures of sediment organic matter. Sediment organic matter ÎŽ13C ranged from â24.4 to â21.9â° without significant differences between regions, substrate types or depths. Nematode ÎŽ13C showed a larger range, from â34.6 to â19.3â°, and was more depleted than sediment organic matter typically by 1â° and by up to 3â° in silty substrata. These, and the isotopically heavy meiofauna at some stations, suggest substantial selectivity of some meiofauna for specific components of the sedimenting plankton. However, 13C-depletion in lipids and a potential contribution of chemoautotrophic carbon in the diet of the abundant genus Sabatieria may confound this interpretation. Carbon sources for Antarctic nematodes were also explored by means of an experiment in which the fate of a fresh pulse of labile carbon to the benthos was followed. This organic carbon was remineralized at a rate (11â20 mg C mâ2 dayâ1) comparable to mineralization rates in continental slope sediments. There was no lag between sedimentation and mineralization; uptake by nematodes, however, did show such a lag. Nematodes contributed negligibly to benthic carbon mineralization
Development of an In Vitro Model for the Multi-Parametric Quantification of the Cellular Interactions between Candida Yeasts and Phagocytes
We developed a new in vitro model for a multi-parameter characterization of the time course interaction of Candida fungal cells with J774 murine macrophages and human neutrophils, based on the use of combined microscopy, fluorometry, flow cytometry and viability assays. Using fluorochromes specific to phagocytes and yeasts, we could accurately quantify various parameters simultaneously in a single infection experiment: at the individual cell level, we measured the association of phagocytes to fungal cells and phagocyte survival, and monitored in parallel the overall phagocytosis process by measuring the part of ingested fungal cells among the total fungal biomass that changed over time. Candida albicans, C. glabrata, and C. lusitaniae were used as a proof of concept: they exhibited species-specific differences in their association rate with phagocytes. The fungal biomass uptaken by the phagocytes differed significantly according to the Candida species. The measure of the survival of fungal and immune cells during the interaction showed that C. albicans was the more aggressive yeast in vitro, destroying the vast majority of the phagocytes within five hours. All three species of Candida were able to survive and to escape macrophage phagocytosis either by the intraphagocytic yeast-to-hyphae transition (C. albicans) and the fungal cell multiplication until phagocytes burst (C. glabrata, C. lusitaniae), or by the avoidance of phagocytosis (C. lusitaniae). We demonstrated that our model was sensitive enough to quantify small variations of the parameters of the interaction. The method has been conceived to be amenable to the high-throughput screening of mutants in order to unravel the molecular mechanisms involved in the interaction between yeasts and host phagocytes
AZASPIRACIDS â Toxicological Evaluation, Test Methods and Identifcation of the Source Organisms (ASTOX II)
Since the Irish monitoring program was set up in 2001 azaspiracids (AZAs) have been detected in shellfish above the regulatory limit every year with the exception of 2004. The south west coast of Ireland is especially prone to the onsets of AZA events. Over this period a number of poisoning incidents associated with this toxin group have occurred, all related to Irish shellfish. In 2003 the Marine Institute was awarded funding for a research project named ASTOX. This project was very successful in producing a range of reference materials (RMs, which are essential for accurate detection and monitoring, and which up to this point were unavailable. The project also examined the toxicity of AZAs, primarily using in vitro cell assays but some in vivo studies were also performed. The overall aims of the ASTOX 2 project were to strengthen knowledge on the causative organism and toxicity of AZAs. The project aims were grouped into three areas: ecology, chemical support and toxicology.Marine Institute Marine Research Sub Programme (NDP 2007 - 2013), co financed under the European Regional Development Fund
Visual mismatch negativity (vMMN): A review and meta-analysis of studies in psychiatric and neurological disorders
The visual mismatch negativity (vMMN) response is an event-related potential (ERP) component, which is automatically elicited by events that violate predictions based on prior events. VMMN experiments use visual stimulus repetition to induce predictions, and vMMN is obtained by subtracting the response to rare unpredicted stimuli from those to frequent stimuli. One increasingly popular interpretation of the mismatch response postulates that vMMN, similar to its auditory counterpart (aMMN), represents a prediction error response generated by cortical mechanisms forming probabilistic representations of sensory signals. Here we discuss the physiological and theoretical basis of vMMN and review thirty-three studies from the emerging field of its clinical applications, presenting a meta-analysis of findings in schizophrenia, mood disorders, substance abuse, neurodegenerative disorders, developmental disorders, deafness, panic disorder and hypertension. Furthermore, we include reports on aging and maturation as they bear upon many clinically relevant conditions. Surveying the literature we found that vMMN is altered in several clinical populations which is in line with aMMN findings. An important potential advantage of vMMN however is that it allows the investigation of deficits in predictive processing in cognitive domains which rely primarily on visual information; a principal sensory modality and thus of vital importance in environmental information processing and response, and a modality which arguably may be more sensitive to some pathological changes. However, due to the relative infancy of research in vMMN compared to aMMN in clinical populations its potential for clinical application is not yet fully appreciated. The aim of this review and meta-analysis therefore is to present, in a detailed systematic manner, the findings from clinically-based vMMN studies, to discuss their potential impact and application, to raise awareness of this measure and to improve our understanding of disease upon fundamental aspects of visual information processing
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