Synthesis of trifluoromethylated isoxazoles and their elaboration through inter- and intra-molecular C-H arylation

We report conditions for the preparation of a range of trifluoromethylated isoxazole building blocks through the cycloaddition reaction of trifluoromethyl nitrile oxide. It was found that controlling the rate (and therefore concentration) of the formation of the trifluoromethyl nitrile oxide was Critical for the preferential formation of the desired isoxazole products versus the furoxan dimer. Different conditions were optimised for both aryl- and alkyl-substituted alkynes. In addition, the reactivity at the isoxazole 4-position has been briefly explored for these building blocks. Conditions for intermolecular C–H arylation, lithiation and electrophile quench, and alkoxylation were all identified with brief substrate scoping that signifies useful tolerance to a range of functionalities. Finally, complementary processes for structural diversification through either intramolecular cyclisation or intermolecular cross-coupling were developed

One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines

A new, three-step, telescoped reaction sequence for the regioselective conversion of N-tosyl hydrazones and aziridines to 3,6-disubstituted and 3,5,6-trisubstituted 1,2,4-triazines is described. The process involves an efficient nucleophilic ring opening of the aziridine, giving access to a wide range of aminohydrazones, isolated with excellent yields. A “one-pot” procedure, combining the ring opening with a cyclization and an oxidation step, allows the preparation of diversified triazines in good yields.This work was supported by a postdoctoral fellowship from Pfizer (L.C.) and EPSRC Grant Nos. EP/K009494/1 and EP/M004120/1 (S.V.L.). We also thank Dr. Andrew D. Bond for conducting X-ray crystallographic analysis

Adolescent brain maturation and cortical folding: evidence for reductions in gyrification

Evidence from anatomical and functional imaging studies have highlighted major modifications of cortical circuits during adolescence. These include reductions of gray matter (GM), increases in the myelination of cortico-cortical connections and changes in the architecture of large-scale cortical networks. It is currently unclear, however, how the ongoing developmental processes impact upon the folding of the cerebral cortex and how changes in gyrification relate to maturation of GM/WM-volume, thickness and surface area. In the current study, we acquired high-resolution (3 Tesla) magnetic resonance imaging (MRI) data from 79 healthy subjects (34 males and 45 females) between the ages of 12 and 23 years and performed whole brain analysis of cortical folding patterns with the gyrification index (GI). In addition to GI-values, we obtained estimates of cortical thickness, surface area, GM and white matter (WM) volume which permitted correlations with changes in gyrification. Our data show pronounced and widespread reductions in GI-values during adolescence in several cortical regions which include precentral, temporal and frontal areas. Decreases in gyrification overlap only partially with changes in the thickness, volume and surface of GM and were characterized overall by a linear developmental trajectory. Our data suggest that the observed reductions in GI-values represent an additional, important modification of the cerebral cortex during late brain maturation which may be related to cognitive development

Coordinated optimization of visual cortical maps (II) Numerical studies

It is an attractive hypothesis that the spatial structure of visual cortical architecture can be explained by the coordinated optimization of multiple visual cortical maps representing orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we defined a class of analytically tractable coordinated optimization models and solved representative examples in which a spatially complex organization of the orientation preference map is induced by inter-map interactions. We found that attractor solutions near symmetry breaking threshold predict a highly ordered map layout and require a substantial OD bias for OP pinwheel stabilization. Here we examine in numerical simulations whether such models exhibit biologically more realistic spatially irregular solutions at a finite distance from threshold and when transients towards attractor states are considered. We also examine whether model behavior qualitatively changes when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. Our numerical results support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the spatially irregular architecture of the visual cortex. We discuss several alternative scenarios and additional factors that may improve the agreement between model solutions and biological observations.Comment: 55 pages, 11 figures. arXiv admin note: substantial text overlap with arXiv:1102.335

Why Self-Induced Pain Feels Less Painful than Externally Generated Pain: Distinct Brain Activation Patterns in Self- and Externally Generated Pain

Voluntary movement generally inhibits sensory systems. However, it is not clear how such movement influences pain. In the present study, subjects actively or passively experienced mechanical pain or pressure during functional MRI scanning. Pain and pressure were induced using two modified grip strengthener rings, each twined with four crystal bead strings, with polyhedral beads to induce pain, or spherical beads to induce pressure. Subjects held one ring in the left hand and were either asked to squeeze their left hand with their right hand (i.e., active pain or pressure), or to have their left hand squeezed by the experimenter (i.e., passive pain or pressure). Subjects rated the intensity and unpleasantness of the pain sensation lower in the active procedure than in the passive one. Correspondingly, pain-related brain areas were inhibited in the case of self-generated pain, including the primary somatosensory cortex (SI), anterior cingulate cortex (ACC), and the thalamus. These results suggest that active movement behaviorally inhibits concomitant mechanical pain, accompanied by an inhibition of pain response in pain-related brain areas such as the SI cortex. This might be part of the mechanisms underlying the kinesitherapy for pain treatment

Reduced auditory steady state responses in autism spectrum disorder

Background Auditory steady state responses (ASSRs) are elicited by clicktrains or amplitude-modulated tones, which entrain auditory cortex at their specific modulation rate. Previous research has reported reductions in ASSRs at 40 Hz for autism spectrum disorder (ASD) participants and first-degree relatives of people diagnosed with ASD (Mol Autism. 2011;2:11, Biol Psychiatry. 2007;62:192–197). Methods Using a 1.5 s-long auditory clicktrain stimulus, designed to elicit an ASSR at 40 Hz, this study attempted to replicate and extend these findings. Magnetencephalography (MEG) data were collected from 18 adolescent ASD participants and 18 typically developing controls. Results The ASSR localised to bilateral primary auditory regions. Regions of interest were thus defined in left and right primary auditory cortex (A1). While the transient gamma-band response (tGBR) from 0-0.1 s following presentation of the clicktrain stimulus was not different between groups, for either left or right A1, the ASD group had reduced oscillatory power at 40 Hz from 0.5 to 1.5 s post-stimulus onset, for both left and right A1. Additionally, the ASD group had reduced inter-trial coherence (phase consistency over trials) at 40 Hz from 0.64-0.82 s for right A1 and 1.04-1.22 s for left A1. Limitations In this study, we did not conduct a clinical autism assessment (e.g. the ADOS), and therefore, it remains unclear whether ASSR power and/or ITC are associated with the clinical symptoms of ASD. Conclusion Overall, our results support a specific reduction in ASSR oscillatory power and inter-trial coherence in ASD, rather than a generalised deficit in gamma-band responses. We argue that this could reflect a developmentally relevant reduction in non-linear neural processing

Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes

BACKGROUND: Elevated white blood cell counts (WBC) in acute coronary syndromes (ACS) increase the risk of recurrent events, but it is not known if this is exacerbated by pro-inflammatory factors. We sought to identify whether pro-inflammatory genetic variants contributed to alterations in WBC and C-reactive protein (CRP) in an ACS population. METHODS: WBC and genotype of interleukin 6 (IL-6 G-174C) and of interleukin-1 receptor antagonist (IL1RN intronic repeat polymorphism) were investigated in 732 Caucasian patients with ACS in the OPUS-TIMI-16 trial. Samples for measurement of WBC and inflammatory factors were taken at baseline, i.e. Within 72 hours of an acute myocardial infarction or an unstable angina event. RESULTS: An increased white blood cell count (WBC) was associated with an increased C-reactive protein (r = 0.23, p < 0.001) and there was also a positive correlation between levels of β-fibrinogen and C-reactive protein (r = 0.42, p < 0.0001). IL1RN and IL6 genotypes had no significant impact upon WBC. The difference in median WBC between the two homozygote IL6 genotypes was 0.21/mm(3 )(95% CI = -0.41, 0.77), and -0.03/mm(3 )(95% CI = -0.55, 0.86) for IL1RN. Moreover, the composite endpoint was not significantly affected by an interaction between WBC and the IL1 (p = 0.61) or IL6 (p = 0.48) genotype. CONCLUSIONS: Cytokine pro-inflammatory genetic variants do not influence the increased inflammatory profile of ACS patients

Kowakare: A New Perspective on the Development of Early Mother–Offspring Relationship

The mother–offspring relationship has components of both positivity and negativity. Kowakare is a new concept introduced to explain an adaptive function of the negativity in the early mother-offspring relationship. Kowakare is the psycho-somatic development of the relationship as the process of accumulation in the otherness of offspring. Early human Kowakare has two frameworks, biological inter-body antagonism and socio-cultural allomothering compensating the antagonism. Some features of feeding/weaning, parental aversion to offspring’s bodily products, and transition from dyad to triad relationship (proto–triad relationship) in tactile play are discussed. Early human Kowakare is promoted by allomothering with the nested systems of objects/persons/institutions as interfaces between mother and offspring. Kowakare makes mother–offspring relationship a mutually autonomous and cooperative companionship

The sense of agency as tracking control

Does sense of agency (SoA) arise merely from action-outcome associations, or does an additional real-time process track each step along the chain? Tracking control predicts that deviant intermediate steps between action and outcome should reduce SoA. In two experiments, participants learned mappings between two finger actions and two tones. In later test blocks, actions triggered a robot hand moving either the same or a different finger, and also triggered tones, which were congruent or incongruent with the mapping. The perceived delay between actions and tones gave a proxy measure for SoA. Action-tone binding was stronger for congruent than incongruent tones, but only when the robot movement was also congruent. Congruent tones also had reduced N amplitudes, but again only when the robot movement was congruent.We suggest that SoA partly depends on a real time tracking control mechanism, since deviant intermediate action of the robot reduced SoA over the tone

Galanin Transgenic Mice with Elevated Circulating Galanin Levels Alleviate Demyelination in a Cuprizone-Induced MS Mouse Model

Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) with a presumed autoimmune etiology. Approved treatments for MS are immunoregulatory and are able to reduce the inflammatory components of the disease. However, these treatments do not suppress progressive clinical disability. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination are likely to improve long-term outcomes and reduce the rate of axonal damage. Galanin (GAL) is a bioactive neuropeptide that is widely distributed throughout the nervous system and has diverse neuromodulatory effects. In this study, using the cuprizone (CPZ) demyelination model of MS, we demonstrate that GAL has pronounced neuroprotective effects with respect to demyelination and remyelination. Using our GAL transgenic mouse (GAL-Tg), we identified a novel attenuation of OLs against CPZ induced demyelination, which was exerted independently of progenitor cells. Alleviation of myelin breakdown in the GAL-Tg mice was observed to be significant. Furthermore, we observed changes in the expression of the GAL receptor GalR1 during the demyelination and remyelination processes. Our data strongly indicate that GAL has the capacity to influence the outcome of primary insults that directly target OLs, as opposed to cases where immune activation is the primary pathogenic event. Taken together, these results suggest that GAL is a promising next-generation target for the treatment of MS