Spin-Glass Model for Inverse Freezing

We analyze the Blume-Emery-Griffiths model with disordered magnetic interaction displaying the inverse freezing phenomenon. The behaviour of this spin-1 model in crystal field is studied throughout the phase diagram and the transition and spinodal lines for the model are computed using the Full Replica Symmetry Breaking Ansatz that always yelds a thermodynamically stable phase. We compare the results both with the quenched disordered model with Ising spins on lattice gas - where no reentrance takes place - and with the model with generalized spin variables recently introduced by Schupper and Shnerb [Phys. Rev. Lett. 93, 037202 (2004)]. The simplest version of all these models, known as Ghatak-Sherrington model, turns out to hold all the general features characterizing an inverse transition to an amorphous phase, including the right thermodynamic behavior.Comment: 6 pages, 4 figures, to appear in the Proceeding for the X International Workshop on Disordered Systems (2006), Molveno, Ital

Decreased blood–brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA

Decreased blood–brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson’s disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function

The landscape of gifted and talented education in England and Wales: How are teachers implementing policy?

This is an Author's Accepted Manuscript of an article published in Research Papers in Education, 27(2), 167-186, 2012, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/02671522.2010.509514.This paper explores the evidence relating to how primary schools are responding to the ‘gifted and talented’ initiative in England and Wales. A questionnaire survey which invited both closed and open-ended responses was carried out with a national sample of primary schools. The survey indicated an increasing proportion of coordinators, compared with a survey carried out in 1996, were identifying their gifted and talented children as well as having associated school policies. However, the survey also highlighted a number of issues which need addressing if the initiative is to achieve its objective of providing the best possible educational opportunities for children. For example, it was found that a significant number of practitioners were not aware of the existence of the National Quality Standards for gifted and talented education, provided by the UK government in 2007, and the subject-specific criteria provided by the UK’s Curriculum Authority for identification and provision have been largely ignored. The process of identifying children to be placed on the ‘gifted and talented’ register seems haphazard and based on pragmatic reasons. Analysis of teachers’ responses also revealed a range of views and theoretical positioning held by them, which have implications for classroom practice. As the ‘gifted and talented’ initiative in the UK is entering a second decade, and yet more significant changes in policy are introduced, pertinent questions need to be raised and given consideration

Multiple doublesex-Related Genes Specify Critical Cell Fates in a C. elegans Male Neural Circuit

In most animal species, males and females exhibit differences in behavior and morphology that relate to their respective roles in reproduction. DM (Doublesex/MAB-3) domain transcription factors are phylogenetically conserved regulators of sexual development. They are thought to establish sexual traits by sex-specifically modifying the activity of general developmental programs. However, there are few examples where the details of these interactions are known, particularly in the nervous system.In this study, we show that two C. elegans DM domain genes, dmd-3 and mab-23, regulate sensory and muscle cell development in a male neural circuit required for mating. Using genetic approaches, we show that in the circuit sensory neurons, dmd-3 and mab-23 establish the correct pattern of dopaminergic (DA) and cholinergic (ACh) fate. We find that the ETS-domain transcription factor gene ast-1, a non-sex-specific, phylogenetically conserved activator of dopamine biosynthesis gene transcription, is broadly expressed in the circuit sensory neuron population. However, dmd-3 and mab-23 repress its activity in most cells, promoting ACh fate instead. A subset of neurons, preferentially exposed to a TGF-beta ligand, escape this repression because signal transduction pathway activity in these cells blocks dmd-3/mab-23 function, allowing DA fate to be established. Through optogenetic and pharmacological approaches, we show that the sensory and muscle cell characteristics controlled by dmd-3 and mab-23 are crucial for circuit function.In the C. elegans male, DM domain genes dmd-3 and mab-23 regulate expression of cell sub-type characteristics that are critical for mating success. In particular, these factors limit the number of DA neurons in the male nervous system by sex-specifically regulating a phylogenetically conserved dopamine biosynthesis gene transcription factor. Homologous interactions between vertebrate counterparts could regulate sex differences in neuron sub-type populations in the brain

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

Temporal clustering of Kawasaki disease cases around the world

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD

Clinical, methodology, and patient/carer expert advice in pediatric drug development by conect4children.

Many medicines are used "off-label" in children outside the terms of the license. Feasible pediatric clinical trials are a challenge to design. Conect4children (c4c) is an Innovative Medicines Initiative project to set up a pan-European pediatric clinical trial network aiming to facilitate the development of new medicines for children. To optimize pediatric trial development by promoting innovative trial design, c4c set up a European multidisciplinary advice service, including the voice of young patients and families, tailored to industry and academia. A network of experts was established to provide multidisciplinary advice to trial sponsors. Experts were selected to join clinical and innovative methodology expert groups. A patient and public involvement (PPI) database, to include the expert opinion of patients and parents/carers was formed. A stepwise process was developed: (1) sponsors contact c4c, (2) scoping interview takes place, (3) ad hoc advice group formed, (5) advice meeting held, and (6) advice report provided. Feedback on the process was collected. Twenty-four clinical and innovative methodology expert groups (>400 experts) and a PPI database of 135 registrants were established. As of September 30, 2022, 36 advice requests were received, with 25 requests completed. Clinical and methodology experts and PPI representatives participated in several advice requests. Sponsors appreciated the advice quality and the multidisciplinary experts from different countries, including experts not known before. Experts and PPI participants were generally satisfied with the process. The c4c project has shown successful proof of concept for a service that presents a new framework to plan innovative and feasible pediatric trials

A Protein-Protein Interaction Map of the Trypanosoma brucei Paraflagellar Rod

We have conducted a protein interaction study of components within a specific sub-compartment of a eukaryotic flagellum. The trypanosome flagellum contains a para-crystalline extra-axonemal structure termed the paraflagellar rod (PFR) with around forty identified components. We have used a Gateway cloning approach coupled with yeast two-hybrid, RNAi and 2D DiGE to define a protein-protein interaction network taking place in this structure. We define two clusters of interactions; the first being characterised by two proteins with a shared domain which is not sufficient for maintaining the interaction. The other cohort is populated by eight proteins, a number of which possess a PFR domain and sub-populations of this network exhibit dependency relationships. Finally, we provide clues as to the structural organisation of the PFR at the molecular level. This multi-strand approach shows that protein interactome data can be generated for insoluble protein complexes