Hyperpolarization of pyridyl fentalogues by signal amplification by reversible exchange (SABRE)

Fentanyl, also known as ‘jackpot’, is a synthetic opiate that is 50–100 times more potent than morphine. Clandestine laboratories produce analogues of fentanyl, known as fentalogues to circumvent legislation regarding its production. Three pyridyl fentalogues were synthesized and then hyperpolarized by signal amplification by reversible exchange (SABRE) to appraise the forensic potential of the technique. A maximum enhancement of ‐168‐fold at 1.4 T was recorded for the ortho pyridyl 1H nuclei. Studies of the activation parameters for the three fentalogues revealed that the ratio of ligand loss trans to hydride and hydride loss in the complex [Ir(IMes)(L)3(H)2]+ (IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene) ranged from 0.52 to 1.83. The fentalogue possessing the ratio closest to unity produced the largest enhancement subsequent to performing SABRE at earth's magnetic field. It was possible to hyperpolarize a pyridyl fentalogue selectively from a matrix that consisted largely of heroin (97 : 3 heroin:fentalogue) to validate the use of SABRE as a forensic tool

Stimulation of Chitin Synthesis Rescues Candida albicans from Echinocandins

Echinocandins are a new generation of novel antifungal agent that inhibit cell wall β(1,3)-glucan synthesis and are normally cidal for the human pathogen Candida albicans. Treatment of C. albicans with low levels of echinocandins stimulated chitin synthase (CHS) gene expression, increased Chs activity, elevated chitin content and reduced efficacy of these drugs. Elevation of chitin synthesis was mediated via the PKC, HOG, and Ca2+-calcineurin signalling pathways. Stimulation of Chs2p and Chs8p by activators of these pathways enabled cells to survive otherwise lethal concentrations of echinocandins, even in the absence of Chs3p and the normally essential Chs1p, which synthesize the chitinous septal ring and primary septum of the fungus. Under such conditions, a novel proximally offset septum was synthesized that restored the capacity for cell division, sustained the viability of the cell, and abrogated morphological and growth defects associated with echinocandin treatment and the chs mutations. These findings anticipate potential resistance mechanisms to echinocandins. However, echinocandins and chitin synthase inhibitors synergized strongly, highlighting the potential for combination therapies with greatly enhanced cidal activity

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page

Cost-effectiveness of a national exercise referral programme for primary care patients in Wales: results of a randomised controlled trial

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The research was independent and funded by the Welsh Assembly Government. RTE is supported by Public Health Wales. Additional support for LM and SM during write up was provided by The Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement (DECIPHer), a UKCRC Public Health Research: Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council (RES-590-28-0005), Medical Research Council, the Welsh Assembly Government and the Wellcome Trust (WT087640MA), under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged

Maternal iron deficiency perturbs embryonic cardiovascular development in mice.

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women

Improving the Deaf community's access to prostate and testicular cancer information: a survey study

BACKGROUND: Members of the Deaf community face communication barriers to accessing health information. To resolve these inequalities, educational programs must be designed in the appropriate format and language to meet their needs. METHODS: Deaf men (102) were surveyed before, immediately following, and two months after viewing a 52-minute prostate and testicular cancer video in American Sign Language (ASL) with open text captioning and voice overlay. To provide the Deaf community with information equivalent to that available to the hearing community, the video addressed two cancer topics in depth. While the inclusion of two cancer topics lengthened the video, it was anticipated to reduce redundancy and encourage men of diverse ages to learn in a supportive, culturally aligned environment while also covering more topics within the partnership's limited budget. Survey data were analyzed to evaluate the video's impact on viewers' pre- and post-intervention understanding of prostate and testicular cancers, as well as respondents' satisfaction with the video, exposure to and use of early detection services, and sources of cancer information. RESULTS: From baseline to immediately post-intervention, participants' overall knowledge increased significantly, and this gain was maintained at the two-month follow-up. Men of diverse ages were successfully recruited, and this worked effectively as a support group. However, combining two complex cancer topics, in depth, in one video appeared to make it more difficult for participants to retain as many relevant details specific to each cancer. Participants related that there was so much information that they would need to watch the video more than once to understand each topic fully. When surveyed about their best sources of health information, participants ranked doctors first and showed a preference for active rather than passive methods of learning. CONCLUSION: After viewing this ASL video, participants showed significant increases in cancer understanding, and the effects remained significant at the two-month follow-up. However, to achieve maximum learning in a single training session, only one topic should be covered in future educational videos

Cold Induces Micro- and Nano-Scale Reorganization of Lipid Raft Markers at Mounds of T-Cell Membrane Fluctuations

Whether and how cold causes changes in cell-membrane or lipid rafts remain poorly characterized. Using the NSOM/QD and confocal imaging systems, we found that cold caused microscale redistribution of lipid raft markers, GM1 for lipid and CD59 for protein, from the peripheral part of microdomains to the central part on Jurkat T cells, and that cold also induced the nanoscale size-enlargement (1/3- to 2/3-fold) of the nanoclusters of lipid raft markers and even the colocalization of GM1 and CD59 nanoclusters. These findings indicate cold-induced lateral rearrangement/coalescence of raft-related membrane heterogeneity. The cold-induced re-distribution of lipid raft markers under a nearly-natural condition provide clues for their alternations, and help to propose a model in which raft lipids associate themselves or interact with protein components to generate functional membrane heterogeneity in response to stimulus. The data also underscore the possible cold-induced artifacts in early-described cold-related experiments and the detergent-resistance-based analyses of lipid rafts at 4°C, and provide a biophysical explanation for recently-reported cold-induced activation of signaling pathways in T cells. Importantly, our fluorescence-topographic NSOM imaging demonstrated that GM1/CD59 raft markers distributed and re-distributed at mounds but not depressions of T-cell membrane fluctuations. Such mound-top distribution of lipid raft markers or lipid rafts provides spatial advantage for lipid rafts or contact molecules interacting readily with neighboring cells or free molecules

A multilevel study of the determinants of area-level inequalities in colorectal cancer survival

Background: In Australia, associations between geographic remoteness, socioeconomic disadvantage, and colorectal cancer (CRC) survival show that survival rates are lowest among residents of geographically remote regions and those living in disadvantaged areas. At present we know very little about the reasons for these inequalities, hence our capacity to intervene to reduce the inequalities is limited. Methods/Design: This study, the first of its type in Australia, examines the association between CRC survival and key area- and individual-level factors. Specifically, we will use a multilevel framework to investigate the possible determinants of area- and individual-level inequalities in CRC survival and quantify the relative contribution of geographic remoteness, socioeconomic and demographic factors, disease stage, and access to diagnostic and treatment services, to these inequalities. The multilevel analysis will be based on survival data relating to people diagnosed with CRC in Queensland between 1996 and 2005 (n = 22,723) from the Queensland Cancer Registry (QCR), area-level data from other data custodians such as the Australian Bureau of Statistics, and individual-level data from the QCR (including extracting stage from pathology records) and Queensland Hospitals. For a subset of this period (2003 and 2004) we will utilise more detailed, individual-level data (n = 1,966) covering a greater range of risk factors from a concurrent research study. Geo-coding and spatial technology will be used to calculate road travel distances from patients’ residence to treatment centres. The analyses will be conducted using a multilevel Cox proportional hazards model with Level 1 comprising individual-level factors (e.g. occupation) and level 2 area level indicators of remoteness and area socioeconomic disadvantage. Discussion: This study focuses on the health inequalities for rural and disadvantaged populations that have often been documented but poorly understood, hence limiting our capacity to intervene. This study utilises and develops emerging statistical and spatial technologies that can then be applied to other cancers and health outcomes. The findings of this study will have direct implications for the targeting and resourcing of cancer control programs designed to reduce the burden of colorectal cancer, and for the provision of diagnostic and treatment services