DEK binding to class II MHC Y-box sequences is gene- and allele-specific

Using electrophoretic mobility shift assays, we examined sequence-specific binding of DEK, a potential autoantigen in juvenile rheumatoid arthritis, to conserved Y-box regulatory sequences in class II MHC gene promoters. Nuclear extracts from several cell lines of different phenotypes contained sequence-specific binding activity recognizing DRA, DQA1*0101, and DQA1*0501 Y-box sequences. Participation of both DEK and NF-Y in the DQA1 Y-box binding complex was confirmed by 'supershifting' with anti-DEK and anti-NF-Y antibodies. Recombinant DEK also bound specifically to the DQA1*0101 Y box and to the polymorphic DQA1*0501 Y box, but not to the consensus DRA Y box. Measurement of the apparent dissociation constants demonstrated a two- to fivefold difference in DEK binding to the DQA1 Y-box sequence in comparison with other class II MHC Y-box sequences. Residues that are crucial for DEK binding to the DQA1*0101 Y box were identified by DNase I footprinting. The specific characteristics of DEK binding to these related sequences suggests a potential role for DEK in differential regulation of class II MHC expression, and thus in the pathogenesis of juvenile rheumatoid arthritis and other autoimmune diseases

The synthesis and structure of an n-terminal dodecanoic acid conjugate of a-conotoxin MII

The alpha-conotoxin MII is a 16 amino acid long peptide toxin isolated from the marine snail, Conus magus. This toxin has been found to be a highly selective and potent inhibitor of neuronal nicotinic acetylcholine receptors of the subtype alpha3beta2. To improve the bioavailability of this peptide, we have coupled to the N-terminus of conotoxin MII, 2-amino-D,L-dodecanoic acid (Laa) creating a lipidic linear peptide which was then successfully oxidised to produce the correctly folded conotoxin MII construct

Manganese tricarbonyl complexes with asymmetric 2 2‑iminopyridine ligands: toward decoupling steric and electronic 3 factors in electrocatalytic CO2 reduction

Manganese tricarbonyl bromide complexes incorporating IP (2-(phenylimino)pyridine) derivatives, [MnBr(CO)3(IP)], are demonstrated as a new group of catalysts for CO2 reduction, which represent the first example of utilization of (phenylimino)pyridine ligands on manganese centers for this purpose. The key feature is the asymmetric structure of the redox-noninnocent ligand that permits independent tuning of its steric and electronic properties. The α-diimine ligands and five new Mn(I) compounds have been synthesized, isolated in high yields, and fully characterized, including X-ray crystallography. Their electrochemical and electrocatalytic behavior was investigated using cyclic voltammetry and UV−vis−IR spectroelectrochemistry within an OTTLE cell. Mechanistic investigations under an inert atmosphere have revealed differences in the nature of the reduction products as a function of steric bulk of the ligand. The direct ECE (electrochemical−chemical−electrochemical) formation of a five-coordinate anion [Mn(CO)3(IP)]−, a product of two-electron reduction of the parent complex, is observed in the case of the bulky DIPIMP (2-[((2,6-diisopropylphenyl)imino)methyl]pyridine), TBIMP (2-[((2-tert-butylphenyl)imino)methyl]-pyridine), and TBIEP (2-[((2-tert-butylphenyl)imino)ethyl]pyridine) derivatives. This process is replaced for the least sterically demanding IP ligand in [MnBr(CO)3(IMP)] (2-[(phenylimino)methyl]pyridine) by the stepwise formation of such a monoanion via an ECEC(E) mechanism involving also the intermediate Mn−Mn dimer [Mn(CO)3(IMP)]2. The complex [MnBr(CO)3(IPIMP)] (2-[((2-diisopropylphenyl)imino)methyl]pyridine), which carries a moderately electron donating, moderately bulky IP ligand, shows an intermediate behavior where both the five-coordinate anion and its dimeric precursor are jointly detected on the time scale of the spectroelectrochemical experiments. Under an atmosphere of CO2 the studied complexes, except for the DIPIMP derivative, rapidly coordinate CO2, forming stable bicarbonate intermediates, with no dimer being observed. Such behavior indicates that the CO2 binding is outcompeting another pathway: viz., the dimerization reaction between the five-coordinate anion and the neutral parent complex. The bicarbonate intermediate species undergo reduction at more negative potentials (ca. −2.2 V vs Fc/Fc+ ), recovering [Mn(CO)3(IP)]− and triggering the catalytic production of CO

A Qualitative Study Exploring Access to Mental Health and Substance Use Support among Individuals Experiencing Homelessness during COVID-19

People experiencing homelessness have higher rates of mental ill-health and substance use and lower access to health services compared to the general population. The COVID-19 pandemic led to changes in service delivery across health and social care services, with many adopting virtual or telephone support for service users. This paper explores the experiences of access to community-based mental health and substance use support for people experiencing homelessness during the COVID-19 pandemic. Qualitative telephone interviews were conducted with 10 women and 16 men (ages 25 to 71) who self-identified as experiencing homelessness in North East England between February and May 2021. With five individuals with lived experience, results were analysed using inductive reflexive thematic analysis. Reactive changes to support provision often led to inadvertent exclusion. Barriers to access included: physical locations, repetition of recovery stories, individual readiness, and limited availability. Participants suggested creating services reflective of need and opportunities for choice and empowerment. Community mental health and substance use support for people experiencing homelessness should ensure the support is personalised, responsive to need, inclusive, and trauma-informed. The findings of this research have important implications for mental health and substance use policy and practice for individuals who experience homelessness during a public health crisis

Sheep Updates 2005 - Part 3

This session covers seven papers from different authors: CUSTOMER 1. Benefits VIAscanR to producers and WAMMCO, Rob Davidson, Supply Development Manager, David Pethick, School of Veterinary and Biomedical Studies, Murdock University. 2. Healthy fats in lamb: how WA lambs compare with others, C. F. Engelke Animal Biology, University of Western Australia, bCSIRO Livestock Industries, Western Australia B.D. Siebert, Department of Animal Science, University of Adelaide, South Australia, K. Gregg, Centre for High-Throughput Agricultural Genetic Analysis, Murdoch University, Western Australia. A-D.G. Wright CSIRO Livestock Industries, Western Australia, P.E Vercoe Animal Biology, University of Western Australia 3. Shelf life of fresh lamb meat: lamb age & electrical stimulation, Dr Robin Jacob, Department of Agriculture, Western Australia 4. Pastures from space - An evaluation of adoption of by Australian woolgrowers, Russell Barnett, Australian Venture Consultants, Joanne Sneddon, University of Western Australia 5. Your clients can learn from ASHEEP\u27s example, Sandra Brown Department of Agriculture Western Australia 6. Lifetime Wool - Farmers attitudes affect their adoption of recommended ewe management, G. Rose Department of Agriculture Western Australia, C. Kabore, Kazresearch, Lower Templestowe Vic, J. Dart, Clear Horizons, Hastings Vic 7. Sustainable certification of Australian Merino, what will customers be looking for? Stuart Adams, i-merino / iZWool International Pty Lt

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders

Searching for Programme theories for a realist evaluation: a case study comparing an academic database search and a simple Google search

Background: Realist methodologies are increasingly being used to evaluate complex interventions in health and social care. Programme theory (ideas and assumptions of how a particular intervention works) development is the first step in a realist evaluation or a realist synthesis, with literature reviews providing important evidence to support this. Deciding how to search for programme theories is challenging and there is limited guidance available. Using an example of identifying programme theories for a realist evaluation of Pressure Ulcer Risk Assessment Instruments in clinical practice, the authors explore and compare several different approaches to literature searching and highlight important methodological considerations for those embarking on a programme theory review. Methods: We compared the performance of an academic database search with a simple Google search and developed an optimised search strategy for the identification primary references (i.e. documents providing the clearest examples of programme theories) associated with the use of Pressure Ulcer Risk Assessment Instruments (PU-RAIs). We identified the number of primary references and the total number of references retrieved per source. We then calculated the number needed to read (NNR) expressed as the total number of titles and abstracts screened to identify one relevant reference from each source. Results: The academic database search (comprising CINAHL, The Cochrane Library, EMBASE, HMIC, Medline) identified 2 /10 primary references with a NNR of 1395.The Google search identified 7/10 primary references with a NNR of 10.1. The combined NNR was 286.3. The optimised search combining Google and CINAHL identified 10/10 primary references with a NNR of 40.2. Conclusion: The striking difference between the efficiency of the review’s academic database and Google searches in finding relevant references prompted an in-depth comparison of the two types of search. The findings indicate the importance of including grey literature sources such as Google in this particular programme theory search, while acknowledging the need for transparency of methods. Further research is needed to facilitate improved guidance for programme theory searches to enhance practice in the realist field and to save researcher time and therefore resource

Feasibility of trial procedures for a randomised controlled trial of a community based group exercise intervention for falls prevention for visually impaired older people: the VIOLET study

Background Visually impaired older people (VIOP) have a higher risk of falling than their sighted peers, and are likely to avoid physical activity. The aim was to adapt the existing Falls Management Exercise (FaME) programme for VIOP, delivered in the community, and to investigate the feasibility of conducting a definitive randomised controlled trial (RCT) of this adapted intervention. Methods Two-centre randomised mixed methods pilot trial and economic evaluation of the adapted group-based FaME programme for VIOP versus usual care. A one hour exercise programme ran weekly over 12 weeks at the study sites (Newcastle and Glasgow), delivered by third sector (voluntary and community) organisations. Participants were advised to exercise at home for an additional two hours over the week. Those randomised to the usual activities group received no intervention. Outcome measures were completed at baseline, 12 and 24 weeks. The potential primary outcome was the Short Form Falls Efficacy Scale – International (SFES-I). Participants’ adherence was assessed by reviewing attendance records and self-reported compliance to the home exercises. Adherence with the course content (fidelity) by instructors was assessed by a researcher. Adverse events were collected in a weekly phone call. Results Eighteen participants, drawn from community-living VIOP were screened; 68 met the inclusion criteria; 64 participants were randomised with 33 allocated to the intervention and 31 to the usual activities arm. 94% of participants provided data at the 12 week visit and 92% at 24 weeks. Adherence was high. The intervention was found to be safe with 76% attending nine or more classes. Median time for home exercise was 50 min per week. There was little or no evidence that fear of falling, balance and falls risk, physical activity, emotional, attitudinal or quality of life outcomes differed between trial arms at follow-up. Conclusions The intervention, FaME, was implemented successfully for VIOP and all progression criteria for a main trial were met. The lack of difference between groups on fear of falling was unsurprising given it was a pilot study but there may have been other contributory factors including suboptimal exercise dose and apparent low risk of falls in participants. These issues need addressing for a future trial

Strengthening and stretching for rheumatoid arthritis of the hand (SARAH):Design of a randomised controlled trial of a hand and upper limb exercise intervention-ISRCTN89936343

Background: Rheumatoid Arthritis (RA) commonly affects the hands and wrists with inflammation, deformity, pain, weakness and restricted mobility leading to reduced function. The effectiveness of exercise for RA hands is uncertain, although evidence from small scale studies is promising. The Strengthening And Stretching for Rheumatoid Arthritis of the Hand (SARAH) trial is a pragmatic, multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of adding an optimised exercise programme for hands and upper limbs to best practice usual care for patients with RA.Methods/design: 480 participants with problematic RA hands will be recruited through 17 NHS trusts. Treatments will be provided by physiotherapists and occupational therapists. Participants will be individually randomised to receive either best practice usual care (joint protection advice, general exercise advice, functional splinting and assistive devices) or best practice usual care supplemented with an individualised exercise programme of strengthening and stretching exercises. The study assessors will be blinded to treatment allocation and will follow participants up at four and 12 months. The primary outcome measure is the Hand function subscale of the Michigan Hand Outcome Questionnaire, and secondary outcomes include hand and wrist impairment measures, quality of life, and resource use. Economic and qualitative studies will also be carried out in parallel.Discussion: This paper describes the design and development of a trial protocol of a complex intervention study based in therapy out-patient departments. The findings will provide evidence to support or refute the use of an optimised exercise programme for RA of the hand in addition to best practice usual care.Trial registration: Current Controlled Trials ISRCTN89936343Keywords: Randomised controlled trial, Rheumatoid arthritis, Exercise, Hand, Rehabilitatio

De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder

BACKGROUND: Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of ∼70-80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints. METHODS: The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC). RESULTS: IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD. CONCLUSIONS: TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith-Magenis and Potocki-Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD