Challenges to the development of antigen-specific breast cancer vaccines

Continued progress in the development of antigen-specific breast cancer vaccines depends on the identification of appropriate target antigens, the establishment of effective immunization strategies, and the ability to circumvent immune escape mechanisms. Methods such as T cell epitope cloning and serological expression cloning (SEREX) have led to the identification of a number target antigens expressed in breast cancer. Improved immunization strategies, such as using dendritic cells to present tumor-associated antigens to T lymphocytes, have been shown to induce antigen-specific T cell responses in vivo and, in some cases, objective clinical responses. An outcome of successful tumor immunity is the evolution of antigen-loss tumor variants. The development of a polyvalent breast cancer vaccine, directed against a panel of tumor-associated antigens, may counteract this form of immune escape

Genomic Expansion of Magnetotactic Bacteria Reveals an Early Common Origin of Magnetotaxis with Lineage-specific Evolution

The origin and evolution of magnetoreception, which in diverse prokaryotes and protozoa is known as magnetotaxis and enables these microorganisms to detect Earth’s magnetic field for orientation and navigation, is not well understood in evolutionary biology. The only known prokaryotes capable of sensing the geomagnetic field are magnetotactic bacteria (MTB), motile microorganisms that biomineralize intracellular, membrane-bounded magnetic single-domain crystals of either magnetite (Fe3O4) or greigite (Fe3S4) called magnetosomes. Magnetosomes are responsible for magnetotaxis in MTB. Here we report the first large-scale metagenomic survey of MTB from both northern and southern hemispheres combined with 28 genomes from uncultivated MTB. These genomes expand greatly the coverage of MTB in the Proteobacteria, Nitrospirae, and Omnitrophica phyla, and provide the first genomic evidence of MTB belonging to the Zetaproteobacteria and “Candidatus Lambdaproteobacteria” classes. The gene content and organization of magnetosome gene clusters, which are physically grouped genes that encode proteins for magnetosome biosynthesis and organization, are more conserved within phylogenetically similar groups than between different taxonomic lineages. Moreover, the phylogenies of core magnetosome proteins form monophyletic clades. Together, these results suggest a common ancient origin of iron-based (Fe3O4 and Fe3S4) magnetotaxis in the domain Bacteria that underwent lineage-specific evolution, shedding new light on the origin and evolution of biomineralization and magnetotaxis, and expanding significantly the phylogenomic representation of MTB

From research to practice: Lay adherence counsellors' fidelity to an evidence-based intervention for promoting adherence to antiretroviral treatment in the Western Cape, South Africa

In the Western Cape, lay counsellors are tasked with supporting antiretroviral (ARV) adherence in public healthcare clinics. Thirty-nine counsellors in 21 Cape Town clinics were trained in Options for Health (Options), an evidence-based intervention based on motivational interviewing (MI). We evaluated counsellors’ ability to deliver Options for addressing poor adherence following 5 days training. Audio-recordings of counselling sessions collected following training were transcribed and translated into English. Thirty-five transcripts of sessions conducted by 35 counsellors were analysed for fidelity to the Options protocol, and using the Motivational Interviewing Treatment and Integrity (MITI) code. Counsellors struggled with some of the strategies associated with MI, such as assessing readiness-to-change and facilitating change talk. Overall, counsellors failed to achieve proficiency in the approach of MI according to the MITI. Counsellors were able to negotiate realistic plans for addressing patients’ barriers to adherence. Further efforts aimed at strengthening the ARV adherence counselling programme are needed.Department of HE and Training approved lis

Caring after Francis: moral failure in nursing reconsidered

This discussion paper considers recent nursing failures. Drawing on a selection of key literature and on-going research, it argues that nursing failures are a possibly inevitable consequence of work in healthcare systems with their combination of cognitive, bureaucratic, professional and work related pressures. It also argues that nursing has a residual tendency to be viewed as primarily character-based moral work and that this can encourage understandings of causes of failures and their solutions in similar terms i.e. as moral failures of caring requiring recruitment of those with the appropriate characters. Drawing on on-going research with those training for the profession at an English university, it suggests that while the profession focuses on the recruitment of those with a ‘caring’ orientation it has not developed an adequate explanation to support new recruits in understanding the causes of inadequate practice. This leaves those entering the profession without a strong model with which to understand their own work or its failures what I refer to as ‘critical resilience’

Evolutionary relationships among barley and <i>Arabidopsis</i> core circadian clock and clock-associated genes

The circadian clock regulates a multitude of plant developmental and metabolic processes. In crop species, it contributes significantly to plant performance and productivity and to the adaptation and geographical range over which crops can be grown. To understand the clock in barley and how it relates to the components in the Arabidopsis thaliana clock, we have performed a systematic analysis of core circadian clock and clock-associated genes in barley, Arabidopsis and another eight species including tomato, potato, a range of monocotyledonous species and the moss, Physcomitrella patens. We have identified orthologues and paralogues of Arabidopsis genes which are conserved in all species, monocot/dicot differences, species-specific differences and variation in gene copy number (e.g. gene duplications among the various species). We propose that the common ancestor of barley and Arabidopsis had two-thirds of the key clock components identified in Arabidopsis prior to the separation of the monocot/dicot groups. After this separation, multiple independent gene duplication events took place in both monocot and dicot ancestors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00239-015-9665-0) contains supplementary material, which is available to authorized users

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Rationale Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. Objective The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. Results Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. Conclusions Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many \u201coff target\u201d effects to be used clinically. However newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence

Short-term acclimation in adults does not predict offspring acclimation potential to hypoxia

Abstract The prevalence of hypoxic areas in coastal waters is predicted to increase and lead to reduced biodiversity. While the adult stages of many estuarine invertebrates can cope with short periods of hypoxia, it remains unclear whether that ability is present if animals are bred and reared under chronic hypoxia. We firstly investigated the effect of moderate, short-term environmental hypoxia (40% air saturation for one week) on metabolic performance in adults of an estuarine amphipod, and the fitness consequences of prolonged exposure. We then reared the offspring of hypoxia-exposed parents under hypoxia, and assessed their oxyregulatory ability under declining oxygen tensions as juveniles and adults. Adults from the parental generation were able to acclimate their metabolism to hypoxia after one week, employing mechanisms typically associated with prolonged exposure. Their progeny, however, did not develop the adult pattern of respiratory regulation when reared under chronic hypoxia, but instead exhibited a poorer oxyregulatory ability than their parents. We conclude that species apparently hypoxia-tolerant when tested in short-term experiments, could be physiologically compromised as adults if they develop under hypoxia. Consequently, we propose that the increased prevalence of hypoxia in coastal regions will have marked effects in some species currently considered hypoxia tolerant

The Barley Genome Sequence Assembly Reveals Three Additional Members of the <i>CslF </i>(1,3;1,4)-b-Glucan Synthase Gene Family

An important component of barley cell walls, particularly in the endosperm, is (1,3;1,4)-β-glucan, a polymer that has proven health benefits in humans and that influences processability in the brewing industry. Genes of the cellulose synthase-like (Csl) F gene family have been shown to be involved in (1,3;1,4)-β-glucan synthesis but many aspects of the biosynthesis are still unclear. Examination of the sequence assembly of the barley genome has revealed the presence of an additional three HvCslF genes (HvCslF11, HvCslF12 and HvCslF13) which may be involved in (1,3;1,4)-β-glucan synthesis. Transcripts of HvCslF11 and HvCslF12 mRNA were found in roots and young leaves, respectively. Transient expression of these genes in Nicotiana benthamiana resulted in phenotypic changes in the infiltrated leaves, although no authentic (1,3;1,4)-β-glucan was detected. Comparisons of the CslF gene families in cereals revealed evidence of intergenic recombination, gene duplications and translocation events. This significant divergence within the gene family might be related to multiple functions of (1,3;1,4)-β-glucans in the Poaceae. Emerging genomic and global expression data for barley and other cereals is a powerful resource for characterising the evolution and dynamics of complete gene families. In the case of the CslF gene family, the results will contribute to a more thorough understanding of carbohydrate metabolism in grass cell walls

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA) ACE Network Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) The Autism Genome Project (AGP) from Autism Speaks (USA) Canadian Institutes of Health Research (CIHR), Genome Canada Health Research Board (Ireland) Hilibrand Foundation (USA) Medical Research Council (UK) National Institutes of Health (USA) Ontario Genomics Institute University of Toronto McLaughlin Centre Simons Foundation Johns Hopkins Autism Consortium of Boston NLM Family foundation National Institute of Health grants National Health Medical Research Council Scottish Rite Spunk Fund, Inc. Rebecca and Solomon Baker Fund APEX Foundation National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) endowment fund of the Nancy Pritzker Laboratory (Stanford) Autism Society of America Janet M. Grace Pervasive Developmental Disorders Fund The Lundbeck Foundation universities and university hospitals of Aarhus and Copenhagen Stanley Foundation Centers for Disease Control and Prevention (CDC) Netherlands Scientific Organization Dutch Brain Foundation VU University Amsterdam Trinity Centre for High Performance Computing through Science Foundation Ireland Autism Genome Project (AGP) from Autism Speak

Walk with Me: a protocol for a pilot RCT of a peer-led walking programme to increase physical activity in inactive older adults

Background: Levels of physical activity decline with age. Some of the most disadvantaged individuals in society, such as those from lower socio-economic position, are also the most inactive. Increasing physical activity levels, particularly among those most inactive, is a public health priority. Peer-led physical activity interventions may offer a model to increase physical activity in the older adult population. This study aims to test the feasibility of a peer-led, multicomponent physical activity intervention in socio-economically disadvantaged community dwelling older adults. Methods: The Medical Research Council framework for developing and evaluating complex interventions will be used to design and test the feasibility of a randomised controlled trial (RCT) of a multicomponent peer-led physical activity intervention. Data will be collected at baseline, immediately after the intervention (12 weeks) and 6 months after baseline measures. The pilot RCT will provide information on recruitment of peer mentors and participants and attrition rates, intervention fidelity, and data on the variability of the primary outcome (minutes of moderate to vigorous physical activity measured with an accelerometer). The pilot trail will also assess the acceptability of the intervention and identify potential resources needed to undertake a definitive study. Data analyses will be descriptive and include an evaluation of eligibility, recruitment, and retention rates. The findings will be used to estimate the sample size required for a definitive trial. A detailed process evaluation using qualitative and quantitative methods will be conducted with a variety of stakeholders to identify areas of success and necessary improvements. Discussion: This paper describes the protocol for the ‘Walk with Me’ pilot RCT which will provide the information necessary to inform the design and delivery of a fully powered trial should the Walk with Me intervention prove feasible