Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22−/− T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22−/− T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22−/− T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22−/− bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response

Full elucidation of the transmembrane anion transport mechanism of squaramides using in silico investigations

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical monosquaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured

Deconstructing compassionate conservation

Compassionate conservation focuses on 4 tenets: first, do no harm; individuals matter; inclusivity of individual animals; and peaceful coexistence between humans and animals. Recently, compassionate conservation has been promoted as an alternative to conventional conservation philosophy. We believe examples presented by compassionate conservationists are deliberately or arbitrarily chosen to focus on mammals; inherently not compassionate; and offer ineffective conservation solutions. Compassionate conservation arbitrarily focuses on charismatic species, notably large predators and megaherbivores. The philosophy is not compassionate when it leaves invasive predators in the environment to cause harm to vastly more individuals of native species or uses the fear of harm by apex predators to terrorize mesopredators. Hindering the control of exotic species (megafauna, predators) in situ will not improve the conservation condition of the majority of biodiversity. The positions taken by so-called compassionate conservationists on particular species and on conservation actions could be extended to hinder other forms of conservation, including translocations, conservation fencing, and fertility control. Animal welfare is incredibly important to conservation, but ironically compassionate conservation does not offer the best welfare outcomes to animals and is often ineffective in achieving conservation goals. Consequently, compassionate conservation may threaten public and governmental support for conservation because of the limited understanding of conservation problems by the general public

Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-α activation via the mitogen-activated protein kinase pathway

INTRODUCTION: Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. METHODS: Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17β-estradiol and progesterone. The 17β-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. RESULTS: IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17β-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the α-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-α in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D(1 )and transforming growth factor-β(3 )in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous rats. CONCLUSION: We argue that tumor initiation (transformation and fixation of mutations) may be similar in parous and age-matched virgin animals, suggesting that the main differences in tumor formation lie in differences in tumor progression caused by the altered hormonal environment associated with parity. Furthermore, we provide evidence supporting the notion that tumor growth promotion seen in IGF-I-treated parous rats is caused by activation of estrogen receptor-α via the Raf/Ras/mitogen-activated protein kinase cascade

The development and evaluation of a five-language multi-perspective standardised measure: clinical decision-making involvement and satisfaction (CDIS).

BACKGROUND: The aim of this study was to develop and evaluate a brief quantitative five-language measure of involvement and satisfaction in clinical decision-making (CDIS) - with versions for patients (CDIS-P) and staff (CDIS-S) - for use in mental health services. METHODS: An English CDIS was developed by reviewing existing measures, focus groups, semistructured interviews and piloting. Translations into Danish, German, Hungarian and Italian followed the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force principles of good practice for translation and cultural adaptation. Psychometricevaluation involved testing the measure in secondary mental health services in Aalborg, Debrecen, London, Naples, Ulm and Zurich. RESULTS: After appraising 14 measures, the Control Preference Scale and Satisfaction With Decision-making English-language scales were modified and evaluated in interviews (n = 9), focus groups (n = 22) and piloting (n = 16). Translations were validated through focus groups (n = 38) and piloting (n = 61). A total of 443 service users and 403 paired staff completed CDIS. The Satisfaction sub-scale had internal consistency of 0.89 (0.86-0.89 after item-level deletion) for staff and 0.90 (0.87-0.90) for service users, both continuous and categorical (utility) versions were associated with symptomatology and both staff-rated and service userrated therapeutic alliance (showing convergent validity), and not with social disability (showing divergent validity), and satisfaction predicted staff-rated (OR 2.43, 95%CI 1.54- 3.83 continuous, OR 5.77, 95%CI 1.90-17.53 utility) and service user-rated (OR 2.21, 95%CI 1.51-3.23 continuous, OR 3.13, 95%CI 1.10-8.94 utility) decision implementation two months later. The Involvement sub-scale had appropriate distribution and no floor or ceiling effects, was associated with stage of recovery, functioning and quality of life (staff only) (showing convergent validity), and not with symptomatology or social disability (showing divergent validity), and staff-rated passive involvement by the service user predicted implementation (OR 3.55, 95%CI 1.53-8.24). Relationships remained after adjusting for clustering by staff. CONCLUSIONS: CDIS demonstrates adequate internal consistency, no evidence of item redundancy, appropriate distribution, and face, content, convergent, divergent and predictive validity. It can be recommended for research and clinical use. CDIS-P and CDIS-S in all 3 five languages can be downloaded at http://www.cedar-net.eu/instruments. TRIAL REGISTRATION: ISRCTN75841675.CEDAR study is funded by a grant from the Seventh Framework Programme (Research Area HEALTH-2007-3.1-4 Improving clinical decision making) of the European Union (Grant no. 223290)

Life, time, and the organism:Temporal registers in the construction of life forms

In this paper, we articulate how time and temporalities are involved in the making of living things. For these purposes, we draw on an instructive episode concerning Norfolk Horn sheep. We attend to historical debates over the nature of the breed, whether it is extinct or not, and whether presently living exemplars are faithful copies of those that came before. We argue that there are features to these debates that are important to understanding contemporary configurations of life, time and the organism, especially as these are articulated within the field of synthetic biology. In particular, we highlight how organisms are configured within different material and semiotic assemblages that are always structured temporally. While we identify three distinct structures, namely the historical, phyletic and molecular registers, we do not regard the list as exhaustive. We also highlight how these structures are related to the care and value invested in the organisms at issue. Finally, because we are interested ultimately in ways of producing time, our subject matter requires us to think about historiographical practice reflexively. This draws us into dialogue with other scholars interested in time, not just historians, but also philosophers and sociologists, and into conversations with them about time as always multiple and never an inert background

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

A large-scale genome-wide association study meta-analysis of cannabis use disorder

Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.Peer reviewe

Route and duration of antibiotic therapy in acute cellulitis: a systematic review and meta-analysis of the effectiveness and harms of antibiotic treatment

Objectives Compared with guideline recommendations, antibiotic overuse is common in treating cellulitis. We conducted a systematic review and meta-analyses on antibiotic route and duration of treatment for cellulitis in adults and children. Methods We searched MEDLINE, EMBASE and trial registries from inception to Dec 11, 2019 for interventional and observational studies of antibiotic treatment for cellulitis. Exclusions included case series/reports, pre-septal/orbital cellulitis and non-English language articles. Random-effects meta-analyses were used to produce summary relative risk (RR) estimates for our primary outcome of clinical response. PROSPERO CRD42018100602. Results We included 47/8423 articles, incorporating data from eleven trials (1855 patients) in two meta-analyses. The overall risk of bias was moderate. Only two trials compared the same antibiotic agent in each group. We found no evidence of difference in clinical response rates for antibiotic route or duration (RR(oral:IV)=1.12, 95%CI 0.98–1.27, I 2=32% and RR(shorter:longer)=0.99, 95%CI 0•96–1.03, I 2 = 0%, respectively). Findings were consistent in observational studies. Follow-up data beyond 30 days were sparse. Conclusions The evidence base for antibiotic treatment decisions in cellulitis is flawed by biased comparisons, short follow-up and lack of data around harms of antibiotic overuse. Future research should focus on developing patient-tailored antibiotic prescribing for cellulitis to reduce unnecessary antibiotic use