Salmonella effector SteE converts the mammalian serine/threonine kinase GSK3 into a tyrosine kinase to direct macrophage polarization.

Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment

Identifying models of delivery, care domains and quality indicators relevant to palliative day services: a scoping review protoco

Abstract Background With an ageing population and increasing numbers of people with life-limiting illness, there is a growing demand for palliative day services. There is a need to measure and demonstrate the quality of these services, but there is currently little agreement on which aspects of care should be used to do this. The aim of the scoping review will be to map the extent, range and nature of the evidence around models of delivery, care domains and existing quality indicators used to evaluate palliative day services. Methods Electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials) will be searched for evidence using consensus development methods; randomised or quasi-randomised controlled trials; mixed methods; and prospective, longitudinal or retrospective case-control studies to develop or test quality indicators for evaluating palliative care within non-residential settings, including day hospices and community or primary care settings. At least two researchers will independently conduct all searches, study selection and data abstraction procedures. Meta-analyses and statistical methods of synthesis are not planned as part of the review. Results will be reported using numerical counts, including number of indicators in each care domain and by using qualitative approach to describe important indicator characteristics. A conceptual model will also be developed to summarise the impact of different aspects of quality in a palliative day service context. Methodological quality relating to indicator development will be assessed using the Appraisal of Indicators through Research and Evaluation (AIRE) tool. Overall strength of evidence will be assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Final decisions on quality assessment will be made via consensus between review authors. Discussion Identifying, developing and implementing evidence-based quality indicators is critical to the evaluation and continued improvement of palliative care. Review findings will be used to support clinicians and policymakers make decisions on which quality indicators are most appropriate for evaluating day services at the patient and service level, and to identify areas for further research

Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment.

The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of ±5° to ±30° between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation

Cancer mortality in East and Southeast Asian migrants to New South Wales, Australia, 1975–1995

Routinely collected data for New South Wales were used to analyse cancer mortality in migrants born in East or Southeast Asia according to duration of residence in Australia. A case-control approach compared deaths from cancer at particular sites with deaths from all other cancers, adjusting for age, sex and calendar period. Compared with the Australian-born, these Asian migrants had a 30-fold higher risk of dying from nasopharyngeal cancer in the first 2 decades of residence, falling to ninefold after 30 years, and for deaths from liver cancer, a 12-fold risk in the first 2 decades, falling to threefold after 30 years. The initial lower risk from colorectal, breast or prostate cancers later converged towards the Australian-born level, the change being apparent in the third decade after migration. The relative risk of dying from lung cancer among these Asian migrants was above unity for each category of duration of stay for women, but at or below unity for men, with no trend in risk over time. An environmental or lifestyle influence for nasopharyngeal and liver cancers is suggested as well as for cancers of colon/rectum, breast and prostate. © 1999 Cancer Research Campaig

Purification and functional characterisation of rhiminopeptidase A, a novel aminopeptidase from the venom of Bitis gabonica rhinoceros

This study describes the discovery and characterisation of a novel aminopeptidase A from the venom of B. g. rhinoceros and highlights its potential biological importance. Similar to mammalian aminopeptidases, rhiminopeptidase A might be capable of playing roles in altering the blood pressure and brain function of victims. Furthermore, it could have additional effects on the biological functions of other host proteins by cleaving their N-terminal amino acids. This study points towards the importance of complete analysis of individual components of snake venom in order to develop effective therapies for snake bites

Numerical and experimental analysis of wrinkling during the cup drawing of an AA5042 aluminium alloy

The recent trend to reduce the thickness of metallic sheets used in forming processes strongly increases the likelihood of the occurrence of wrinkling. Thus, in order to obtain defect-free components, the prediction of this kind of defect becomes extremely important in the tool design and selection of process parameters. In this study, the sheet metal forming process proposed as a benchmark in the Numisheet 2014 conference is selected to analyse the influence of the tool geometry on wrinkling behaviour, as well as the reliability of the developed numerical model. The side-wall wrinkling during the deep drawing process of a cylindrical cup in AA5042 aluminium alloy is investigated through finite element simulation and experimental measurements. The material plastic anisotropy is modelled with an advanced yield criterion beyond the isotropic (von Mises) material behaviour. The results show that the shape of the wrinkles predicted by the numerical model is strongly affected by the finite element mesh used in the blank discretization. The accurate modelling of the plastic anisotropy of the aluminium alloy yields numerical results that are in good agreement with the experiments, particularly the shape and location of the wrinkles. The predicted punch force evolution is strongly influenced by the friction coefficient used in the model. Moreover, the two punch geometries provide drawn cups with different wrinkle waves, mainly differing in amplitude.The authors gratefully acknowledge the financial support of the Portuguese Foundation for Science and Technology (FCT) under project PTDC/EMS-TEC/1805/2012. The first author is also grateful to the FCT for the Postdoctoral grant SFRH/BPD/101334/2014 and P.D. Barros is grateful to the FCT for the PhD Grant SFRH/BD/98545/2013info:eu-repo/semantics/publishedVersio

Quantitative imaging of concentrated suspensions under flow

We review recent advances in imaging the flow of concentrated suspensions, focussing on the use of confocal microscopy to obtain time-resolved information on the single-particle level in these systems. After motivating the need for quantitative (confocal) imaging in suspension rheology, we briefly describe the particles, sample environments, microscopy tools and analysis algorithms needed to perform this kind of experiments. The second part of the review focusses on microscopic aspects of the flow of concentrated model hard-sphere-like suspensions, and the relation to non-linear rheological phenomena such as yielding, shear localization, wall slip and shear-induced ordering. Both Brownian and non-Brownian systems will be described. We show how quantitative imaging can improve our understanding of the connection between microscopic dynamics and bulk flow.Comment: Review on imaging hard-sphere suspensions, incl summary of methodology. Submitted for special volume 'High Solid Dispersions' ed. M. Cloitre, Vol. xx of 'Advances and Polymer Science' (Springer, Berlin, 2009); 22 pages, 16 fig

Stem cell-based therapy for human diseases.

Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment

QTc and psychopharmacs: are there any differences between monotherapy and polytherapy

<p>Abstract</p> <p>Background</p> <p>Some psychotropic drugs are connected with prolongation of QT interval, increased risk of cardiac arrhythmias and greater incidence of sudden death, especially when used in combination. Concomitant use of antipsychotics and antidepressants is not rare in our clinical practice. The study compares the length of QT interval in patients on monotherapy with an antipsychotic or an antidepressant and patients taking polytherapy (an antipsychotic agent combined with an antidepressant).</p> <p>Methods</p> <p>Sixty-one hospitalized women who met the ICD-10 criteria for schizophrenia, schizoaffective psychosis, delusional disorder and mood disorder were included in the study. The monotherapy group was consisted of thirty-two women treated with an antipsychotic or an antidepressant while the polytherapy group was composed of twenty-nine women treated with an antipsychotic agent plus an antidepressant. Two electrocardiograms (ECGs) were obtained for each patient: the first was carried out before the treatment and the second after two weeks of treatment.</p> <p>Statistical analysis was carried out by SPSS program and included unpaired and paired t test and Fisher's exact test.</p> <p>Results</p> <p>Mean baseline QTc values did not differ between the groups (439 ± 22 ms was the same value found in the both groups; unpaired t test, p > 0.5). Mean QTc intervals after two weeks of treatment were also similar (439 ± 24 ms in the monotherapy group and 440 ± 20 ms in the polytherapy group; unpaired t test, p > 0.5). Fisher's exact test did not reveal significant difference in the number of patients with borderline (451–470 ms) or prolonged (> 470 ms) QTc between groups, neither before treatment nor after two weeks of treatment. Twenty two women of the total of sixty one patients (36%) had QTc > 450 ms before applying therapy.</p> <p>Conclusion</p> <p>We did not find significant QT prolongation in our patients after two weeks of treatment with antipsychotics and/or antidepressants. The QTc interval length did not differ significantly in the monotherapy and the polytherapy group. More than one third of included women exceeded the threshold value of borderline QTc interval (450 ms) before starting treatment. This finding calls for caution when prescribing drugs to female psychiatric patients, especially if they have other health problems.</p

Methods for conducting systematic reviews of risk factors in low- and middle-income countries.

BACKGROUND: Rates of youth violence are disproportionately high in many low- and middle-income countries [LMICs] but existing reviews of risk factors focus almost exclusively on high-income countries. Different search strategies, including non-English language searches, might be required to identify relevant evidence in LMICs. This paper discusses methodological issues in systematic reviews aiming to include evidence from LMICs, using the example of a recent review of risk factors for child conduct problems and youth violence in LMICs. METHODS: We searched the main international databases, such as PsycINFO, Medline and EMBASE in English, as well as 12 regional databases in Arabic, Chinese, English, French, Spanish, Portuguese and Russian. In addition, we used internet search engines and Google Scholar, and contacted over 200 researchers and organizations to identify potentially eligible studies in LMICs. RESULTS: The majority of relevant studies were identified in the mainstream databases, but additional studies were also found through regional databases, such as CNKI, Wangfang, LILACS and SciELO. Overall, 85% of eligible studies were in English, and 15% were reported in Chinese, Spanish, Portuguese, Russian or French. Among eligible studies in languages other than English, two-thirds were identified only by regional databases and one-third was also indexed in the main international databases. CONCLUSIONS: There are many studies on child conduct problems and youth violence in LMICs which have not been included in prior reviews. Most research on these subjects in LMICs has been produced in the last two-three decades and mostly in middle-income countries, such as China, Brazil, Turkey, South Africa and Russia. Based on our findings, it appears that many studies of child conduct problems and youth violence in LMICs are reported in English, Chinese, Spanish and Portuguese, but few such studies are published in French, Arabic or Russian. If non-English language searches and screening had not been conducted in the current review, 15% of eligible studies would have been missed. Although there are benefits to non-English language searches and the inclusion of non-English studies in meta-analyses, systematic reviewers also need to consider the resources required to incorporate multi-lingual research.We are grateful to the Wellcome Trust [089963/Z/09/Z] and Bernard van Leer Foundation for financial support for the research