First order parent formulation for generic gauge field theories

We show how a generic gauge field theory described by a BRST differential can systematically be reformulated as a first order parent system whose spacetime part is determined by the de Rham differential. In the spirit of Vasiliev's unfolded approach, this is done by extending the original space of fields so as to include their derivatives as new independent fields together with associated form fields. Through the inclusion of the antifield dependent part of the BRST differential, the parent formulation can be used both for on and off-shell formulations. For diffeomorphism invariant models, the parent formulation can be reformulated as an AKSZ-type sigma model. Several examples, such as the relativistic particle, parametrized theories, Yang-Mills theory, general relativity and the two dimensional sigma model are worked out in details.Comment: 36 pages, additional sections and minor correction

Serial Killing of Tumor Cells by Human Natural Killer Cells – Enhancement by Therapeutic Antibodies

BACKGROUND: Natural killer cells are an important component of the innate immune system. Anti-cancer therapies utilizing monoclonal antibodies also rely on the cytotoxicity of NK cells for their effectiveness. Here, we study the dynamics of NK cell cytotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: We observe that IL-2 activated human NK cells can serially hit multiple targets. Using functional assays, we demonstrate that on an average, a single IL-2 activated NK cell can kill four target cells. Data using live video microscopy suggest that an individual NK cell can make serial contacts with multiple targets and majority of contacts lead to lysis of target cells. Serial killing is associated with a loss of Perforin and Granzyme B content. A large majority of NK cells survive serial killing, and IL-2 can replenish their granular stock and restore the diminished cytotoxicity of ‘exhausted’ NK cells. IL-2 and IL-15 are equally effective in enhancing the killing frequency of resting NK cells. Significantly, Rituximab, a therapeutic monoclonal antibody increases the killing frequency of both resting and IL-2 activated NK cells. CONCLUSION/SIGNIFICANCE: Our data suggest that NK cell-based therapies for overcoming tumors rely on their serial killing ability. Therefore, strategies augmenting the killing ability of NK cells can boost the immune system and enhance the effectiveness of monoclonal antibody-based therapies

Daily life stress and the cortisol awakening response : testing the anticipation hypothesis

Acknowledgments We thank Paul Stewart for his contribution to data collection and Dr Matthew Jones for programming the handheld computers. Author Contributions Conceived and designed the experiments: WS DJP. Performed the experiments: DJP. Analyzed the data: WS. Wrote the paper: WS DJP.Peer reviewedPublisher PD

Order recall in verbal short-term memory: The role of semantic networks

In their recent article, Acheson, MacDonald, and Postle (Journal of Experimental Psychology: Learning, Memory, and Cognition 37:44-59, 2011) made an important but controversial suggestion: They hypothesized that (a) semantic information has an effect on order information in short-term memory (STM) and (b) order recall in STM is based on the level of activation of items within the relevant lexico-semantic long-term memory (LTM) network. However, verbal STM research has typically led to the conclusion that factors such as semantic category have a large effect on the number of correctly recalled items, but little or no impact on order recall (Poirier & Saint-Aubin, Quarterly Journal of Experimental Psychology 48A:384-404, 1995; Saint-Aubin, Ouellette, & Poirier, Psychonomic Bulletin & Review 12:171-177, 2005; Tse, Memory 17:874-891, 2009). Moreover, most formal models of short-term order memory currently suggest a separate mechanism for order coding-that is, one that is separate from item representation and not associated with LTM lexico-semantic networks. Both of the experiments reported here tested the predictions that we derived from Acheson et al. The findings show that, as predicted, manipulations aiming to affect the activation of item representations significantly impacted order memory

Progression to microalbuminuria in type 1 diabetes: development and validation of a prediction rule

AIMS/HYPOTHESIS: Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria. METHODS: Data from the European Diabetes Prospective Complications Study (n = 1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study). RESULTS: Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n = 87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively). CONCLUSIONS/INTERPRETATION: We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complication

Inhibitors of Bcl-2 protein family deplete ER Ca2+ stores in pancreatic acinar cells

Physiological stimulation of pancreatic acinar cells by cholecystokinin and acetylcholine activate a spatial-temporal pattern of cytosolic [Ca+2] changes that are regulated by a coordinated response of inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs) and calcium-induced calcium release (CICR). For the present study, we designed experiments to determine the potential role of Bcl-2 proteins in these patterns of cytosolic [Ca+2] responses. We used small molecule inhibitors that disrupt the interactions between prosurvival Bcl-2 proteins (i.e. Bcl-2 and Bcl-xl) and proapoptotic Bcl-2 proteins (i.e. Bax) and fluorescence microfluorimetry techniques to measure both cytosolic [Ca+2] and endoplasmic reticulum [Ca+2]. We found that the inhibitors of Bcl-2 protein interactions caused a slow and complete release of intracellular agonist-sensitive stores of calcium. The release was attenuated by inhibitors of IP3Rs and RyRs and substantially reduced by strong [Ca2+] buffering. Inhibition of IP3Rs and RyRs also dramatically reduced activation of apoptosis by BH3I-2′. CICR induced by different doses of BH3I-2′ in Bcl-2 overexpressing cells was markedly decreased compared with control. The results suggest that Bcl-2 proteins regulate calcium release from the intracellular stores and suggest that the spatial-temporal patterns of agonist-stimulated cytosolic [Ca+2] changes are regulated by differential cellular distribution of interacting pairs of prosurvival and proapoptotic Bcl-2 proteins

Progression to microalbuminuria in patients with type 1 diabetes: a seven-year prospective study

<p>Abstract</p> <p>Background</p> <p>The presence of microalbuminuria can be associated with overt nephropathy and cardiovascular disease in patients with type 1 diabetes (T1D). We aimed to determine the incidence and evaluate the baseline predictors for the development of microalbuminuria in patients with T1D.</p> <p>Methods</p> <p>This study is a longitudinal cohort study of 122 normoalbuminuric patients with T1D who were receiving routine clinical care at baseline. A detailed medical history was taken, and a physical examination was performed at baseline. All of the patients were regularly examined for diabetes-associated complications. An analysis of predictors was performed using the Cox regression.</p> <p>Results</p> <p>Over 6.81 (3.59-9.75) years of follow-up, 50 (41%) of the patients developed microalbuminuria. The incidence density was 6.79/100 people per year (95% CI 5.04-8.95), and the microalbuminuria developed after 5.9 (2.44-7.76) and 11 (5-15) years of follow-up and diabetes duration, respectively. After an individual Cox regression, the baseline variables associated with the development of microalbuminuria were age, age at diagnosis, duration of diabetes, systolic and diastolic blood pressure, fasting glycemia, body mass index (BMI), total cholesterol and triglycerides levels, cholesterol/HDL ratio and a family history of type 2 diabetes.After a multivariate Cox regression, the only independent factors associated with the development of microalbuminuria were BMI [HR 1.12 (1.03-1.21)] and cholesterol/HDL ratio [HR 1.32 (1.05-1.67)].</p> <p>Conclusions</p> <p>A higher BMI and cholesterol/HDL ratio increased the risk of developing microalbuminuria in young patients with T1D after a short follow-up. Both risk factors are modifiable and should be identified early and followed closely.</p

Erythrocyte and Porcine Intestinal Glycosphingolipids Recognized by F4 Fimbriae of Enterotoxigenic Escherichia coli

Enterotoxigenic F4-fimbriated Escherichia coli is associated with diarrheal disease in neonatal and postweaning pigs. The F4 fimbriae mediate attachment of the bacteria to the pig intestinal epithelium, enabling an efficient delivery of diarrhea-inducing enterotoxins to the target epithelial cells. There are three variants of F4 fimbriae designated F4ab, F4ac and F4ad, respectively, having different antigenic and adhesive properties. In the present study, the binding of isolated F4ab, F4ac and F4ad fimbriae, and F4ab/ac/ad-fimbriated E. coli, to glycosphingolipids from erythrocytes and from porcine small intestinal epithelium was examined, in order to get a comprehensive view of the F4-binding glycosphingolipids involved in F4-mediated hemagglutination and adhesion to the epithelial cells of porcine intestine. Specific interactions between the F4ab, F4ac and F4ad fimbriae and both acid and non-acid glycosphingolipids were obtained, and after isolation of binding-active glycosphingolipids and characterization by mass spectrometry and proton NMR, distinct carbohydrate binding patterns were defined for each fimbrial subtype. Two novel glycosphingolipids were isolated from chicken erythrocytes, and characterized as GalNAcα3GalNAcß3Galß4Glcß1Cer and GalNAcα3GalNAcß3Galß4GlcNAcß3Galß4Glcß1Cer. These two compounds, and lactosylceramide (Galß4Glcß1Cer) with phytosphingosine and hydroxy fatty acid, were recognized by all three variants of F4 fimbriae. No binding of the F4ad fimbriae or F4ad-fimbriated E. coli to the porcine intestinal glycosphingolipids occurred. However, for F4ab and F4ac two distinct binding patterns were observed. The F4ac fimbriae and the F4ac-expressing E. coli selectively bound to galactosylceramide (Galß1Cer) with sphingosine and hydroxy 24:0 fatty acid, while the porcine intestinal glycosphingolipids recognized by F4ab fimbriae and the F4ab-fimbriated bacteria were characterized as galactosylceramide, sulfatide (SO3-3Galß1Cer), sulf-lactosylceramide (SO3-3Galß4Glcß1Cer), and globotriaosylceramide (Galα4Galß4Glcß1Cer) with phytosphingosine and hydroxy 24:0 fatty acid. Finally, the F4ad fimbriae and the F4ad-fimbriated E. coli, but not the F4ab or F4ac subtypes, bound to reference gangliotriaosylceramide (GalNAcß4Galß4Glcß1Cer), gangliotetraosylceramide (Galß3GalNAcß4Galß4Glcß1Cer), isoglobotriaosylceramide (Galα3Galß4Glcß1Cer), and neolactotetraosylceramide (Galß4GlcNAcß3Galß4Glcß1Cer)

A new framework for cortico-striatal plasticity: behavioural theory meets In vitro data at the reinforcement-action interface

Operant learning requires that reinforcement signals interact with action representations at a suitable neural interface. Much evidence suggests that this occurs when phasic dopamine, acting as a reinforcement prediction error, gates plasticity at cortico-striatal synapses, and thereby changes the future likelihood of selecting the action(s) coded by striatal neurons. But this hypothesis faces serious challenges. First, cortico-striatal plasticity is inexplicably complex, depending on spike timing, dopamine level, and dopamine receptor type. Second, there is a credit assignment problem—action selection signals occur long before the consequent dopamine reinforcement signal. Third, the two types of striatal output neuron have apparently opposite effects on action selection. Whether these factors rule out the interface hypothesis and how they interact to produce reinforcement learning is unknown. We present a computational framework that addresses these challenges. We first predict the expected activity changes over an operant task for both types of action-coding striatal neuron, and show they co-operate to promote action selection in learning and compete to promote action suppression in extinction. Separately, we derive a complete model of dopamine and spike-timing dependent cortico-striatal plasticity from in vitro data. We then show this model produces the predicted activity changes necessary for learning and extinction in an operant task, a remarkable convergence of a bottom-up data-driven plasticity model with the top-down behavioural requirements of learning theory. Moreover, we show the complex dependencies of cortico-striatal plasticity are not only sufficient but necessary for learning and extinction. Validating the model, we show it can account for behavioural data describing extinction, renewal, and reacquisition, and replicate in vitro experimental data on cortico-striatal plasticity. By bridging the levels between the single synapse and behaviour, our model shows how striatum acts as the action-reinforcement interface