Investigating the Evolution of Amati Parameters with Redshift

Gamma Ray Bursts (GRB) are among the brightest objects in the Universe and hence can be observed up to a very high redshift. Properly calibrated empirical correlations between intensity and spectral correlations of GRBs can be used to estimate the cosmological parameters. However, the possibility of the evolution of GRBs with the redshift is a long-standing puzzle. In this work, we used 162 long-duration GRBs to determine whether GRBs below and above a certain redshift have different properties. The GRBs are split into two groups, and we fit the Amati relation for each group separately. Our findings demonstrate that estimations of the Amati parameters for the two groups are substantially dissimilar. We perform simulations to investigate whether the selection effects could cause the difference. Our analysis shows that the differences may be intrinsic, and the selection effects are not their true origin.Comment: 6 pages, 8 figure

Interleukin-1β orchestrates underlying inflammatory responses in microglia via Kruppel-like factor 4

Microglia are the resident macrophages of the CNS, which secrete several pro‐ and anti‐inflammatory cyto‐chemokines including interleukin‐1β (IL‐1β), in response to pathogenic stimuli. Once secreted, IL‐1β binds to IL‐1 receptor present on microglia and initiates the production of inflammatory cytokines in microglia. However, the detailed information regarding the molecular mechanisms of IL‐1β triggered inflammatory pathways in microglia is lacking. Our studies focused on the role of Krüppel‐like factor 4 (Klf4) in mediating the regulation of pro‐inflammatory gene expression upon IL‐1β stimulation in microglia. Our studies show that stimulation of microglia with IL‐1β robustly induces Klf4 via PI3K/Akt pathway which positively regulates the production of endogenous IL‐1β as well as other pro‐inflammatory markers, cyclooxygenase‐2, monocyte chemoattractant protein‐1 and interleukin‐6 (IL‐6). In addition, we report that Klf4 negatively regulates the expression of inducible nitric oxide synthase, thereby playing a key role in regulating the immunomodulatory activities of microglia. IL‐1β is a potent pro‐inflammatory cytokine which regulates inflammation in brain via activation of microglia. In this regard, we unravelled mechanisms for IL‐1β mediated regulation of downstream Cox‐2, iNOS (inducible nitric oxide synthase) as well as other cyto‐chemokines in microglia and have established a role for Klf4 in mediating microglial activation. We further report that Klf4 mediates the production of endogenous IL‐1β in response to exogenous IL‐1β stimulation. We hereby propose a novel transcription factor underlying IL‐1β mediated modulation of inflammation in the CNS

Worsening of unrecognized tumour-induced osteomalacia with inadvertent use of recombinant human parathyroid hormone

Not required for Clinical Vignette

NLRP3 Inflammasome: Key Mediator of Neuroinflammation in Murine Japanese Encephalitis

Background: Japanese Encephalitis virus (JEV) is a common cause of acute and epidemic viral encephalitis. JEV infection is associated with microglial activation resulting in the production of pro-inflammatory cytokines including Interleukin-1 b (IL-1b) and Interleukin-18 (IL-18). The Pattern Recognition Receptors (PRRs) and the underlying mechanism by which microglia identify the viral particle leading to the production of these cytokines is unknown. Methodology/Principal Findings: For our studies, we have used murine model of JEV infection as well as BV-2 mouse microglia cell line. In this study, we have identified a signalling pathway which leads to the activation of caspase-1 as the key enzyme responsible for the maturation of both IL-1b and IL-18 in NACHT, LRR and PYD domains-containing protein-3 (NLRP3) dependent manner. Depletion of NLRP3 results in the reduction of caspase-1 activity and subsequent production of these cytokines. Conclusion/Significance: Our results identify a mechanism mediated by Reactive Oxygen Species (ROS) production and potassium efflux as the two danger signals that link JEV infection to caspase-1 activation resulting in subsequent IL-1b an

Therapeutic targeting of Krüppel-like factor 4 abrogates microglial activation

<p>Abstract</p> <p>Background</p> <p>Neuroinflammation occurs as a result of microglial activation in response to invading micro-organisms or other inflammatory stimuli within the central nervous system. According to our earlier findings, Krüppel-like factor 4 (Klf4), a zinc finger transcription factor, is involved in microglial activation and subsequent release of proinflammatory cytokines, tumor necrosis factor alpha, macrophage chemoattractant protein-1 and interleukin-6 as well as proinflammatory enzymes, inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-treated microglial cells. Our current study focuses on finding the molecular mechanism of the anti-inflammatory activities of honokiol in lipopolysaccharide-treated microglia with emphasis on the regulation of Klf4.</p> <p>Methods</p> <p>For <it>in vitro </it>studies, mouse microglial BV-2 cell lines as well as primary microglia were treated with 500 ng/mL lipopolysaccharide as well as 1 μM and 10 μM of honokiol. We cloned full-length Klf4 cDNA in pcDNA3.1 expression vector and transfected BV-2 cells with this construct using lipofectamine for overexpression studies. For <it>in vivo </it>studies, brain tissues were isolated from BALB/c mice treated with 5 mg/kg body weight of lipopolysaccharide either with or without 2.5 or 5 mg/kg body weight of honokiol. Expression of Klf4, cyclooxygenase-2, inducible nitric oxide synthase and phospho-nuclear factor-kappa B was measured using immunoblotting. We also measured the levels of cytokines, reactive oxygen species and nitric oxide in different conditions.</p> <p>Results</p> <p>Our findings suggest that honokiol can substantially downregulate the production of proinflammatory cytokines and inflammatory enzymes in lipopolysaccharide-stimulated microglia. In addition, honokiol downregulates lipopolysaccharide-induced upregulation of both Klf4 and phospho-nuclear factor-kappa B in these cells. We also found that overexpression of Klf4 in BV-2 cells suppresses the anti-inflammatory action of honokiol.</p> <p>Conclusions</p> <p>Honokiol potentially reduces inflammation in activated microglia in a Klf4-dependent manner.</p

Performance Evaluation of High-Resolution Ultrasound versus Magnetic Resonance Imaging in Diagnosing Peripheral Nerve Pathologies

Background High-resolution ultrasound (HRUS) and magnetic resonance neurography (MRN) are considered complementary to clinical and neurophysiological assessment for neuropathies. Aims The aim of our study was to compare the accuracy of HRUS and MRN for detecting various peripheral nerve pathologies, to choose the correct investigation to facilitate prompt patient management. Materials and Methods This prospective study was done using HRUS with 14 MHz linear-transducer and 3 or 1.5T MR in cases referred for the assessment of peripheral nerve pathologies. Image interpretation was done using a scoring system (score 0–3 confidence level) to assess for nerve continuity/discontinuity, increased nerve signal/edema, fascicular change, caliber change, and neuroma/mass lesion. We determined the accuracy, sensitivity, and specificity of these modalities compared with the diagnostic standard determined by surgical and/or histopathological, if not performed then clinical and/or electrodiagnostic evaluation. Results The overall accuracy of MRN was 89.3% (specificity: 66.6%, sensitivity: 92.6%, negative predictive value [NPV]: 57.1%, positive predictive value [PPV]: 95%) and that of HRUS was 82.9% (specificity: 100%, sensitivity: 80.4%, NPV: 42.8, PPV: 100). The confidence level for detecting nerve discontinuity and change in nerve caliber was found to be higher on ultrasonography than magnetic resonance imaging (MRI) (100 vs. 70% and 100 vs. 50%, respectively). Pathology of submillimeter caliber nerves was accurately detected by HRUS and these could not be well-visualized on MRI. Conclusion HRUS is a powerful tool that may be used as the first-line imaging modality for the evaluation of peripheral nerve pathologies, and a better means of evaluation of peripheral nerves with submillimeter caliber

Association of Toll-Like Receptor 4 Polymorphisms with Diabetic Foot Ulcers and Application of Artificial Neural Network in DFU Risk Assessment in Type 2 Diabetes Patients

The Toll-Like receptor 4 (TLR4) plays an important role in immunity, tissue repair, and regeneration. The objective of the present work was to evaluate the association of TLR4 single nucleotide polymorphisms (SNPs) rs4986790, rs4986791, rs11536858 (merged into rs10759931), rs1927911, and rs1927914 with increased diabetic foot ulcer (DFU) risk in patients with type 2 diabetes mellitus (T2DM). PCR-RFLP was used for genotyping TLR4 SNPs in 125 T2DM patients with DFU and 130 controls. The haplotypes and linkage disequilibrium between the SNPs were determined using Haploview software. Multivariate linear regression (MLR) and artificial neural network (ANN) modeling was done to observe their predictability for the risk of DFU in T2DM patients. Risk genotypes of all SNPs except rs1927914 were significantly associated with DFU. Haplotype ACATC (P value = 9.3E-5) showed strong association with DFU risk. Two haplotypes ATATC (P value = 0.0119) and ATGTT (P value = 0.0087) were found to be protective against DFU. In conclusion TLR4 SNPs and their haplotypes may increase the risk of impairment of wound healing in T2DM patients. ANN model (83%) is found to be better than the MLR model (76%) and can be used as a tool for the DFU risk assessment in T2DM patients

Association of Toll-like receptor 4 polymorphisms with diabetic foot ulcers and application of artificial neural network in DFU risk assessment in type 2 diabetes patients. Biomed Res Int 2013;2013

The Toll-Like receptor 4 (TLR4) plays an important role in immunity, tissue repair, and regeneration. The objective of the present work was to evaluate the association of TLR4 single nucleotide polymorphisms (SNPs) rs4986790, rs4986791, rs11536858 (merged into rs10759931), rs1927911, and rs1927914 with increased diabetic foot ulcer (DFU) risk in patients with type 2 diabetes mellitus (T2DM). PCR-RFLP was used for genotyping TLR4 SNPs in 125 T2DM patients with DFU and 130 controls. The haplotypes and linkage disequilibrium between the SNPs were determined using Haploview software. Multivariate linear regression (MLR) and artificial neural network (ANN) modeling was done to observe their predictability for the risk of DFU in T2DM patients. Risk genotypes of all SNPs except rs1927914 were significantly associated with DFU. Haplotype ACATC ( value = 9.3 − 5) showed strong association with DFU risk. Two haplotypes ATATC ( value = 0.0119) and ATGTT ( value = 0.0087) were found to be protective against DFU. In conclusion TLR4 SNPs and their haplotypes may increase the risk of impairment of wound healing in T2DM patients. ANN model (83%) is found to be better than the MLR model (76%) and can be used as a tool for the DFU risk assessment in T2DM patients

Caspase-1 activity is required for the production of IL-1β and IL-18 during JEV infection.

<p>BV-2 cells were incubated with 5 µM YVAD for 30 min to inhibit caspase-1 activity followed by JEV infection. (<b>A–B</b>) ELISA for IL-1β and IL-18 was carried out in JEV infected BV-2 cells upon caspase-1 inhibition. The cytokine levels were then measured using ELISA and the values are represented in pg/ml. Data represent mean ± SEM from 3 independent experiments performed in duplicate. Statistical differences were evaluated using one way ANOVA with Bonferroni's post hoc test. **, Statistical difference in comparison to mock-infected control values (** p<0.01) and #, Statistical difference with respect to JEV infected condition (p<0.01).</p