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1.
Association of TNF-beta polymorphism with disease severity among patients infected with hepatitis C virus 总被引:2,自引:0,他引:2
Goyal A Kazim SN Sakhuja P Malhotra V Arora N Sarin SK 《Journal of medical virology》2004,72(1):60-65
The pathogenesis of chronic hepatitis C virus (HCV) infection remains unclear. Tumour necrosis factor alpha (TNF-alpha) is alleged to contribute in the pathogenesis of chronic HCV infection. Single nucleotide polymorphism in TNF-alpha and -beta genes could influence the outcome of HCV infection. The aim was to study single nucleotide polymorphism in TNF-alpha promoter region and Nco I polymorphisms in the TNF-beta gene in patients with chronic hepatitis C. Fifty-two patients with histologically proven chronic hepatitis, who had raised ALT levels (>1.5 x ULN) and were HCV RNA positive, were studied. Genotyping of -308 promoter variant of TNF-alpha was performed by PCR with primers that incorporated an Nco I restriction site. For PCR typing of the TNF-beta Nco I restriction fragment length polymorphism, sequence specific primers were used. Polymorphism in the TNF-alpha G/G, G/A and A/A allele was not different between HCV patients and healthy controls. TNF-beta A/A allele was significantly more common (P = 0.02) in patients (28.8%) as compared to controls (12.8%), whereas no significant difference was observed for TNF-beta G/A and G/G alleles [corrected]. Nco I TNF-beta A/A was strongly associated with -308 TNF-alpha G/G (RR of HCV persistence = 4.9), indicating possible linkage between TNF-beta A/A and TNF-alpha G/G allele. Patients with severe hepatic fibrosis more frequently had the TNF-beta A/A allele as compared to patients with mild disease (P = 0.04). Immunogenetic factors, such as single nucleotide polymorphisms in TNF-beta (A/A allele), may affect the natural course of HCV infection, in particular, the disease progression. Larger studies including cytokine expression profiles are needed to fully understand the contribution of the polymorphisms described in the pathogenesis of chronic hepatitis C. 相似文献
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Chetan S. Patil Hongbin Li Natalie E. Lavine Ruoyang Shi Ankur Bodalia Tabrez J. Siddiqui Michael F. Jackson 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(36)
Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca2+ sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus–recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca2+ entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.Glutamatergic signaling plays a critical role in diverse processes linked to learning and memory formation. Ca2+ signals generated by the N-methyl D-aspartate (NMDA) subtype of glutamate receptors (NMDARs) are indispensable for several forms of synaptic plasticity, including long-term potentiation (LTP), a prototypic form of plasticity linked to memory formation (1–3). NMDAR-initiated Ca2+ signals (e.g., time course, amplitude, and spatial spread) are shaped by secondary events, including those engendered via the endoplasmic reticulum (ER) (4, 5). Ca2+ entry via NMDARs can promote Ca2+-induced Ca2+ release from ER stores by stimulating ryanodine (RyRs) (6–8) and/or IP3 receptors (IP3Rs) (9). In turn, NMDAR-initiated Ca2+ store depletion recruits ER-resident and Ca2+-sensing STIM proteins (10) to negatively regulate L-type voltage-gated Ca2+ channels (VGCCs) (13). This establishes the notion that Ca2+ entry via NMDARs can stimulate ER- and STIM-dependent cascades that regulate secondary routes of Ca2+ entry, thereby sculpting intracellular Ca2+ dynamics and in turn the cellular functions influenced by them. As part of a broader search to identify candidate Ca2+ channels able to respond to ER signaling dynamics, we found that Pannexin-1 (Panx1) can be activated through ER-based signaling following sarcoendoplasmic reticulum calcium adenosine triphosphatase (ATPase) (SERCA) pump inhibition by thapsigargin. This led us to consider the role of STIM1/2 as a candidate Panx1 activation mechanism.Panx1 is a large-pore nonselective ion and solute permeable channel with prominent central nervous system (CNS) expression (14, 15). Panx1 activation has been linked to pathophysiological disorders, such as excitotoxicity, stroke, migraine, chronic pain, and epilepsy (16–18). However, Panx1 also mediates physiological processes in the CNS, including contributions to neural development (19, 20), spine formation (21, 22), and NMDAR-dependent synaptic plasticity (23, 24). In this context, there remains an important gap in understanding the mechanisms by which Panx1 can mediate such disparate physiological and pathological functions. Intriguingly, evidence suggests that Panx1 ion versus solute permeability may be mediated by distinct channel pore configurations (i.e., small anion vs. large solute permeable) recruited via distinct activation modalities (25). Thus, identifying novel activation mechanisms is fundamental to understanding context- and modality-specific channel function.Here, we uncover a mechanism by which Panx1 is activated in response to ER-initiated signaling, which we demonstrate is dependent on Panx1 interaction with ER-resident STIM1/2. STIM1/2 recruitment and activation stimulates large-pore Panx1 opening, evident on the basis of increased permeability to Ca2+ and the large inorganic ion N-methyl-D-glucamine (NMDG). We map the STIM1/2 binding interface to a hydrophobic region in the N terminus of Panx1, a region not previously linked to channel gating. Our detailed structure-function analysis reveals that the Panx1 N-terminal region is necessary for its STIM1/2 responsiveness, but not for its responsiveness to hypotonic stress, demonstrating that this region mediates modality-specific regulation of Panx1 function. Using reverse genetics, ectopic rescue with Panx1 N-terminal deletion mutants, as well as a function inhibiting antibody targeting the critical N-terminal region of Panx1 identified by us, we demonstrate that NMDARs activate Panx1 in hippocampal neurons in a manner contingent upon ER-initiated signaling and reliant upon STIM proteins. Collectively, our data reveal the molecular mechanism by which STIM1/2 activates Panx1 and establishes a previously unrecognized essential role of its N-terminal region in regulating the transition of Panx1 to its large-pore solute permeable state. Our work will benefit studies aimed at understanding diverse functions of Panx1, including those linked to NMDAR-dependent signaling, stimulated in a modality- and context-specific manner by STIM proteins. 相似文献
4.
Anish Tiwari Shivani Agarwal Kriti Shrivastava Takayuki Ichikawa Ankur Jain Rini Singh 《Materials》2022,15(21)
The superior hydrogen storage properties makes the KSiH3 system a potential hydrogen storage material for practical applications. A theoretical capacity of 4.3 wt% bring this material to the front line of all the available hydrogen storage materials; however, the activation barrier of the reaction restricts the system to absorb and desorb hydrogen reversibly at elevated temperatures even if the thermodynamics suggest its room temperature operation. Several catalysts have already been tested to enhance its kinetic properties. In this work, the efforts were made to reduce the activation energy by using Zr-based catalysts to the KSi/KSiH3 system. The value of activation energy was found to be lowest (i.e., 87 kJ mol−1) for the ZrH2-added KSiH3 system. The mechanism of this improvement was investigated by using X-ray photoelectron spectroscopy (XPS). 相似文献
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Prabhu Manivannan Ankur Ahuja Hara Prasad Pati 《Indian journal of hematology & blood transfusion》2017,33(4):453-462
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder with its protean clinical manifestations. This is due to partial or complete absence of ‘glycophosphatidyl-inositol-anchor proteins’ (GPI-AP). The main aim of this review is to highlight various diagnostic modalities available, basic principle of each test and recent advances in the diagnosis of PNH. Recently among various tests available, the flow cytometry has become ‘the gold standard’ for PNH testing. In order to overcome the difficulties encountered by the testing and research laboratories throughout the world, International Clinical Cytometry Society has come up with guidelines regarding the indications for testing, protocol for sample collection, processing, panel of antibodies as well as gating strategies to be used, how to interpret the test and reporting format to be used. It is essential to test at least two GPI-linked markers on at least two different lineages particularly on red cells and granulocytes/monocytes. The fluorescent aerolysin combined with other monoclonal antibodies in multicolour flow cytometry offered an improved assay not only for diagnosis but also for monitoring of PNH clones. It is equally important to diagnose this rare entity with high index of suspicion. 相似文献
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Priyadarshi Soumyaranjan Sahu Jyotsna Seepana Sudarsini Padela Abani Kanta Sahu Swarna Subbarayudu Ankur Barua 《Revista do Instituto de Medicina Tropical de S?o Paulo》2014,56(3):253-258
Neurocysticercosis (NCC) is one of the major causes of childhood seizures
in developing countries including India and Latin America. In this study neurological
pediatric cases presenting with afebrile seizures were screened for anti-Cysticercus
antibodies (IgG) in their sera in order to estimate the possible burden of
cysticercal etiology. The study included a total of 61 pediatric afebrile seizure
subjects (aged one to 15 years old); there was a male predominance. All the sera were
tested using a pre-evaluated commercially procured IgG-ELISA kit (UB-Magiwell
Cysticercosis Kit ™). Anti-Cysticercus antibody in serum was positive in 23 of 61 (37.7%)
cases. The majority of cases with a positive ELISA test presented with generalized
seizure (52.17%), followed by complex partial seizure (26.08%), and simple partial
seizure (21.73%). Headaches were the major complaint (73.91%). Other presentations
were vomiting (47.82%), pallor (34.78%), altered sensorium (26.08%), and muscle
weakness (13.04%). There was one hemiparesis case diagnosed to be NCC. In this study
one child without any significant findings on imaging was also found to be positive
by serology. There was a statistically significant association found between the
cases with multiple lesions on the brain and the ELISA-positivity (p
= 0.017). Overall positivity of the ELISA showed a potential cysticercal etiology.
Hence, neurocysticercosis should be suspected in every child presenting with afebrile
seizure especially with a radio-imaging supportive diagnosis in tropical developing
countries or areas endemic for taeniasis/cysticercosis. 相似文献