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Background & aimsSrc homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure, and recruitment of inflammatory cells.MethodsLiver biopsy samples from patients with AH vs healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. Shc knockdown (hypomorph) and age-matched wild-type mice were pair-fed according to the chronic-plus-binge alcohol diet. To analyze hepatocyte-specific effects, adeno-associated virus 8-thyroxine binding globulin-Cre (hepatocyte-specific Shc knockout)-mediated deletion was performed in flox/flox Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratio, as well as cleaved caspase 8, B-cell-receptor-associated protein 31 (BAP31), Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist killer (Bak), were assessed in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with phosphorylated-eukaryotic initiation factor 2 alpha, BAP31, caspase 8, and Bax/Bak. The effects of idebenone, a novel Shc inhibitor, was studied in alcohol/pair-fed mice.ResultsShc was significantly induced in patients with AH (P < .01). Alanine aminotransferase, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratios, production of redox radicals, and lipid peroxidation improved (P < .05), and interleukin 1β, monocyte chemoattractant protein 1, and C-X-C chemokine ligand 10 were reduced in Shc knockdown and hepatocyte-specific Shc knockout mice. In vivo, Shc-dependent induction, and, in hepatocytes, a p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage, and membrane translocation of CRT/endoplasmic reticulum-resident protein 57 were seen. Idebenone protected against alcohol-mediated liver injury.ConclusionsAlcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a damage-associated molecular pattern, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.

Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-β fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFβR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines.

BackgroundRecent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology.MethodsUsing murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis.ResultsResults showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β.ConclusionIn conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.

Evidence from pediatric studies show that infants and children are at risk for early exposure to microcystin. The present report tests the hypothesis that early life exposure to microcystin (MC), a principal component of harmful algal blooms followed by a juvenile exposure to high-fat diet feeding potentiate the development of nonalcoholic fatty liver disease phenotype in adulthood. Results showed classical symptoms of early NAFLD linked inflammation. Cytokines and chemokines such as CD68, IL-1β, MCP-1, and TNF-α, as well as α-SMA were increased in the groups that were exposed to MC-LR with the high-fat diet compared to the vehicle group. Also, mechanistically, NLRP3 KO mice showed a significant decrease in the inflammation and NAFLD phenotype and resisted the metabolic changes such as insulin resistance and glucose metabolism in the liver. The data suggested that MC-LR exposure and subsequent NLRP3 inflammasome activation in childhood could impact liver health in juveniles.

The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive. Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1β and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro. Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity.

Efficient digital simulators set the very large-scale integration (VLSI) design process one step easier by augmenting scalability, circuit reusability, testability, code portability, and so on. Cloud-based open source CircuitVerse simulator is supplemented with a versatile hardware component library. This instructional simulator can introduce a lot for the improvement of performance scaling metrics of digital designs. The novelty of this work is to uniquely correlate the flow integrity in CircuitVerse with digital VLSI-fronted design. A way to the optimization of design complexity and hardware requirements is achieved alongside. [ABSTRACT FROM AUTHOR]

A study was conducted in the Odisha region of India to assess genetic parameters, heritability, and trait associations in twenty traditional pigmented and non-pigmented rice landraces. The evaluation focused on twenty-five physical, phytochemical, and antioxidant properties. The results showed potential for enhancing desired traits in pigmented rice due to a wide range of genotypic variation, high heritability, and substantial genetic advances. These improvements were particularly observed in characteristics such as porosity, total soluble sugar, phytochemicals, and antioxidant properties in pigmented rice. Additionally, properties like the length-breadth ratio of grains, thickness, diameter, thousand grain weight, and bulk density of grains can be used for trait improvement in non-pigmented rice. Physical attributes like thickness, grain weight, and porosity, as well as phytochemical traits like total soluble sugar and protein content, were notably higher in pigmented rice. Correlations between traits indicated that Pigmented rice was associated with phytochemical and antioxidant properties, while Nonpigmented rice was linked to amylose content, density, and the length-breadth ratio of grains. Two promising pigmented genotypes, Bodikaberi and Mahipaljeera, were identified and could be valuable for future rice breeding programs. Moreover, these genotypes have potential applications in the food industry for creating value-added products to enhance nutritional quality and could also be relevant to the cosmetic industry due to their superior antioxidant properties. [ABSTRACT FROM AUTHOR]

Accurate detection of spectrum holes is a useful requirement for cognitive radios that improves the efficiency of spectrum usage. The authors propose three novel, simple, and entropy‐based detectors for spectrum sensing in cognitive radio. The authors evaluate the probability of detection of these three detectors: Vasicek's entropy detector, truncated Vasicek's entropy detector, and Van Es' entropy detector, over a predefined probability of false‐alarm. In particular, the authors provide the approximate and asymptotic test statistics for these detectors in the presence and absence of Nakagami‐m fading, noise variance uncertainty, and optimised detection threshold. Furthermore, the authors provide a detailed comparison study among all the detectors via Monte Carlo simulations and justify authors results through real‐world data. The authors' experimental results establish a superior performance of truncated Vasicek's entropy detector over Vasicek's entropy detector, energy detector, differential entropy detector and Van Es' entropy detector in practically viable scenarios. [ABSTRACT FROM AUTHOR]

Cognitive radio (CR) systems are configured to dynamically assess the spectrum utilisation and contribute towards an improved spectrum efficiency. Hence, accurate detection of the incumbent signal in a given channel, popularly known as spectrum sensing (SS), is essential for CR. Here, in the domain of SS, the authors introduce a new goodness‐of‐fit test (GoFT) founded on p‐norm of the observations at the receiver node. To capture the heavy‐tailed nature of noise distribution in practical communication channels, the authors utilise generalised Gaussian distribution (GGD) as a noise model. A novel p‐norm detector (PND) and a geometric power detector (GPD) is proposed and corresponding probability density function (PDF) under GGD is derived. Via Monte Carlo simulations, the authors show a match of the derived PDFs with the simulation results. Using Neyman‐Pearson framework the performances of PND and GPD are compared with an existing differential entropy detector (DED), the well‐known energy detector (ED) and joint correlation and energy detector (CED) under GGD noise model. Evaluation of proposed PND and GPD utilising Monte Carlo simulations indicate a superior performance. Further, the experiments employing real‐world data establish superiority of the proposed detectors as compared to existing techniques. The authors derive and implement an optimised threshold for PND, providing further improvement in performance. [ABSTRACT FROM AUTHOR]