Acute liver injuries have wide and varied etiologies and they occur both in patients with and without pre-existent chronic liver disease. Whilst the pathophysiological mechanisms remain distinct, ...both acute and acute-on-chronic liver injury is typified by deranged serum transaminase levels and if severe or persistent can result in liver failure manifest by a combination of jaundice, coagulopathy and encephalopathy. It is well established that platelets exhibit diverse functions as immune cells and are active participants in inflammation through processes including immunothrombosis or thromboinflammation. Growing evidence suggests platelets play a dualistic role in liver inflammation, shaping the immune response through direct interactions and release of soluble mediators modulating function of liver sinusoidal endothelial cells, stromal cells as well as migrating and tissue-resident leucocytes. Elucidating the pathways involved in initiation, propagation and resolution of the immune response are of interest to identify therapeutic targets. In this review the provocative role of platelets is outlined, highlighting beneficial and detrimental effects in a spatial, temporal and disease-specific manner.
Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive ...irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.
The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) ...promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (Erg
) and inducible homozygous deficient mice (Erg
), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL
)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.The transcription factor ERG is key to endothelial lineage specification and vascular homeostasis. Here the authors show that ERG balances TGFβ signalling through the SMAD1 and SMAD3 pathways, protecting the endothelium from endothelial-to-mesenchymal transition and consequent liver fibrosis in mice via a SMAD3-dependent mechanism.
Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet ...number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
The world receives more than 200 thousand people in a day and it is expected that the total world population will reach 9.6 billion by the year 2050. This will result in extra food demand, which can ...only be met from enhanced crop yield. Therefore, modernization of the agricultural sector becomes the need of the hour. There are many constraints that are responsible for the low production of crops, which can be overcome by using drone technology in the agriculture sector. This paper presents an analysis of drone technologies and their modifications with time in the agriculture sector in the last decade. The application of drones in the area of crop monitoring, and pesticide spraying for Precision Agriculture (PA) has been covered. The work done related to drone structure, multiple sensor development, innovation in spot area spraying has been presented. Moreover, the use of Artificial Intelligent (AI) and deep learning for the remote monitoring of crops has been discussed.
Malnutrition encompassing both macro- and micro-nutrient deficiency, remains one of the most frequent complications of alcohol-related liver disease (ArLD). Protein-energy malnutrition can cause ...significant complications including sarcopenia, frailty and immunodepression in cirrhotic patients. Malnutrition reduces patient's survival and negatively affects the quality of life of individuals with ArLD. Moreover, nutritional deficit increases the likelihood of hepatic decompensation in cirrhosis. Prompt recognition of at-risk individuals, early diagnosis and treatment of malnutrition remains a key component of ArLD management. In this review, we describe the pathophysiology of malnutrition in ArLD, review the screening tools available for nutritional assessment and discuss nutritional management strategies relevant to the different stages of ArLD, ranging from acute alcoholic hepatitis through to decompensated end stage liver disease.
Towards higher stability of perovskite solar cells, Cu has been observed to be more suitable electrode material compared to conventional Al and Ag electrodes. The photo-stability of such devices has ...not been explored much in the literature, therefore we present here the investigation carried out towards the photo-stability of PSCs based on top Cu electrodes. The PSCs were prepared in normal geometry and stored in dark, under continuous illumination of a white LED lamp inside the laboratory and under direct sunlight outside the laboratory and tested as per the international summit on organic photovoltaics stability protocols. In dark storage the encapsulated solar cells exhibited highest stability but under illumination they exhibited degradation in their performance and the degradation was fastest in the direct sunlight. Degradation under illumination has been attributed to the photo-oxidation of the perovskite film. Cu has been observed to diffuse into and react with the underlying perovskite film and the ultraviolet and infrared contents in direct sunlight accelerated the photo-oxidation and chemical reactions between Cu and perovskite film. The chemical reactions of Cu electrode with perovskite constituents made it disappear after some time. These investigations suggest that Cu too is not a very stable electrode material for PSCs under natural operating conditions.
ABSTRACT
fink is a broker designed to enable science with large time-domain alert streams such as the one from the upcoming Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST). It ...exhibits traditional astronomy broker features such as automatized ingestion, annotation, selection, and redistribution of promising alerts for transient science. It is also designed to go beyond traditional broker features by providing real-time transient classification that is continuously improved by using state-of-the-art deep learning and adaptive learning techniques. These evolving added values will enable more accurate scientific output from LSST photometric data for diverse science cases while also leading to a higher incidence of new discoveries which shall accompany the evolution of the survey. In this paper, we introduce fink, its science motivation, architecture, and current status including first science verification cases using the Zwicky Transient Facility alert stream.
Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as ...antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.
•Trp86 helps in π interactions with OP bearing an aromatic ring.•Distance between ligand and Trp86 found within cutoff range during MD simulation.•IC50 of Phoxim ethyl phosphonate = 29.99 μM ...(R2 = 0.996 and P < 0.0001).•Trp86 is key residue in human AChE beside the phosphorylation site Ser203.
Organophosphates (OP) inhibit the acetylcholinesterase (AChE) activity and devastate the nervous system of pest however its mode of action is ubiquitous and acts similarly on human AChE (hAChE). Screening of OP was carried out by molecular docking with hAChE using Glide docking module of Schrodinger suite as the structural information of hAChE and OP together as co-crystal structure is rarely available. The docking was done at three different precision levels, high throughput virtual screening (HTVS), standard precision and extra precision. The ranking was done using over all binding energy i.e. dock score and molecular modelling generalized born surface area (MM-GBSA).
Investigation reported Tryptophan (Trp86) residue involved in most interactions by forming a π-cation interaction apart from Ser203 on anionic subsite of hAChE. The top rank ligand was Phoxim ethyl phosphonate (PEP) interacting with Trp86, Gly121 and Ser203. However contact with Gly121 was lost during simulation and Asp74 appeared and sustained. Molecular dynamic simulation (GROMACS 4.5.5) of hAChE-PEP complex for 4 × 104 pico-second with SPC16 water system at 310 K temperature explained the evident role of Trp86 in stabilizing the ligand at P-site of the enzyme. Asp74 and Tyr124 were noticed in conveying H-bonds. Trp86 has shown consistent and better stability of bond based on distance between residues and ligand. The top ranked OP i.e. PEP was used to establish a dose response relationship between OP and hAChE. PEP inhibits half of the enzyme activity at concertation of 29.99 μM (calculated by sigmoid plot) at R2 = 0.996 and P < 0.0001.
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