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Supplementation with fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) effectively reduces acute and chronic alcohol-induced hepatic steatosis. We aimed to find molecular mechanisms underlying the effects of n-3 PUFAs in alcohol-induced hepatic steatosis. Because free fatty acid receptor 4 (FFA4, also known as GPR120) has been found as a receptor for n-3 PUFAs in an ethanol-induced liver steatosis model, we investigated whether n-3 PUFAs protect against liver steatosis via FFA4 using AH7614, an FFA4 antagonist, and Ffa4 knockout (KO) mice. N-3 PUFAs and compound A (CpdA), a selective FFA4 agonist, reduced the ethanol-induced increase in lipid accumulation in hepatocytes, triglyceride content, and serum ALT levels, which were not observed in Ffa4 KO mice. N-3 PUFAs and CpdA also reduced the ethanol-induced increase in lipogenic sterol regulatory element-binding protein-1c expression in an FFA4-dependent manner. In Kupffer cells, treatment with n-3 PUFA and CpdA reversed the ethanol-induced increase in tumor necrosis factor-α, cyclooxygenase-2, and NLR family pyrin domain-containing 3 expression levels in an FFA4-dependent manner. In summary, n-3 PUFAs protect against ethanol-induced hepatic steatosis via the anti-inflammatory actions of FFA4 on Kupffer cells. Our findings suggest FFA4 as a therapeutic target for alcoholic hepatic steatosis. [ABSTRACT FROM AUTHOR]

Forest is an important resource for human survival, and forest fires are a serious threat to forest protection. Therefore, the early detection of fire and smoke is particularly important. Based on the manually set feature extraction method, the detection accuracy of the machine learning forest fire detection method is limited, and it is unable to deal with complex scenes. Meanwhile, most deep learning methods are difficult to deploy due to high computational costs. To address these issues, this paper proposes a lightweight forest fire detection model based on YOLOv8 (FFYOLO). Firstly, in order to better extract the features of fire and smoke, a channel prior dilatation attention module (CPDA) is proposed. Secondly, the mixed-classification detection head (MCDH), a new detection head, is designed. Furthermore, MPDIoU is introduced to enhance the regression and classification accuracy of the model. Then, in the Neck section, a lightweight GSConv module is applied to reduce parameters while maintaining model accuracy. Finally, the knowledge distillation strategy is used during training stage to enhance the generalization ability of the model and reduce the false detection. Experimental outcomes demonstrate that, in comparison to the original model, FFYOLO realizes an mAP0.5 of 88.8% on a custom forest fire dataset, which is 3.4% better than the original model, with 25.3% lower parameters and 9.3% higher frames per second (FPS). [ABSTRACT FROM AUTHOR]

Objectives: To study the changes in red cell indices and counts over a period of 42 days in blood stored in blood bags. Materials and Methods: This research was done in Blood Bank, Khyber Teaching Hospital, Peshawar in collaboration with the main laboratory, Khyber Teaching Hospital, Peshawar. About 450 ml of whole blood was taken from 200 donors into Citrate Phosphate Dextrose Adenine blood bags. The storage temperature for the blood bags was maintained between 2-8°C. Blood samples were collected from blood bags. At days 1 and 42, using a haematology analyser, parameters including haemoglobin, RBC count, WBC count, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and platelet counts were measured. Mean and standard deviation were used for quantitative variables. Frequency and percentages were used for qualitative variables. Results: Through days 1 to 42, Haemoglobin (Hb) level decreased from 13.4gm/dl to 12.78 gm/dl, white cell count (WBC) decreased from 6.03x109/l to 2.95 x109/l, platelets count fell from 207 x109/l to 121 x109/l, neutrophils decreased from 59.6% to 23.8% while lymphocyte count increased from 28.36% to 66.3%. Conclusion: There is a decrease in haemoglobin level and white cell count over a period of 42 days of storage of blood bags. Lymphocyte counts increased during the storage duration of blood bags. [ABSTRACT FROM AUTHOR]

This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRAs, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to their reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRAs. The review also provides insights into the safe pharmacological profile of synephrine. [ABSTRACT FROM AUTHOR]

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Introdução à homenagem feita para a professora Eli de Fátima Napoleão de Lima que reúne pequenos textos escritos por amigos e ex-alunos. na época de seu falecimento, em janeiro de 2022.

O artigo faz uma homenagem à professora Eli Napoleão de Lima a partir de revisão de sua obra acadêmica que deixa um legado importante para os estudos do mundo rural brasileiro. As fontes para este debate serão capítulos de livros, artigos, trabalhos de orientados e orientandas e ementas das disciplinas ministradas pela professora Eli nas décadas de trabalho de formação, pesquisa, docência no CPDA/UFRRJ. O texto “vaivém” dentro de edição e seleção de três eixos temáticos. O primeiro trata da interdisciplinaridade e paixão na encruzilhada de história, ciências sociais e literatura a partir do tema do sertão e o “lugar” no imaginário de região/nação. Os estudos de Eli Napoleão de Lima analisaram a construção nacional, regionalismos e projetos de Estado, tendo foco a obra de Euclides da Cunha e sua influência durante século XX. Um segundo eixo é o de literatura e mundo rural como fonte de análise: “saber ler e saber perguntar como um texto funciona” foi o lema dos trabalhos de Eli Napoleão de Lima em um arco que vai de Euclides da Cunha até debates com autores como Graciliano Ramos e mesmo clássicos da literatura mundial. Um terceiro eixo trata de sua atividade docente: das orientações acadêmicas a intervenções feitas em eventos comemorativos do Programa de Pós-graduação de Ciências Sociais em Desenvolvimento, Agricultura e Sociedade e, principalmente, pela disciplina Raízes agrárias da formação social brasileira, que marcou gerações de alunos e alunas do CPDA.

Discovering how program components affect one another plays a fundamental role in aiding engineers comprehend and maintain a software system. Despite the fact that the degree to which one program component depends upon another can vary in strength, traditional dependence analysis typically ignores such nuance. To account for this nuance in dependence-based analysis, we propose Causal Program Dependence Analysis (CPDA), a framework based on causal inference that captures the degree (or strength) of the dependence between program elements. For a given program, CPDA intervenes in the program execution to observe changes in value at selected points in the source code. It observes the association between program elements by constructing and executing modified versions of a program (requiring only light-weight parsing rather than sophisticated static analysis). CPDA applies causal inference to the observed changes to identify and estimate the strength of the dependence relations between program elements. We explore the advantages of CPDA's quantified dependence by presenting results for several applications. Our further qualitative evaluation demonstrates 1) that observing different levels of dependence facilitates grouping various functional aspects found in a program and 2) how focusing on the relative strength of the dependences for a particular program element provides a detailed context for that element. Furthermore, a case study that applies CPDA to debugging illustrates how it can improve engineer productivity. [ABSTRACT FROM AUTHOR]

As a significant part of the Internet of things, wireless sensor networks (WSNs) is frequently implemented in our daily life. Data aggregation in WSNs can realize limited transmission and save energy. In the process of data aggregation, node data information is vulnerable to be eavesdropped and attacked. Therefore, it is of great significance to the research of data aggregation privacy protection in WSNs. We propose a secure and efficient privacy-preserving data aggregation algorithm (SECPDA) based on the original clustering privacy data aggregation algorithm. In this algorithm, we utilize SEP protocol to dynamically select cluster head nodes, introduce slicing idea for the private data slicing, and generate false information for interference. A comprehensive experimental evaluation is conducted to assess the data traffic and privacy protection performance. The results demonstrate that the proposed SECPDA algorithm can effectively reduce data traffic and further improve data privacy of nodes. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are often used as an adjuvant therapy to reduce the adverse effects of chemotherapy in breast cancer patients. Moreover, GCs can display pro-proliferative or anti-proliferative effects on BC cells depending on their molecular subtype. In addition, long-term use of GCs can induce drug resistance and tumor progression. The biological activity of GCs is mediated by glucocorticoid receptor (GR) via either transrepression or transactivation. The anti-inflammatory effects of GCs are thought to be due to transrepression, while side effects, drug resistance and tumor progression/metastasis are associated with transactivation. We have previously demonstrated that Compound A, a selective GR agonist (SEGRA), has a GR-dependent antitumor effect on blood cancer cells in vitro, not triggering the GR transactivation. This study was focused on the analysis of the CpdA activity in BC models in vitro. We demonstrated the antiproliferative effect of CpdA on BC cells and its ability to induce transrepression of GR-depended genes such as CCND1-3, COX-2, iNOS without the induction of transactivation. A comparative analysis showed that CpdA was an effective and safe alternative to dexamethasone in adjuvant chemotherapy for breast cancer.

Biochemical and metabolic changes in stored RBC may influence the clinical outcome. We aimed to study the temporal changes in the biochemical parameters and the effect of buffy-coat reduction on RBC storage lesions. A prospective observational study was conducted on fifteen RBC units five each of buffy coat reduced CPD/SAGM (quadruple bags), non-buffycoat reduced CPD/SAGM (triple bags) and non-buffycoat reduced CPDA (double bags). Biochemical parameters such as K+, LDH, pH plasma hemoglobin and percentage hemolysis were measured sequentially on day 7,14, 21, 28, 35 and 42. The data was analyzed using SPSS version 20. Extracellular K+ and LDH increased rapidly starting from the first week of storage. And the all the parameters including percentage hemolysis were significantly higher in RBC stored in CPDA (double bags) compared to that stored in SAGM (triple and quadruple). The difference observed in buffy-coat reduced units in comparison to the non-leukocyte reduced units were statistically not significant. The quality of red cells stored in SAGM was superior to that suspended in CPDA measured in terms of percent hemolysis, plasma hemoglobin, potassium and LDH. There was no effect of buffy-coat leukocyte reduction on the red cell storage lesion. [ABSTRACT FROM AUTHOR]

Introduction: The development of the autoimmune process during type 1 diabetes (DM1) contributes to insulitis; in this context, both β-cell stress and subsequent insulin secretory deficiency precede clinical signs of disease. Hyperglycemia triggers excess production of mitochondrial reactive oxygen species (ROS) that overwhelm the anti-oxidative capacity of β-cells, leading to oxidative stress. Islet inflammatory microenvironment during the autoimmune attack contributes to the activation of oxidative and endoplasmic reticulum (ER) stress resulting in β-cell dysfunction and death. The transcription factor Nrf2 regulates the expression of cytoprotective genes in response to oxidative stress, its induction is crucial for the normal β-cell physiology. We reported that Compound A (CpdA), a dissociative glucocorticoid receptor-ligand, is an effective modulator of key immune cells involved in insulitis, T and dendritic cells. In addition, we observed that CpdA ameliorates cytokine (IL-1b+IFN-g; CYT)-induced ER stress in β-cells and that in vivo CpdA administration leads to a significant delay of disease onset in an accelerated murine model of DM1. The development of new agents, with anti-inflammatory and immunomodulatory action and protective potential directed against dysfunctional signaling of β-cells is of clinical interest in diabetes. Objectives: The aim of this study was to explore the effect of CpdA on Nrf2 signaling pathway and CYT-induced oxidative stress in β-cells. Materials & Methods: A rat insulinoma cell line (INS-1E) was used as experimental model. CpdA chemical formula: 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride. A reporter plasmid (ARE-LUC) was used for the evaluation of Nrf2 transcriptional activity (luminometry); RTqPCR (Sybr Green) for analysis of mRNA expression; WB for protein expression analysis; a DCFDA based commercial kit to evaluate ROS (fluorometry); MTT assay for cell viability analysis and ELISA for insulin.

Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy. [ABSTRACT FROM AUTHOR]

Cyclic-3',5'-adenosine monophosphate (cAMP) is a universal second messenger that regulates vital activities in bacteria and eukaryotes. Enzymes that hydrolyze cAMP, called phosphodiesterases (PDEs), negatively regulate the levels of this messenger molecule and are therefore crucial for signal 'termination'. In this minireview, I shall summarize the available literature on bacterial cAMP-PDEs, with particular emphasis on enzymes belonging to the ubiquitously encoded Class III PDE family exemplified by CpdA from Escherichia coli and Rv0805 from Mycobacterium tuberculosis. Using available biochemical, structural and biological information, I shall make a case for re-examining the functions of these enzymes as merely regulators of intrabacterial cAMP levels and suggest that some members of this class may have evolved cAMP-independent functions as well. Finally, I shall highlight the major lacunae in our understanding of these enzymes and present unanswered questions in the area. [ABSTRACT FROM AUTHOR]

SUMMARY Background Potassium levels in stored blood bags increases as they age. Hyperkalemia in transfused blood has undesirable cardiac effects. Materials and methods Within a 19-month period, baseline and weekly samples from 15 CPDA-1 whole blood bags were collected till 28 days of storage and analysed for potassium, sodium, uric acid, albumin and whole blood haemoglobin. Results One unit increase in baseline (0 day) potassium in extracellular fluid of blood units was associated with the following increases in potassium levels on later days of storage: around two unit increase at 1 week ( r2 = 0·50, P < 0·01) of storage; four units increase at 2 weeks ( r2 = 0·64, P < 0·001) and 3 weeks ( r2 = 0·51, P < 0·01) of storage; six units at 4 weeks ( r2 = 0·53, P < 0·01) of storage. Baseline whole blood haemoglobin showed a moderate association with baseline potassium ( r2 = 0·36, P < 0·05) and 2-week potassium ( r2 = 0·35, P < 0·05) values. Conclusion For CPDA-1 blood bags (i) low baseline potassium blood bags might be preferred for transfusion in cases demanding a low potassium load and (ii) coordinating the 'first-in-first-out' ( FIFO) policy with 'early release of blood-bags with high initial potassium' might be helpful in improving the release of suitable blood units from blood-banks. [ABSTRACT FROM AUTHOR]

Abstract: Transfusion of allogeneic blood products is associated with adverse reactions and complications. Some of the negative effects of RBC transfusion are associated with the storage lesion. The importance of RBC oxidative damage in the storage lesion is not well documented. We monitored the storage-induced membrane protein oxidation in CPDA-preserved non-leukodepleted RBCs units from five blood donors in the course of the storage period, as assessed by protein carbonylation levels estimation. Carbonylated protein content was determined following 2,4-dinitrophenylhydrazine derivatization and SDS-polyacrylamide gel electrophoresis coupled with Western blotting. Immunoblotting with dinitrophenol-specific antibody revealed increased RBC membrane protein carbonyls with prolonged storage in CPDA units. This finding supports the idea of oxidation as a part of the storage lesion. [Copyright &y& Elsevier]

A variety of bacteria, including Escherichia coli, are known to enter the viable but non-culturable (VBNC) state under various stress conditions. During this state, cells lose colony-forming activities on conventional agar plates while retaining signs of viability. Diverse environmental stresses including starvation induce the VBNC state. However, little is known about the genetic mechanism inducing this state. Here, we aimed to reveal the genetic determinants of the VBNC state of E. coli. We hypothesized that the VBNC state is a process wherein specific gene products important for colony formation are depleted during the extended period of stress conditions. If so, higher expression of these genes would maintain colony-forming activities, thereby restraining cells from entering the VBNC state. From an E. coli plasmid-encoded ORF library, we identified genes that were responsible for maintaining high colony-forming activities after exposure to starvation condition. Among these, cpdA encoding cAMP phosphodiesterase exhibited higher performance in the maintenance of colony-forming activities. As cpdA overexpression decreases intracellular cAMP, cAMP or its complex with cAMP-receptor protein (CRP) may negatively regulate colony-forming activities under stress conditions. We confirmed this using deletion mutants lacking adenylate cyclase or CRP. These mutants fully maintained colony-forming activities even after a long period of starvation, while wild-type cells lost most of this activity. Thus, we concluded that the lack of cAMP-CRP effectively retains high colony-forming activities, indicating that cAMP-CRP acts as a positive regulator necessary for the induction of the VBNC state in E. coli.

Introduction: Recently extracellular vesicles (exosomes, microparticles also referred to as microvesicles and apoptotic bodies) have attracted substantial interest as potential biomarkers and therapeutic vehicles. However, analysis of microparticles in biological fluids is confounded by many factors such as the activation of cells in the blood collection tube that leads to in vitro vesiculation. In this study we aimed at identifying an anticoagulant that prevents in vitro vesiculation in blood plasma samples., Materials and Methods: We compared the levels of platelet microparticles and non-platelet-derived microparticles in platelet-free plasma samples of healthy donors. Platelet-free plasma samples were isolated using different anticoagulant tubes, and were analyzed by flow cytometry and Zymuphen assay. The extent of in vitro vesiculation was compared in citrate and acid-citrate-dextrose (ACD) tubes., Results: Agitation and storage of blood samples at 37 °C for 1 hour induced a strong release of both platelet microparticles and non-platelet-derived microparticles. Strikingly, in vitro vesiculation related to blood sample handling and storage was prevented in samples in ACD tubes. Importantly, microparticle levels elevated in vivo remained detectable in ACD tubes., Conclusions: We propose the general use of the ACD tube instead of other conventional anticoagulant tubes for the assessment of plasma microparticles since it gives a more realistic picture of the in vivo levels of circulating microparticles and does not interfere with downstream protein or RNA analyses., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Measurement of carnitine and acylcarnitines in plasma is important in diagnosis of fatty acid β-oxidation disorders and organic acidemia. The usual method uses flow injection tandem mass spectrometry (FIA-MS/MS), which has limitations. A rapid and more accurate method was developed to be used for high-risk screening and diagnosis. Carnitine and acylcarnitines were separated by hydrophilic interaction liquid chromatography (HILIC) without derivatization and detected with a QTRAP MS/MS System. Total analysis time was 9.0min. The imprecision of within- and between-run were less than 6% and 17%, respectively. Recoveries were in the range of 85-110% at three concentrations. Some acylcarnitine isomers could be separated, such as dicarboxylic and hydroxyl acylcarnitines. The method could also separate interferent to avoid false positive results. 216 normal samples and 116 patient samples were detected with the validated method, and 49 patients were identified with fatty acid oxidation disorders or organic acidemias., (Copyright © 2013 Elsevier B.V. All rights reserved.)