Search results for: cannabinoid receptors

Authors: John G. Skelly, Peter K. Dearden, Thomas W. R. Harrop, Sarah N. Inwood, Joseph Guhlin

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The Argentine stem weevil (ASW; L. bonariensis) is an economically important pasture pest in New Zealand, which causes about $200 million of damage per annum. Microctonus hyperodae (Mh), a parasite of the ASW in its natural range in South America, was introduced into New Zealand to curb the pasture damage caused by the ASW. Mh is an endoparasitic wasp that lays its eggs in the ASW halting its reproduction. Mh was initially successful at preventing ASW proliferation and reducing pasture damage. The effectiveness of Mh has since declined due to decreased parasitism rates and has resulted in increased pasture damage. Although the mechanism through which ASW has developed resistance to Mh has not been discovered, it has been proposed to be due to the different reproductive modes used by Mh and the ASW in New Zealand. The ASW reproduces sexually, whereas Mh reproduces asexually, which has been hypothesised to have allowed the ASW to ‘out evolve’ Mh. Other species within the Microctonus genus reproduce both sexually and asexually. Strains of Microctonus aethiopoides (Ma), a species closely related to Mh, reproduce either by sexual or asexual reproduction. Comparing the genomes of sexual and asexual Microctonus may allow for the identification of the mechanism of asexual reproduction and other characteristics that may improve Mh as a biocontrol agent. The genomes of Mh and three strains of Ma, two of which reproduce sexually and one reproduces asexually, have been sequenced and annotated. The French (MaFR) and Moroccan (MaMO) reproduce sexually, whereas the Irish strain (MaIR) reproduces asexually. Like Mh, The Ma strains are also used as biocontrol agents, but for different weevil species. The genomes of Mh and MaIR were subsequently upgraded using Hi-C, resulting in a set of high quality, highly contiguous genomes. A subset of the genes involved in mitosis and meiosis, which have been identified though the use of Hidden Markov Models generated from genes involved in these processes in other Hymenoptera, have been catalogued in Mh and the strains of Ma. Meiosis and mitosis genes were broadly conserved in both sexual and asexual Microctonus species. This implies that either the asexual species have retained a subset of the molecular components required for sexual reproduction or that the molecular mechanisms of mitosis and meiosis are different or differently regulated in Microctonus to other insect species in which these mechanisms are more broadly characterised. Bioinformatic analysis of the chemoreceptor compliment in Microctonus has revealed some variation in the number of olfactory receptors, which may be related to host preference. Phylogenetic analysis of olfactory receptors highlights variation, which may be able to explain different host range preferences in the Microctonus. Hi-C clustering implies that Mh has 12 chromosomes, and MaIR has 8. Hence there may be variation in gene regulation between species. Genome alignment of Mh and MaIR implies that there may be large scale genome structural variation. Greater insight into the genetics of these agriculturally important group of parasitic wasps may be beneficial in restoring or maintaining their biocontrol efficacy.

Keywords: argentine stem weevil, asexual, genomics, Microctonus hyperodae

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Authors: Mazo Kone, Rachida Salah, Harir Noria

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Background and objectives: c-Cbl and Cbl-b are two members of the Cbl family proteins, with a crucial role of downregulation of tyrosine kinase receptors. They act as E3 ubiquitin ligases and are multivalent adaptor proteins, making them important in maintaining homeostasis in the body. This study investigated the expression level in thymus and testis in normal conditions. Methods: The expression level was assessed by immunochemistry of tissue microarrays of normal thymus and testis biopsies. Results: Cbl-b and c-Cbl proteins were found to be highly expressed in normal testis and thymus, indicated as yellowish brown granules in the cytomembrane and cytoplasm compared to controls. The c-Cbl appears to be more highly expressed than the Cbl-b in the thymus, while c-Cbl appears slightly stronger than Cbl-b in the testis. The thymus was found with a higher grade compared to the testis. Conclusion: In this work we concluded, that in normal condition, thymus tissue expresses more Cbl family proteins(c-Cbl and Cbl-b) than the testis tissue in humans.

Keywords: Human C-Cbl proteins, Human Cbl-b protein, Testis, Thymus

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Authors: Narin Salehiyan, Ramin Ghasemi Shayan

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In order to investigate coronavirus RNA replication, transcription, recombination, protein processing and transport, virion assembly, the identification of coronavirus-specific cell receptors, and polymerase processing, the manipulation of coronavirus clones and complementary DNAs (cDNAs) of defective-interfering (DI) RNAs is the subject of this chapter. The idea of the Covid genome is nonsegmented, single-abandoned, and positive-sense RNA. When compared to other RNA viruses, its size is significantly greater, ranging from 27 to 32 kb. The quality encoding the enormous surface glycoprotein depends on 4.4 kb, encoding a forcing trimeric, profoundly glycosylated protein. This takes off exactly 20 nm over the virion envelope, giving the infection the appearance-with a little creative mind of a crown or coronet. Covid research has added to the comprehension of numerous parts of atomic science as a general rule, like the component of RNA union, translational control, and protein transport and handling. It stays a fortune equipped for creating startling experiences.

Keywords: covid-19, corona, virus, genome, genetic

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Authors: Fei Xu, Guofan Zhang, Xiao Liu

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Many major marine invertebrate phyla are characterized by indirect development. These animals transit from planktonic larvae to benthic adults via settlement and metamorphosis, which has many advantages for organisms to adapt marine environment. Studying the biological process of metamorphosis is thus a key to understand the origin and evolution of indirect development. Although the mechanism of metamorphosis has been largely studied on their relationships with the marine environment, microorganisms, as well as the neurohormones, little is known on the gene regulation network (GRN) during metamorphosis. We treated competent oyster pediveligers with epinephrine, which was known to be able to effectively induce oyster metamorphosis, and analyzed the dynamics of gene and proteins with transcriptomics and proteomics methods. The result indicated significant upregulation of protein synthesis system, as well as some transcription factors including Homeobox, basic helix-loop-helix, and nuclear receptors. The result suggested the GRN complexity of the transition stage during oyster metamorphosis.

Keywords: indirect development, gene regulation network, protein synthesis, transcription factors

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Authors: Federico Cevoli

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Purinergic P2X7 receptors (P2X7R) are ligand-gated non-selective cation channels involved in several physiological and pathological processes. They are particularly promising pharmacological targets as they are present in an increasing number of different cells types. P2X7R activation is triggered following elevated concentrations of extracellular ATP, similarly to those observed in tissues injury, chronic inflammation and T-cell activation, as well as in the scrambling of phospholipids leading to membrane blebbing and apoptosis. Another hallmark of P2X7 is cell permeabilization, commonly known as “macropore” formation allowing the passage of nanometer-sized molecules up to 900Da. Recently, full-length P2X7 Cryo-EM structures revealed unique functional sites, including two cytoplasmic domains - the cytoplasmic "anchor" and "ballast". To date, the molecular units/complex by which P2X7R exerts its pathophysiological functions are unknown. Using custom-made cell-penetrating HIV-1 TAT peptides, we show for the first-time potential implications of P2X7 cytoplasmic anchor in the regulation of caspase3/7 activation as well as TNFα regulation.

Keywords: P2X7R, immunology, TAT-peptide, cell death

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Authors: Srie Rezeki Nur Endah, Richa Mardianingrum

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Cancer is one of the most feared diseases and is considered the leading cause of death worldwide. Generally, cancer drugs are synthetic drugs with relatively more expensive prices and have harmful side effects, so many people turn to traditional medicine, for example by utilizing herbal medicine. Erythrina poeppigiana is one of the plants that can be used as a medicinal plant containing 10,11-dihidroerisodin compounds that are useful anticancer etnofarmakologi. The purpose of this study was to identify the target of 10,11 dihydroerisodin receptor compound as in silico anticancer candidate. The pure isolate was tested physicochemically by MS (Mass Spectrometry), UV-Vis (Ultraviolet – Visible), IR (Infra Red), 13C-NMR (Carbon-13 Nuclear Magnetic Resonance), 1H-NMR (Hydrogen-1 Nuclear Magnetic Resonance), to obtain the structure of 10,11-dihydroerisodin alkaloid compound then identified to target receptors in silico. From the results of the study, it was found that 10,11-dihydroerisodin compound can work on the Serine / threonine-protein kinase Chk1 receptor that serves as an anti-cancer candidate.

Keywords: anti-cancer, Erythrina poeppigiana, target receptor, 10, 11- dihidroerisodin

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Authors: Bianca Peterson, Tomasz J. Sańko, Carlos C. Bezuidenhout, Johnnie Van Den Berg

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Busseola fusca (Fuller) (Lepidoptera: Noctuidae), the maize stem borer, is a major pest in sub-Saharan Africa. It causes economic damage to maize and sorghum crops and has evolved non-recessive resistance to genetically modified (GM) maize expressing the Cry1Ab insecticidal toxin. Since B. fusca is a non-model organism, very little genomic information is publicly available, and is limited to some cytochrome c oxidase I, cytochrome b, and microsatellite data. The biology of B. fusca is well-described, but still poorly understood. This, in combination with its larval-specific behavior, may pose problems for limiting the spread of current resistant B. fusca populations or preventing resistance evolution in other susceptible populations. As part of on-going research into resistance evolution, B. fusca larvae were collected from Bt and non-Bt maize in South Africa, followed by RNA isolation (15 specimens) and sequencing on the Illumina HiSeq 2500 platform. Quality of reads was assessed with FastQC, after which Trimmomatic was used to trim adapters and remove low quality, short reads. Trinity was used for the de novo assembly, whereas TransRate was used for assembly quality assessment. Transcript identification employed BLAST (BLASTn, BLASTp, and tBLASTx comparisons), for which two libraries (nucleotide and protein) were created from 3.27 million lepidopteran sequences. Several transcripts that have previously been implicated in Cry toxin resistance was identified for B. fusca. These included aminopeptidase N, cadherin, alkaline phosphatase, ATP-binding cassette transporter proteins, and mitogen-activated protein kinase. MEGA7 was used to align these transcripts to reference sequences from Lepidoptera to detect mutations that might potentially be contributing to Cry toxin resistance in this pest. RSEM and Bioconductor were used to perform differential gene expression analysis on groups of B. fusca larvae challenged and unchallenged with the Cry1Ab toxin. Pairwise expression comparisons of transcripts that were at least 16-fold expressed at a false-discovery corrected statistical significance (p) ≤ 0.001 were extracted and visualized in a hierarchically clustered heatmap using R. A total of 329,194 transcripts with an N50 of 1,019 bp were generated from the over 167.5 million high-quality paired-end reads. Furthermore, 110 transcripts were over 10 kbp long, of which the largest one was 29,395 bp. BLAST comparisons resulted in identification of 157,099 (47.72%) transcripts, among which only 3,718 (2.37%) were identified as Cry toxin receptors from lepidopteran insects. According to transcript expression profiles, transcripts were grouped into three subclusters according to the similarity of their expression patterns. Several immune-related transcripts (pathogen recognition receptors, antimicrobial peptides, and inhibitors) were up-regulated in the larvae feeding on Bt maize, indicating an enhanced immune status in response to toxin exposure. Above all, extremely up-regulated arylphorin genes suggest that enhanced epithelial healing is one of the resistance mechanisms employed by B. fusca larvae against the Cry1Ab toxin. This study is the first to provide a resource base and some insights into a potential mechanism of Cry1Ab toxin resistance in B. fusca. Transcriptomic data generated in this study allows identification of genes that can be targeted by biotechnological improvements of GM crops.

Keywords: epithelial healing, Lepidoptera, resistance, transcriptome

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Authors: A. Newman-Tancredi, R. Depoortère, P. Gruca, E. Litwa, M. Lason, M. Papp

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The N-methyl-D-aspartic acid (NMDA) receptor antagonist, ketamine, can elicit rapid-acting antidepressant (RAAD) effects in treatment-resistant patients, but it requires parenteral co-administration with a classical antidepressant under medical supervision. In addition, ketamine can also produce serious side effects that limit its long-term use, and there is much interest in identifying RAADs based on ketamine’s mechanism of action but with safer profiles. Ketamine elicits GABAergic interneuron inhibition, glutamatergic neuron stimulation, and, notably, activation of serotonin 5-HT1A receptors in the prefrontal cortex (PFC). Direct activation of the latter receptor subpopulation with selective ‘biased agonists’ may therefore be a promising strategy to identify novel RAADs and, consistent with this hypothesis, the prototypical cortical biased agonist, NLX-101, exhibited robust RAAD-like activity in the chronic mild stress model of depression (CMS). The present study compared the effects of a novel, selective 5-HT1A receptor-biased agonist, NLX-204, with those of ketamine and NLX-101. Materials and methods: CMS procedure was conducted on Wistar rats; drugs were administered either intraperitoneally (i.p.) or by bilateral intracortical microinjection. Ketamine: 10 mg/kg i.p. or 10 µg/side in PFC; NLX-204 and NLX-101: 0.08 and 0.16 mg/kg i.p. or 16 µg/side in PFC. In addition, interaction studies were carried out with systemic NLX-204 or NLX-101 (each at 0.16 mg/kg i.p.) in combination with intracortical WAY-100635 (selective 5-HT1A receptor antagonist; 2 µg/side) or muscimol (GABA-A receptor agonist, 12.5 ng/side). Anhedonia was assessed by CMS-induced decrease in sucrose solution consumption; anxiety-like behavior was assessed using the Elevated Plus Maze (EPM), and cognitive impairment was assessed by the Novel Object Recognition (NOR) test. Results: A single administration of NLX-204 was sufficient to reverse the CMS-induced deficit in sucrose consumption, similarly to ketamine and NLX-101. NLX-204 also reduced CMS-induced anxiety in the EPM and abolished CMS-induced NOR deficits. These effects were maintained (EPM and NOR) or enhanced (sucrose consumption) over a subsequent 2-week period of treatment. The anti-anhedonic response of the drugs was also maintained for several weeks Following treatment discontinuation, suggesting that they had sustained effects on neuronal networks. A single PFC administration of NLX-204 reversed deficient sucrose consumption, similarly to ketamine and NLX-101. Moreover, the anti-anhedonic activities of systemic NLX-204 and NLX 101 were abolished by coadministration with intracortical WAY-100635 or muscimol. Conclusions: (i) The antidepressant-like activity of NLX-204 in the rat CMS model was as rapid as that of ketamine or NLX-101, supporting targeting cortical 5-HT1A receptors with selective, biased agonists to achieve RAAD effects. (ii)The anti-anhedonic activity of systemic NLX-204 was mimicked by local administration of the compound in the PFC, confirming the involvement of cortical circuits in its RAAD-like effects. (iii) Notably, the effects of systemic NLX-204 and NLX-101 were abolished by PFC administration of muscimol, indicating that they act by (indirectly) eliciting a reduction in cortical GABAergic neurotransmission. This is consistent with ketamine’s mechanism of action and suggests that there are converging NMDA and 5-HT1A receptor signaling cascades in PFC underlying the RAAD-like activities of ketamine and NLX-204. Acknowledgements: The study was financially supported by NCN grant no. 2019/35/B/NZ7/00787.

Keywords: depression, ketamine, serotonin, 5-HT1A receptor, chronic mild stress

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Authors: Suliman Khan, Rabeea Siddique, Mengzhou Xue

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Background: Patients with neurological disorders often display altered circadian rhythms. The disrupted circadian rhythms through chronic jetlag or shiftwork are thought to increase the risk and severity of human disease, including cancer, psychiatric, and related brain diseases. In this study, we investigated the impact of shiftwork or chronic jetlag (CJL) like conditions on mice’s brains. Transcriptome profiling based on RNA sequencing revealed that genes associated with serious neurological disorders were differentially expressed in the nucleus accumbens (NAc) and prefrontal cortex (PFC). According to the qPCR analysis, several key regulatory genes associated with neurological disorders were significantly altered in the NAc, PFC, hypothalamus, hippocampus, and striatum. Serotonin levels and the expression levels of serotonin transporters and receptors were significantly altered in mice treated with CJL. Overall, these results indicate that CJL may increase the risk of neurological disorders by disrupting the key regulatory genes, biological functions, serotonin, and corticosterone. These molecular linkages can further be studied to investigate the mechanism underlying CJL or shiftwork-mediated neurological disorders in order to develop treatment strategies.

Keywords: chronic jetlag, molecular profiles, brain disorders, circadian rhythms

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Authors: M. Mousavi-Daramoroudi, H. Yousefnia, F. Abbasi-Davani, S. Zolghadri, S. Kakaei

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Despite the appropriate characteristics of ¹⁷⁷Lu and DOTATOC, to our best knowledge, the therapeutic benefit of ¹⁷⁷Lu-DOTATOC complex in breast cancer has not been reported until now. In this study, biodistribution of ¹⁷⁷Lu-DOTA-TOC in mouse tumor model for evaluation of possible utilization of this complex in breast cancer treatment was investigated.¹⁷⁷Lu was prepared with the specific activity of 2.6-3 GBq.mg^-1 and radionuclidic purity higher than 99%. The radiolabeled complex was prepared in the optimized conditions with the radiochemical purity higher than 99%. The final solution was injected to the BALB/c mice with adenocarcinoma breast cancer. The biodistribution results showed major accumulation in the kidneys as the major excretion route and the somatostatin receptor-positive tissues such as pancreas compared with the other tissues. Also, significant uptake was observed in tumor even in longer time after injection. According to the results obtained in this research study, somatostatin receptors expressed in breast cancers can be targeted with DOTATOC analogues especially with ¹⁷⁷Lu-DOTATOC as an ideal therapeutic agent.

Keywords: ¹⁷⁷Lu, adenocarcinoma breast cancer, DOTATOC, BALB/c mice

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Authors: Mehdi Sheikhi, Marjan Nassiri-Asl, Esmail Abbasi, Mahsa Shafiee

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Various synthetic derivatives of natural flavonoids are known to have neuroactive properties. The present study aimed to investigate the effects of vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), a flavonoid found in such plants as tartary buckwheat sprouts, wheat leaves phenolome, Mimosa pudica Linn and Passiflora spp, on scopolamine-induced memory impairment in rats. To achieve this goal, we assessed the effects of vitexin on memory retrieval in the presence or absence of scopolamine using a step-through passive avoidance trial. In the first part of the study, vitexin (25, 50, and 100 μM) was administered intracerebroventricularly (i.c.v.) before acquisition trials. In the second part, vitexin, at the same doses, was administered before scopolamine (10 μg, i.c.v.) and before the acquisition trials. During retention tests, vitexin (100 μM) in the absence of scopolamine significantly increased the stepthrough latencies compared to scopolamine. In addition, vitexin (100 μM) significantly reversed the shorter step-through latencies induced by scopolamine (P < 0.05). These results indicate that vitexin has a potential role in enhancing memory retrieval. A possible mechanism is modulation of cholinergic receptors; however, other mechanisms may be involved in its effects in acute exposure.

Keywords: flavonoid, memory retrieval, passive avoidance, scopolamine, vitexin

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Authors: Paul Awolade, Parvesh Singh

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The global threat of pathogenic resistance to available therapeutic agents has become a menace to clinical practice, public health and man’s existence inconsequential. This has therefore led to an exigency in the development of new molecular scaffolds with profound activity profiles. In this vein, a versatile synthetic tool for accessing new molecules by incorporating two or more pharmacophores into a single entity with the unique ability to be recognized by multiple receptors hence leading to an improved bioactivity, known as molecular hybridization, has been explored with tremendous success. Accordingly, aware of the similarity in pharmacological activity spectrum of quinoline and 1,2,3-triazole pharmacophores such as; anti-Alzheimer, anticancer, anti-HIV, antimalarial and antimicrobial to mention but a few, the present study sets out to synthesize hybrids of quinoline and 1,2,3-triazole. The hybrids were accessed via click chemistry using copper catalysed azide-alkyne 1,3-dipolar cycloaddition reaction. All synthesized compounds were evaluated for their pharmaco-potential in an antimicrobial assay out of which the 3-OH derivative emerged as the most active with MIC value of 4 μg/mL against Cryptococcus neoformans; a value superior to standard Fluconazole and comparable to Amphotericin B. Structures of synthesized hybrids were elucidated using appropriate spectroscopic techniques (1H, 13C and 2D NMR, FT-IR and HRMS).

Keywords: bioisostere, click chemistry, molecular hybridization, quinoline, 1, 2, 3-triazole

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Authors: Thanthrige Thiunuwan Priyathilaka, Don Anushka Sandaruwan Elvitigala, Bong-Soo Lim, Hyung-Bok Jeong, Jehee Lee

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Toll like receptors (TLRs) are a phylogeneticaly conserved family of pattern recognition receptors, which participates in the host immune responses against various pathogens and pathogen derived mitogen. TLR21, a non-mammalian type, is almost restricted to the fish species even though those can be identified rarely in avians and amphibians. Herein, this study was carried out to identify and characterize TLR21 from rock bream (Oplegnathus fasciatus) designated as RbTLR21, at transcriptional and genomic level. In this study, the full length cDNA and genomic sequence of RbTLR21 was identified using previously constructed cDNA sequence database and BAC library, respectively. Identified RbTLR21 sequence was characterized using several bioinformatics tools. The quantitative real time PCR (qPCR) experiment was conducted to determine tissue specific expressional distribution of RbTLR21. Further, transcriptional modulation of RbTLR21 upon the stimulation with Streptococcus iniae (S. iniae), rock bream iridovirus (RBIV) and Edwardsiella tarda (E. tarda) was analyzed in spleen tissues. The complete coding sequence of RbTLR21 was 2919 bp in length which can encode a protein consisting of 973 amino acid residues with molecular mass of 112 kDa and theoretical isoelectric point of 8.6. The anticipated protein sequence resembled a typical TLR domain architecture including C-terminal ectodomain with 16 leucine rich repeats, a transmembrane domain, cytoplasmic TIR domain and signal peptide with 23 amino acid residues. Moreover, protein folding pattern prediction of RbTLR21 exhibited well-structured and folded ectodomain, transmembrane domain and cytoplasmc TIR domain. According to the pair wise sequence analysis data, RbTLR21 showed closest homology with orange-spotted grouper (Epinephelus coioides) TLR21with 76.9% amino acid identity. Furthermore, our phylogenetic analysis revealed that RbTLR21 shows a close evolutionary relationship with its ortholog from Danio rerio. Genomic structure of RbTLR21 consisted of single exon similar to its ortholog of zebra fish. Sevaral putative transcription factor binding sites were also identified in 5ʹ flanking region of RbTLR21. The RBTLR 21 was ubiquitously expressed in all the tissues we tested. Relatively, high expression levels were found in spleen, liver and blood tissues. Upon induction with rock bream iridovirus, RbTLR21 expression was upregulated at the early phase of post induction period even though RbTLR21 expression level was fluctuated at the latter phase of post induction period. Post Edwardsiella tarda injection, RbTLR transcripts were upregulated throughout the experiment. Similarly, Streptococcus iniae induction exhibited significant upregulations of RbTLR21 mRNA expression in the spleen tissues. Collectively, our findings suggest that RbTLR21 is indeed a homolog of TLR21 family members and RbTLR21 may be involved in host immune responses against bacterial and DNA viral infections.

Keywords: rock bream, toll like receptor 21 (TLR21), pattern recognition receptor, genomic characterization

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Authors: Marina Passero, Tianhua Zhai, Zuyi (Jacky) Huang

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Alzheimer’s disease has become a major public health issue, as indicated by the increasing populations of Americans living with Alzheimer’s disease. After decades of extensive research in Alzheimer’s disease, only seven drugs have been approved by Food and Drug Administration (FDA) to treat Alzheimer’s disease. Five of these drugs were designed to treat the dementia symptoms, and only two drugs (i.e., Aducanumab and Lecanemab) target the progression of Alzheimer’s disease, especially the accumulation of amyloid-b plaques. However, controversial comments were raised for the accelerated approvals of either Aducanumab or Lecanemab, especially with concerns on safety and side effects of these two drugs. There is still an urgent need for further drug discovery to target the biological processes involved in the progression of Alzheimer’s disease. Excessive cholesterol has been found to accumulate in the brain of those with Alzheimer’s disease. Cholesterol can be synthesized in both the blood and the brain, but the majority of biosynthesis in the adult brain takes place in astrocytes and is then transported to the neurons via ApoE. The blood brain barrier separates cholesterol metabolism in the brain from the rest of the body. Various proteins contribute to the metabolism of cholesterol in the brain, which offer potential targets for Alzheimer’s treatment. In the astrocytes, SREBP cleavage-activating protein (SCAP) binds to Sterol Regulatory Element-binding Protein 2 (SREBP2) in order to transport the complex from the endoplasmic reticulum to the Golgi apparatus. Cholesterol is secreted out of the astrocytes by ATP-Binding Cassette A1 (ABCA1) transporter. Lipoprotein receptors such as triggering receptor expressed on myeloid cells 2 (TREM2) internalize cholesterol into the microglia, while lipoprotein receptors such as Low-density lipoprotein receptor-related protein 1 (LRP1) internalize cholesterol into the neuron. Cytochrome P450 Family 46 Subfamily A Member 1 (CYP46A1) converts excess cholesterol to 24S-hydroxycholesterol (24S-OHC). Cholesterol has been approved for its direct effect on the production of amyloid-beta and tau proteins. The addition of cholesterol to the brain promotes the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), secretase, and amyloid precursor protein (APP), which all aid in amyloid-beta production. The reduction of cholesterol esters in the brain have been found to reduce phosphorylated tau levels in mice. In this work, a computational pipeline was developed to identify the protein targets involved in cholesterol regulation in brain and further to identify chemical compounds as the inhibitors of a selected protein target. Since extensive evidence shows the strong correlation between brain cholesterol regulation and Alzheimer’s disease, a detailed literature review on genes or pathways related to the brain cholesterol synthesis and regulation was first conducted in this work. An interaction network was then built for those genes so that the top gene targets were identified. The involvement of these genes in Alzheimer’s disease progression was discussed, which was followed by the investigation of existing clinical trials for those targets. A ligand-protein docking program was finally developed to screen 1.5 million chemical compounds for the selected protein target. A machine learning program was developed to evaluate and predict the binding interaction between chemical compounds and the protein target. The results from this work pave the way for further drug discovery to regulate brain cholesterol to combat Alzheimer’s disease.

Keywords: Alzheimer’s disease, drug discovery, ligand-protein docking, gene-network analysis, cholesterol regulation

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Authors: Ziba Omidi, Min-Ki Kim

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This research presents the design, fabrication and application of a flavor sensor for an integrated electronic tongue and electronic nose that can allow rapid characterization of multi-component mixtures in a solution. The odor gas and liquid are separated using hydrophobic porous membrane in micro fluidic channel. The sensor uses an array composed of microbeads in micromachined cavities localized on silicon wafer. Sensing occurs via colorimetric and fluorescence changes to receptors and indicator molecules that are attached to termination sites on the polymeric microbeads. As a result, the sensor array system enables simultaneous and near-real-time analyses using small samples and reagent volumes with the capacity to incorporate significant redundancies. One of the key parts of the system is a passive pump driven only by capillary force. The hydrophilic surface of the fluidic structure draws the sample into the sensor array without any moving mechanical parts. Since there is no moving mechanical component in the structure, the size of the fluidic structure can be compact and the fabrication becomes simple when compared to the device including active microfluidic components. These factors should make the proposed system inexpensive to mass-produce, portable and compatible with biomedical applications.

Keywords: optical sensor, semiconductor manufacturing, smell sensor, taste sensor

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Authors: Aliakbar Hafezi, Jalal Taherian, Mahsa Elahi, Jamshid Abedi

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Background: Patients with breast cancer with different molecular subtypes may have different pathological responses to neoadjuvant chemotherapy (NAC). The aim of this study was to evaluate the pathological response to NAC in patients with locally advanced breast cancer based on molecular subtypes. Method: In this retrospective cohort study, 210 female patients with breast cancer candidate for NAC referred to the radiation oncology departments in southern Iran between August 2019 and September 2024 were evaluated in terms of pathologic complete response (pCR) based on immunohistochemical molecular markers (estrogen and progesterone receptors, Her-2/neu and Ki-67), overall survival (OS) and disease-free survival (DFS). Results: The mean age of the patients was 38.22 ± 10.34 years, and 68 patients (32.4%) had a positive family history of breast cancer. The pCR rate was 17.6% (37 patients), which in the subtypes of luminal A, luminal B, Her-2/neu positive and triple negative was 7.7%, 16.9%, 26.5% and 21.05%, respectively. Patients with pCR had significantly better OS (78.4% vs. 49.1%, P = 0.014) and DFS (83.8% vs. 51.4%, P = 0.020) than patients with partial/no pathological response. Conclusion: It seems that the molecular subtype plays a decisive role in the clinical outcome and the pathological response to NAC in patients with locally advanced breast cancer.

Keywords: locally advanced breast cancer, neoadjuvant chemotherapy, pathologic complete response, clinical outcomes

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Authors: Xian-Peng Jiang, Catherine C. Baucom, Toby Jiang, Robert L. Elliott

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HLA-G binds to the inhibitory receptors of uterine NK cells and plays an important role in protection of fetal cells from maternal NK lysis. HLA-G also mediates tumor escape, but the immunosuppressive role is often neglected. These studies have focused on the examination of HLA-G expression in human breast carcinoma and HLA-G immunosuppressive role in NK cytolysis. We examined HLA-G expression in breast cell lines by real time PCR, ELISA and immunofluorescent staining. We treated the breast cancer cell lines with anti-human HLA-G antibody or progesterone. Then, NK cytolysis was measured by using MTT assay. We find that breast carcinoma cell lines increase the expression of HLA-G mRNA and protein, compared to normal cells. Blocking HLA-G of the breast cancer cells by the antibody increases NK cytolysis. Progesterone upregulates HLA-G mRNA and protein of human breast cancer cell lines. The increased HLA-G expression suppresses NK cytolysis. In summary, human breast carcinoma overexpress HLA-G immunosuppressive molecules. Blocking HLA-G protein by antibody improves NK cytolysis. In contrast, upregulation of HLA-G expression by progesterone impairs NK cytolytic function. Thus, HLA-G is a new immunosuppressive checkpoint and potential cancer immunotherapeutic target.

Keywords: HLA-G, Breast carcinoma, NK cells, Immunosuppressive checkpoint

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Authors: Wellemans Isabelle, Remmelink Myriam, Foucart Annick, Rusu Stefan, Compère Christophe

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Primary pulmonary meningioma (PPM) is a very rare tumor, and its occurrence has been reported only sporadically. Multiple PPMs are even more exceptional, and herein, we report, to the best of our knowledge, the fourth case, focusing on the clinicopathological features of the tumor. Moreover, the possible relationship between the use of progesterone–only contraceptives and the development of these neoplasms will be discussed. Case Report: We report a case of a 51-year-old female presenting three solid pulmonary nodules, with the following localizations: right upper lobe, middle lobe, and left lower lobe, described as incidental findings on computed tomography (CT) during a pre-bariatric surgery check-up. The patient revealed no drinking or smoking history. The physical exam was unremarkable except for the obesity. The lesions ranged in size between 6 and 24 mm and presented as solid nodules with lobulated contours. The largest lesion situated in the middle lobe had mild fluorodeoxyglucose (FDG) uptake on F-18 FDG positron emission tomography (PET)/CT, highly suggestive of primary lung neoplasm. For pathological assessment, video-assisted thoracoscopic middle lobectomy and wedge resection of the right upper nodule was performed. Histological examination revealed relatively well-circumscribed solid proliferation of bland meningothelial cells growing in whorls and lobular nests, presenting intranuclear pseudo-inclusions and psammoma bodies. No signs of anaplasia were observed. The meningothelial cells expressed diffusely Vimentin, focally Progesterone receptors and were negative for epithelial (cytokeratin (CK) AE1/AE3, CK7, CK20, Epithelial Membrane Antigen (EMA)), neuroendocrine markers (Synaptophysin, Chromogranin, CD56) and Estrogenic receptors. The proliferation labelling index Ki-67 was low (<5%). Metastatic meningioma was ruled out by brain and spine magnetic resonance imaging (MRI) scans. The third lesion localized in the left lower lobe was followed-up and resected three years later because of its slow but significant growth (14 mm to 16 mm), alongside two new infra centimetric lesions. Those three lesions showed a morphological and immunohistochemical profile similar to previously resected lesions. The patient was disease-free one year post-last surgery. Discussion: Although PPMs are mostly benign and slow-growing tumors with an excellent prognosis, they do not present specific radiological characteristics, and it is difficult to differentiate it from other lung tumors, histopathologic examination being essential. Aggressive behavior is associated with atypical or anaplastic features (WHO grades II–III) The etiology is still uncertain and different mechanisms have been proposed. A causal connection between sexual hormones and meningothelial proliferation has long been suspected and few studies examining progesterone only contraception and meningioma risk have all suggested an association. In line with this, our patient was treated with Levonorgestrel, a progesterone agonist, intra-uterine device (IUD). Conclusions: PPM, defined by the typical histological and immunohistochemical features of meningioma in the lungs and the absence of central nervous system lesions, is an extremely rare neoplasm, mainly solitary and associating, and indolent growth. Because of the unspecific radiologic findings, it should always be considered in the differential diagnosis of lung neoplasms. Regarding multiple PPM, only three cases are reported in the literature, and this is the first described in a woman treated by a progesterone-only IUD to the best of our knowledge.

Keywords: pulmonary meningioma, multiple meningioma, meningioma, pulmonary nodules

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Authors: Mansha Kotwani

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The specific spatio-temporal calcium concentration patterns are required by the fibroblasts to maintain its structure and functions. Thus, calcium concentration is regulated in cell at different levels in various activities of the cell. The variations in cytosolic calcium concentration largely depend on the buffers present in cytosol and influx of calcium into cytosol from ER through IP3Rs or Raynodine receptors followed by reuptake of calcium into ER through sarcoplasmic/endoplasmic reticulum ATPs (SERCA) pump. In order to understand the mechanisms of wound repair, tissue remodeling and growth performed by fibroblasts, it is of crucial importance to understand the mechanisms of calcium concentration regulation in fibroblasts. In this paper, a model has been developed to study calcium distribution in NRK fibroblast in the presence of buffers and ER flux with SERCA pump. The model has been developed for two dimensional unsteady state case. Appropriate initial and boundary conditions have been framed along with physiology of the cell. Finite element technique has been employed to obtain the solution. The numerical results have been used to study the effect of buffers, ER flux and source amplitude on calcium distribution in fibroblast cell.

Keywords: buffers, IP3R, ER flux, SERCA pump, source amplitude

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Authors: Kah Yan How, Peh Fern Ong, Keang Peng Song

Abstract:

Porphyromonas gingivalis is a black-pigmented, anaerobic Gram-negative bacterium that is important in the progression of chronic and severe periodontitis. This organism has an essential requirement for iron, which is usually obtained from hemin, using specific membrane receptors, proteases, and lipoproteins. In this study, we report the characterization of a novel 24 kDa hemin-binding protein, HmuX, in P. gingivalis W50. The hmuX gene is 651 bp long which encodes for a 217 amino acid protein. HmuX was found to be identical at the C-terminus to the previously reported HmuY protein, differing by an additional 74 amino acids at the N-terminus. Recombinant HmuX demonstrated hemin-binding ability by LDS- PAGE and TMBZ staining. Sequence analysis of HmuX revealed a putative lipoprotein attachment site, suggesting its possible role as a lipoprotein. HmuX was also localized to the outer cell surface by transmission electron microscopy. Northern analysis showed hmuX to be transcribed as a single gene and that hmuX mRNA was tightly regulated by the availability of extra-cellular hemin. P. gingivalis isogenic mutant deficient in hmuX gene exhibited significant growth retardation under hemin-limited conditions. Taken together, these results suggest that HmuX is a hemin-binding lipoprotein, important in hemin utilization for the growth of P. gingivalis.

Keywords: Porphyromonas gingivalis, periodontal diseases, HmuX, protein characterization

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Authors: G. V. Novikov, V. S. Sivozhelezov, S. S. Kolesnikov, K. V. Shaitan

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The study reports about the influence of binding of orthosteric ligands as well as point mutations on the conformational dynamics of β-2-adrenoreceptor. Using molecular dynamics simulation we found that there was a little fraction of active states of the receptor in its apo (ligand free) ensemble corresponded to its constitutive activity. Analysis of MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion in intracellular part of its alpha-helices. Thus receptor’s constitutive activity directly results from its conformational dynamics. On the other hand the binding of a full agonist resulted in a significant shift of the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized the receptor in its inactive state. It is likely that the binding of inverse agonists might be a universal way of constitutive activity inhibition in vivo. Our results indicate that ligand binding redistribute pre-existing conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) of the receptor rather than cause induced fit in it. Therefore, the ensemble of biologically relevant receptor conformations is encoded in its spatial structure, and individual conformations from that ensemble might be used by the cell in conformity with the physiological behaviour.

Keywords: seven-transmembrane receptors, constitutive activity, activation, x-ray crystallography, principal component analysis, molecular dynamics simulation

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Authors: Su Bin Wang, Jin Hee Ahn, Tong-Shin Chang

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The peroxisome proliferator-activated receptors (PPARs) are member of nuclear receptor superfamily that act as a ligand-activated transcription factors. Although platelets lack a nucleus, previous studies have shown that PPARγ agonists, rosiglitazone, inhibited platelet activation induced by collagen. In this study, we investigated the inhibitory effects of KR-62980, a newly synthesized PPARγ agonist, on collagen receptor-stimulated platelet activation. The specific tyrosine phosphorylations of key components (Syk, Vav1, Btk and PLCγ2) for collagen receptor signaling pathways were suppressed by KR-62980. KR-62980 also attenuated downstream responses including cytosolic calcium elevation, P-selectin surface exposure, and integrin αIIbβ3 activation. PPARγ was found to associate with multiple proteins within the LAT signaling complex in collagen-stimulated platelets. This association was prevented by KR-62980, indicating a potential mechanism for PPARγ function in collagen-stimulated platelet activation. Furthermore, KR-62980 inhibited platelet aggregation and adhesion in response to collagen in vitro and prolonged in vivo thrombotic response in carotid arteries of mice. Collectively, these data suggest that KR-62980 inhibits collagen-stimulated platelet activation and thrombus formation through modulating the collagen receptor signaling pathways.

Keywords: KR-62980, PPARγ, antiplatelet, thrombosis

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Authors: Rafat M. Mohareb

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Several D-ring alkylated estrone analogues display exceptionally high affinity for estrogen receptors. In particular, compounds in which an E-ring is formed are known to be involved in the inhibition of steroidogenic enzymes. Such compounds also have an effect on steroid dehydrogenase activity and the ability to inhibit the detrimental action of the steroid sulfatase enzyme. Generally, E-ring extended steroids have been accessed by modification of the C17-ketone in the D-ring by either arylimine or oximino formation, addition of a carbon nucleophile or hydrazone formation. Other approaches have included ketone reduction, silyl enol ether formation or ring-closing metathesis (giving five- or six-membered E-rings). Chemical modification of the steroid D-ring provides a way to alter the functional groups, sizes and stereochemistry of the D-ring, and numerous structure-activity relationships have been established by such synthetic alterations. Steroids bearing heterocycles fused to the D-ring of the steroid nucleus have been of pharmaceutical interest. In the present paper, we report on the efficient synthesis of estrone possessing pyran, pyrimidine and thiazole ring systems. This study focused on the synthesis and biochemical evaluation of newly synthesized heterocyclic compounds which were then subjected through inhibitory evaluations towards human cancer and normal cell lines.

Keywords: estrone, heterocyclization, cytotoxicity, biomedicine

Procedia PDF Downloads 295

Authors: E. Solfaroli Camillocci, C. Mancini-Terracciano, V. Bocci, A. Carollo, M. Colandrea, F. Collamati, M. Cremonesi, M. E. Ferrari, P. Ferroli, F. Ghielmetti, C. M. Grana, M. Marafini, S. Morganti, M. Patane, G. Pedroli, B. Pollo, L. Recchia, A. Russomando, M. Schiariti, M. Toppi, G. Traini, R. Faccini

Abstract:

A Radio-Guided Surgery technique exploiting β− emitting radio-tracers has been suggested to overcome the impact of the large penetration of γ radiation. The detection of electrons in low radiation background provides a clearer delineation of the margins of lesioned tissues. As a start, the clinical cases were selected between the tumors known to express receptors to a β− emitting radio-tracer: 90Y-labelled DOTATOC. The results of tests on ex-vivo specimens of meningioma brain tumor and abdominal neuroendocrine tumors are presented. Voluntary patients were enrolled according to the standard uptake value (SUV > 2 g/ml) and the expected tumor-to-non-tumor ratios (TNR∼10) estimated from PET images after administration of 68Ga-DOTATOC. All these tests validated this technique yielding a significant signal on the bulk tumor and a negligible background from the nearby healthy tissue. Even injecting as low as 1.4 MBq/kg of radiotracer, tumor remnants of 0.1 ml would be detectable. The negligible medical staff exposure was confirmed and among the biological wastes only urine had a significant activity.

Keywords: ex-vivo test, meningioma, neuroendocrine tumor, radio-guided surgery

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Authors: Man-Ho Oh

Abstract:

Membrane localized Leucine-Rich-Repeat Receptor-Like Kinases (LRR-RLKs) play crucial roles in plant growth and abiotic/biotic stress responses in higher plants including Arabidopsis and Brassica species. Among several Receptor-Like Kinases (RLKs), Leucine-Rich-Repeat Receptor-Like-Kinases (LRR-RLKs) are the major group of genes that play crucial roles related to growth, development and stress conditions in plant system. Since it is involved in several functional roles, it seems to be very important to investigate their roles in higher plants. We are particularly interested in brassinosteroid (BR) signaling, which is mediated by the BRASSINOSTEROID INSENSITIVE 1 (BRI1) receptor kinase and its co-receptor, BRI1-ASSOCIATED KINASE 1 (BAK1). Autophosphorylation of receptor kinases is recognized to be an important process in activation of signaling in higher plants. Although the plant receptors are generally classified as Ser/Thr protein kinases, many other receptor kinases including BRI1 and BAK1 are shown to autophosphorylate on Tyr residues in addition to Ser/Thr. As an interesting result, we determined that several 14-3-3 regulatory proteins bind to BRI1-CD and are phosphorylated by several receptor kinases in vitro, suggesting that BRI1 is critical for diverse signaling.

Keywords: autophosphorylation, brassinosteroid, BRASSINOSTEROID INSENSITIVE 1, BRI1-ASSOCIATED KINASE 1, Leucine-Rich-Repeat Receptor-Like Kinases (LRR-RLKs)

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Authors: Najla M. Salkho, Vinod Paul, Pierre Kawak, Rute F. Vitor, Ana M. Martin, Nahid Awad, Mohammad Al Sayah, Ghaleb A. Husseini

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Liposomes are popular lipid bilayer nanoparticles that are highly efficient in encapsulating both hydrophilic and hydrophobic therapeutic drugs. Liposomes promote a low risk controlled release of the drug avoiding the side effects of the conventional chemotherapy. One of the great potentials of liposomes is the ability to attach a wide range of ligands to their surface producing ligand-mediated active targeting of cancer tumour with limited adverse off-target effects. Ultrasound can also aid in the controlled and specified release of the drug from the liposomes by breaking it apart and releasing the drug in the specific location where the ultrasound is applied. Our research focuses on the synthesis of PEGylated liposomes (contain poly-ethylene glycol) encapsulated with the model drug calcein and studying the effect of low frequency ultrasound applied at different power densities on calcein release. In addition, moieties are attached to the surface of the liposomes for specific targeting of the cancerous cells which over-express the receptors of these moieties, ultrasound is then applied and the release results are compared with the moiety free liposomes. The results showed that attaching these moieties to the surface of the PEGylated liposomes not only enhance their active targeting but also stimulate calcein release from these liposomes.

Keywords: active targeting, liposomes, moieties, ultrasound

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Authors: Bruno D. Souza, Gerson G. Cunha, Michael O. Ferreira, Roberto Rosenhaim, Robson C. Santos, Sergio O. Santos

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Devices and applications that use satellite-based positioning are becoming more popular day-by-day. Thus, evolution and improvement in this technology are mandatory. Accordingly, satellite georeferenced systems need to accomplish the same evolution rhythm. Either GPS (Global Positioning System) or its similar Russian GLONASS (Global Navigation Satellite System) are system samples that offer us powerful tools to plot coordinates on the earth surface. The development of this research aims the study of several aspects related to use of GPS and GLONASS technologies, given its application and collected data improvement during geodetic data acquisition. So, both relevant theoretic and practical aspects are considered. In this context, at the theoretical part, the main systems' characteristics are shown, observing its similarities and differences. At the practical part, a series of experiences are performed and obtained data packages are compared in order to demonstrate equivalence or differences among them. The evaluation methodology targets both quantitative and qualitative analysis provided by GPS and GPS/GLONASS receptors. Meanwhile, a specific collected data storage system was developed to better compare and analyze them (SisGeo - Georeferenced Research Comparison Support System).

Keywords: satellites, systems, applications, experiments, receivers

Procedia PDF Downloads 255

Authors: Jay Ananth

Abstract:

The drug discovery process currently requires numerous years of clinical testing as well as money just for a single drug to earn FDA approval. For drugs that even make it this far in the process, there is a very slim chance of receiving FDA approval, resulting in detrimental hurdles to drug accessibility. To minimize these inefficiencies, numerous studies have implemented computational methods, although few computational investigations have focused on a crucial feature of drugs: lipophilicity. Lipophilicity is a physical attribute of a compound that measures its solubility in lipids and is a determinant of drug efficacy. This project leverages Artificial Intelligence to predict the impact of a drug’s lipophilicity on its performance by accounting for factors such as binding affinity and toxicity. The model predicted lipophilicity and binding affinity in the validation set with very high R² scores of 0.921 and 0.788, respectively, while also being applicable to a variety of target receptors. The results expressed a strong positive correlation between lipophilicity and both binding affinity and toxicity. The model helps in both drug development and discovery, providing every pharmaceutical company with recommended lipophilicity levels for drug candidates as well as a rapid assessment of early-stage drugs prior to any testing, eliminating significant amounts of time and resources currently restricting drug accessibility.

Keywords: drug discovery, lipophilicity, ligand-receptor interactions, machine learning, drug development

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Authors: Sdiqeh Jalali, M. R. Khazdair

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Liver X receptors (LXR) have an essential role in the regulation of cholesterol metabolism, and their activation increase ABCG5 and ABCG8 genes expression for the improvement of cholesterol excretion from the body during reverse cholesterol transport (RCT). The aim of this study was to investigate the effects of high-intensity interval (HIT) and low intensity continuous (LIT) trainings on gene expression of these substances after a high-fat diet in Wistar rats. Materials and Methods: Fifteen male Wistar rats were divided into 3 groups: control group (n = 5), HIT exercise group (n = 5) and LIT exercise group (n = 5). All groups used a high-fat diet for 13 weeks, and the HIT and LIT groups performed the specific training program. The expression of LXRβ, ABCG5, and ABCG8 genes was measured after the training period. Findings: Data analysis showed significantly higher levels of LXRβ, ABCG5, and ABCG8 gene expression in HIT and LIT groups compared to the control group (P ≤ 0.05). Conclusion: HIT and LIT trainings after a high-fat diet have beneficial effects on RCT that prevent heart attack. Also, HIT training may have a greater effect on cholesterol excretion during the reverse cholesterol transport mechanism than LIT.

Keywords: liver X receptor, atherosclerosis, interval training, endurance training

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Authors: Muhammad Mazhar, Yong Zhu, Likang Qin

Abstract:

Foods contain endogenous components known as dietary fibers, which are classified into soluble and insoluble forms. Dietary fibers are resistant to gut digestive enzymes, modulating anaerobic intestinal microbiota (AIM) and fabricating short-chain fatty acids (SCFAs). Acetate, butyrate, and propionate dominate in the gut, and different pathways, including Wood-Ljungdahl and acrylate pathways, generate these SCFAs. In pancreatic dysfunction, the release of insulin/glucagon is impaired, which leads to hyperglycemia. SCFAs enhance insulin sensitivity or secretion, beta-cell functions, leptin release, mitochondrial functions, and intestinal gluconeogenesis in human organs, which positively affect type 2 diabetes (T2D). Research models presented that SCFAs either enhance the release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) from L-cells (entero-endocrine) or promote the release of leptin hormone satiation in adipose tissues through G-protein receptors, i.e., GPR-41/GPR-43. Dietary fibers are the components of foods that influence AIM and produce SCFAs, which may be offering beneficial effects on T2D. This review addresses the effectiveness of SCFAs in modulating gut AIM in the fermentation of dietary fiber and their worth against T2D.

Keywords: dietary fibers, intestinal microbiota, short-chain fatty acids, fermentation, type 2 diabetes

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