Biochemistry and Pharmacology - Research Publications

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Now showing 1 - 10 of 1985
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    Exploring nomophobia among university students: Identifying risk factors, correlates, and predictive insights through machine learning
    Reza, MS ; Tasnim, MZ ; Afroz, MA ; Ruhi, S (Growing Science, 2024)
    Nomophobia is a term describing a growing fear in today’s world, the fear of being without a mobile device or beyond mobile phone contact. It is the biggest non-drug addiction of the 21st century and is mainly affected by teen-aged students. Those experiencing nomophobia may feel a sense of panic, anxiety, or distress when they are separated from their mobile phones. This work uses different statistical tools to identify the risk factor of nomophobia and machine learning techniques to propose a fresh way to measure and understand nomophobia. To create a predictive model for nomophobia, we gathered information from a broad sample (n = 357) of smartphone users and used a variety of machine learning methods. Using a questionnaire on 17 different factors and performing a statistically significant test (p<0.05) and ordinal logistic regression analysis on respondents age, level of education, CGPA, self-evaluation, per-day mobile phone usage, and use of media, we can recognize the most important features causative of nomophobia. The context of maximum phone usage is an important feature that highly affects nomophobia. About 201 respondents are at a moderate level. To develop a predictive model, decision tree (DT), random forest (RF), Gaussian Naïve Bayes (NB), and support vector machine (SVM) are utilized in this study for recognition of nomophobia addiction. Proposing an ensemble method to refine the predictive performance. From the analysis, we have found that the SVM feature selector with ensemble algorithm has classified the extent of smartphone addiction with a 57% accuracy rate. Our findings show that nomophobia tendencies can be accurately captured and predicted by machine learning approaches. The model distinguished between students who had symptoms of nomophobia and those who did not with remarkable accuracy. This study of machine learning-based methods presents a viable tool for diagnosing and treating nomophobia in students, eventually assisting in the creation of focused interventions and preventive measures.
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    The effect of bariatric surgery on the expression of gastrointestinal taste receptors: A systematic review
    Walmsley, R ; Chong, L ; Hii, MW ; Brown, RM ; Sumithran, P (SPRINGER, 2024-01-11)
    Gastrointestinal nutrient sensing via taste receptors may contribute to weight loss, metabolic improvements, and a reduced preference for sweet and fatty foods following bariatric surgery. This review aimed to investigate the effect of bariatric surgery on the expression of oral and post-oral gastrointestinal taste receptors and associations between taste receptor alterations and clinical outcomes of bariatric surgery. A systematic review was conducted to capture data from both human and animal studies on changes in the expression of taste receptors in oral or post-oral gastrointestinal tissue following any type of bariatric surgery. Databases searched included Medline, Embase, Emcare, APA PsychInfo, Cochrane Library, and CINAHL. Two human and 21 animal studies were included. Bariatric surgery alters the quantity of many sweet, umami, and fatty acid taste receptors in the gastrointestinal tract. Changes to the expression of sweet and amino acid receptors occur most often in intestinal segments surgically repositioned more proximally, such as the alimentary limb after gastric bypass. Conversely, changes to fatty acid receptors were observed more frequently in the colon than in the small intestine. Significant heterogeneity in the methodology of included studies limited conclusions regarding the direction of change in taste receptor expression induced by bariatric surgeries. Few studies have investigated associations between taste receptor expression and clinical outcomes of bariatric surgery. As such, future studies should look to investigate the relationship between bariatric surgery-induced changes to gut taste receptor expression and function and the impact of surgery on taste preferences, food palatability, and eating behaviour.Registration code in PROSPERO: CRD42022313992.
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    Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice
    Murphy, MA ; Schnall, RG ; Venter, DJ ; Barnett, L ; Bertoncello, I ; Thien, CBF ; Langdon, WY ; Bowtell, DDL (AMER SOC MICROBIOLOGY, 1998-08)
    The c-Cbl protein is tyrosine phosphorylated and forms complexes with a wide range of signalling partners in response to various growth factors. How c-Cbl interacts with proteins, such as Grb2, phosphatidylinositol 3-kinase, and phosphorylated receptors, is well understood, but its role in these complexes is unclear. Recently, the Caenorhabditis elegans Cbl homolog, Sli-1, was shown to act as a negative regulator of epidermal growth factor receptor signalling. This finding forced a reassessment of the role of Cbl proteins and highlighted the desirability of testing genetically whether c-Cbl acts as a negative regulator of mammalian signalling. Here we investigate the role of c-Cbl in development and homeostasis in mice by targeted disruption of the c-Cbl locus. c-Cbl-deficient mice were viable, fertile, and outwardly normal in appearance. Bone development and remodelling also appeared normal in c-Cbl mutants, despite a previously reported requirement for c-Cbl in osteoclast function. However, consistent with a high level of expression of c-Cbl in the hemopoietic compartment, c-Cbl-deficient mice displayed marked changes in their hemopoietic profiles, including altered T-cell receptor expression, lymphoid hyperplasia, and primary splenic extramedullary hemopoiesis. The mammary fat pads of mutant female mice also showed increased ductal density and branching compared to those of their wild-type littermates, indicating an unanticipated role for c-Cbl in regulating mammary growth. Collectively, the hyperplastic histological changes seen in c-Cbl mutant mice are indicative of a normal role for c-Cbl in negatively regulating signalling events that control cell growth. Consistent with this view, we observed greatly increased intracellular protein tyrosine phosphorylation in thymocytes following CD3epsilon cross-linking. In particular, phosphorylation of ZAP-70 kinase in thymocytes was uncoupled from a requirement for CD4-mediated Lck activation. This study provides the first biochemical characterization of any organism that is deficient in a member of this unique protein family. Our findings demonstrate critical roles for c-Cbl in hemopoiesis and in controlling cellular proliferation and signalling by the Syk/ZAP-70 family of protein kinases.
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    Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture
    Thomas, T ; Dixon, MP ; Kueh, AJ ; Voss, AK (AMER SOC MICROBIOLOGY, 2008-08)
    Acetylation of histone tails is a hallmark of transcriptionally active chromatin. Mof (males absent on the first; also called MYST1 or KAT8) is a member of the MYST family of histone acetyltransferases and was originally discovered as an essential component of the X chromosome dosage compensation system in Drosophila. In order to examine the role of Mof in mammals in vivo, we generated mice carrying a null mutation of the Mof gene. All Mof-deficient embryos fail to develop beyond the expanded blastocyst stage and die at implantation in vivo. Mof-deficient cell lines cannot be derived from Mof(-/-) embryos in vitro. Mof(-/-) embryos fail to acetylate histone 4 lysine 16 (H4K16) but have normal acetylation of other N-terminal histone lysine residues. Mof(-/-) cell nuclei exhibit abnormal chromatin aggregation preceding activation of caspase 3 and DNA fragmentation. We conclude that Mof is functionally nonredundant with the closely related MYST histone acetyltransferase Tip60. Our results show that Mof performs a different role in mammals from that in flies at the organism level, although the molecular function is conserved. We demonstrate that Mof is required specifically for the maintenance of H4K16 acetylation and normal chromatin architecture of all cells of early male and female embryos.
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    The yeast inositol polyphosphate 5-phosphatases Inp52p and Inp53p translocate to actin patches following hyperosmotic stress: Mechanism for regulating phosphatidylinositol 4,5-bisphosphate at plasma membrane invaginations
    Ooms, LM ; McColl, BK ; Wiradjaja, F ; Wijayaratnam, APW ; Gleeson, P ; Gething, MJ ; Sambrook, J ; Mitchell, CA (AMER SOC MICROBIOLOGY, 2000-12)
    The Saccharomyces cerevisiae inositol polyphosphate 5-phosphatases (Inp51p, Inp52p, and Inp53p) each contain an N-terminal Sac1 domain, followed by a 5-phosphatase domain and a C-terminal proline-rich domain. Disruption of any two of these 5-phosphatases results in abnormal vacuolar and plasma membrane morphology. We have cloned and characterized the Sac1-containing 5-phosphatases Inp52p and Inp53p. Purified recombinant Inp52p lacking the Sac1 domain hydrolyzed phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)] and PtdIns(3, 5)P(2). Inp52p and Inp53p were expressed in yeast as N-terminal fusion proteins with green fluorescent protein (GFP). In resting cells recombinant GFP-tagged 5-phosphatases were expressed diffusely throughout the cell but were excluded from the nucleus. Following hyperosmotic stress the GFP-tagged 5-phosphatases rapidly and transiently associated with actin patches, independent of actin, in both the mother and daughter cells of budding yeast as demonstrated by colocalization with rhodamine phalloidin. Both the Sac1 domain and proline-rich domains were able to independently mediate translocation of Inp52p to actin patches, following hyperosmotic stress, while the Inp53p proline-rich domain alone was sufficient for stress-mediated localization. Overexpression of Inp52p or Inp53p, but not catalytically inactive Inp52p, which lacked PtdIns(4,5)P(2) 5-phosphatase activity, resulted in a dramatic reduction in the repolarization time of actin patches following hyperosmotic stress. We propose that the osmotic-stress-induced translocation of Inp52p and Inp53p results in the localized regulation of PtdIns(3,5)P(2) and PtdIns(4,5)P(2) at actin patches and associated plasma membrane invaginations. This may provide a mechanism for regulating actin polymerization and cell growth as an acute adaptive response to hyperosmotic stress.
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    Impaired cardiac contractility response to hemodynamic stress in S100A1-deficient mice
    Du, XJ ; Cole, TJ ; Tenis, N ; Gao, XM ; Köntgen, F ; Kemp, BE ; Heierhorst, J (AMER SOC MICROBIOLOGY, 2002-04)
    Ca(2+) signaling plays a central role in cardiac contractility and adaptation to increased hemodynamic demand. We have generated mice with a targeted deletion of the S100A1 gene coding for the major cardiac isoform of the large multigenic S100 family of EF hand Ca(2+)-binding proteins. S100A1(-/-) mice have normal cardiac function under baseline conditions but have significantly reduced contraction rate and relaxation rate responses to beta-adrenergic stimulation that are associated with a reduced Ca(2+) sensitivity. In S100A1(-/-) mice, basal left-ventricular contractility deteriorated following 3-week pressure overload by thoracic aorta constriction despite a normal adaptive hypertrophy. Surprisingly, heterozygotes also had an impaired response to acute beta-adrenergic stimulation but maintained normal contractility in response to chronic pressure overload that coincided with S100A1 upregulation to wild-type levels. In contrast to other genetic models with impaired cardiac contractility, loss of S100A1 did not lead to cardiac hypertrophy or dilation in aged mice. The data demonstrate that high S100A1 protein levels are essential for the cardiac reserve and adaptation to acute and chronic hemodynamic stress in vivo.
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    The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
    Alexander, SPH ; Christopoulos, A ; Davenport, AP ; Kelly, E ; Mathie, AA ; Peters, JA ; Veale, EL ; Armstrong, JF ; Faccenda, E ; Harding, SD ; Davies, JA ; Abbracchio, MP ; Abraham, G ; Agoulnik, A ; Alexander, W ; Al-hosaini, K ; Baeck, M ; Baker, JG ; Barnes, NM ; Bathgate, R ; Beaulieu, J-M ; Beck-Sickinger, AG ; Behrens, M ; Bernstein, KE ; Bettler, B ; Birdsall, NJM ; Blaho, V ; Boulay, F ; Bousquet, C ; Braeuner-Osborne, H ; Burnstock, G ; Calo, G ; Castano, JP ; Catt, KJ ; Ceruti, S ; Chazot, P ; Chiang, N ; Chini, B ; Chun, J ; Cianciulli, A ; Civelli, O ; Clapp, LH ; Couture, R ; Cox, HM ; Csaba, Z ; Dahlgren, C ; Dent, G ; Douglas, SD ; Dournaud, P ; Eguchi, S ; Escher, E ; Filardo, EJ ; Fong, T ; Fumagalli, M ; Gainetdinov, RR ; Garelja, ML ; de Gasparo, M ; Gerard, C ; Gershengorn, M ; Gobeil, F ; Goodfriend, TL ; Goudet, C ; Graetz, L ; Gregory, KJ ; Gundlach, AL ; Hamann, J ; Hanson, J ; Hauger, RL ; Hay, DL ; Heinemann, A ; Herr, D ; Hollenberg, MD ; Holliday, ND ; Horiuchi, M ; Hoyer, D ; Hunyady, L ; Husain, A ; Ijzerman, AP ; Inagami, T ; Jacobson, KA ; Jensen, RT ; Jockers, R ; Jonnalagadda, D ; Karnik, S ; Kaupmann, K ; Kemp, J ; Kennedy, C ; Kihara, Y ; Kitazawa, T ; Kozielewicz, P ; Kreienkamp, H-J ; Kukkonen, JP ; Langenhan, T ; Larhammar, D ; Leach, K ; Lecca, D ; Lee, JD ; Leeman, SE ; Leprince, J ; Li, XX ; Lolait, SJ ; Lupp, A ; Macrae, R ; Maguire, J ; Malfacini, D ; Mazella, J ; Mcardle, CA ; Melmed, S ; Michel, MC ; Miller, LJ ; Mitolo, V ; Mouillac, B ; Mueller, CE ; Murphy, PM ; Nahon, J-L ; Ngo, T ; Norel, X ; Nyimanu, D ; O'Carroll, A-M ; Offermanns, S ; Panaro, MA ; Parmentier, M ; Pertwee, RG ; Pin, J-P ; Prossnitz, ER ; Quinn, M ; Ramachandran, R ; Ray, M ; Reinscheid, RK ; Rondard, P ; Rovati, GE ; Ruzza, C ; Sanger, GJ ; Schoeneberg, T ; Schulte, G ; Schulz, S ; Segaloff, DL ; Serhan, CN ; Singh, KD ; Smith, CM ; Stoddart, LA ; Sugimoto, Y ; Summers, R ; Tan, VP ; Thal, D ; Thomas, WW ; Timmermans, PBMWM ; Tirupula, K ; Toll, L ; Tulipano, G ; Unal, H ; Unger, T ; Valant, C ; Vanderheyden, P ; Vaudry, D ; Vaudry, H ; Vilardaga, J-P ; Walker, CS ; Wang, JM ; Ward, DT ; Wester, H-J ; Willars, GB ; Williams, TL ; Woodruff, TM ; Yao, C ; Ye, RD (WILEY, 2023-10)
    The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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    Integrated Transcriptomic and Metabolomic Mapping Reveals the Mechanism of Action of Ceftazidime/Avibactam against Pan-Drug-Resistant Klebsiella pneumoniae
    Hussein, M ; Allobawi, R ; Zhao, J ; Yu, H ; Neville, SL ; Wilksch, J ; Wong, LJM ; Baker, M ; McDevitt, CA ; Rao, GG ; Li, J ; Velkov, T (AMER CHEMICAL SOC, 2023-10-25)
    Here, we employed an integrated metabolomics and transcriptomics approach to investigate the molecular mechanism(s) of action of ceftazidime/avibactam against a pan-drug-resistant K. pneumoniae clinical isolate from a patient with urinary tract infection. Ceftazidime/avibactam induced time-dependent perturbations in the metabolome and transcriptome of the bacterium, mainly at 6 h, with minimal effects at 1 and 3 h. Metabolomics analysis revealed a notable reduction in essential lipids involved in outer membrane glycerolipid biogenesis. This disruption effect extended to peptidoglycan and lipopolysaccharide biosynthetic pathways, including lipid A and O-antigen assembly. Importantly, ceftazidime/avibactam not only affected the final steps of peptidoglycan biosynthesis in the periplasm, a common mechanism of ceftazidime action, but also influenced the synthesis of lipid-linked intermediates and early stages of cytoplasmic peptidoglycan synthesis. Furthermore, ceftazidime/avibactam substantially inhibited central carbon metabolism (e.g., the pentose phosphate pathway and tricarboxylic acid cycle). Consistently, the dysregulation of genes governing these metabolic pathways aligned with the metabolomics findings. Certain metabolomics and transcriptomics signatures associated with ceftazidime resistance were also perturbed. Consistent with the primary target of antibiotic activity, biochemical assays also confirmed the direct impact of ceftazidime/avibactam on peptidoglycan production. This study explored the intricate interactions of ceftazidime and avibactam within bacterial cells, including their impact on cell envelope biogenesis and central carbon metabolism. Our findings revealed the complexities of how ceftazidime/avibactam operates, such as hindering peptidoglycan formation in different cellular compartments. In summary, this study confirms the existing hypotheses about the antibacterial and resistance mechanisms of ceftazidime/avibactam while uncovering novel insights, including its impact on lipopolysaccharide formation.
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    Selective transduction and photoinhibition of pre-Bötzinger complex neurons that project to the facial nucleus in rats affects nasofacial activity
    Melo, MR ; Wykes, AD ; Connelly, AA ; Bassi, JK ; Cheung, SD ; Mcdougall, SJ ; Menuet, C ; Bathgate, RAD ; Allen, AM (eLIFE SCIENCES PUBL LTD, 2023-09-29)
    The pre-Bötzinger complex (preBötC), a key primary generator of the inspiratory breathing rhythm, contains neurons that project directly to facial nucleus (7n) motoneurons to coordinate orofacial and nasofacial activity. To further understand the identity of 7n-projecting preBötC neurons, we used a combination of optogenetic viral transgenic approaches to demonstrate that selective photoinhibition of these neurons affects mystacial pad activity, with minimal effects on breathing. These effects are altered by the type of anesthetic employed and also between anesthetized and conscious states. The population of 7n-projecting preBötC neurons we transduced consisted of both excitatory and inhibitory neurons that also send collaterals to multiple brainstem nuclei involved with the regulation of autonomic activity. We show that modulation of subgroups of preBötC neurons, based on their axonal projections, is a useful strategy to improve our understanding of the mechanisms that coordinate and integrate breathing with different motor and physiological behaviors. This is of fundamental importance, given that abnormal respiratory modulation of autonomic activity and orofacial behaviors have been associated with the development and progression of diseases.
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    Quantitative Spatial Analysis of Neuroligin-3 mRNA Expression in the Enteric Nervous System Reveals a Potential Role in Neuronal-Glial Synapses and Reduced Expression in Nlgn3R451C Mice
    Herath, M ; Cho, E ; Marklund, U ; Franks, AE ; Bornstein, JC ; Hill-Yardin, EL (MDPI, 2023-07)
    Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 mRNA expression in cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells in both WT and Nlgn3R451C mutant mice. We measured Nlgn3 mRNA neuronal and glial expression via quantitative three-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single-cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for neuroligin-3 in mediating enteric neuron-glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not in VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin, nNOS-labelled neurons and S100 β -labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD.