Sphingosine kinase enzymes (SK1 and SK2) catalyse the conversion of sphingosine into sphingosine 1-phosphate and play a key role in lipid signaling and cellular responses. Mapping of isoform amino acid sequence differences for SK2 onto the recently available crystal structures of SK1 suggests that subtle structural differences exist in the foot of the lipid-binding 'J-channel' in SK2, the structure of which has yet to be defined by structural biology techniques. We have probed these isoform differences with a ligand series derived from the potent SK1-selective inhibitor, PF-543. Here we show how it is possible, even with relatively conservative changes in compound structure, to systematically tune the activity profile of a ligand from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2 inhibition, to reversed 100-fold SK2 selectivity, with retention of nanomolar potency. -phosphate (S1P) is a key signalling lipid derived from sphingosine (Sph) by the action of sphingosine kinases (SK1 and SK2). S1P is transported to the extracellular environment, where it functions as a ligand for a family of five S1P-specific G protein coupled receptors (S1P 1-5 ), but it also acts on specific intracellular target proteins, such as histone deacetylases 1/2 (HDAC1/2). 1, 2 Irreversible cleavage of S1P is catalysed by S1P lyase, producing (E)-2hexadecenal and phosphoethanolamine, 3 but S1P is also reversibly dephosphorylated by S1P phosphatase to regenerate Sph, 4-6 levels of which are additionally influenced by flux through the ceramide (Cer) synthesis pathway. 7 The effects of S1P on cell function favour proliferation, migration, differentiation and survival and are generally opposed by Cer, which induces apoptosis, senescence and growth arrest. 8,9 As a consequence the concept of the 'sphingolipid rheostat' was proposed, 10,11 in which the inter-conversion of Cer via Sph to S1P controls cellular fate (recently reviewed 12,13 ). Altered S1P signalling has been associated with numerous pathophysiologies, including cancer, cardiovascular disease, neurodegenerative conditions, diabetes and inflammatory disease. 14 The possibility of manipulating the sphingolipid rheostat for therapeutic purposes has therefore provided a rationale for exploring the development of SK inhibitors and their potential to reduce S1P formation and signalling and to raise pro-apoptotic Cer levels.The SK1 and SK2 enzymes are encoded by distinct genes and differ in their subcellular localisation, biochemical properties and functions; there are three N-terminal variants of SK1 and two N-terminal variants of SK2. 15,16 A number of classes of SK inhibitors have emerged in the last two decades, including the recent discovery of an ATP-competitive SK inhibitor chemotype that decreases cellular S1P levels, elevates Sph/Cer, induces apoptosis, and that inhibits cell proliferation and colony formation. 17 Most work to date, however, has focused on the development Sph-competitive inhibitors. This includes the development of inhibitors selective for SK1 t...

BackgroundSeasonal influenza vaccine can reduce the risk of influenza-associated hospitalizations and deaths among children. Given that parents are the primary decision makers, this study examined the parental attitude toward childhood influenza vaccine and identified determinants of vaccine hesitancy (VH) in the Eastern Mediterranean region (EMR).MethodsA cross-sectional study was conducted using an anonymous online survey in 14 EMR countries. Parents of children aged 6 months to 18 years were included. The Parent Attitude about Childhood Vaccines (PACV) was used to assess VH. Chi square test and independent t-test were used to test for association of qualitative and quantitative variables, respectively. A structural equations model (SEM) was used to identify direct and indirect determinants of parental VH.ResultsAlmost half of the parents were hesitant about vaccinating their children against influenza (50.8%). Parental VH was significantly higher among older mothers (37.06 ± 8.8 years, p = 0.006), rural residents (53.6%, p < 0.001), high-income countries residents (50.6%, p < 0.001), and mothers with higher educational levels (52.1%, p < 0.001). Parents of school-aged children (5–9 years) (55.6%, p < 0.001), children free from any comorbidities (52.5%, p < 0.001), children who did not receive routine vaccination at all (51.5%, p = 0.03), children who were not vaccinated against COVID-19 (54.3%, p < 0.001), in addition to parents who were not vaccinated against influenza (57.1%, p < 0.001) were significantly associated with increased likelihood of VH. Parents who were depending on healthcare provider as a source of information regarding vaccines were less likely to report VH (47.9%, p < 0.001), meanwhile those who used social media as their source of health information showed a significantly higher VH (57.2%, p < 0.001). The SEM suggested that mother’s age, residence, country income level, child gender, total number of children and source of information regarding vaccines had a direct effect on VH. Meanwhile, parents vaccinated against influenza, children completely or partially vaccinated with routine vaccines and children vaccinated against Coronavirus disease 2019 (COVID-19) had an indirect effect on VH.ConclusionA high proportion of included parents were hesitant to vaccinate their children against seasonal influenza. This attitude is due to many modifiable and non-modifiable factors that can be targeted to improve vaccination coverage.

Compounds with more than one bioactive motif become of great interest. In this regard, a new tridentate 1,2-unsymmetrical ligand consists of flexible and rigid bioactive arms spaced by benzene ring in an ortho position designed to form a bifunctional molecule. The 2-((3-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile (PPMB) synthesized under phase transfer reaction and characterized using 1H-NMR and mass spectroscopy and studied as potent kinase inhibitors. Theoretically, the molecule structure was investigated at the B3LYP/6-311++G(d,p) level of theory in the gas phase and revealed that all bond lengths and bond angles within the accepted limit. The frontier molecular orbitals (FMO) energies (HOMO and LUMO), energy gap, dipole moment, chemical softness and chemical hardness were calculated. Pharmacologically, the ligand activity was investigated in silico using SWISS ADME. Furthermore, the compound was docked into the transforming growth factor (TGF) beta type I receptor kinase active site to evaluate the ability of ligand as a kinase inhibitor. Keywords: DFT, pyrazolyl-pyridine, physiochemical, properties molecular docking, bioactive molecules, unsymmetrical ligands