Studies towards the synthesis of the core of Sarains A, B, & C

Sarains A-C are alkaloids isolated from the Mediterranean sponge Reniera sarai, which possess moderate antibacterial, insecticidal and antitumour properties. These alkaloids are popular targets for total synthesis, thanks to their rather unusual and challenging structure, which consists of a central diazatricyclic cage attached to two peripheral macrocycles. Arguably the most challenging aspect of their synthesis is that of the tricyclic core, and our approach involves a novel rearrangement of a simpler bicyclic aminal system. This thesis describes various attempts to synthesise cis-fused octahydropyrrolo[2,3-b]pyrrole ring systems that bear an endo acetaldehyde-derived substituent in the 3-position. The research into the synthesis of this ring system began with enantioselective approaches, utilising asymmetric Diels-Alder reactions to establish the stereochemistry required for subsequent transformations into the bicyclic aminal. Progress from these reactions was troublesome. In racemic approaches, the use of a Michael reaction was unsuccessful, but successful installation of the required stereochemistry was achieved by use of a thio-Claisen rearrangement. Using this method, the aforementioned functionalised acetaldehyde was produced in good yield in ten steps from simple starting materials. This provided a branching point for the exploration of four different, but related routes to the sarain core involving the generation of diazoketones, a bromoketone and hydroxy-aldehydes. Substrates to test our proposed rearrangement reaction were synthesised, but transformations into the sarain core proved unfruitful. However, a different tricyclic compound has been produced from a hydroxy-aldehyde approach. In a separate investigation instigated by a result from previous research into synthesis of the sarain core, it was found that treatment of tertiary formamides with a silylated diazoester in the presence of rhodium acetate leads to formation of 3-amino-2- silyloxyacrylates in good yields. The scope and limitations of this novel reaction were investigated

Development, Characterization and Cross-species Transferability of Expressed Sequence Tag-simple Sequence Repeat (EST-SSR) Markers Derived from Kelampayan Tree Transcriptome

Neolamarckia cadamba (or locally known as kelampayan) is an important fast growing plantation tree species that confers various advantages for timber industry as a strategy for reducing the logging pressure on natural forests for wood production to an acceptable level. Hence, attempts were made to develop a set of EST-SSR markers for kelampayan trees based on the EST sequences of kelampayan (NcdbEST) and further assessed the polymorphisms and transferability of the markers to other species. In this study, 155 (2.34%) out of 6,622 EST sequences which contain 232 SSRs were mined from NcdbEST. Of these, 97 ESTs were assigned with putative functions and gene ontology terms. Eighteen EST-SSR markers were developed according to the criteria, and further characterized and validated by using 50 individuals of kelampayan from two selected mother trees. The markers exhibited a considerable high level of polymorphism in kelampayan trees with an average of 4.17 and 4.11 alleles per locus, and PIC values of 0.465 and 0.537, respectively for mother trees T1 and T2. Parentage assignment analysis suggests a high probability for kelampayan trees to be predominantly outcrossed. The transferability rate was ranging from 16.7-94.4% among the five cross-genera species of kelampayan. The present study is the first report of the development of EST-SSR markers in kelampayan. These markers will be valuable genomic resources that could pave the way for exploiting the genotype data for comparative genome mapping, association genetics, population genetics studies and molecular breeding of kelampayan and other indigenous tropical tree species in future

Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2

Influenza A virus’s (IAV’s) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV’s genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem–loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA_WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term ‘programmable antivirals’, with implications for antiviral prophylaxis and post-exposure therapy

Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-ls) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-l1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes.Ee Shan Pang, Ghazal Daraj, Katherine R. Balka, Dominic De Nardo, Christophe Macri, Hubertus Hochrein, Kelly-Anne Masterman, Peck S. Tan, Angus Shoppee, Zoe Magill, Nazneen Jahan, Mariam Bafit, Yifan Zhan, Benjamin T. Kile, Kate E. Lawlor, Kristen J. Radford, Mark D. Wright, and Meredith O, Keeff

Association of maternal Vitamin D status with glucose tolerance and caesarean section in a multi-ethnic Asian cohort: the growing up in Singapore towards healthy outcomes study

10.1371/journal.pone.0142239PLoS ONE10111-16GUSTO (Growing up towards Healthy Outcomes

Multidimensional quantum solitons with nondegenerate parametric interactions: Photonic and Bose-Einstein condensate environments

We consider the quantum theory of three fields interacting via parametric and repulsive quartic couplings. This can be applied to treat photonic chi((2)) and chi((3)) interactions, and interactions in atomic Bose-Einstein condensates or quantum Fermi gases, describing coherent molecule formation together with a-wave scattering. The simplest two-particle quantum solitons or bound-state solutions of the idealized Hamiltonian, without a momentum cutoff, are obtained exactly. They have a pointlike structure in two and three dimensions-even though the corresponding classical theory is nonsingular. We show that the solutions can be regularized with a momentum cutoff. The parametric quantum solitons have much more realistic length scales and binding energies than chi((3)) quantum solitons, and the resulting effects could potentially be experimentally tested in highly nonlinear optical parametric media or interacting matter-wave systems. N-particle quantum solitons and the ground state energy are analyzed using a variational approach. Applications to atomic/molecular Bose-Einstein condensates (BEC's) are given, where we predict the possibility of forming coupled BEC solitons in three space dimensions, and analyze superchemistry dynamics

Search for heavy resonances decaying into a Z or W boson and a Higgs boson in final states with leptons and b-jets in 139 fb−1 of pp collisions at s√ = 13 TeV with the ATLAS detector

This article presents a search for new resonances decaying into a Z or W boson and a 125 GeV Higgs boson h, and it targets the νν¯¯¯bb¯¯, ℓ+ℓ−bb¯¯, or ℓ±νbb¯¯ final states, where ℓ = e or μ, in proton-proton collisions at s√ = 13 TeV. The data used correspond to a total integrated luminosity of 139 fb−1 collected by the ATLAS detector during Run 2 of the LHC at CERN. The search is conducted by examining the reconstructed invariant or transverse mass distributions of Zh or Wh candidates for evidence of a localised excess in the mass range from 220 GeV to 5 TeV. No significant excess is observed and 95% confidence-level upper limits between 1.3 pb and 0.3 fb are placed on the production cross section times branching fraction of neutral and charged spin-1 resonances and CP-odd scalar bosons. These limits are converted into constraints on the parameter space of the Heavy Vector Triplet model and the two-Higgs-doublet model

The ATLAS trigger system for LHC Run 3 and trigger performance in 2022

The ATLAS trigger system is a crucial component of the ATLAS experiment at the LHC. It is responsible for selecting events in line with the ATLAS physics programme. This paper presents an overview of the changes to the trigger and data acquisition system during the second long shutdown of the LHC, and shows the performance of the trigger system and its components in the proton-proton collisions during the 2022 commissioning period as well as its expected performance in proton-proton and heavy-ion collisions for the remainder of the third LHC data-taking period (2022–2025)

Search for the Zγ decay mode of new high-mass resonances in pp collisions at √s = 13 TeV with the ATLAS detector

This letter presents a search for narrow, high-mass resonances in the Zγ final state with the Z boson decaying into a pair of electrons or muons. The √s = 13 TeV pp collision data were recorded by the ATLAS detector at the CERN Large Hadron Collider and have an integrated luminosity of 140 fb−1. The data are found to be in agreement with the Standard Model background expectation. Upper limits are set on the resonance production cross section times the decay branching ratio into Zγ. For spin-0 resonances produced via gluon–gluon fusion, the observed limits at 95% confidence level vary between 65.5 fb and 0.6 fb, while for spin-2 resonances produced via gluon–gluon fusion (or quark–antiquark initial states) limits vary between 77.4 (76.1) fb and 0.6 (0.5) fb, for the mass range from 220 GeV to 3400 GeV