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Odd and even homologues of some n-alkane-based systems are known to exhibit notably different trends in solid-state properties; a well-known illustration is the zigzag plot of their melting point versus chain length. Odd–even effects in the solid state often arise from intermolecular interactions that involve fully extended molecules. These effects have also been observed in less condensed phases, such as self-assembled monolayers; however, the origins of these effects in such systems can be difficult to determine. Here we combined NMR and computational analysis to show that all-syn contiguously methyl-substituted hydrocarbons, with chain lengths from C6 to C11, exhibit a dramatic odd–even effect in helical propensity. The even- and odd-numbered hydrocarbons populate regular and less-controlled helical conformations, respectively. This knowledge will guide the design of helical hydrocarbons as rigid scaffolds or as hydrophobic components in soft materials.Even- and odd-numbered homologues of some hydrocarbons are known to exhibit different trends in solid-state properties. Now, experimental and computational investigations on a homologous series of a stereochemically well-defined hydrocarbon have revealed an odd–even effect in conformational behaviour in solution that is caused by a single gauche interaction.

Leucine-rich-repeat kinase 2 (LRRK2), a potential therapeutic target for the treatment of Parkinson’s disease (PD), is highly expressed in monocytes and macrophages and may play a role in the regulation of inflammatory pathways. To determine how LRRK2 protein levels and/or its activity modulate inflammatory cytokine/chemokine levels in human immune cells, isogenic human induced pluripotent stem cells (iPSC) with the LRRK2-activating G2019S mutation, wild-type LRRK2, and iPSC deficient in LRRK2 were differentiated to monocytes and macrophages and stimulated with inflammatory toll-like receptor (TLR) agonists in the presence and absence of LRRK2 kinase inhibitors. The effect of LRRK2 inhibitors and the effect of increasing LRRK2 levels with interferon gamma on TLR-stimulated cytokines were also assessed in primary peripheral blood-derived monocytes. Monocytes and macrophages with the LRRK2 G2019S mutation had significantly higher levels of cytokines and chemokines in tissue culture media following stimulation with TLR agonists compared to isogenic controls. Knockout of LRRK2 impaired phagocytosis but did not significantly affect TLR-mediated cytokine levels. Interferon gamma significantly increased the levels of LRRK2 and phosphorylation of its downstream Rab10 substrate, and potentiated TLR-mediated cytokine levels. LRRK2 kinase inhibitors did not have a major effect on TLR-stimulated cytokine levels. Results suggest that the LRRK2 G2019S mutation may potentiate inflammation following activation of TLRs. However, this was not dependent on LRRK2 kinase activity. Indeed, LRRK2 kinase inhibitors had little effect on TLR-mediated inflammation under the conditions employed in this study.

Heterozygous mutations in GBA1, which encodes the lysosomal hydrolase glucocerebrosidase (GCase) are a common risk factor for the neurodegenerative movement disorder Parkinson's disease (PD). Consequently, therapeutic options targeting the GCase enzyme are in development. An important aspect of this development is determining the effect of potential modifying compounds on GCase activity, which can be complicated by different methods and substrate probes that are commonly employed for this purpose. In this study we have employed the GCase substrate probe 5-(pentafluorobenzoylamino)fluorescein di--D-glucopyranoside (PFB-FDGlu) in combination with live cell imaging to measure GCase activity in situ, in the lysosome. The live cell assay was validated using the GCase inhibitor conduritol-B-epoxide and with GBA1 knockout neural cells, and then used to assess GCase activity in iPSC differentiated to neural stem cells and neurons that were obtained from idiopathic PD patients and PD patients with the LRRK2 G2019S mutation and GBA N370S mutation, as well as controls (n=4 per group). Heterogeneity in GCase activity was observed across all groups, however, a significant inverse correlation between GCase activity and levels of alpha-synuclein protein was observed. The live cell imaging assay for GCase activity could be useful for further understanding the role of GCase in PD, as well as for screening of potential modifying compounds in differentiated human cell models.

There are three main crystal forms of TiO2 in nature: rutile, anatase and brookite. In this paper, the GGA-PBE method of density functional theory was used to study the H2O molecules adsorbed (110) surface of these three kinds of titanium dioxide. H2O molecules tend to polymerize into dimmers due to the increase of H-O bond length on the surface of rutile than anatase. The lowest adsorption energies of H2O molecules adsorbed on these three structures are −5.479, −0.085 and 4.278 eV, respectively. H2O molecule is most likely to be adsorbed on the (110) surface of anatase. As for H2O molecules adsorbed in the (110) surface of these structures, rutile exhibits the smallest changes of both host TiO2 and H2O molecules.

Low-molecular-weight organic acids (LMWOAs) that have a wide variety of biological activities can affect the mobilization of heavy metals in soil. In this study, the effects of three kinds of LMWOAs on the remobilization of Cd, Cr, Pb, and As were investigated. The results showed that the concentrations of Cr, Pb, and As reached the maximum values at 7 d, and then decreased at 58 d, indicating that the LMWOAs induced the release of these elements from soil. The ability of LMWOAs to affect the mobility of Cr and As followed the order citric acid (1.32 and 2.51mg/L) > malic acid > oxalic acid, while the order for Pb was malic acid (4.49mg/L) > citric acid > oxalic acid. In addition, the sequential extraction indicated that the LMWOAs advanced the reactivation of Pb, Cd, and As, but led to the immobilization of Cr after a long-term reaction.

Experimental and computed nuclear magnetic resonance data and an iterative synthetic strategy have revealed the correct structures of the baulamycins, potentially important antimicrobial compounds, allowing them to be chemically synthesized. Pinning down the structure of a flexible antibiotic Molecules are often drawn as though they are static chemical structures, but of course in reality they adopt a number of different conformations. The structures of flexible compounds are especially difficult to pin down by conventional means as they can appear as a mixture of conformational isomers. Baulamycins, polyketide antibiotics with long, flexible carbon chains, are one such example and, although they have been the target of synthetic efforts, the true structure of the natural product is unclear. Here, Varinder Aggarwal and colleagues elucidate the structure of the baulamycins by a method based on the correlation of experimental and computed nuclear magnetic resonance data and an iterative synthetic strategy to the target compounds. This approach allowed the unambiguous and correct assignment of the stereocentres and the structure of these natural products and could be applied to other such complex, flexible systems. Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines 1 . Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule—including assigning its relative and absolute configurations—is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging 2 . The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J -based configurational analysis 3 , 4 , but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory—combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared—enabled us rapidly to pinpoint and synthesize the correct structures.

There are three main crystal forms of TiO 2 in nature: rutile, anatase and brookite. In this paper, the GGA-PBE method of density functional theory was used to study the H 2 O molecules adsorbed (110) surface of these three kinds of titanium dioxide. H 2 O molecules tend to polymerize into dimmers due to the increase of H-O bond length on the surface of rutile than anatase. The lowest adsorption energies of H 2 O molecules adsorbed on these three structures are −5.479, −0.085 and 4.278 eV, respectively. H 2 O molecule is most likely to be adsorbed on the (110) surface of anatase. As for H 2 O molecules adsorbed in the (110) surface of these structures, rutile exhibits the smallest changes of both host TiO 2 and H 2 O molecules.

This thesis reports the application of computational modelling, NMR spectroscopy and stereospecific iterative homologation of boronic esters to the three-dimensional structural elucidation of flexible organic small molecules, and the design and synthesis of flexible molecules with tailored conformations. Firstly, the configuration of a recently isolated polyketide baulamycin A, which exhibits potent antibacterial activity, was reassigned using a combination of Density Functional theory (DFT) calculations, NMR spectroscopy and synthesis. In this work, DFT calculations were employed to predict the complex dynamic conformations of eight possible diastereomers of baulamycins and to compute the ensemble-averaged chemical shifts, 1H-1H scalar coupling constants and 1H-1H distances. Comparison between the computed NMR parameters of each diastereomer with the experimentally determined values eliminated 112 out of the possible 128 diastereomeric candidates. Finally, synthesis allowed the relative and absolute configuration of baulamycin A to be positively identified. Secondly, inspired by the conformational control exerted by quaternary centres, a range of conformationally defined unnatural amino esters were designed with the aid of computational modelling. Two of the amino esters were synthesised and their solution state conformations were elucidated by a combination of DFT calculations and quantitative analysis of 1H-1H and 1H-13C scalar coupling constants. Their side chains are shown to take on defined orientations (syn-periplanar or turn a 120° corner) with controllable distances and could find application in areas such as drug design. Finally, factors controlling the helical screw-sense of hydrocarbons with all-syn contiguous methyl substituents was investigated. The solution-state conformational behaviour of hydrocarbons with different numbers of methyl substituents (from six to 11) was studied using a combination of DFT calculations and quantitative analysis of 1H-1H scalar coupling constants and 1H-1H distances. It was discovered that only hydrocarbons with even numbers of methyl substituents adopt regular helical conformation, whereas hydrocarbons with odd number of methyl substituents do not have a strong preference for a particular conformation. The preference of screw sense (if any) in each case was rationalised by the minimisation of gauche interactions.

Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue (1). However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand (2). Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. The most prevalent KRAS variants which drive tumour growth in a major share of cancer patients can be targeted with a single small molecule degrader.

Laryngeal disease classification is a relatively hard task in medical image processing resulting from its complex structures and varying viewpoints in data collection. Some existing methods try to tackle this task via the convolutional neural network, but they more or less ignore the intrinsic difficulty differences among different input samples and suffer from high training complexity. In order to better resolve these problems, an end-to-end Hierarchical Dynamic Convolutional Network (HDCNet) is proposed, which can dynamically process the input samples based on their difficulty. For the easy-classified samples, the HDCNet processes them with a smaller resolution and a relatively small network, while the difficult samples are passed to a large network with a larger resolution for more accurate classification results. Furthermore, a Feature Reuse Module (FRM) is designed to transfer the features learned by the small network to the corresponding block in the deep network to enhance the overall performance of some rather complicated samples. To validate the effectiveness of the proposed HDCNet, comprehensive experiments are conducted on the public available laryngeal disease classification dataset and HDCNet provides superior performances compared with other current state-of-the-art methods.