The extension of commercial life and the reduction of postharvest losses of perishable fruits is mainly based on storage at low temperatures alone or in combination with modified atmospheres (MAs) ...and controlled atmospheres (CAs), directed primarily at reducing their overall metabolism thus delaying ripening and senescence. Fruits react to postharvest conditions with desirable changes if appropriate protocols are applied, but otherwise can develop negative and unacceptable traits due to the onset of physiological disorders. Extended cold storage periods and/or inappropriate temperatures can result in development of chilling injuries (CIs). The etiology, incidence, and severity of such symptoms vary even within cultivars of the same species, indicating the genotype significance. Carbohydrates and amino acids have protective/regulating roles in CI development. MA/CA storage protocols involve storage under hypoxic conditions and high carbon dioxide concentrations that can maximize quality over extended storage periods but are also affected by the cultivar, exposure time, and storage temperatures. Pyruvate metabolism is highly reactive to changes in oxygen concentration and is greatly affected by the shift from aerobic to anaerobic metabolism. Ethylene-induced changes in fruits can also have deleterious effects under cold storage and MA/CA conditions, affecting susceptibility to chilling and carbon dioxide injuries. The availability of the inhibitor of ethylene perception 1-methylcyclopropene (1-MCP) has not only resulted in development of a new technology but has also been used to increase understanding of the role of ethylene in ripening of both non-climacteric and climacteric fruits. Temperature, MA/CA, and 1-MCP alter fruit physiology and biochemistry, resulting in compositional changes in carbon- and nitrogen-related metabolisms and compounds. Successful application of these storage technologies to fruits must consider their effects on the metabolism of carbohydrates, organic acids, amino acids and lipids.
Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess ...distinct charge distribution, lipophilicity, conformation and metabolic stability
. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group
. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another
. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre
. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.
Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic ...inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states.
Polarons in metal oxides are important in processes such as catalysis, high temperature superconductivity, and dielectric breakdown in nanoscale electronics. Here, we study the behavior of electron ...small polarons associated with oxygen vacancies at rutile TiO_{2}(110), using a combination of low temperature scanning tunneling microscopy (STM), density functional theory, and classical molecular dynamics calculations. We find that the electrons are symmetrically distributed around isolated vacancies at 78 K, but as the temperature is reduced, their distributions become increasingly asymmetric, confirming their polaronic nature. By manipulating isolated vacancies with the STM tip, we show that particular configurations of polarons are preferred for given locations of the vacancies, which we ascribe to small residual electric fields in the surface. We also form a series of vacancy complexes and manipulate the Ti ions surrounding them, both of which change the associated electronic distributions. Thus, we demonstrate that the configurations of polarons can be engineered, paving the way for the construction of conductive pathways relevant to resistive switching devices.
X-ray scattering is uniquely suited to the study of disordered systems and thus has the potential to provide insight into dynamic processes where diffraction methods fail. In particular, while X-ray ...crystallography has been a staple of structural biology for more than half a century and will continue to remain so, a major limitation of this technique has been the lack of dynamic information. Solution X-ray scattering has become an invaluable tool in structural and mechanistic studies of biological macromolecules where large conformational changes are involved. Such systems include allosteric enzymes that play key roles in directing metabolic fluxes of biochemical pathways, as well as large, assembly-line type enzymes that synthesize secondary metabolites with pharmaceutical applications. Furthermore, crystallography has the potential to provide information on protein dynamics via the diffuse scattering patterns that are overlaid with Bragg diffraction. Historically, these patterns have been very difficult to interpret, but recent advances in X-ray detection have led to a renewed interest in diffuse scattering analysis as a way to probe correlated motions. Here, we will review X-ray scattering theory and highlight recent advances in scattering-based investigations of protein solutions and crystals, with a particular focus on complex enzymes.
Drug‐induced liver injury (DILI) is considered to be a diagnosis of exclusion. Liver biopsy may contribute to diagnostic accuracy, but the histological features of DILI and their relationship to ...biochemical parameters and outcomes are not well defined. We have classified the pathological pattern of liver injury and systematically evaluated histological changes in liver biopsies obtained from 249 patients with suspected DILI enrolled in the prospective, observational study conducted by the Drug Induced Liver Injury Network. Histological features were analyzed for their frequency within different clinical phenotypes of liver injury and to identify associations between clinical and laboratory findings and histological features. The most common histological patterns were acute (21%) and chronic hepatitis (14%), acute (9%) and chronic cholestasis (10%), and cholestatic hepatitis (29%). Liver histology from 128 patients presenting with hepatocellular injury had more severe inflammation, necrosis, and apoptosis and more frequently demonstrated lobular disarray, rosette formation, and hemorrhage than those with cholestasis. Conversely, histology of the 73 patients with cholestatic injury more often demonstrated bile plugs and duct paucity. Severe or fatal hepatic injury in 46 patients was associated with higher degrees of necrosis, fibrosis stage, microvesicular steatosis, and ductular reaction among other findings, whereas eosinophils and granulomas were found more often in those with milder injury. Conclusion: We describe an approach for evaluating liver histology in DILI and demonstrate numerous associations between pathological findings and clinical presentations that may serve as a foundation for future studies correlating DILI pathology with its causality and outcome. (Hepatology 2014;59:661–670)
Drug-induced liver injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market; this is partially due to the inability to identify patients who ...are at risk
. In this study, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies
. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over ten different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed 'polygenicity-in-a-dish' strategy might potentially inform designs of safer, more efficient and robust clinical trials.
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