Gold(I)-catalysed one-pot synthesis of chromans using allylic alcohols and phenols

A gold(I)-catalysed reaction of allylic alcohols and phenols produces chromans regioselectively via a one-pot Friedel–Crafts allylation/intramolecular hydroalkoxylation sequence. The reaction is mild, practical and tolerant of a wide variety of substituents on the phenol

Design of ternary signals for MIMO identification in the presence of noise and nonlinear distortion

A new approach to designing sets of ternary periodic signals with different periods for multi-input multi-output system identification is described. The signals are pseudo-random signals with uniform nonzero harmonics, generated from Galois field GF(q), where q is a prime or a power of a prime. The signals are designed to be uncorrelated, so that effects of different inputs can be easily decoupled. However, correlated harmonics can be included if necessary, for applications in the identification of ill-conditioned processes. A design table is given for q les 31. An example is presented for the design of five uncorrelated signals with a common period N = 168 . Three of these signals are applied to identify the transfer function matrix as well as the singular values of a simulated distillation column. Results obtained are compared with those achieved using two alternative methods

Gold(I)-Catalysed Direct Thioetherifications Using Allylic Alcohols: an Experimental and Computational Study

A gold(I)-catalysed direct thioetherification reaction between allylic alcohols and thiols is presented. The reaction is generally highly regioselective (S(N)2′). This dehydrative allylation procedure is very mild and atom economical, producing only water as the by-product and avoiding any unnecessary waste/steps associated with installing a leaving or activating group on the substrate. Computational studies are presented to gain insight into the mechanism of the reaction. Calculations indicate that the regioselectivity is under equilibrium control and is ultimately dictated by the thermodynamic stability of the products

Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications of Unactivated Alcohols:Experimental and Computational Study

Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, γ-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive π-bound Au–allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.British Society for Antimicrobial Chemotherapy BSAC-2018-0095NC3Rs NC/V001582/1Biological Sciences Research Council BB/V007823/1Academy of Medical Sciences SBF006\104

Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort

BACKGROUND: The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves. METHODS: The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. RESULTS: There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. CONCLUSION: There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present

Review of the mathematical foundations of data fusion techniques in surface metrology

The recent proliferation of engineered surfaces, including freeform and structured surfaces, is challenging current metrology techniques. Measurement using multiple sensors has been proposed to achieve enhanced benefits, mainly in terms of spatial frequency bandwidth, which a single sensor cannot provide. When using data from different sensors, a process of data fusion is required and there is much active research in this area. In this paper, current data fusion methods and applications are reviewed, with a focus on the mathematical foundations of the subject. Common research questions in the fusion of surface metrology data are raised and potential fusion algorithms are discussed

Polyelectrolyte-Clay-Protein Layer Films on Microfluidic PDMS Bioreactor Surfaces for Primary Murine Bone Marrow Culture

Poly(dimethylsiloxane) (PDMS) microbioreactors with computerized perfusion controls would be useful for engineering the bone marrow microenvironment. However, previous efforts to grow primary bone marrow cells on PDMS substrates have not been successful due to the weak attachment of cells to the PDMS surface even with adsorption of cell adhesive proteins such as collagen or fibronectin. In this work, modification of the surface of PDMS with biofunctional multilayer coatings is shown to promote marrow cell attachment and spreading. An automated microfluidic perfusion system is used to create multiple types of polyelectrolyte nanoscale coatings simultaneously in multiple channels based on layer-by-layer deposition of PDDA (poly(diallyldimethyl ammonium chloride)), clay, type IV collagen and fibronectin. Adherent primary bone marrow cells attached and spread best on a surface with composition of (PDDA/clay) 5 (Collagen/Fibronectin) 2 with negatively charged fibronectin exposed on the top, remaining well spread and proliferating for at least two weeks. Compared to traditional more macroscopic layer-by-layer methods, this microfluidic nanocomposite process has advantages of greater flow control, automatic processing, multiplexed fabrication, and use of lesser amounts of polymers and protein solutions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57408/1/2701_ftp.pd

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Interactions between the Nse3 and Nse4 Components of the SMC5-6 Complex Identify Evolutionarily Conserved Interactions between MAGE and EID Families

The SMC5-6 protein complex is involved in the cellular response to DNA damage. It is composed of 6-8 polypeptides, of which Nse1, Nse3 and Nse4 form a tight sub-complex. MAGEG1, the mammalian ortholog of Nse3, is the founding member of the MAGE (melanoma-associated antigen) protein family and Nse4 is related to the EID (E1A-like inhibitor of differentiation) family of transcriptional repressors.Using site-directed mutagenesis, protein-protein interaction analyses and molecular modelling, we have identified a conserved hydrophobic surface on the C-terminal domain of Nse3 that interacts with Nse4 and identified residues in its N-terminal domain that are essential for interaction with Nse1. We show that these interactions are conserved in the human orthologs. Furthermore, interaction of MAGEG1, the mammalian ortholog of Nse3, with NSE4b, one of the mammalian orthologs of Nse4, results in transcriptional co-activation of the nuclear receptor, steroidogenic factor 1 (SF1). In an examination of the evolutionary conservation of the Nse3-Nse4 interactions, we find that several MAGE proteins can interact with at least one of the NSE4/EID proteins.We have found that, despite the evolutionary diversification of the MAGE family, the characteristic hydrophobic surface shared by all MAGE proteins from yeast to humans mediates its binding to NSE4/EID proteins. Our work provides new insights into the interactions, evolution and functions of the enigmatic MAGE proteins