Development and synthesis of novel organocatalysts

The unfavourable use of metal-based catalysts in organic synthesis can be overcome by using small organic molecules; organocatalysts. Herein we report the development and synthesis of a novel range of organocatalysts derived from amino acids incorporating imidazole, thiourea and phosphoramide moieties to confer the capability to act as bifunctional organocatalysts. Our organocatalyst, a phosphoramide derived from valine, showed initial success in the catalytic allylation of aldimine with allyltrichlorosilane, producing 40% ee. Oxazoline catalysts derived from 2-pyridines have been shown to be effective activators of trichlorosilane for the reduction of ketones and ketimines. The reaction however suffered from chloride promoted ring opening of the catalyst. By replacing the oxygen of the oxazoline moiety with sulphur we were able to successfully avoid this problem. Further expansion of the substrate scope was achieved, heterocyclic imines were reduced in good enantioselectivity, up to 89% ee

The K-Server Dual and Loose Competitiveness for Paging

This paper has two results. The first is based on the surprising observation that the well-known ``least-recently-used'' paging algorithm and the ``balance'' algorithm for weighted caching are linear-programming primal-dual algorithms. This observation leads to a strategy (called ``Greedy-Dual'') that generalizes them both and has an optimal performance guarantee for weighted caching. For the second result, the paper presents empirical studies of paging algorithms, documenting that in practice, on ``typical'' cache sizes and sequences, the performance of paging strategies are much better than their worst-case analyses in the standard model suggest. The paper then presents theoretical results that support and explain this. For example: on any input sequence, with almost all cache sizes, either the performance guarantee of least-recently-used is O(log k) or the fault rate (in an absolute sense) is insignificant. Both of these results are strengthened and generalized in``On-line File Caching'' (1998).Comment: conference version: "On-Line Caching as Cache Size Varies", SODA (1991

Sliding Mode Implementation of an Attitude Command Flight Control System for a Helicopter in Hover

This paper presents an investigation into the design of a flight control system, using a decoupled non-linear sliding mode control structure, designed using a linearised, 9th order representation of the dynamics of a PUMA helicopter in hover. The controllers are then tested upon a higher order, non-linear helicopter model, called RASCAL. This design approach is used for attitude command flight control implementation and the control performance is assessed in the terms of handling qualities through the Aeronautical Design Standards for Rotorcraft (ADS-33). In this context a linearised approximation of the helicopter system is used to design an SMC control scheme. These controllers have been found to yield a system that satisfies the Level 1 handling qualities set out by ADS-33.

Respiratory tract infections and gut microbiome modifications: A systematic review

Respiratory tract infections (RTIs) are extremely common and can cause gastrointestinal tract symptoms and changes to the gut microbiota, yet these effects are poorly understood. We conducted a systematic review to evaluate the reported evidence of gut microbiome alterations in patients with a RTI compared to healthy controls (PROSPERO: CRD42019138853). We systematically searched Medline, Embase, Web of Science, Cochrane and the Clinical Trial Database for studies published between January 2015 and June 2021. Studies were eligible for inclusion if they were human cohorts describing the gut microbiome in patients with an RTI compared to healthy controls and the infection was caused by a viral or bacterial pathogen. Dual data screening and extraction with narrative synthesis was performed. We identified 1,593 articles and assessed 11 full texts for inclusion. Included studies (some nested) reported gut microbiome changes in the context of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (n = 5), influenza (H1N1 and H7N9) (n = 2), Tuberculosis (TB) (n = 4), Community-Acquired Pneumonia CAP (n = 2) and recurrent RTIs (rRTI) (n = 1) infections. We found studies of patients with an RTI compared to controls reported a decrease in gut microbiome diversity (Shannon) of 1.45 units (95% CI, 0.15–2.50 [p, <0.0001]) and a lower abundance of taxa (p, 0.0086). Meta-analysis of the Shannon value showed considerable heterogeneity between studies (I(2), 94.42). Unbiased analysis displayed as a funnel plot revealed a depletion of Lachnospiraceae, Ruminococcaceae and Ruminococcus and enrichment of Enterococcus. There was an important absence in the lack of cohort studies reporting gut microbiome changes and high heterogeneity between studies may be explained by variations in microbiome methods and confounder effects. Further human cohort studies are needed to understand RTI-induced gut microbiome changes to better understand interplay between microbes and respiratory health

Archaeal MCM has separable processivity, substrate choice and helicase domains

The mini-chromosome maintenance (MCM) complex is the principal candidate for the replicative helicase of archaea and eukaryotes. Here, we describe a functional dissection of the roles of the three principal structural modules of the homomultimeric MCM of the hyperthermophilic archaeon Sulfolobus solfataricus. Our results include the first analysis of the central AAA+ domain in isolation. This domain possesses ATPase and helicase activity, defining this as the minimal helicase domain. Reconstitution experiments show that the helicase activity of the AAA+ domain can be stimulated by addition of the isolated N-terminal half in trans. Addition of the N-terminus influences both the processivity of the helicase and the choice of substrate that can be melted by the ATPase domain. The degenerate helix-turn-helix domain at the C-terminus of MCM exerts a negative effect on the helicase activity of the complex. These results provide the first evidence for extensive regulatory inter-domain communication within the MCM complex

Hybrid quantum annealing for larger-than-QPU lattice-structured problems

Quantum processing units (QPUs) executing annealing algorithms have shown promise in optimization and simulation applications. Hybrid algorithms are a natural bridge to additional applications of larger scale. We present a straightforward and effective method for solving larger-than-QPU lattice-structured Ising optimization problems. Performance is compared against simulated annealing with promising results, and improvement is shown as a function of the generation of D-Wave QPU used.Comment: 21 pages, 15 figures, supplementary code attachmen

DNA replication: archaeal oriGINS

GINS is an essential eukaryotic DNA replication factor that is found in a simplified form in Archaea. A new study in this issue of BMC Biology reveals the first structure of the archaeal GINS complex. The structure reveals the anticipated similarity to the previously determined eukaryotic complex but also has some intriguing differences in the relative disposition of subunit domains

A Genome-Wide Comparative Evolutionary Analysis of Herpes Simplex Virus Type 1 and Varicella Zoster Virus

Herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) are closely related viruses causing lifelong infections. They are typically associated with mucocutaneous or skin lesions, but may also cause severe neurological or ophthalmic diseases, possibly due to viral- and/or host-genetic factors. Although these viruses are well characterized, genome-wide evolutionary studies have hitherto only been presented for VZV. Here, we present a genome-wide study on HSV-1. We also compared the evolutionary characteristics of HSV-1 with those for VZV. We demonstrate that, in contrast to VZV for which only a few ancient recombination events have been suggested, all HSV-1 genomes contain mosaic patterns of segments with different evolutionary origins. Thus, recombination seems to occur extremely frequent for HSV-1. We conclude by proposing a timescale for HSV-1 evolution, and by discussing putative underlying mechanisms for why these otherwise biologically similar viruses have such striking evolutionary differences

Risk Prediction Models for Colorectal Cancer Incorporating Common Genetic Variants: A Systematic Review.

Colorectal cancer screening reduces colorectal cancer incidence and mortality. Risk models based on phenotypic variables have relatively good discrimination in external validation and may improve efficiency of screening. Models incorporating genetic variables may perform better. In this review, we updated our previous review by searching Medline and EMBASE from the end date of that review (January 2014) to February 2019 to identify models incorporating at least one SNP and applicable to asymptomatic individuals in the general population. We identified 23 new models, giving a total of 29. Of those in which the SNP selection was on the basis of published genome-wide association studies, in external or split-sample validation the AUROC was 0.56 to 0.57 for models that included SNPs alone, 0.61 to 0.63 for SNPs in combination with other risk factors, and 0.56 to 0.70 when age was included. Calibration was only reported for four. The addition of SNPs to other risk factors increases discrimination by 0.01 to 0.06. Public health modeling studies suggest that, if determined by risk models, the range of starting ages for screening would be several years greater than using family history alone. Further validation and calibration studies are needed alongside modeling studies to assess the population-level impact of introducing genetic risk-based screening programs