Iterative approach to computational enzyme design

A general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes

Whole System Approach for Women Offenders - Final Evaluation Report

The evaluation has found that the WSA provides a good example of a gendered approach to supporting women in contact with the criminal justice system or at risk of offending and has been successful in responding to a number of its key aims. These include: creating opportunities to divert women from charge, court and custody; supporting women in ways which reduce their repeat criminalisation; and the provision of safe women-only spaces which can contribute to a reduction in the damage that involvement in the criminal justice system can have on women and their families. It is doing so by empowering women and improving their wellbeing and safety. Other key features of the approach include providing gender specific support to women across Greater Manchester, at all stages of the criminal justice system, based on multi-agency working, built around the network of women’s centres. This summary will now consider the evidence of impact against each of these aims in turn

Properties of a random attachment growing network

In this study we introduce and analyze the statistical structural properties of a model of growing networks which may be relevant to social networks. At each step a new node is added which selects 'k' possible partners from the existing network and joins them with probability delta by undirected edges. The 'activity' of the node ends here; it will get new partners only if it is selected by a newcomer. The model produces an infinite-order phase transition when a giant component appears at a specific value of delta, which depends on k. The average component size is discontinuous at the transition. In contrast, the network behaves significantly different for k=1. There is no giant component formed for any delta and thus in this sense there is no phase transition. However, the average component size diverges for delta greater or equal than one half.Comment: LaTeX, 19 pages, 6 figures. Discussion section, comments, a new figure and a new reference are added. Equations simplifie

Olivine major and trace element compositions coupled with spinel chemistry to unravel the magmatic systems feeding monogenetic basaltic volcanoes

Monogenetic basaltic volcanic systems, despite their considerable smaller size and shorter lifetime compared to polygenetic volcanoes, can have complex pre-eruptive histories and composite volcanic facies architectures. Their source-to-surface investigation is essential for our better understanding of monogenetic volcanism and requires high-resolution mineral-scale analyses. In this study, we focus on diversely zoned olivine crystals and their spinel inclusions from alkaline basaltic volcanics that are the result of mixing of numerous magmas, crystals and fragments of various origins. The Fekete-hegy volcanic complex is one of the largest and most composite eruptive centers in the intracontinental monogenetic Bakony–Balaton Highland Volcanic Field (western Pannonian Basin, Eastern Central Europe). It is a compound multi-vent system built up by multiple eruption episodes: initial maar-forming phreatomagmatic eruptions were followed by massive lava flows and magmatic explosive activity. We performed stratigraphically controlled sampling in order to reveal the history of the successively erupted magma batches represented by the distinct eruptive units, as well as to discover the petrogenetic processes that controlled the evolution of the magmatic system. The juvenile pyroclasts of the phreatomagmatic eruption products (unit 1) contain a remarkably diverse mineral assemblage including five different olivine types and three distinct spinel groups. In addition, they comprise various xenoliths. Based on detailed textural investigations combined with in situ electron microprobe analyses, high-resolution laser ablation ICP-MS trace element mapping and single spot measurements on the variably zoned olivines of unit 1 samples, eight distinct environments are inferred to have been involved in their formation. Four of these environments account for the significant compositional variation of the olivine-hosted spinel inclusions. A complex set of open- and closed-system petrogenetic processes operated during the evolution of the magmatic system: magma stalling, accumulation, storage, fractionation, mixing, replenishments, cumulate remobilization, incorporation of foreign fragments and crystals from the wall rocks. All these diverse environments and processes resulted in the mixed character of the erupted magmas during the initial phreatomagmatic eruptive phase. In contrast, the uniform petrological features and the small variations shown by the olivines and spinels from unit 2‐–3 indicate that the later magmatic explosive – effusive phase was preceded by a considerable change in the magmatic system; it experienced a simple evolution through olivine + spinel fractional crystallization without any of the complexities seen during the initial phase. The present study emphasizes the importance of high-resolution mineral-scale textural and chemical investigations to unravel the complexity of the sub-volcanic magmatic systems feeding monogenetic basaltic volcanoes. Compared to the application of whole-rock geochemistry alone, this approach enables a direct and more detailed insight into the architecture and evolution of these systems

Free classification of large sets of everyday objects is more thematic than taxonomic

Traditionally it has been thought that the overall organisation of categories in the brain is taxonomic. To examine this assumption, we had adults sort 140–150 diverse, familiar objects from different basic-level categories. Almost all the participants (80/81) sorted the objects more thematically than taxonomically. Sorting was only weakly modulated by taxonomic priming, and people still produced many thematically structured clusters when explicitly instructed to sort taxonomically. The first clusters that people produced were rated as having equal taxonomic and thematic structure. However, later clusters were rated as being increasingly thematically organised. A minority of items were consistently clustered taxonomically, but the overall dominance of thematically structured clusters suggests that people know more thematic than taxonomic relations among everyday objects. A final study showed that the semantic relations used to sort a given item in the initial studies predicted the proportion of thematic to taxonomic word associates generated to that item. However, unlike the results of the sorting task, most of these single word associates were related taxonomically. This latter difference between the results of large-scale, free sorting tasks versus single word association tasks suggests that thematic relations may be more numerous, but weaker, than taxonomic associations in our stored conceptual network. Novel statistical and numerical methods for objectively measuring sorting consistency were developed during the course of this investigation, and have been made publicly available

Clinical Oncology Society of Australia: Position statement on cancer-related malnutrition and sarcopenia

© 2020 The Authors. Nutrition & Dietetics published by John Wiley & Sons Australia, Ltd on behalf of Dietitians Australia. This position statement describes the recommendations of the Clinical Oncology Society of Australia (COSA) regarding management of cancer-related malnutrition and sarcopenia. A multidisciplinary working group completed a review of the literature, focused on evidence-based guidelines, systematic reviews and meta-analyses, to develop recommendations for the position statement. National consultation of the position statement content was undertaken through COSA members. All people with cancer should be screened for malnutrition and sarcopenia in all health settings at diagnosis and as the clinical situation changes throughout treatment and recovery. People identified as “at risk” of malnutrition or with a high-risk cancer diagnosis or treatment plan should have a comprehensive nutrition assessment; people identified as “at risk” of sarcopenia should have a comprehensive evaluation of muscle status using a combination of assessments for muscle mass, muscle strength and function. All people with cancer-related malnutrition and sarcopenia should have access to the core components of treatment, including medical nutrition therapy, targeted exercise prescription and physical and psychological symptom management. Treatment for cancer-related malnutrition and sarcopenia should be individualised, in collaboration with the multidisciplinary team (MDT), and tailored to meet needs at each stage of cancer treatment. Health services should ensure a broad range of health care professionals across the MDT have the skills and confidence to recognise malnutrition and sarcopenia to facilitate timely referrals and treatment. The position statement is expected to provide guidance at a national level to improve the multidisciplinary management of cancer-related malnutrition and sarcopenia

Visual cues given by humans are not sufficient for Asian elephants (Elephas maximus) to find hidden food.

Recent research suggests that domesticated species--due to artificial selection by humans for specific, preferred behavioral traits--are better than wild animals at responding to visual cues given by humans about the location of hidden food. \Although this seems to be supported by studies on a range of domesticated (including dogs, goats and horses) and wild (including wolves and chimpanzees) animals, there is also evidence that exposure to humans positively influences the ability of both wild and domesticated animals to follow these same cues. Here, we test the performance of Asian elephants (Elephas maximus) on an object choice task that provides them with visual-only cues given by humans about the location of hidden food. Captive elephants are interesting candidates for investigating how both domestication and human exposure may impact cue-following as they represent a non-domesticated species with almost constant human interaction. As a group, the elephants (n = 7) in our study were unable to follow pointing, body orientation or a combination of both as honest signals of food location. They were, however, able to follow vocal commands with which they were already familiar in a novel context, suggesting the elephants are able to follow cues if they are sufficiently salient. Although the elephants' inability to follow the visual cues provides partial support for the domestication hypothesis, an alternative explanation is that elephants may rely more heavily on other sensory modalities, specifically olfaction and audition. Further research will be needed to rule out this alternative explanation

How can risk of COVID-19 transmission be minimised in domiciliary care for older people: development, parameterisation and initial results of a simple mathematical model

This paper proposes and analyses a stochastic model for the spread of an infectious disease transmitted between clients and care workers in the UK domiciliary (home) care setting. Interactions between clients and care workers are modelled using specially generated networks, with network parameters reflecting realistic patterns of care needs and visit allocation. These networks are then used to simulate and SEIR-type epidemic dynamics with different numbers of infectious and recovery stages. The results indicate that with the same overall capacity provided by care workers, the minimum peak proportion of infection, and the smallest overall size of infection are achieved for the highest proportion of overlap between visit allocation, i.e. when care workers have the highest chances of being allocated a visit to the same client they have visited before. An intuitive explanation of this is that while providing the required care coverage, maximising overlap in visit allocation reduces the possibility of an infectious care worker inadvertently spreading the infection to other clients. The model is generic and can be adapted to any directly transmitted infectious disease, such as, more recently, COVID-19, provided accurate estimates of disease parameters can be obtained from real data

Syntactic microvariation and methodology: problems and perspectives

Variation in empirical data has been a perseverant problem for theoretical linguistics, especially syntax. Data inconsistencies among authors allegedly analyzing the same phenomenon are ubiquitous in the syntactic literature (e.g., literature on focus-raising in Hungarian; É. Kiss 1987 vs. Lipták 1998), and partly result from the highly informal methodology of data collection. However, even if adequate controls are used to exclude potential biases, variation might remain. The general practice in syntactic research has been to ignore these „microvariations”-mainly in the lack of any systematic empirical method to detect them. The present paper shows that this practice leads to serious theoretical problems and proposes a new empirical method, cluster analysis, to discover, explore and systematize these variations. It also illustrates how this richer empirical basis gives rise to a more fine-grained theoretical analysis

Heterodimerization of the human RNase P/MRP subunits Rpp20 and Rpp25 is a prerequisite for interaction with the P3 arm of RNase MRP RNA

Rpp20 and Rpp25 are two key subunits of the human endoribonucleases RNase P and MRP. Formation of an Rpp20–Rpp25 complex is critical for enzyme function and sub-cellular localization. We present the first detailed in vitro analysis of their conformational properties, and a biochemical and biophysical characterization of their mutual interaction and RNA recognition. This study specifically examines the role of the Rpp20/Rpp25 association in the formation of the ribonucleoprotein complex. The interaction of the individual subunits with the P3 arm of the RNase MRP RNA is revealed to be negligible whereas the 1:1 Rpp20:Rpp25 complex binds to the same target with an affinity of the order of nM. These results unambiguously demonstrate that Rpp20 and Rpp25 interact with the P3 RNA as a heterodimer, which is formed prior to RNA binding. This creates a platform for the design of future experiments aimed at a better understanding of the function and organization of RNase P and MRP. Finally, analyses of interactions with deletion mutant proteins constructed with successively shorter N- and C-terminal sequences indicate that the Alba-type core domain of both Rpp20 and Rpp25 contains most of the determinants for mutual association and P3 RNA recognition