A mean field model for movement induced changes in the beta rhythm

In electrophysiological recordings of the brain, the transition from high amplitude to low amplitude signals are most likely caused by a change in the synchrony of underlying neuronal population firing patterns. Classic examples of such modulations are the strong stimulus-related oscillatory phenomena known as the movement related beta decrease (MRBD) and post-movement beta rebound (PMBR). A sharp decrease in neural oscillatory power is observed during movement (MRBD) followed by an increase above baseline on movement cessation (PMBR). MRBD and PMBR represent important neuroscientific phenomena which have been shown to have clinical relevance. Here, we present a parsimonious model for the dynamics of synchrony within a synaptically coupled spiking network that is able to replicate a human MEG power spectrogram showing the evolution from MRBD to PMBR. Importantly, the high-dimensional spiking model has an exact mean field description in terms of four ordinary differential equations that allows considerable insight to be obtained into the cause of the experimentally observed time-lag from movement termination to the onset of PMBR (~ 0.5 s), as well as the subsequent long duration of PMBR (~ 1-10 s). Our model represents the first to predict these commonly observed and robust phenomena and represents a key step in their understanding, in health and disease

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Reducing the genetic complexity of glycolysis in Saccharomyces cerevisiae

Glycolysis, a biochemical pathway that oxidizes glucose to pyruvate, is at the core of sugar metabolism in Saccharomyces cerevisiae (bakers’ yeast). Glycolysis is not only a catabolic route involved in energy conservation, but also provides building blocks for anabolism. From an applied perspective, several glycolytic intermediates are key precursors for the production of a wide range of highly valuable compounds. The most obvious case is the production of ethanol from pyruvate. Its ability to rapidly ferment sugars to ethanol has made S. cerevisiae the major microbial player in large scale biofuel production. Because of its importance in cellular processes and in the biotechnology industry, glycolysis in S. cerevisiae has been studied in detail. However, despite the large amount of information generated about all the components in glycolysis, the limited understanding on how these components interact and are co-ordinately regulated to ensure a robust and balanced pathway, has to date defied all metabolic engineering attempts to significantly accelerate glycolytic flux. So far, the mechanisms that govern the glycolytic flux are not fully known. A particularly poorly understood factor in glycolysis is its high genetic redundancy. This phenomenon is observed in many organisms, but is highly pronounced in S. cerevisiae which, for most glycolytic reactions, harbours multiple isoenzymes and corresponding paralogous genes. The contribution of the glycolytic paralogs to the glycolytic flux is unknown and the simultaneous presence of different isoenzymes – with potentially different kinetic and regulatory properties - complicates the mathematical modelling that is required for a deeper understanding of the regulation of this industrially relevant pathway. Saccharomyces cerevisiae’s glycolytic pathway consist of ten biochemical reactions. In this Crabtree positive yeast, glycolysis is under most growth conditions linked to ethanol formation. Without considering the very complex transport of glucose from the extracellular environment to the intracellular compartment, glycolysis and ethanol fermentation together encompass 12 biochemical reactions. These biochemical reactions are catalysed by enzymes encoded in 27 glycolytic genes, separated in eight paralog families and four unique structural genes. S. cerevisiae evolved from an ancestor that, approximately 100 million years ago, underwent a whole genome duplication (WGD). Many of its hallmark phenotypic characteristics have been proposed to be the result of this duplication event and the subsequent genome rearrangement, gene loss and gains through evolution. In S. cerevisiae, no fewer than eight of the ten enzyme reactions in glycolysis are represented by multiple paralogs genes. This incidence of paralogous combinations represents a significant overrepresentation relative to the ca. 26 % of the yeast genome that consists of paralogous combinations. The WGD event and resulting duplication of glycolytic genes has been proposed to have contributed to the strong tendency of this yeast to produce ethanol under aerobic conditions (Crabtree effect) and to its high glycolytic capacity. However, the impact of reducing the number of glycolytic paralogs on these and other physiological characteristics of S. cerevisiae has not been systematically explored. All glycolytic reactions are equally essential for yeast growth on glucose. However, for all paralogs gene sets in yeast glycolysis, with the notable exception of phosphofructokinase, gene expression and gene deletion studies support the definition of a single, major paralog and one to four minor paralogs. Additionally, except for the pseudogenes GPM2 and GPM3, all paralogs have retained their original catalytic function, although their context-dependent expression profiles differ. Furthermore, deletion of minor paralogs for individual glycolytic enzymes has minor effects on enzyme activities in cell extracts and on specific growth rate under standard laboratory conditions. Reduction of the genetic complexity in S. cerevisiae’s glycolysis could deliver a more predictable and malleable glycolytic pathway. These characteristics could greatly benefit the biotechnology industry and our understanding about glycolysis. Thus, the main goal of this thesis was the construction and analysis of a strain with a minimal set of glycolytic enzymes. Despite the astonishing genetic accessibility of S. cerevisiae and its broad genetic toolbox, large-scale deletion strategies, like the deletion of 13 genes undertaken in the present thesis, were a challenging endeavour at the outset of this project, that only few previous studies had tackled. Despite the large collection of selectable marker genes for genetic modification available for S. cerevisiae, marker availability still presented a hurdle when dozens of genetic deletions were required. Additionally, the presence of the selectable markers in the host genome can influence the fitness or performance of the strain, thus, different methods for marker removal were required. Deletion of the hexose transporter genes (HXT’s) in S. cerevisiae has, for over a decade, represented the paradigm for elimination of complexity in a large, redundant paralog family. This yeast harbours a large group of tightly controlled transporters with different characteristics for glucose uptake. This family is composed of genes with similar function but that are expressed under different conditions, thereby allowing yeast to grow and cope with large and dynamic changes in glucose concentration. Interestingly, deletion of single or several HXT’s does not abolish growth on glucose. In 1999, Eckhard Boles and his team took on the enormous endeavour of removing all transporters capable to import glucose in S. cerevisiae, resulting in the strain EBY.VW4000. Ever since its construction, EBY.VW4000 has become a widely used platform for the discovery and characterization of transporters from a wide range of organisms and as a platform strain for metabolic engineering approaches. Additionally, EBY.VW4000, with its reduced genetic redundancy in glucose transport, could serve as an splendid platform for the construction of a minimal glycolytic pathway. Despite the extensive usage of this strain, the genome of EBY.VW4000 had hitherto not been characterized in detail. Chapter 2 addresses this information gap and presents the whole-genome sequence of EBY.VW4000. To abolish glucose uptake in this strain, 21 genes (including all HXT’s) had been knocked-out across 16 successive deletion rounds with the LoxP/Cre system. Based on a combination of whole-genome sequencing, karyotyping and molecular confirmation, we demonstrated that the construction of EBY.VW4000 resulted in gene losses and chromosomal rearrangements guided by LoxP/Cre. In contrast, only 13 single nucleotide variations (SNV’s) were identified. Recombinations between LoxP scars led to the assembly of four neo-chromosomes, truncation of two chromosomes and the loss of two telomeric regions. By karyotyping the EBY.VW4000 lineage, it became clear that its current chromosomal architecture has resulted from four translocations events that occurred between the 6th and the 12th rounds of deletion/marker recycling. Additionally, sporulation and spore germination were found to be severely impaired in EBY.VW4000. This work also demonstrated that, due to the massive LoxP/Cre-induced genome modifications observed, neither EBY.VW4000 nor LoxP/Cre were suitable for the construction of a minimal glycolysis strain. Therefore, a combination of classical genetic deletion and novel tools and methodologies were developed and implemented. In Chapter 3 the new recyclable dominant marker cassette amdSYM, formed by the Ashbya gossypii TEF2 promoter and terminator and a codon-optimized acetamidase gene (Aspergillus nidulans amdS) is presented. This module confers laboratory, wild and industrial Saccharomyces strains the ability to use acetamide as sole nitrogen source. Direct repeats flanking the marker cassette allow for its efficient recombinative excision. This cassette loss can be rapidly selected for by growth in the presence of fluoroacetamide. The amdSYM cassette can be used in different genetic backgrounds and represents the first counterselectable dominant marker gene cassette for use in Saccharomyces strains. Furthermore, using astute cassette design, amdSYM excision could be performed without leaving a scar or heterologous sequences in the targeted genome. The amdSYM cassette is available for the scientific community via the Euroscarf collection. Including the amdSYM marker cassette, only four counter-selectable markers for S. cerevisiae are available. Extensive strain engineering is severely hampered by this limited marker availability and by the reduced genome stability that occurs upon repeated use of heterologous recombinase-based marker removal methods such as LoxP/Cre system. Chapter 4 introduces an efficient method to recycle multiple markers in S. cerevisiae simultaneously, thereby circumventing shortcomings of existing techniques and substantially accelerating the process of selection-excision. This method relies on artificial generation of double strand breaks around the selection marker cassette by the meganuclease I-SceI and the subsequent repair of these breaks by the yeast homologous recombination machinery, guided by direct repeats. Simultaneous removal of up to three marker cassettes was achieved with high efficiencies (up to 56%). This locus- and marker-independent method can be used for both dominant and auxotrophy-complementing marker genes. Chapter 5 describes the experimental exploration of genetic redundancy in yeast glycolysis by cumulative deletion of minor paralogs and presents a new experimental platform for fundamental yeast research by constructing a yeast strain with a functional minimal glycolysis. The construction of this strain was performed with a combination of classical genetics tools and the newly developed methodologies presented in this thesis. It encompassed the deletion of 13 glycolytic paralogs considered to have a minor contribution to flux. After thorough experimental analysis, using quantitative and systems approaches, under growth conditions leading to a high glycolytic flux and after semi-quantitative analysis under a wide range of growth conditions, the most remarkable feature of the minimal glycolysis strain was the lack of visible phenotypic response to the deletion of 13 genes. The high glycolytic rates in anaerobic cultures of the minimal glycolysis strain and the small effect on the transcriptome argue against gene dosage or back-up effects as means for fixing minor glycolytic paralogs in the yeast genome. The near-wild type growth kinetics of the minimal glycolysis strain in aerobic and anaerobic cultures are difficult to reconcile with the hypothesis that duplication of glycolytic genes during the WGD event played a major role in increasing its glycolytic capacity or in causing the Crabtree effect. This reduction of genetic complexity contributed to the understanding of yeast glycolysis by, for the first time, studying the synergetic effects of multiple deletions of glycolytic genes. Moreover, it eliminated intrinsic uncertainties caused by the simultaneous, context-dependent expression of different isoenzymes, facilitating the formulation and validation of mathematical models that describe the kinetics of this key metabolic pathway. Analysis of the physiology and fitness of the minimal glycolysis strain under dynamic man-made and natural conditions may contribute to the daunting but exciting task of resolving the origin, fate, evolution and role of glycolytic paralogs. Additionally, it will serve as a basis for a more extreme genetic and pathway engineering strategy, in which different glycolytic pathways can be redesigned and interchanged in two simple steps.Biotechnology DepartmentApplied Science

Classification of Rhythmic Cortical Activity Elicited by Whole-Body Balance Perturbations Suggests the Cortical Representation of Direction-Specific Changes in Postural Stability

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