Evolution with recombination as Gibbs sampling.

This work presents a population genetic model of evolution, which includes haploid selection, mutation, recombination, and drift. The mutation-selection equilibrium can be expressed exactly in closed form for arbitrary fitness functions without resorting to diffusion approximations. Tractability is achieved by generating new offspring using n-parent rather than 2-parent recombination. While this enforces linkage equilibrium among offspring, it allows analysis of the whole population under linkage disequilibrium. We derive a general and exact relationship between fitness fluctuations and response to selection. Our assumptions allow analytical calculation of the stationary distribution of the model for a variety of non-trivial fitness functions. These results allow us to speak to genetic architecture, i.e., what stationary distributions result from different fitness functions. This paper presents methods for exactly deriving stationary states for finite and infinite populations. This method can be applied to many fitness functions, and we give exact calculations for four of these. These results allow us to investigate metastability, tradeoffs between fitness functions, and even consider error-correcting codes.

Prediction as a basis for skilled reading: insights from modern language models.

Reading is not an inborn human capability, and yet, English-speaking adults read with impressive speed. This study considered how predictions of upcoming words impact on this skilled behaviour. We used a powerful language model (GPT-2) to derive predictions of upcoming words in text passages. These predictions were highly accurate and showed a tight relationship to fine-grained aspects of eye-movement behaviour when adults read those same passages, including whether to skip the next word and how long to spend on it. Strong predictions that were incorrect resulted in a prediction error cost on fixation durations. Our findings suggest that predictions for upcoming words can be made based on the analysis of text statistics and that these predictions guide how our eyes interrogate text at very short timescales. These findings open new perspectives on reading and language comprehension and illustrate the capability of modern language models to inform understanding of human language processing.

An accessible, efficient and global approach for the large-scale sequencing of bacterial genomes.

We have developed an efficient and inexpensive pipeline for streamlining large-scale collection and genome sequencing of bacterial isolates. Evaluation of this method involved a worldwide research collaboration focused on the model organism Salmonella enterica, the 10KSG consortium. Following the optimization of a logistics pipeline that involved shipping isolates as thermolysates in ambient conditions, the project assembled a diverse collection of 10,419 isolates from low- and middle-income countries. The genomes were sequenced using the LITE pipeline for library construction, with a total reagent cost of less than USD$10 per genome. Our method can be applied to other large bacterial collections to underpin global collaborations.

What is semantic diversity and why does it facilitate visual word recognition?

Previous research has speculated that semantic diversity and lexical ambiguity may be closely related constructs. Our research sought to test this claim in respect of the semantic diversity measure proposed by Hoffman et al. (2013). To this end, we replicated the procedure described by Hoffman et al., Behavior Research Methods, 45(3), 718-730 (2013) for computing multidimensional representations of contextual information using Latent Semantic Analysis, and from these we derived semantic diversity values for 28,555 words. We then replicated the facilitatory effect of semantic diversity on word recognition using existing data resources and observed this effect to be greater for low-frequency words. Yet, we found no relationship between this measure and lexical ambiguity effects in word recognition. Further analysis of the LSA-based contextual representations used to compute Hoffman et al. (2013) measure of semantic diversity revealed that they do not capture the distinct meanings of ambiguous words. Instead, these contextual representations appear to capture general information about the topics and types of written material in which words occur. These analyses suggest that the semantic diversity metric previously proposed by Hoffman et al. (2013) facilitates word recognition because high-diversity words are likely to have been encountered no matter what one has read, whereas many participants may not have encountered lower-diversity words simply because the topics and types of written material in which they occur are more restricted.

Rapid Creation of an Online Discussion Space (r/nipah) During a Serious Disease Outbreak: Observational Study.

BACKGROUND: During health emergencies, the people within affected communities ask many questions at a time when professional medics and health agencies are overstretched and struggling to cope. Our previous research has shown that, during the 2014-2015 West Africa Ebola crisis, volunteer-moderated online discussion forums were able to provide peer-to-peer reliable, trustworthy, and well-managed information. We speculated that with the right mix of epistemic and experiential knowledge, such a discussion forum could be set up rapidly during a future serious disease outbreak. OBJECTIVE: The aim of this study was to set up a peer-to-peer health information exchange forum within the shortest time possible after the emergence of a real outbreak of a serious infectious disease. An outbreak of Nipah virus in Kerala, India, in May 2018 provided the opportunity to test our theories. METHODS: We initiated a Nipah virus discussion forum on the platform Reddit, recruiting volunteer moderators from within the existing Reddit community. This facilitated posts and comments to the forum from genuine Reddit users. We gathered and analyzed data on the number of posts, comments, page views, and subscribers during the period of May 24 to June 23, 2018, by using the data analysis tools embedded in the Reddit platform. RESULTS: We were able to set up a functioning health information exchange platform by May 24, 2018, within two weeks of the index case and one week of the official World Health Organization verification of a Nipah virus outbreak. Over the following five weeks, the forum received a steady flow of traffic including posts (36) and comments (21) submitted, page views (840), and subscribers (33). On the busiest day, 368 page views were recorded. The forum provided information in the languages spoken in the outbreak region as well as in English on how the virus spreads, symptoms of the disease, and how to take measures to avoid contracting it. Information on government helpline numbers and frequently asked questions was also provided to the community at risk. CONCLUSIONS: The delivery of a fully functional discussion forum within a short space of time during an actual health emergency demonstrates that our suggestion is fully practical. Our theory that Reddit could provide a suitable platform to host such a forum was upheld. This offers great potential for public health communication during future serious disease outbreaks.

Realtime Tracking of Passengers on the London Underground Transport by Matching Smartphone Accelerometer Footprints.

Passengers travelling on the London underground tubes currently have no means of knowing their whereabouts between stations. The challenge for providing such service is that the London underground tunnels have no GPS, Wi-Fi, Bluetooth, or any kind of terrestrial signals to leverage. This paper presents a novel yet practical idea to track passengers in realtime using the smartphone accelerometer and a training database of the entire London underground network. Our rationales are that London tubes are self-driving transports with predictable accelerations, decelerations, and travelling time and that they always travel on the same fixed rail lines between stations with distinctive bumps and vibrations, which permit us to generate an accelerometer map of the tubes' movements on each line. Given the passenger's accelerometer data, we identify in realtime what line they are travelling on and what station they depart from, using a pattern-matching algorithm, with an accuracy of up to about 90% when the sampling length is equivalent to at least 3 station stops. We incorporate Principal Component Analysis to perform inertial tracking of passengers' positions along the line when trains break away from scheduled movements during rush hours. Our proposal was painstakingly assessed on the entire London underground, covering approximately 940 km of travelling distance, spanning across 381 stations on 11 different lines.

Health Advice from Internet Discussion Forums: How Bad Is Dangerous?

BACKGROUND: Concerns over online health information-seeking behavior point to the potential harm incorrect, incomplete, or biased information may cause. However, systematic reviews of health information have found few examples of documented harm that can be directly attributed to poor quality information found online. OBJECTIVE: The aim of this study was to improve our understanding of the quality and quality characteristics of information found in online discussion forum websites so that their likely value as a peer-to-peer health information-sharing platform could be assessed. METHODS: A total of 25 health discussion threads were selected across 3 websites (Reddit, Mumsnet, and Patient) covering 3 health conditions (human immunodeficiency virus [HIV], diabetes, and chickenpox). Assessors were asked to rate information found in the discussion threads according to 5 criteria: accuracy, completeness, how sensible the replies were, how they thought the questioner would act, and how useful they thought the questioner would find the replies. RESULTS: In all, 78 fully completed assessments were returned by 17 individuals (8 were qualified medical doctors, 9 were not). When the ratings awarded in the assessments were analyzed, 25 of the assessments placed the discussion threads in the highest possible score band rating them between 5 and 10 overall, 38 rated them between 11 and 15, 12 rated them between 16 and 20, and 3 placed the discussion thread they assessed in the lowest rating band (21-25). This suggests that health threads on Internet discussion forum websites are more likely than not (by a factor of 4:1) to contain information of high or reasonably high quality. Extremely poor information is rare; the lowest available assessment rating was awarded only 11 times out of a possible 353, whereas the highest was awarded 54 times. Only 3 of 78 fully completed assessments rated a discussion thread in the lowest possible overall band of 21 to 25, whereas 25 of 78 rated it in the highest of 5 to 10. Quality assessments differed depending on the health condition (chickenpox appeared 17 times in the 20 lowest-rated threads, HIV twice, and diabetes once). Although assessors tended to agree on which discussion threads contained good quality information, what constituted poor quality information appeared to be more subjective. CONCLUSIONS: Most of the information assessed in this study was considered by qualified medical doctors and nonmedically qualified respondents to be of reasonably good quality. Although a small amount of information was assessed as poor, not all respondents agreed that the original questioner would have been led to act inappropriately based on the information presented. This suggests that discussion forum websites may be a useful platform through which people can ask health-related questions and receive answers of acceptable quality.

International employees' concerns during serious disease outbreaks and the potential impact on business continuity: Lessons identified from the 2014-15 West African Ebola outbreak.

This paper presents the findings of research carried out into the information-seeking behaviour, and information requirements of a small sample of international workers stationed in West Africa during the Zaire Ebola virus outbreak of 2014-15. The research study under which these results were obtained was part of exploratory research for a PhD focused on the use, and potential uses, of social media platforms during serious disease outbreaks that might be used to inform policy planning for public health and emergency response interventions. Thus, the findings from this study may provide valuable insights to business continuity managers and emergency planners in making future decisions about information exchange and crisis decision-making during future serious disease outbreaks.

Pioneering government-sponsored drug repositioning collaborations: progress and learning.

A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. Through two pioneering initiatives - one involving the Medical Research Council in the United Kingdom and one involving the National Center for Advancing Translational Sciences of the National Institutes of Health in the United States - new investigations of highly characterized investigational compounds have been funded and are leading to the exploration of known mechanisms in new disease areas. This model has been extended beyond these first two initiatives. Here, we discuss the progress to date and the unique requirements and challenges for this model.

Immune Tolerance Maintained by Cooperative Interactions between T Cells and Antigen Presenting Cells Shapes a Diverse TCR Repertoire.

The T cell population in an individual needs to avoid harmful activation by self peptides while maintaining the ability to respond to an unknown set of foreign peptides. This property is acquired by a combination of thymic and extra-thymic mechanisms. We extend current models for the development of self/non-self discrimination to consider the acquisition of self-tolerance as an emergent system level property of the overall T cell receptor repertoire. We propose that tolerance is established at the level of the antigen presenting cell/T cell cluster, which facilitates and integrates cooperative interactions between T cells of different specificities. The threshold for self-reactivity is therefore imposed at a population level, and not at the level of the individual T cell/antigen encounter. Mathematically, the model can be formulated as a linear programing optimization problem that can be implemented as a multiplicative update algorithm, which shows a rapid convergence to a stable state. The model constrains self-reactivity within a predefined threshold, but maintains repertoire diversity and cross reactivity which are key characteristics of human T cell immunity. We show further that the size of individual clones in the model repertoire becomes heterogeneous, and that new clones can establish themselves even when the repertoire has stabilized. Our study combines the salient features of the "danger" model of self/non-self discrimination with the concepts of quorum sensing, and extends repertoire generation models to encompass the establishment of tolerance. Furthermore, the dynamic and continuous repertoire reshaping, which underlies tolerance in this model, suggests opportunities for therapeutic intervention to achieve long-term tolerance following transplantation.

Acquire: an open-source comprehensive cancer biobanking system.

MOTIVATION: The probability of effective treatment of cancer with a targeted therapeutic can be improved for patients with defined genotypes containing actionable mutations. To this end, many human cancer biobanks are integrating more tightly with genomic sequencing facilities and with those creating and maintaining patient-derived xenografts (PDX) and cell lines to provide renewable resources for translational research. RESULTS: To support the complex data management needs and workflows of several such biobanks, we developed Acquire. It is a robust, secure, web-based, database-backed open-source system that supports all major needs of a modern cancer biobank. Its modules allow for i) up-to-the-minute 'scoreboard' and graphical reporting of collections; ii) end user roles and permissions; iii) specimen inventory through caTissue Suite; iv) shipping forms for distribution of specimens to pathology, genomic analysis and PDX/cell line creation facilities; v) robust ad hoc querying; vi) molecular and cellular quality control metrics to track specimens' progress and quality; vii) public researcher request; viii) resource allocation committee distribution request review and oversight and ix) linkage to available derivatives of specimen.

Complete Genome Sequence of the Model Rhizosphere Strain Azospirillum brasilense Az39, Successfully Applied in Agriculture.

We present the complete genome sequence of Azospirillum brasilense Az39, isolated from wheat roots in the central region of Argentina and used as inoculant in extensive and intensive agriculture during the last four decades. The genome consists of 7.39 Mb, distributed in six replicons: one chromosome, three chromids, and two plasmids.

Nitric oxide inhibition of alcohol dehydrogenase in fresh-cut apples ( Malus domestica Borkh).

The effects of nitric oxide (NO) and nitrite treatment on alcohol dehydrogenase activity and the shelf life of apple tissue were investigated. Fresh-cut apple slices were stored for 2 days at 6 °C in 0.25-1% NO (v/v, balance N2) or 100% N2 atmospheres. Slices were also treated with 1% NO or 2 mM sodium nitrite (NaNO2) for 20 min, stored for 6 weeks in 100% N2 at 6 °C, and analyzed for acetaldehyde, ethanol, and ethyl acetate accumulation, firmness, and color. Compared with N2 or deionized water controls, treatment with 1% NO or 2 mM NaNO2 inhibited ethanol accumulation, whereas that of acetaldehyde increased. Ethyl acetate accumulation was inhibited only by NO. Slice firmness was not affected by NO or NaNO2 treatment, but slices were darker than the untreated controls. NO and nitrite may extend the shelf life of fresh-cut produce with low concentrations of phenolic compounds.

Biomarker development for external CO2 injury prediction in apples through exploration of both transcriptome and DNA methylation changes.

Several apple cultivars are susceptible to CO2 injury, a physiological disorder that can be expressed either externally or internally, and which can cause major losses of fruit during controlled atmosphere (CA) storage. Disorder development can also be enhanced using SmartFresh™ technology, based on the inhibition of ethylene perception by 1-methylcyclopropene (1-MCP). Injury development is associated with less mature fruit with lower ethylene production, but the aetiology of the disorder is poorly understood. Here we report on the progress made using mRNAseq approaches to explore the transcriptome during the development of external CO2 injury. Next-generation sequencing was used to mine the apple transcriptome for gene expression changes that are associated with the development of external CO2 injury. 'Empire' apples from a single orchard were treated with either 1 µL L(-1) 1-MCP or 1 g L(-1) diphenylamine or left untreated, and then stored in a CA of 5 kPa CO2 and 2 kPa O2. In addition, susceptibility to the disorder in the 'Empire' apples from five different orchards was investigated and the methylation state of the ACS1 promoter investigated using McrBC endonuclease digestion and real-time quantitative polymerase chain reaction. Expression of over 30 000 genes, aligned to the apple genome, was monitored, with clear divergence of expression among treatments after 1 day of CA storage. Symptom development, internal ethylene concentrations (IECs) and methylation state of the ACS1 promoter were different for each of five orchards. With transcriptomic changes affected by treatment, this dataset will be useful in discovering biomarkers that assess disorder susceptibility. An inverse correlation between the frequency of this disorder and the IEC was detected in a multiple orchard trial. Differential methylation state of the ACS1 promoter correlated with both IEC and injury occurrence, indicating epigenetic regulation of ethylene biosynthesis and possibly events leading to disorder development.

The spread of awareness and its impact on epidemic outbreaks.

When a disease breaks out in a human population, changes in behavior in response to the outbreak can alter the progression of the infectious agent. In particular, people aware of a disease in their proximity can take measures to reduce their susceptibility. Even if no centralized information is provided about the presence of a disease, such awareness can arise through first-hand observation and word of mouth. To understand the effects this can have on the spread of a disease, we formulate and analyze a mathematical model for the spread of awareness in a host population, and then link this to an epidemiological model by having more informed hosts reduce their susceptibility. We find that, in a well-mixed population, this can result in a lower size of the outbreak, but does not affect the epidemic threshold. If, however, the behavioral response is treated as a local effect arising in the proximity of an outbreak, it can completely stop a disease from spreading, although only if the infection rate is below a threshold. We show that the impact of locally spreading awareness is amplified if the social network of potential infection events and the network over which individuals communicate overlap, especially so if the networks have a high level of clustering. These findings suggest that care needs to be taken both in the interpretation of disease parameters, as well as in the prediction of the fate of future outbreaks.

Ethylene and alpha-farnesene metabolism in green and red skin of three apple cultivars in response to 1-methylcyclopropene (1-MCP) treatment.

Relationships among alpha-farnesene synthesis and oxidation, ethylene production and perception, antioxidative enzyme activities, and superficial scald development in fruit of three commercial apple cultivars were investigated at the biochemical and gene transcriptional levels. Scald-susceptible Cortland and Law Rome and scald-resistant Idared apples were untreated or treated with the ethylene action inhibitor 1-methylcyclopropene (1-MCP) and stored for up to 25 weeks at 0.5 degrees C. Separate blushed (red) and unblushed (green) peel tissue samples were taken at harvest and after 2, 4, 6, 10, 15, 20, and 25 weeks of storage. Large increases in peel tissue concentrations of alpha-farnesene and its conjugated trienol (CTol) oxidation products occurred in untreated Cortland and Law Rome and were about 4-9-fold greater than those in Idared. In both Cortland and Law Rome, accumulation of CTols in green peel was nearly twice that in red peel. 1-MCP treatment delayed and attenuated alpha-farnesene and CTol accumulation in each cultivar. Activities of peroxidase (POX) and catalase (CAT) were lower in red peel than in green peel, with the exception of CAT in Law Rome, whereas no effects of 1-MCP on enzyme activities were detected except for Cortland. In control fruit, internal ethylene concentrations (IECs) increased during the first 4-6 weeks to reach highest levels in Cortland, intermediate levels in Law Rome, and low levels in Idared. In 1-MCP-treated fruit, IECs increased gradually to modest levels by 25 weeks in Cortland and Law Rome but were almost nil in Idared. Expression patterns of the alpha-farnesene synthase gene MdAFS1, the ethylene receptor gene MdERS1, and the ethylene biosynthetic genes MdACS1 and MdACO1 were generally in accord with the patterns of alpha-farnesene and ethylene production. In particular, MdAFS1 and MdACS1 showed similar patterns of expression in each cultivar. Among the controls, transcript levels increased more rapidly in Cortland and Law Rome than in Idared during the first few weeks of storage. In 1-MCP-treated fruit, transcript abundance in Cortland and Law Rome rose to untreated control levels after 10-15 weeks but remained low in Idared. Scald symptoms were restricted to unblushed skin, and the incidence in controls after 25 weeks was nearly 100% in Cortland and Law Rome compared with 1% in Idared. 1-MCP treatment reduced scald incidence to 14, 3, and 0% in Cortland, Law Rome, and Idared, respectively. Overall, the results support the proposed role of CTols in scald induction and indicate that alpha-farnesene synthesis is tightly regulated by ethylene. However, gene transcription alone does not account for the big differences in ethylene and alpha-farnesene production in Cortland, Law Rome, and Idared apples.

A reevaluation of the key factors that influence tomato fruit softening and integrity.

The softening of fleshy fruits, such as tomato (Solanum lycopersicum), during ripening is generally reported to result principally from disassembly of the primary cell wall and middle lamella. However, unsuccessful attempts to prolong fruit firmness by suppressing the expression of a range of wall-modifying proteins in transgenic tomato fruits do not support such a simple model. 'Delayed Fruit Deterioration' (DFD) is a previously unreported tomato cultivar that provides a unique opportunity to assess the contribution of wall metabolism to fruit firmness, since DFD fruits exhibit minimal softening but undergo otherwise normal ripening, unlike all known nonsoftening tomato mutants reported to date. Wall disassembly, reduced intercellular adhesion, and the expression of genes associated with wall degradation were similar in DFD fruit and those of the normally softening 'Ailsa Craig'. However, ripening DFD fruit showed minimal transpirational water loss and substantially elevated cellular turgor. This allowed an evaluation of the relative contribution and timing of wall disassembly and water loss to fruit softening, which suggested that both processes have a critical influence. Biochemical and biomechanical analyses identified several unusual features of DFD cuticles and the data indicate that, as with wall metabolism, changes in cuticle composition and architecture are an integral and regulated part of the ripening program. A model is proposed in which the cuticle affects the softening of intact tomato fruit both directly, by providing a physical support, and indirectly, by regulating water status.

The use of 1-methylcyclopropene (1-MCP) on fruits and vegetables.

The recent availability of the inhibitor of ethylene perception, 1-methylcyclopropene (1-MCP), has resulted in an explosion of research on its effects on fruits and vegetables, both as a tool to further investigate the role of ethylene in ripening and senescence, and as a commercial technology to improve maintenance of product quality. The commercialization of 1-MCP was followed by rapid adoption by many apple industries around the world, and strengths and weaknesses of the new technology have been identified. However, use of 1-MCP remains limited for other products, and therefore it is still necessary to speculate on its commercial potential for most fruits and vegetables. In this review, the effects of 1-MCP on fruits and vegetables are considered from two aspects. First, a selected number of fruit (apple, avocado, banana, pear, peaches and nectarines, plums and tomato) are used to illustrate the range of responses to 1-MCP, and indicate possible benefits and limitations for commercialization of 1-MCP-based technology. Second, an outline of general physiological and biochemical responses of fruits and vegetables to the chemical is provided to illustrate the potential for use of 1-MCP to better understand the role of ethylene in ripening and senescence processes.

Nuclear Receptor Signaling Atlas (www.nursa.org): hyperlinking the nuclear receptor signaling community.

The nuclear receptor signaling (NRS) field has generated a substantial body of information on nuclear receptors, their ligands and coregulators, with the ultimate goal of constructing coherent models of the biological and clinical significance of these molecules. As a component of the Nuclear Receptor Signaling Atlas (NURSA)--the development of a functional atlas of nuclear receptor biology--the NURSA Bioinformatics Resource is developing a strategy to organize and integrate legacy and future information on these molecules in a single web-based resource (www.nursa.org). This entails parallel efforts of (i) developing an appropriate software framework for handling datasets from NURSA laboratories and (ii) designing strategies for the curation and presentation of public data relevant to NRS. To illustrate our approach, we have described here in detail the development of a web-based interface for the NURSA quantitative PCR nuclear receptor expression dataset, incorporating bioinformatics analysis which provides novel perspectives on functional relationships between these molecules. We anticipate that the free and open access of the community to a platform for data mining and hypothesis generation strategies will be a significant contribution to the progress of research in this field.

Disabling musculoskeletal pain and its relation to somatization: a community-based postal survey.

BACKGROUND: Somatization (a tendency to report distress from somatic symptoms) is a little studied, but potentially important, confounder and effect modifier in occupational studies of musculoskeletal disease. AIMS: To assess the role of somatization as a risk factor for disabling regional pain. METHODS: A questionnaire was mailed to 4998 subjects of working age. Questions were asked about chronic and disabling pain in the past 12 months affecting the arm, low back, knee or combinations of these sites. Distress from physical symptoms was assessed using elements of the Brief Symptom Inventory and mental well-being was assessed using the short-form 36 (SF-36). Associations were examined by modified Cox regression and expressed as hazard ratios (HRs) with 95% confidence intervals (CI). RESULTS: Among 2632 responders, 24% reported chronic pain and 25% disabling pain at one or several sites. Risk of chronic or disabling pain increased strongly according to the number of somatic symptoms reported as bothersome. For example, the HR for chronic upper limb pain in those distressed by > or =2 somatic symptoms in the past 7 days versus none was 3.9 (95% CI 2.9-5.3), and that of disabling upper limb pain was 5.8 (95% CI 4.1-8.3). Similar patterns were found for the low back and knee, and there was a gradient of increasing risk according to the number of sites with disabling pain. In comparison, associations with SF-36 mental well-being score were weaker. CONCLUSION: Somatizing tendency should be evaluated as a possible confounder or effect modifier in studies of occupational risk factors for musculoskeletal pain.