The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice.

BACKGROUND: Specification of primordial germ cells in mice depends on instructive signalling events, which act first to confer germ cell competence on epiblast cells, and second, to impose a germ cell fate upon competent precursors. fragilis, an interferon-inducible gene coding for a transmembrane protein, is the first gene to be implicated in the acquisition of germ cell competence. RESULTS: Here, we describe four additional fragilis-related genes, fragilis2-5, which are clustered within a 68 kb region in the vicinity of the fragilis locus on Chr 7. These genes exist in a number of mammalian species, which in the human are also clustered on the syntenic region on Chr 11. In the mouse, fragilis2 and fragilis3, which are proximate to fragilis, exhibit expression that overlaps with the latter in the region of specification of primordial germ cells. Using single cell analysis, we confirm that all these three fragilis-related genes are predominant in nascent primordial germ cells, as well as in gonadal germ cells. CONCLUSION: The Fragilis family of interferon-inducible genes is tightly associated with germ cell specification in mice. Furthermore, its evolutionary conservation suggests that it probably plays a critical role in all mammals. Detailed analysis of these genes may also elucidate the role of interferons as signalling molecules during development

Annual report on surveillance of respiratory infectious diseases 2013, the Netherlands

Het griepseizoen (influenza) 2013/2014 was erg mild, na de uitzonderlijk langdurende epidemie in het seizoen 2012/2013. Ook was het een mild seizoen wat betreft het aantal mensen dat een longontsteking (pneumonie) opliep. In 2013 waren er geen grote uitbraken van de meldingsplichtige luchtweginfectieziekten legionellose (308 meldingen), papegaaienziekte (psittacose; 51 meldingen), Q-koorts (19 meldingen) en tuberculose (848 meldingen). Deze aantallen waren in het verslagjaar vergelijkbaar of lager dan het aantal meldingen in voorgaande jaren. Dit blijkt uit de jaarlijkse surveillance luchtweginfectieziekten 2013 van het RIVM. Griep en longontsteking leiden tot veel ziekenhuisopnames en sterfte in Nederland, waardoor het RIVM ze actief volgt. In vergelijking met griep komen de meldingsplichtige luchtweginfecties in Nederlands maar weinig voor. Ze zijn meldingsplichtig, omdat tijdige maatregelen, zoals de besmettingsbron opsporen, belangrijk kunnen zijn om uitbraken of verdere verspreiding van de ziekte te voorkomen. Het RIVM volgt ook potentieel gevaarlijke nieuwe luchtweginfecties die elders in de wereld voorkomen. In mei 2014 werden voor het eerst in Nederland twee patiënten gediagnostiseerd met het MERS coronavirus. In het seizoen 2013/2014 lag het aantal mensen dat met griepachtige klachten bij de huisarts kwam begin 2014 gedurende vier weken boven de grens waarmee een griepepidemie wordt geduid. Bij de patiënten met griepachtige klachten kwam naast influenzavirus vaak RSV (respiratoir syncytieel virus) en neusverkoudheid (rhinovirus) voor. Er kwamen minder mensen met een longontsteking bij de huisarts dan voorgaande seizoenen, maar het aantal longontstekingpatiënten in verpleeghuizen bleef gelijk.The 2013/2014 influenza season was extremely mild in the Netherlands, compared to the exceptionally long-lasting epidemic in 2012/2013. In addition, the number of pneumonia patients and overall mortality, possible complications of influenza, were low. In 2013, no major outbreaks of the notifiable respiratory infectious diseases legionellosis (308 notifications), psittacosis (51 notifications), Q-fever (19 notifications) and tuberculosis (848 notifications) occurred. These incidences are either comparable to or lower than preceding years. These are the outcomes of the annual report: 'Surveillance of respiratory infectious diseases 2013, the Netherlands', published by the Dutch National Institute for Public Health and the Environment (RIVM). Influenza and pneumonia are an important cause of hospital admissions and death in the Netherlands, a reason for the RIVM to actively monitor these diseases. In comparison to influenza, notifiable respiratory infectious diseases only rarely occur. These diseases are notifiable, as timely measures like source finding, are important for preventing outbreaks and/ or ongoing transmission of the disease. The RIVM also monitors potential threats to public health from new (worldwide) respiratory infections. In May 2014, the first two cases of MERS coronavirus were diagnosed in the Netherlands. During the 2013/2014 influenza-season, the number of patients with influenza-like illness (ILI) consulting a general practitioner, was above the threshold set for an influenza epidemic for four weeks at the beginning of 2014. In nose and throat samples of ILI-patients, RSV (respiratory syncytial virus) and rhinovirus were found in addition to the influenza virus. During the 2013/2014 influenza-season, fewer patients consulted the general practitioner for pneumonia than in previous years, however the number of pneumonia patients in nursing homes was similar.Ministerie van VW

Teleology and Realism in Leibniz's Philosophy of Science

This paper argues for an interpretation of Leibniz’s claim that physics requires both mechanical and teleological principles as a view regarding the interpretation of physical theories. Granting that Leibniz’s fundamental ontology remains non-physical, or mentalistic, it argues that teleological principles nevertheless ground a realist commitment about mechanical descriptions of phenomena. The empirical results of the new sciences, according to Leibniz, have genuine truth conditions: there is a fact of the matter about the regularities observed in experience. Taking this stance, however, requires bringing non-empirical reasons to bear upon mechanical causal claims. This paper first evaluates extant interpretations of Leibniz’s thesis that there are two realms in physics as describing parallel, self-sufficient sets of laws. It then examines Leibniz’s use of teleological principles to interpret scientific results in the context of his interventions in debates in seventeenth-century kinematic theory, and in the teaching of Copernicanism. Leibniz’s use of the principle of continuity and the principle of simplicity, for instance, reveal an underlying commitment to the truth-aptness, or approximate truth-aptness, of the new natural sciences. The paper concludes with a brief remark on the relation between metaphysics, theology, and physics in Leibniz

Evolutionary relationships between Rhynchosporium lolii sp. nov. and other Rhynchosporium species on grass.

Copyright: 2013 King et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThe fungal genus Rhynchosporium (causative agent of leaf blotch) contains several host-specialised species, including R. commune (colonising barley and brome-grass), R. agropyri (couch-grass), R. secalis (rye and triticale) and the more distantly related R. orthosporum (cocksfoot). This study used molecular fingerprinting, multilocus DNA sequence data, conidial morphology, host range tests and scanning electron microscopy to investigate the relationship between Rhynchosporium species on ryegrasses, both economically important forage grasses and common wild grasses in many cereal growing areas, and other plant species. Two different types of Rhynchosporium were found on ryegrasses in the UK. Firstly, there were isolates of R. commune that were pathogenic to both barley and Italian ryegrass. Secondly, there were isolates of a new species, here named R. lolii, that were pathogenic only to ryegrass species. R. lolii was most closely related to R. orthosporum, but exhibited clear molecular, morphological and host range differences. The species was estimated to have diverged from R. orthosporum ca. 5735 years before the present. The colonisation strategy of all of the different Rhynchosporium species involved extensive hyphal growth in the sub-cuticular regions of the leaves. Finally, new species-specific PCR diagnostic tests were developed that could distinguish between these five closely related Rhynchosporium species.Peer reviewedFinal Published versio

Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome

BACKGROUND: Fatigue is a crucial sensation that triggers rest, yet its underlying neuronal mechanisms remain unclear. Intense long-term fatigue is a symptom of chronic fatigue syndrome, which is used as a model to study the mechanisms underlying fatigue. METHODS: Using magnetic resonance imaging, we conducted voxel-based morphometry of 16 patients and 49 age-matched healthy control subjects. RESULTS: We found that patients with chronic fatigue syndrome had reduced gray-matter volume in the bilateral prefrontal cortex. Within these areas, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue of the subjects. CONCLUSION: These results are consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, which is one of the biochemical markers of chronic fatigue syndrome, in the prefrontal cortex. Thus, the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue

The evolutionary dynamics of extrachromosomal DNA in human cancers

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer

Transcranial direct current stimulation of right dorsolateral prefrontal cortex does not affect model-based or model-free reinforcement learning in humans

There is broad consensus that the prefrontal cortex supports goal-directed, model-based decision-making. Consistent with this, we have recently shown that model-based control can be impaired through transcranial magnetic stimulation of right dorsolateral prefrontal cortex in humans. We hypothesized that an enhancement of model-based control might be achieved by anodal transcranial direct current stimulation of the same region. We tested 22 healthy adult human participants in a within-subject, double-blind design in which participants were given Active or Sham stimulation over two sessions. We show Active stimulation had no effect on model-based control or on model-free ('habitual') control compared to Sham stimulation. These null effects are substantiated by a power analysis, which suggests that our study had at least 60% power to detect a true effect, and by a Bayesian model comparison, which favors a model of the data that assumes stimulation had no effect over models that assume stimulation had an effect on behavioral control. Although we cannot entirely exclude more trivial explanations for our null effect, for example related to (faults in) our experimental setup, these data suggest that anodal transcranial direct current stimulation over right dorsolateral prefrontal cortex does not improve model-based control, despite existing evidence that transcranial magnetic stimulation can disrupt such control in the same brain region

The Darlington and Northallerton Long Term Asthma Study: pulmonary function

BACKGROUND: The Darlington and Northallerton Asthma Study is an observational cohort study started in 1983. At that time little was published about long term outcome in asthma and the contribution of change in reversible disease or airway remodelling to any excess deterioration in function. The study design included regular review of overall and fixed function lung. We report the trends over fifteen years. METHODS: All asthmatics attending secondary care in 1983, 1988 and 1993 were recruited. Pulmonary function was recorded at attendance and potential best function estimated according to protocol. Rate of decline was calculated over each 5-year period and by linear regression analysis in those seen every time. The influence of potential explanatory variables on this decline was explored. RESULTS: 1724 satisfactory 5-year measurements were obtained in 912 subjects and in 200 subjects on all occasions. Overall rate of decline (ml/year (95%CI)) calculated from 5-year periods was FEV1 ♂41.0 (34.7–47.3), ♀28.9 (23.2–34.6) and best FVC ♂63.1 (55.1–71.2)ml/year, ♀45.8 (40.0–51.6).The principal association was with age. A dominant cubic factor suggested fluctuations in the rate of change in middle life with less rapid decline in youth and more rapid decline in the elderly. Rapid decline was possibly associated with short duration. Treatment step did not predict rate of deterioration. CONCLUSIONS: Function declined non-linearly and more rapidly than predicted from normal subjects. It reports for the first time a cubic relationship between age and pulmonary function. This should be taken into account when interpreting other articles reporting change in function over time

Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.