Type I-F CRISPR-Cas resistance against virulent phages results in abortive infection and provides population-level immunity

This is the final version. Available from the publisher via the DOI in this record.Type I CRISPR-Cas systems are abundant and widespread adaptive immune systems in bacteria and can greatly enhance bacterial survival in the face of phage infection. Upon phage infection, some CRISPR-Cas immune responses result in bacterial dormancy or slowed growth, which suggests the outcomes for infected cells may vary between systems. Here we demonstrate that type I CRISPR immunity of Pectobacterium atrosepticum leads to suppression of two unrelated virulent phages, ɸTE and ɸM1. Immunity results in an abortive infection response, where infected cells do not survive, but viral propagation is severely decreased, resulting in population protection due to the reduced phage epidemic. Our findings challenge the view of CRISPR-Cas as a system that protects the individual cell and supports growing evidence of abortive infection by some types of CRISPR-Cas systems

Optimal search strategies for identifying sound clinical prediction studies in EMBASE

BACKGROUND: Clinical prediction guides assist clinicians by pointing to specific elements of the patient's clinical presentation that should be considered when forming a diagnosis, prognosis or judgment regarding treatment outcome. The numbers of validated clinical prediction guides are growing in the medical literature, but their retrieval from large biomedical databases remains problematic and this presents a barrier to their uptake in medical practice. We undertook the systematic development of search strategies ("hedges") for retrieval of empirically tested clinical prediction guides from EMBASE. METHODS: An analytic survey was conducted, testing the retrieval performance of search strategies run in EMBASE against the gold standard of hand searching, using a sample of all 27,769 articles identified in 55 journals for the 2000 publishing year. All articles were categorized as original studies, review articles, general papers, or case reports. The original and review articles were then tagged as 'pass' or 'fail' for methodologic rigor in the areas of clinical prediction guides and other clinical topics. Search terms that depicted clinical prediction guides were selected from a pool of index terms and text words gathered in house and through request to clinicians, librarians and professional searchers. A total of 36,232 search strategies composed of single and multiple term phrases were trialed for retrieval of clinical prediction studies. The sensitivity, specificity, precision, and accuracy of search strategies were calculated to identify which were the best. RESULTS: 163 clinical prediction studies were identified, of which 69 (42.3%) passed criteria for scientific merit. A 3-term strategy optimized sensitivity at 91.3% and specificity at 90.2%. Higher sensitivity (97.1%) was reached with a different 3-term strategy, but with a 16% drop in specificity. The best measure of specificity (98.8%) was found in a 2-term strategy, but with a considerable fall in sensitivity to 60.9%. All single term strategies performed less well than 2- and 3-term strategies. CONCLUSION: The retrieval of sound clinical prediction studies from EMBASE is supported by several search strategies

An extension of Laplace's method

Asymptotic expansions are obtained for contour integrals of the form $$\int_a^b \exp \left( - zp(t) + z^{\nu /\mu } r(t) \right)q(t)dt,$$ in which $z$ is a large real or complex parameter, $p(t)$, $q(t)$ and $r(t)$ are analytic functions of $t$, and the positive constants $\mu$ and $\nu$ are related to the local behaviour of the functions $p(t)$ and $r(t)$ near the endpoint $a$. Our main theorem includes as special cases several important asymptotic methods for integrals such as those of Laplace, Watson, Erd\'elyi and Olver. Asymptotic expansions similar to ours were derived earlier by Dingle using formal, non-rigorous methods. The results of the paper also serve to place Dingle's investigations on a rigorous mathematical foundation. The new results have potential applications in the asymptotic theory of special functions in transition regions, and we illustrate this by two examples.Comment: 19 pages, 2 figures, revised version, accepted for publication in Constructive Approximatio

Mindlessness Revisited: Sequential Request Techniques Foster Compliance by Draining Self-control Resources

The present research extends previous findings suggesting that sequential request techniques, such as the Foot-in-the-Door (FITD) or Door-in-the-Face (DITF) technique, are primarily effective under conditions conducive of mindlessness. We forward that this mindlessness may be the product of the influence technique itself. More specifically, based on the notion of self-control as a limited resource, we hypothesize that actively responding to the initial request-phase of a FITD-compliance gaining procedure drains the target of his/her self-regulatory resources, thus creating the mindlessness so often observed in social influence settings. This resource depletion opens the door for compliance with the target request. The results were in line with these expectations. More specifically, we observed that active responding to an initial request of a FITD technique reduced the availability of self-regulatory resources. This state of resource depletion mediated the effect of the technique on behavioral compliance. In addition, the results of this study ruled out the alternate explanation that the effects were attributable to mood or a general tendency for acquiescence

\u201cGive, but Give until It Hurts\u201d: The Modulatory Role of Trait Emotional Intelligence on the Motivation to Help

Two studies investigated the effect of trait Emotional Intelligence (trait EI) on people\u2019s moti- vation to help. In Study 1, we developed a new computer-based paradigm that tested partic- ipants\u2019 motivation to help by measuring their performance on a task in which they could gain a hypothetical amount of money to help children in need. Crucially, we manipulated partici- pants\u2019 perceived efficacy by informing them that they had been either able to save the chil- dren (positive feedback) or unable to save the children (negative feedback). We measured trait EI using the Trait Emotional Intelligence Questionnaire\u2013Short Form (TEIQue-SF) and assessed participants\u2019 affective reactions during the experiment using the PANAS-X. Results showed that high and low trait EI participants performed differently after the presen- tation of feedback on their ineffectiveness in helping others in need. Both groups showed increasing negative affective states during the experiment when the feedback was negative; however, high trait EI participants better managed their affective reactions, modulating the impact of their emotions on performance and maintaining a high level of motivation to help. In Study 2, we used a similar computerized task and tested a control situation to explore the effect of trait EI on participants\u2019 behavior when facing failure or success in a scenario unre- lated to helping others in need. No effect of feedback emerged on participants\u2019 emotional states in the second study. Taken together our results show that trait EI influences the impact of success and failure on behavior only in affect-rich situation like those in which people are asked to help others in need

GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis

The Parkinson’s disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1-/-), using CRISPR/Cas technology. gch1-/- zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 dpf, movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-Dopa treatment of gch1-/- larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1-/- larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphological and functional evidence of microglial activation in gch1-/-. The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for GWAS risk factors and further emphasises the important role of inflammation in the pathogenesis of PD

The sphere-in-contact model of carbon materials

A sphere-in-contact model is presented that is used to build physical models of carbon materials such as graphite, graphene, carbon nanotubes and fullerene. Unlike other molecular models, these models have correct scale and proportions because the carbon atoms are represented by their atomic radius, in contrast to the more commonly used space-fill models, where carbon atoms are represented by their van der Waals radii. Based on a survey taken among 65 undergraduate chemistry students and 28 PhD/postdoctoral students with a background in molecular modeling, we found misconceptions arising from incorrect visualization of the size and location of the electron density located in carbon materials. Based on analysis of the survey and on a conceptual basis we show that the sphere-in-contact model provides an improved molecular representation of the electron density of carbon materials compared to other molecular models commonly used in science textbooks (i.e., wire-frame, ball-and-stick, space-fill). We therefore suggest that its use in chemistry textbooks along with the ball-and-stick model would significantly enhance the visualization of molecular structures according to their electron density

Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE

The PINE study: rationale and design of a randomised comparison of epidural injection of local anaesthetics and steroids versus care-as-usual to prevent postherpetic neuralgia in the elderly [ISRCTN32866390]

BACKGROUND: Postherpetic neuralgia (PHN) is by far the most common complication of herpes zoster (HZ) and one of the most intractable pain disorders. Since PHN is seen most often in the elderly, the number of patients with this disorder is expected to increase in our ageing society. PHN may last for months to years and has a high impact on the quality of life. The results of PHN treatment are rather disappointing. Epidural injection of local anaesthetics and steroids in the acute phase of HZ is a promising therapy for the prevention of PHN. Since randomised trials on the effectiveness of this intervention are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. The PINE study compares the effectiveness and cost-effectiveness of a single epidural injection of local anaesthetics and steroids during the acute phase of HZ with that of care-as-usual (i.e. antivirals and analgesics) in preventing PHN in elderly patients. METHODS / DESIGN: The PINE study is an open, multicenter clinical trial in which 550 elderly (age ≥ 50 yr.) patients who consult their general practitioner in the acute phase of HZ (rash < 7 days) are randomised to one of the treatment groups. The primary clinical endpoint is the presence of HZ-related pain one month after the onset of the rash. Secondary endpoints include duration and severity of pain, re-interventions aiming to treat the existing pain, side effects, quality of life, and cost-effectiveness. CONCLUSION: The PINE study is aimed to quantify the (cost-) effectiveness of a single epidural injection during the acute phase of HZ on the prevention of PHN