A unified treatment of syntax with binders

International audienceAtoms and de Bruijn indices are two well-known representation techniques for data structures that involve names and binders. However, using either technique, it is all too easy to make a programming error that causes one name to be used where another was intended. We propose an abstract interface to names and binders that rules out many of these errors. This interface is implemented as a library in Agda. It allows defining and manipulating term representations in nominal style and in de Bruijn style. The programmer is not forced to choose between these styles: on the contrary, the library allows using both styles in the same program, if desired. Whereas indexing the types of names and terms with a natural number is a well-known technique to better control the use of de Bruijn indices, we index types with worlds. Worlds are at the same time more precise and more abstract than natural numbers. Via logical relations and parametricity, we are able to demonstrate in what sense our library is safe, and to obtain theorems for free about world-polymorphic functions. For instance, we prove that a world-polymorphic term transformation function must commute with any renaming of the free variables. The proof is entirely carried out in Agda

The effect of word prediction settings (frequency of use) on text input speed in persons with cervical spinal cord injury: a prospective study

International audiencePurpose: To determine whether activation of the frequency of use and automatic learning parameters ofword prediction software has an impact on text input speed.Methods: Forty-five participants with cervical spinal cord injury between C4 and C8 Asia A or B acceptedto participate to this study. Participants were separated in two groups: a high lesion group for participantswith lesion level is at or above C5 Asia AIS A or B and a low lesion group for participants with lesion isbetween C6 and C8 Asia AIS A or B. A single evaluation session was carried out for each participant. Textinput speed was evaluated during three copying tasks:- without word prediction software (WITHOUT condition)- with automatic learning of words and frequency of use deactivated (NOT_ACTIV condition)- with automatic learning of words and frequency of use activated (ACTIV condition)Results: Text input speed was significantly higher in the WITHOUT than the NOT_ACTIV (p<0.001) orACTIV conditions (p¼0.02) for participants with low lesions. Text input speed was significantly higher inthe ACTIV than in the NOT_ACTIV (p¼0.002) or WITHOUT (p<0.001) conditions for participants with highlesions.Conclusions: Use of word prediction software with the activation of frequency of use and automatic learningincreased text input speed in participants with high-level tetraplegia. For participants with low-leveltetraplegia, the use of word prediction software with frequency of use and automatic learning activatedonly decreased the number of errors

Influence of the Number of Predicted Words on Text Input Speed in Participants With Cervical Spinal Cord Injury: Influence of the number of predicted words in persons with SCI

International audienceObjective - To determine if the number of words displayed in the Word Prediction Software (WPS) list affects Text Input Speed (TIS) in people with cervical Spinal Cord Injury (SCI) and if any influence is dependent on the level of the lesion.Design - A cross-sectional trial.Setting - A rehabilitation center in France.Participants - Ninety persons with cervical SCI fulfilled the inclusion/exclusion criteria, 45 of whom agreed to participate. Lesion level was high (C4 and C5 Asia A or B) for 15 participants (high lesion group) and was between C6 and C8 Asia A or B for 30 participants (low lesion group).Methods - TIS was evaluated during 4. 10-minute copying tasks: -without WPS (Without)-with a display of 3 predicted words (3Words)-with a display of 6 predicted words (6Words)-with a display of 8 predicted (8Words)Outcome Measures -During the 4 copying tasks, TIS was measured objectively (characters per minute, number of errors) and subjectively through subject report (fatigue, perception of speed, cognitive load, satisfaction)Results -For participants with low cervical SCI, text input speed without WPS was faster than with WPS, regardless of the number of words displayed (p<0.001). For participants with high cervical SCI, the use of WPS did not influence TIS (p=0.99). There was no influence of the number of words displayed in a word prediction list on TIS, however perception of TIS differed according to lesion level.Conclusion - For persons with low cervical SCI, a small number of words should be displayed, or WPS should not be used at all. For persons with high cervical SCI, a larger number of words displayed increases the comfort of use of WP

In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile

William Evans and colleagues investigate the genomic determinants of methotrexate resistance and interpatient differences in methotrexate response in patients newly diagnosed with childhood acute lymphoblastic leukemia

TYROBP genetic variants in early-onset Alzheimer's disease

We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP, previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls (p = 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with in vitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression

miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al

Identification of Keratinocyte Growth Factor as a Target of microRNA-155 in Lung Fibroblasts: Implication in Epithelial-Mesenchymal Interactions

International audienceBACKGROUND: Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-alpha, IL-1beta and TGF-beta. METHODOLOGY/PRINCIPAL FINDINGS: MiR-155 was significantly induced by inflammatory cytokines TNF-alpha and IL-1beta while it was down-regulated by TGF-beta. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to "cell to cell signalling", "cell morphology" and "cellular movement". This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3'-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest a physiological function of miR-155 in lung fibroblasts. Altogether, this study implicates this miRNA in the regulation by mesenchymal cells of surrounding lung epithelium, making it a potential key player during tissue injury

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely