Stimulation of translation by human Unr requires cold shock domains 2 and 4, and correlates with poly(A) binding protein interaction

The RNA binding protein Unr, which contains five cold shock domains, has several specific roles in post-transcriptional control of gene expression. It can act as an activator or inhibitor of translation initiation, promote mRNA turnover, or stabilise mRNA. Its role depends on the mRNA and other proteins to which it binds, which includes cytoplasmic poly(A) binding protein 1 (PABP1). Since PABP1 binds to all polyadenylated mRNAs, and is involved in translation initiation by interaction with eukaryotic translation initiation factor 4G (eIF4G), we investigated whether Unr has a general role in translational control. We found that Unr strongly stimulates translation in vitro, and mutation of cold shock domains 2 or 4 inhibited its translation activity. The ability of Unr and its mutants to stimulate translation correlated with its ability to bind RNA, and to interact with PABP1. We found that Unr stimulated the binding of PABP1 to mRNA, and that Unr was required for the stable interaction of PABP1 and eIF4G in cells. siRNA-mediated knockdown of Unr reduced the overall level of cellular translation in cells, as well as that of cap-dependent and IRES-dependent reporters. These data describe a novel role for Unr in regulating cellular gene expression

Clinical measurements performed during alfaxalone total intravenous anaesthesia for radiography and neurophysiological investigations in dogs

Objective: To describe clinically relevant, physiological measurements collected during a 3- hour duration alfaxalone total intravenous anaesthesia.Study design: Case series.Animals: A total of 112 client-owned middle aged or older dogs.Methods: Dogs were premedicated with intramuscular acepromazine (0.03 mg kg-1). Anaesthesia was induced and subsequently maintained for up to 3 hours with alfaxalone administered intravenously. Dogs breathed 100% oxygen via an endotracheal tube. Heart rate, respiratory rate, and blood pressure were evaluated 30 minutes after administration of acepromazine and used as baseline values for comparisons of intra-anaesthetic data. Blood glucose was measured one week prior to anaesthesia and every hour during alfaxalone anaesthesia. Quality and duration of recovery were recorded. Mean data for physiological variables were compared over three time points; before induction of anaesthesia, forthe first hour of anaesthesia and from 60 minutes to discontinuation of anaesthesia.Results: Mean induction dose of alfaxalone was 1.4 (95% CI 1.3 - 1.5) mg kg-1. Post induction apnoea for greater than 60 seconds occurred in 13 (11.6%) dogs. Mean alfaxalone infusion rate during the first 60 minutes of anaesthesia was 0.099 mg kg-1 minute-1; from 60 minutes until discontinuation of anaesthesia, mean infusion rate was 0.092 mg kg-1 minute-1. Heart rate was well maintained; hypotension (mean arterial blood pressure less than 60 mmHg) was encountered in 23 (21%) of dogs. Blood glucose levels did not alter during anaesthesia. Median time between discontinuation of alfaxalone infusion and extubation was 17 (7 – 35 minutes), time to assuming sternal recumbency was 75 (58 - 110 minutes), and time to standing was 109 (88 - 140 minutes).Conclusions and clinical relevance: Alfaxalone infusion provided effective anaesthesia in this population. In a minority of cases respiratory and haemodynamic support of the patient was required

Changing gender roles and attitudes and their implications for well-being around the new millennium

<b>Purpose</b><p></p> Given evidence that gender role attitudes (GRAs) and actual gender roles impact on well-being, we examine associations between GRAs, three roles (marital status, household chore division, couple employment) and psychological distress in working-age men and women. We investigate time-trends reflecting broader social and economic changes, by focusing on three age groups at two dates.<p></p> <b>Methods</b><p></p> We used British Household Panel Survey data from 20- to 64-year-olds in heterosexual couple households in 1991 (N = 5,302) and 2007 (N = 6,621). We examined: levels of traditional GRAs according to gender, age, date, household and employment roles; associations which GRAs and roles had with psychological distress (measured via the GHQ-12); whether psychological distress increased when GRAs conflicted with actual roles; and whether any of these associations differed according to gender, age or date.<p></p> <b>Results</b><p></p> Gender traditionalism was lower among women, younger people, those participating in 2007 and in ‘less traditional’ relationships and households. Psychological distress was higher among those with more traditional GRAs and, particularly among men, for those not employed, and there was some evidence of different patterns of association according to age-group. There was limited evidence, among women only, of increased psychological distress when GRAs and actual roles conflicted and/or reductions when GRAs and roles agreed, particularly in respect of household chores and paid employment.<p></p> <b>Conclusions</b><p></p> Although some aspects of gender roles and attitudes (traditionalism and paid employment) are associated with well-being, others (marital status and household chores), and attitude-role consistency, may have little impact on the well-being of contemporary UK adults.<p></p&gt

Electrophysiological characterisation of central sensitisation in canine spontaneous osteoarthritis

In man, central sensitisation (CS) contributes to the pain of osteoarthritis (OA). Dogs with spontaneous OA may also exhibit CS. Electrophysiological reflex measurements are more objective than behavioural assessments, and can be used to evaluate CS in preclinical and clinical studies. It was hypothesised that dogs suffering from OA would exhibit electrophysiological characteristics indicative of CS, associated with reduced diffuse noxious inhibitory controls (DNIC). 117 client owned dogs were recruited to the study. Hindlimb nociceptive withdrawal reflex (NWR) thresholds, stimulus response, and temporal summation characteristics were recorded, during alfaxalone anaesthesia, from 46 OA dogs, 29 OA dogs receiving non-steroidal anti-inflammatory drugs (OANSAID), and 27 breed- and weight-matched control dogs. Efficacy of DNIC was evaluated in 12 control and 11 of the OA dogs, by application of a mechanical conditioning stimulus to the contralateral forelimb. NWR thresholds were higher in OA compared with control dogs (p = 0.02). Stimulus response characteristics demonstrated an augmented response in OANSAID dogs compared with OA (p < 0.001) and control (p < 0.001) dogs. Temporal summation demonstrated exaggerated C-fibre mediated responses in both OA (p < 0.001) and OANSAID (p = 0.005) groups, compared with control animals. Conditioning stimulus application resulted in inhibition of test reflex responses in both OA and control animals (p < 0.001); control animals demonstrated greater inhibition compared with OA (p = 0.0499). These data provide evidence of neurophysiological changes consistent with CS in dogs with spontaneous OA, and demonstrate that canine OA is associated with reduced DNIC

A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13).

BACKGROUND: Rhinovirus infection is a major cause of asthma exacerbations. OBJECTIVES: We studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations. METHODS: We used nasosorption on days 0, 2-5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n=28) and healthy non-atopic controls (n=11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay. RESULTS: Following rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P<0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0-7, all P<0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P<0.01) and levels increased by days 3 and 4 (P<0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P<0.05). CONCLUSIONS: Precision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. METHODS: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. FINDINGS: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. INTERPRETATION: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. FUNDING: National Institute for Health Research, Health Technology Assessment programme

Opportunities for mesoscopics in thermometry and refrigeration: Physics and applications

This review presents an overview of the thermal properties of mesoscopic structures. The discussion is based on the concept of electron energy distribution, and, in particular, on controlling and probing it. The temperature of an electron gas is determined by this distribution: refrigeration is equivalent to narrowing it, and thermometry is probing its convolution with a function characterizing the measuring device. Temperature exists, strictly speaking, only in quasiequilibrium in which the distribution follows the Fermi-Dirac form. Interesting nonequilibrium deviations can occur due to slow relaxation rates of the electrons, e.g., among themselves or with lattice phonons. Observation and applications of nonequilibrium phenomena are also discussed. The focus in this paper is at low temperatures, primarily below 4 K, where physical phenomena on mesoscopic scales and hybrid combinations of various types of materials, e.g., superconductors, normal metals, insulators, and doped semiconductors, open up a rich variety of device concepts. This review starts with an introduction to theoretical concepts and experimental results on thermal properties of mesoscopic structures. Then thermometry and refrigeration are examined with an emphasis on experiments. An immediate application of solid-state refrigeration and thermometry is in ultrasensitive radiation detection, which is discussed in depth. This review concludes with a summary of pertinent fabrication methods of presented devices.Comment: Close to the version published in RMP; 59 pages, 35 figure

Visual perceptual load induces inattentional deafness

In this article, we establish a new phenomenon of “inattentional deafness” and highlight the level of load on visual attention as a critical determinant of this phenomenon. In three experiments, we modified an inattentional blindness paradigm to assess inattentional deafness. Participants made either a low- or high-load visual discrimination concerning a cross shape (respectively, a discrimination of line color or of line length with a subtle length difference). A brief pure tone was presented simultaneously with the visual task display on a final trial. Failures to notice the presence of this tone (i.e., inattentional deafness) reached a rate of 79% in the high-visual-load condition, significantly more than in the low-load condition. These findings establish the phenomenon of inattentional deafness under visual load, thereby extending the load theory of attention (e.g., Lavie, Journal of Experimental Psychology. Human Perception and Performance, 25, 596–616, 1995) to address the cross-modal effects of visual perceptual load

Calibration of Traffic Simulation Models using SPSA

Εθνικό Μετσόβιο Πολυτεχνείο--Μεταπτυχιακή Εργασία. Διεπιστημονικό-Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) “Γεωπληροφορική