Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements

Label-free biosensor technology based on dynamic mass redistribution (DMR) of cellular constituents promises to translate GPCR signaling into complex optical 'fingerprints' in real time in living cells. Here we present a strategy to map cellular mechanisms that define label-free responses, and we compare DMR technology with traditional second-messenger assays that are currently the state of the art in GPCR drug discovery. The holistic nature of DMR measurements enabled us to (i) probe GPCR functionality along all four G-protein signaling pathways, something presently beyond reach of most other assay platforms; (ii) dissect complex GPCR signaling patterns even in primary human cells with unprecedented accuracy; (iii) define heterotrimeric G proteins as triggers for the complex optical fingerprints; and (iv) disclose previously undetected features of GPCR behavior. Our results suggest that DMR technology will have a substantial impact on systems biology and systems pharmacology as well as for the discovery of drugs with novel mechanisms

Soothing the Threatened Brain: Leveraging Contact Comfort with Emotionally Focused Therapy

Social relationships are tightly linked to health and well-being. Recent work suggests that social relationships can even serve vital emotion regulation functions by minimizing threat-related neural activity. But relationship distress remains a significant public health problem in North America and elsewhere. A promising approach to helping couples both resolve relationship distress and nurture effective interpersonal functioning is Emotionally Focused Therapy for couples (EFT), a manualized, empirically supported therapy that is strongly focused on repairing adult attachment bonds. We sought to examine a neural index of social emotion regulation as a potential mediator of the effects of EFT. Specifically, we examined the effectiveness of EFT for modifying the social regulation of neural threat responding using an fMRI-based handholding procedure. Results suggest that EFT altered the brain\u27s representation of threat cues in the presence of a romantic partner. EFT-related changes during stranger handholding were also observed, but stranger effects were dependent upon self-reported relationship quality. EFT also appeared to increase threat-related brain activity in regions associated with self-regulation during the no-handholding condition. These findings provide a critical window into the regulatory mechanisms of close relationships in general and EFT in particular

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

A longitudinal evaluation of cognitive fatigue on a task of sustained attention in early relapsing-remitting multiple sclerosis

Background: Cognitive fatigue can be objectively measured on tasks of sustained attention and can be defined as decreased performance as a result of sustained cognitive effort. Individuals with multiple sclerosis (MS) early in their disease are vulnerable to cognitive fatigue, although this has yet to be evaluated longitudinally. We aimed to evaluate cognitive fatigue over a 3-year interval in individuals with early-phase relapsing-remitting MS (RRMS). The sensitivity of the Paced Auditory Serial Addition Test (PASAT) at detecting cognitive fatigue was evaluated, as was the impact of scoring method. Methods: 32 people with MS and 32 controls completed the 3- and 2-second PASAT (PASAT-3" and -2") as a measure of sustained attention at baseline and 3-year follow-up. Results: Performance on the PASAT remained stable across time, with improvement noted on the PASAT- 2" likely due to practice and the small sample size. Cognitive fatigue was noted at both times, although sensitivity varied based on scoring method. No evidence of worsening cognitive fatigue was noted over time. The MS group performed worse only when cognitive fatigue was the outcome variable. Conclusions: Although individuals with MS continue to be vulnerable to cognitive fatigue at follow-up, severity does not seem to increase with time. Cognitive fatigue may be a more sensitive marker of cognitive impairment than overall task performance in those with early-phase RRMS, which has important implications given t

Predictive Models of Cognitive Fatigue in Multiple Sclerosis

Objective: Cognitive fatigue (CF) can be defined as decreased performance with sustained cognitive effort. The present study examined the interrelatedness of disease severity, fatigue, depression, and sleep quality in order to evaluate their predictive roles of CF in MS. Four theoretical models examining these variables were assessed. Methods: Fifty-eight individuals with a diagnosis of MS were recruited. CF was measured by examining last third versus first third performance on the Paced Auditory Serial Addition Test (PASAT). The PASAT and self-report measures of fatigue, depression, and sleep quality were administered. Path analysis was used to evaluate each of the models. Results: CF was correlated only with depression (r = .362, p = .006) and sleep quality (r = .433, p = .001). Sleep quality was the greatest significant independent predictor of CF (β = .433, t(1,55) = 3.53, p < .001), accounting for 17.3% of the total variance. The best fitting model showed sleep quality as the largest contributor to CF; however, depression played a smaller predictive role. Furthermore, depression emerged as the strongest predictor of sleep quality and fatigue. Disease severity weakly predicted depression. Conclusions: Sleep quality is the most significant predictor of CF in MS. As such, sleep quality may be a treatable cause of CF. Sleep quality itself, however, accounted for only 17.3% of the variance in C

Abnormal response inhibition in criminal psychopaths: Evidence from event-related fMRI

Introduction Psychopathy is a personality disorder characterised by disturbance in affective, interpersonal, and behavioural domains. Typically, it is the behavioural disturbances, including impulsivity, poor behavioural controls, and persistent contravention of societal norms, that brings the psychopath to the attention of society. The psychopaths’ behavioural disturbance has been conceptualized as arising from impaired response inhibition. Event-related potential research (Kiehl et al., 2000, Biological Psychiatry, 48) suggests that psychopathy is associated with abnormal neural activity during suppression of inappropriate responses. We used event-related fMRI to elucidate the neurobiological correlates of response inhibition during performance of a Go/NoGo task. Using this task in healthy controls Liddle et al. (2001, Human Brain Mapping, 12) demonstrated the importance of lateral frontal cortex in response inhibition. We hypothesised that psychopaths would show less activation in lateral frontal cortex during processing of NoGo stimuli than would healthy controls. Methods Fourteen psychopaths were recruited from a maximum-security prison and compared with fourteen healthy control participants selected from the general population. Psychopathy was assessed using the Hare Psychopathy Checklist-Revised (PCL-R) (Hare, 1991). Groups were matched for age, parental socioeconomic status, and IQ. All participants were right-handed, native English speakers, without history of head injury or psychotic illness. Task procedures are as described in Liddle et al. (2001). The visual stimuli for the Go and NoGo trials were the letters ‘X’ and ‘A’ respectively, presented for a period of 250 msecs each. Each trial commenced with a descending count of asterisks in order to increase motor response preparation. Twenty-four Go and 24 NoGo trials were randomly presented in a single scanning session. Imaging was performed using a General Electric 1.5 T whole body system fitted with a Horizon echo-speed upgrade. Functional image volumes were collected with a gradient-echo sequence (TR/IE 2500/50 ms, flip angle 90”, FOV 24x24 cm, 64x64 matrix, 62.5 kHz bandwidth, 3.75x3.75 mm in plane resolution, 4 mm slice thickness, 29 slices). Functional images were realigned, normalised, and smoothed using Statistical Parametric Mapping (SPM99). Event-related responses to the Go and NoGo stimuli were modeled with a synthetic haemodynamic response function composed of two gamma functions and their temporal derivatives. To test the hypothesis of reduced activation in lateral frontal cortex in psychopaths, we tested for significant group differences in activation during NoGo trials within I0mm diameter spherical regions centred on the loci of activation in lateral frontal cortex reported by Liddle et al. (2001). Results No significant differences between groups in accuracy of performance were observed. In accordance with the hypothesis, psychopaths exhibited significantly less activation in lateral frontal cortex, bilaterally, than healthy controls during NoGo trials: xyz = -48 -4 52, Z=3.78; xyz = 36 0 36, Z=3.66. Discussion We have demonstrated that inhibiting a behavioural response is associated with less lateral frontal activation in psychopaths compared to healthy control subjects. This is consistent with previous electrophysiological findings. Kiehl et al. (2000) reported that psychopaths exhibited a reduced amplitude of the frontal negative potential (N275) during NoGo trials. Taken together, these findings indicate that the cerebral mechanism for response inhibition is impaired in psychopathy