Weak cubic CaSiO3 perovskite in the Earth's mantle.

Cubic CaSiO3 perovskite is a major phase in subducted oceanic crust, where it forms at a depth of about 550 kilometres from majoritic garnet1,2,28. However, its rheological properties at temperatures and pressures typical of the lower mantle are poorly known. Here we measured the plastic strength of cubic CaSiO3 perovskite at pressure and temperature conditions typical for a subducting slab up to a depth of about 1,200 kilometres. In contrast to tetragonal CaSiO3, previously investigated at room temperature3,4, we find that cubic CaSiO3 perovskite is a comparably weak phase at the temperatures of the lower mantle. We find that its strength and viscosity are substantially lower than that of bridgmanite and ferropericlase, possibly making cubic CaSiO3 perovskite the weakest lower-mantle phase. Our findings suggest that cubic CaSiO3 perovskite governs the dynamics of subducting slabs. Weak CaSiO3 perovskite further provides a mechanism to separate subducted oceanic crust from the underlying mantle. Depending on the depth of the separation, basaltic crust could accumulate at the boundary between the upper and lower mantle, where cubic CaSiO3 perovskite may contribute to the seismically observed regions of low shear-wave velocities in the uppermost lower mantle5,6, or sink to the core-mantle boundary and explain the seismic anomalies associated with large low-shear-velocity provinces beneath Africa and the Pacific7-9.

X-ray dichroism in polyimide caused by non-resonant scattering.

Dichroism is one of the most important optical effects in both the visible and the X-ray range. Besides absorption, scattering can also contribute to dichroism. This paper demonstrates that, based on the example of polyimide, materials can show tiny dichroism even far from electronic resonances due to scattering. Although the effect is small, it can lead to a measurable polarization change and might have influence on highly sensitive polarimetric experiments.

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study.

BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

Presence of a 34-gene signature is a favorable prognostic marker in squamous non-small cell lung carcinoma.

BACKGROUND: The tumor immune microenvironment is a heterogeneous entity. Gene expression analysis allows us to perform comprehensive immunoprofiling and may assist in dissecting the different components of the immune infiltrate. As gene expression analysis also provides information regarding tumor cells, differences in interactions between the immune system and specific tumor characteristics can also be explored. This study aims to gain further insights in the composition of the tumor immune infiltrate and to correlate these components to histology and overall survival in non-small cell lung cancer (NSCLC). METHODS: Archival tissues from 530 early stage, resected NSCLC patients with annotated tumor and patient characteristics were analyzed using the NanoString nCounter Analysis system. RESULTS: Unsupervised clustering of the samples was mainly driven by the overall level of inflammation, which was not correlated with survival in this patient set. Adenocarcinoma (AD) showed a significantly higher degree of immune infiltration compared to squamous cell carcinoma (SCC). A 34-gene signature, which did not correlate with the overall level of immune infiltration, was identified and showed an OS benefit in SCC. Strikingly, this benefit was not observed in AD. This difference in OS in SCC specifically was confirmed in two independent NSCLC cohorts. The highest correlation between expression of the 34-gene signature and specific immune cell populations was observed for NK cells, but although a plausible mechanism for NK cell intervention in tumor growth could be established in SCC over AD, this could not be translated back to immunohistochemistry, which showed that NK cell infiltration is scarce irrespective of histology. CONCLUSIONS: These findings suggest that the ability of immune cell infiltration and the interaction between tumor and immune cells may be different between AD and SCC histology and that a subgroup of SCC tumors seems more susceptible to Natural Killer cell recognition and killing, whereas this may not occur in AD tumors. A highly sensitive technique like NanoString was able to detect this subgroup based on a 34-gene signature, but further research will be needed to assist in explaining the biological rationale of such low-level expression signatures.

Circulating factors cause proteinuria in parabiotic zebrafish.

Proteinuria can be induced by impairment of any component of the glomerular filtration barrier (GFB). To determine the role of circulating permeability factors on glomerular damage, we developed a parabiosis-based zebrafish model to generate a common circulation between zebrafish larvae. A morpholino-mediated knockdown of a podocyte specific gene (nephronectin) was induced in one zebrafish larva which was then fused to an un-manipulated fish. Notably, proteinuria and glomerular damage were present in the manipulated fish and in the parabiotically-fused partner. Thus, circulating permeability factors may be induced by proteinuria even when an induced podocyte gene dysregulation is the initiating cause.

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

The effect of surface roughness and viscoelasticity on rubber adhesion.

Adhesion between silica glass or acrylic balls and silicone elastomers and various industrial rubbers is investigated. The work of adhesion during pull-off is found to strongly vary depending on the system, which we attribute to the two opposite effects: (1) viscoelastic energy dissipation close to an opening crack tip and (2) surface roughness. Introducing surface roughness on the glass ball is found to increase the work of adhesion for soft elastomers, while for the stiffer elastomers it results in a strong reduction in the work of adhesion. For the soft silicone elastomers a strong increase in the work of adhesion with increasing pull-off velocity is observed, which may result from the non-adiabatic processes associated with molecular chain pull-out. In general, the work of adhesion is decreased after repeated contacts due to the transfer of molecules from the elastomers to the glass ball. Thus, extracting the free chains (oligomers) from the silicone elastomers is shown to make the work of adhesion independent of the number of contacts. The viscoelastic properties (linear and nonlinear) of all of the rubber compounds are measured, and the velocity dependent crack opening propagation energy at the interface is calculated. Silicone elastomers show a good agreement between the measured work of adhesion and the predicted results, but carbon black filled hydrogenated nitrile butadiene rubber compounds reveal that strain softening at the crack tip may play an important role in determining the work of adhesion. Additionally, adhesion measurement under submerged conditions in distilled water and water + soap solutions are also performed: a strong reduction in the work of adhesion is measured for the silicone elastomers submerged in water, and a complete elimination of adhesion is found for the water + soap solution attributed to an osmotic repulsion between the negatively charged surface of the glass and the elastomer.

What accounts for ethnic differences in newborn skinfold thickness comparing South Asians and White Caucasians? Findings from the START and FAMILY Birth Cohorts.

OBJECTIVE: South Asians are a high-risk group for type 2 diabetes and coronary heart disease. We sought to determine ethnic differences in newborn adiposity comparing South Asians (SA) to White Caucasians (Whites). METHODS: Seven hundred ninety pregnant women (401 SA, 389 Whites) and their full-term offspring from two birth cohorts in Canada were analyzed. Pregnant women completed a health assessment including a 75-g oral glucose tolerance test to assess for dysglycemia. Birthweight, length, waist and hip circumference, and triceps and subscapular skinfold thickness (a surrogate measure of body adiposity) were measured in all newborns. Multivariate regression was used to identify maternal factors associated with newborn skinfold measurements. RESULTS: South Asian women were younger (30.1 vs 31.8 years, P<0.001), their prepregnancy body mass index was lower (23.7 vs 26.2, P<0.0001) and gestational diabetes was substantially higher (21% vs 13%, P=0.005) compared with Whites. Among full-term newborns, South Asians had lower birthweight (3283 vs 3517 g, P=0.0001), had greater skinfold thickness (11.7 vs 10.6 mm; P=0.0001) and higher waist circumference (31.1 vs 29.9 cm, P=0.0001) compared with Whites. Risk factors for newborn skinfold thickness included South Asian ethnicity (standardized estimate (s.e.): 0.24; P<0.0001), maternal glucose (s.e.: 0.079; P=0.04) and maternal body fat (s.e.: 0.14; P=0.0002). CONCLUSIONS: South Asian newborns are lower birthweight and have greater skinfold thickness, compared with White newborns, and this is influenced by maternal body fat and glucose. Interventions aimed at reducing body fat prior to pregnancy and gestational diabetes during pregnancy in South Asians may favorably alter newborn body composition and require evaluation.

Persistence of immune responses to the HPV-16/18 AS04-adjuvanted vaccine in women aged 15-55 years and first-time modelling of antibody responses in mature women: results from an open-label 6-year follow-up study.

OBJECTIVE: Evaluation of the long-term HPV-16/18 AS04-adjuvanted vaccine immunogenicity persistence in women. DESIGN: Multicentre, open-label, long-term follow-up (NCT00947115) of a primary phase-III study (NCT00196937). SETTING: Six centres in Germany and Poland. POPULATION: 488 healthy women (aged 15-55 years, age-stratified into groups: 15-25, 26-45, and 46-55 years) who received three vaccine doses in the primary study. METHODS: Immune responses were evaluated in serum and cervicovaginal secretion (CVS) samples 6 years after dose 1. Anti-HPV-16/18 geometric mean titres (GMTs) were measured by enzyme-linked immunosorbent assay (ELISA), and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) were recorded. MAIN OUTCOME MEASURES: Anti-HPV-16/18 seropositivity rates and GMTs 6 years after dose 1. RESULTS: At 6 years after dose 1, all women were seropositive for anti-HPV-16 and ≥97% were seropositive for anti-HPV-18 antibodies. GMTs ranged from 277.7 to 1344.6 EU/ml, and from 97.6 to 438.2 EU/ml, for anti-HPV-16 and anti-HPV-18, respectively. In all age groups, GMTs were higher (anti-HPV-16, 9.3-45.1-fold; anti-HPV-18, 4.3-19.4-fold) than levels associated with natural infection (29.8 EU/ml). A strong correlation between serum and CVS anti-HPV-16/18 levels was observed, with correlation coefficients of 0.81-0.96 (anti-HPV-16) and 0.69-0.84 (anti-HPV-18). Exploratory modelling based on the 6-year data predicted vaccine-induced anti-HPV-16/18 levels above natural infection levels for at least 20 years, except for anti-HPV-18 in the older age group (piecewise model). One vaccine-related and two fatal SAEs were reported. CONCLUSIONS: At 6 years after vaccination, immune responses induced by the HPV-16/18 AS04-adjuvanted vaccine were sustained in all age groups.

Expression of antimicrobial peptides and interleukin-8 during early stages of inflammation: An experimental gingivitis study.

BACKGROUND AND OBJECTIVES: In the oral cavity, the epithelial surface is constantly exposed to a number of different microorganisms that are organized in a well-structured biofilm. The aim of this study was to monitor gingival expression of antimicrobial peptides (AMPs) and interleukin-8 (IL-8) in an early gingivitis model. MATERIAL AND METHODS: Experimental gingivitis was allowed to develop in healthy volunteers (n = 17). Bleeding on probing (BOP%) and gingival crevicular fluid volume (GCF) were assessed at baseline and day 1, 3, 5, 7 and 14. Expression of AMPs (human beta-defensin-2, hBD-2; CC-chemokine ligand 20, CCL20; psoriasin, pso/S100A7) and IL-8 was analyzed by immunohistochemistry in gingival biopsies. In addition, hBD-2 and IL-8 protein expression was monitored in GCF using the ELISA technology. RESULTS: Experimental gingivitis gradually developed with an increase in BOP scores and GCF volume over time. In GCF, elevated concentrations of hBD-2 and IL-8 were monitored at day 1, 5 and 7 (p ≤ 0.0002). Immunohistochemical analysis of gingival sections demonstrated increased staining for hBD-2 at day 3, whereas the CCL20, pso/S100A7, and IL-8 expression was increased at later time points (p < 0.05). CONCLUSION: For the first time, this study showed the time-dependent regulation of AMPs, following clinical signs of experimentally induced gingival inflammation. Differential temporal expression for AMPs may ensure a constant antimicrobial activity against changes in the bacterial composition of the growing dental biofilm.

Polymer fluctuation lubrication in hydrogel gemini interfaces.

Interfacial sliding speed and contact pressure between the sub-units of particulate soft matter assemblies can vary dramatically across systems and with dynamic conditions. By extension, frictional interactions between particles may play a key role in their assembly, global configuration, collective motion, and bulk material properties. For example, in tightly packed assemblies of microgels - colloidal microspheres made of hydrogel - particle stiffness controls the fragility of the glassy state formed by the particles. The interplay between particle stiffness and shear stress is likely mediated by particle-particle normal forces, highlighting the potential role of hydrogel-hydrogel friction. Here we study friction at a twinned "Gemini" interface between hydrogels. We construct a lubrication curve that spans four orders of magnitude in sliding speed, and find qualitatively different behaviour from traditional lubrication of engineering material surfaces; fundamentally different types of lubrication occur at the hydrogel Gemini interface. We also explore the role played by polymer solubility and hydrogel-hydrogel adhesion in hydrogel friction. We find that polymer network elasticity, mesh size, and single-chain relaxation times can describe friction at the gel-gel interface, including a transition between lubrication regimes with varying sliding speed.

Determining cutting efficiency of nickel-titanium coronal flaring instruments used in lateral action.

AIM: To develop a method to evaluate the cutting behaviour of nickel-titanium (NiTi) coronal flaring instruments. METHODOLOGY: BioRaCe BR0 (BR), HyFlex CM 1 (HY), ProFile OS No. 2 (PF) and ProTaper Sx (PT) instruments were used in simulated coronal flaring using a lateral action against bovine dentine blocks, at 250 and 500 rpm. Cutting efficiency was assessed by three methods: first, areas of notches produced by instruments were directly measured under a stereomicroscope. Second, dentine specimens were then analysed by surface profilometry to determine the maximum cutting depth and finally by microcomputed tomography to assess the volume of removed dentine. Data were compared using parametric tests with the significance level set at 0.05. RESULTS: For all three methods, HY and PF were the most and the least cutting-efficient instruments, respectively (P < 0.05). Significant differences were detected between 250 and 500 rpm for HY and PT (area); for BR, HY and PT (depth); and for BR and HY (volume). There were strong positive correlations between the results obtained with those three different methods with r-values ranging from 0.81 to 0.92. CONCLUSION: Measuring the amount of material removed in a specific time under stereomicroscopy is a simple and rational way to assess the cutting behaviour of NiTi rotary instruments in lateral action. HyFlex, manufactured with thermomechanically treated NiTi wire, was the most efficient instrument, and increased rotational speed was associated with increased cutting efficiency.

Cross-sectional assessment of pain and physical function in skeletal dysplasia patients.

Short stature skeletal dysplasia (SD) patients have orthopedic and neurologic complications causing significant pain and physical disability. We conducted a large cross-sectional online survey in 361 people with short stature SD (>10 years) to describe pain prevalence, characteristics, and the relationship between pain and function. Chronic pain prevalence per Brief Pain Inventory (BPI) was 70.3%. Women reported more pain than men (73% vs 63% p = 0.04). Pain Severity Score (average of current, worst, least and average pain) averaged 3.3 ± 2, while the Pain Interference Score (with daily activities) averaged 3.4 ± 2.7 on a 10-point scale. Per Bleck scale, 20.5% had little or no functional capacity. Increasing age and decreased ambulation independently predicted chronic pain. Chronic pain is prevalent in short stature SD patients and associated with poor physical function. Further study is required to clarify the temporal relationship among pain, function and treatments.

High-precision x-ray polarimetry.

The polarization purity of 6.457- and 12.914-keV x rays has been improved to the level of 2.4×10(-10) and 5.7×10(-10). The polarizers are channel-cut silicon crystals using six 90° reflections. Their performance and possible applications are demonstrated in the measurement of the optical activity of a sucrose solution.

Exotic dense-matter states pumped by a relativistic laser plasma in the radiation-dominated regime.

In high-spectral resolution experiments with the petawatt Vulcan laser, strong x-ray radiation of KK hollow atoms (atoms without n = 1 electrons) from thin Al foils was observed at pulse intensities of 3 × 10(20) W/cm(2). The observations of spectra from these exotic states of matter are supported by detailed kinetics calculations, and are consistent with a picture in which an intense polychromatic x-ray field, formed from Thomson scattering and bremsstrahlung in the electrostatic fields at the target surface, drives the KK hollow atom production. We estimate that this x-ray field has an intensity of >5 × 10(18) W/cm(2) and is in the 3 keV range.

Ir-192 radioisotope replacement with a hand-portable 1 MeV Ku-band electron linear accelerator.

Although linear accelerators are used in many security, industrial and medical applications, the existing technologies are too large and expensive for several critical applications such as radioactive source replacement, field radiography and mobile cargo scanners. One of the main requirements for these sources is to be highly portable to allow field operation. In response to this problem, RadiaBeam has designed a hand-portable 1 MeV X-ray source, scalable to higher energies, based on Ku-band split electron linac, that can be used for Ir-192 radioisotope replacement. In this paper, we present its multiphysics and engineering design studies, as well as an accelerating structure prototype along with RF measurements.

Neural correlates of strategy use during auditory working memory in musicians and non-musicians.

Working memory (WM) performance in humans can be improved by structuring and organizing the material to be remembered. For visual and verbal information, this process of structuring has been associated with the involvement of a prefrontal-parietal network, but for non-verbal auditory material, the brain areas that facilitate WM for structured information have remained elusive. Using functional magnetic resonance imaging, this study compared neural correlates underlying encoding and rehearsal of auditory WM for structured and unstructured material. Musicians and non-musicians performed a WM task on five-tone sequences that were either tonally structured (with all tones belonging to one tonal key) or tonally unstructured (atonal) sequences. Functional differences were observed for musicians (who are experts in the music domain), but not for non-musicians - The right pars orbitalis was activated more strongly in musicians during the encoding of unstructured (atonal) vs. structured (tonal) sequences. In addition, data for musicians showed that a lateral (pre)frontal-parietal network (including the right premotor cortex, right inferior precentral sulcus and left intraparietal sulcus) was activated during WM rehearsal of structured, as compared with unstructured, sequences. Our findings indicate that this network plays a role in strategy-based WM for non-verbal auditory information, corroborating previous results showing a similar network for strategy-based WM for visual and verbal information.

Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis?

BACKGROUND: Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. METHOD: The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. RESULTS: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. CONCLUSIONS: The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle.

Exaggerated neural response to emotional faces in patients with bipolar disorder and their first-degree relatives.

Neuroimaging studies have demonstrated abnormalities in patients with bipolar disorder, including overactivity in anterior limbic structures in response to fearful or happy facial expressions. We investigated whether such anomalies might constitute heritable deviations underlying bipolar disorder, by virtue of being detectable in unaffected relatives carrying genetic liability for illness. Twenty patients with bipolar I disorder, twenty of their unaffected 1st degree relatives and twenty healthy volunteers participated in functional magnetic resonance imaging experiments of facial emotion processing. In one of these experiments, the participants watched faces expressing fear of varying intensities (moderate and high), intermixed with the non-emotional faces, and in another experiment - faces expressing moderate or high degrees of happiness intermixed with non-emotional faces. Repeated measures 2x3x3 ANOVA with emotion (fear and happy), intensity (neutral, moderate, and high) as within-subjects variables and group (patients, relatives, and controls) as between-subjects variable produced two clusters of differential activation, located in medial prefrontal cortex and left putamen. Activity in medial prefrontal cortex was greater in patients and in relatives compared with healthy volunteers in response to both fearful and happy faces. Activity in left putamen in response to moderate fear was greater in patients and in relatives compared with controls. Patients (but not relatives) showed also a greater activation in response to high intensity happy faces, compared with controls. Region of Interest analysis of amygdala activation showed increased activity in left amygdala in both patients and relatives groups in response to intensively happy faces. Exaggerated medial prefrontal cortical and subcortical (putamen and amygdala) responses to emotional signals may represent heritable neurobiological abnormalities underlying bipolar disorder.