Membrane-Mediated Allosteric Action of Serotonin on a Noncognate G-Protein-Coupled Receptor.

The structure and dynamics of the lipid membrane can affect the activity of membrane proteins. Therefore, small lipophilic molecules that alter membrane properties (such as the neurotransmitter serotonin) can potentially modulate receptor activity without binding to the receptor. Here, we investigated how the activity of neuropeptide Y type 4 receptor (Y4R, reconstituted in lipid bicelles) is modulated by serotonin, which has no known interaction with Y4R. We found a serotonin-concentration-dependent decrease (down to 0.1 mM of serotonin) in the ligand affinity of Y4R. This effect correlates with a serotonin-induced reduction of the resistance of the bilayer to indentation (measured by atomic force microscopy) and bilayer thickness (measured by solid state NMR) in two different types of zwitterionic lipid bicelles. Our findings indicate a "membrane-mediated allosteric effect" of serotonin on the activation of Y4R and suggest the potential for developing pharmacophores, which can modulate cellular signaling without directly interacting with any receptor.

Ruthenacarborane and Quinoline: A Promising Combination for the Treatment of Brain Tumors.

Gliomas and glioblastomas are very aggressive forms of brain tumors, prone to the development of a multitude of resistance mechanisms to therapeutic treatments, including cytoprotective autophagy. In this work, we investigated the role and mechanism of action of the combination of a ruthenacarborane derivative with 8-hydroxyquinoline (8-HQ), linked via an ester bond (complex 2), in rat astrocytoma C6 and human glioma U251 cells, in comparison with the two compounds alone, i.e., the free carboxylic acid (complex 1) and 8-HQ, and their non-covalent combination ([1 + 8-HQ], in 1:1 molar ratio). We found that only complex 2 was able to significantly affect cellular viability in glioma U251 cells (IC50 11.4 µM) via inhibition of the autophagic machinery, most likely acting at the early stages of the autophagic cascade. Contrary to 8-HQ alone, complex 2 was also able to impair cellular viability under conditions of glucose deprivation. We thus suggest different mechanisms of action of ruthenacarborane complex 2 than purely organic quinoline-based drugs, making complex 2 a very attractive candidate for evading the known resistances of brain tumors to chloroquine-based therapies.

Preparing (Metalla)carboranes for Nanomedicine.

"There's plenty of room at the bottom" (Richard Feynman, 1959): an invitation for (metalla)carboranes to enter the (new) field of nanomedicine. For two decades, the number of publications on boron cluster compounds designed for potential applications in medicine has been constantly increasing. Hundreds of compounds have been screened in vitro or in vivo for a variety of biological activities (chemotherapeutics, radiotherapeutics, antiviral, etc.), and some have shown rather promising potential for further development. However, until now, no boron cluster compounds have made it to the clinic, and even clinical trials have been very sparse. This review introduces a new perspective in the field of medicinal boron chemistry, namely that boron-based drugs should be regarded as nanomedicine platforms, due to their peculiar self-assembly behaviour in aqueous solutions, and treated as such. Examples for boron-based 12- and 11-vertex clusters and appropriate comparative studies from medicinal (in)organic chemistry and nanomedicine, highlighting similarities, differences and gaps in physicochemical and biological characterisation methods, are provided to encourage medicinal boron chemists to fill in the gaps between chemistry laboratory and real applications in living systems by employing bioanalytical and biophysical methods for characterising and controlling the aggregation behaviour of the clusters in solution.

Quinoline-Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action.

The role of autophagy in cancer is often complex, ranging from tumor-promoting to -suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo-[3-(η6 -p-cymene)-1-(quinolin-8-yl-acetate)-3,1,2-RuC2 B9 H10 ] (4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor-promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy-prone glioblastomas.

New keys for old locks: carborane-containing drugs as platforms for mechanism-based therapies.

Icosahedral carboranes in medicine are still an emerging class of compounds with potential beneficial applications in drug design. These highly hydrophobic clusters are potential "new keys for old locks" which open up an exciting field of research for well-known, but challenging important therapeutic substrates, as demonstrated by the numerous examples discussed in this review.

Antiproliferative activity of (η6-arene)ruthenacarborane sandwich complexes against HCT116 and MCF7 cell lines.

Three [(η6-arene)RuC2B9H11] complexes (arene = p-cymene (2), biphenyl (3) and 1-Me-4-COOEt-C6H4 (4)) were synthesised according to modified literature procedures and fully characterised. 2-4 were found to be moderately active against two types of tumour cell lines (HCT116 and MCF7), with IC50 values in the low micromolar range. However, viability of normal, healthy cells (MRC-5 cell line, MLEC and mouse macrophages) was not affected by treatment with 2-4, indicating high selectivity of the metallacarborane complexes towards tumour cell lines, compared to the unselective antitumour agent cisplatin and other potential RuII drugs. Moreover, flow cytometric analysis suggested that 4 induces cell death via a caspase-dependent apoptotic mechanism. DFT calculations of the frontier molecular orbitals showed that the HOMO-LUMO gap in 2-4 is smaller than in the corresponding cyclopentadienyl complexes 2-Cp-4-Cp (e.g. 5.47 (2) vs. 6.31 eV (2-Cp)). In order to assess the stability of 2-4, particularly the ruthenium-dicarbollide bond, energy decomposition analysis (EDA) of 2-4, together with the respective cyclopentadienyl analogues 2-Cp-4-Cp, was performed. EDA suggests that the ruthenium(ii)-dicarbollide bond in the three complexes is mostly ionic and far stronger than the ruthenium(ii)-arene bond.

Effects of Oxytocin and Vasopressin on Preferential Brain Responses to Negative Social Feedback.

Receiving negative social feedback can be detrimental to emotional, cognitive, and physical well-being, and fear of negative social feedback is a prominent feature of mental illnesses that involve social anxiety. A large body of evidence has implicated the neuropeptides oxytocin and vasopressin in the modulation of human neural activity underlying social cognition, including negative emotion processing; however, the influence of oxytocin and vasopressin on neural activity elicited during negative social evaluation remains unknown. Here 21 healthy men underwent functional magnetic resonance imaging in a double-blind, placebo-controlled, crossover design to determine how intranasally administered oxytocin and vasopressin modulated neural activity when receiving negative feedback on task performance from a study investigator. We found that under placebo, a preferential response to negative social feedback compared with positive social feedback was evoked in brain regions putatively involved in theory of mind (temporoparietal junction), pain processing (anterior insula and supplementary motor area), and identification of emotionally important visual cues in social perception (right fusiform). These activations weakened with oxytocin and vasopressin administration such that neural responses to receiving negative social feedback were not significantly greater than positive social feedback. Our results show effects of both oxytocin and vasopressin on the brain network involved in negative social feedback, informing the possible use of a pharmacological approach targeting these regions in multiple disorders with impairments in social information processing.

Compared to what? Early brain overgrowth in autism and the perils of population norms.

BACKGROUND: Early brain overgrowth (EBO) in autism spectrum disorder (ASD) is among the best replicated biological associations in psychiatry. Most positive reports have compared head circumference (HC) in ASD (an excellent proxy for early brain size) with well-known reference norms. We sought to reappraise evidence for the EBO hypothesis given 1) the recent proliferation of longitudinal HC studies in ASD, and 2) emerging reports that several of the reference norms used to define EBO in ASD may be biased toward detecting HC overgrowth in contemporary samples of healthy children. METHODS: Systematic review of all published HC studies in children with ASD. Comparison of 330 longitudinally gathered HC measures between birth and 18 months from male children with autism (n = 35) and typically developing control subjects (n = 22). RESULTS: In systematic review, comparisons with locally recruited control subjects were significantly less likely to identify EBO in ASD than norm-based studies (p < .001). Through systematic review and analysis of new data, we replicate seminal reports of EBO in ASD relative to classical HC norms but show that this overgrowth relative to norms is mimicked by patterns of HC growth age in a large contemporary community-based sample of US children (n ~ 75,000). Controlling for known HC norm biases leaves inconsistent support for a subtle, later emerging and subgroup specific pattern of EBO in clinically ascertained ASD versus community control subjects. CONCLUSIONS: The best-replicated aspects of EBO reflect generalizable HC norm biases rather than disease-specific biomarkers. The potential HC norm biases we detail are not specific to ASD research but apply throughout clinical and academic medicine.

Diffusion tensor imaging in young children with autism: biological effects and potential confounds.

BACKGROUND: Diffusion tensor imaging (DTI) has been used over the past decade to study structural differences in the brains of children with autism compared with typically developing children. These studies generally find reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in children with autism; however, the regional pattern of findings varies greatly. METHODS: We used DTI to investigate the brains of sedated children with autism (n = 39) and naturally asleep typically developing children (n = 39) between 2 and 8 years of age. Tract based spatial statistics and whole brain voxel-wise analysis were performed to investigate the regional distribution of differences between groups. RESULTS: In children with autism, we found significantly reduced FA in widespread regions and increased MD only in posterior brain regions. Significant age × group interaction was found, indicating a difference in developmental trends of FA and MD between children with autism and typically developing children. The magnitude of the measured differences between groups was small, on the order of approximately 1%-2%. Subjects and control subjects showed distinct regional differences in imaging artifacts that can affect DTI measures. CONCLUSIONS: We found statistically significant differences in DTI metrics between children with autism and typically developing children, including different developmental trends of these metrics. However, this study indicates that between-group differences in DTI studies of autism should be interpreted with caution, because their small magnitude make these measurements particularly vulnerable to the effects of artifacts and confounds, which might lead to false positive and/or false negative biological inferences.

A magnetization transfer imaging study of corpus callosum myelination in young children with autism.

BACKGROUND: Several lines of evidence suggest that autism may be associated with abnormalities in white matter development. However, inconsistencies remain in the literature regarding the nature and extent of these abnormalities, partly because of the limited types of measurements that have been used. Here, we used magnetization transfer imaging to provide insight into the myelination of the corpus callosum in children with autism. METHODS: Magnetization transfer imaging scans were obtained in 101 children with autism and 35 typically developing children who did not significantly differ with regard to gender or age. The midsagittal area of the corpus callosum was manually traced and the magnetization transfer ratio (MTR) was calculated for each voxel within the corpus callosum. Mean MTR and height and location of the MTR histogram peak were analyzed. RESULTS: Mean MTR and MTR histogram peak height and location were significantly higher in children with autism than in typically developing children, suggesting abnormal myelination of the corpus callosum in autism. CONCLUSIONS: The differences in callosal myelination suggested by these results may reflect an alteration in the normally well-regulated process of myelination of the brain, with broad implications for neuropathology, diagnosis, and treatment of autism.

Mapping cortical anatomy in preschool aged children with autism using surface-based morphometry.

The challenges of gathering in-vivo measures of brain anatomy from young children have limited the number of independent studies examining neuroanatomical differences between children with autism and typically developing controls (TDCs) during early life, and almost all studies in this critical developmental window focus on global or lobar measures of brain volume. Using a novel cohort of young males with Autistic Disorder and TDCs aged 2 to 5 years, we (i) tested for group differences in traditional measures of global anatomy (total brain, total white, total gray and total cortical volume), and (ii) employed surface-based methods for cortical morphometry to directly measure the two biologically distinct sub-components of cortical volume (CV) at high spatial resolution-cortical thickness (CT) and surface area (SA). While measures of global brain anatomy did not show statistically significant group differences, children with autism showed focal, and CT-specific anatomical disruptions compared to TDCs, consisting of relative cortical thickening in regions with central roles in behavioral regulation, and the processing of language, biological movement and social information. Our findings demonstrate the focal nature of brain involvement in early autism, and provide more spatially and morphometrically specific anatomical phenotypes for subsequent translational study.

Recruitment of intuitive versus analytic thinking strategies affects the role of working memory in a gambling task.

Previous studies found mixed results concerning the role of working memory (WM) in the gambling task (GT). Here, we aimed at reconciling inconsistencies by showing that the standard version of the task can be solved using intuitive strategies operating automatically, while more complex versions require analytic strategies drawing on executive functions. In Study 1, where good performance on the GT could be achieved using intuitive strategies, participants performed well both with and without a concurrent WM load. In Study 2, where analytical strategies were required to solve a more complex version of the GT, participants without WM load performed well, while participants with WM load performed poorly. In Study 3, where the complexity of the GT was further increased, participants in both conditions performed poorly. In addition to the standard performance measure, we used participants' subjective expected utility, showing that it differs from the standard measure in some important aspects.

Looking for an explanation for the low sign span. Is order involved?

Although signed and speech-based languages have a similar internal organization of verbal short-term memory, sign span is lower than word span. We investigated whether this is due to the fact that signs are not suited for serial recall, as proposed by Bavelier, Newport, Hall, Supalla, and Boutla (2008. Ordered short-term memory differs in signers and speakers: Implications for models of short-term memory. Cognition, 107, 433-459). We administered a serial recall task with stimuli in Italian Sign Language to 12 deaf people, and we compared their performance with that of twelve age-, gender-, and education-matched hearing participants who performed the task in Italian. The results do not offer evidence for the hypothesis that serial order per se is a detrimental factor for deaf participants. An alternative explanation for the lower sign span based on signs being phonologically heavier than words is considered.

Interest in politics modulates neural activity in the amygdala and ventral striatum.

Studies on political participation have found that a person's interest in politics contributes to the likelihood that he or she will be involved in the political process. Here, we looked at whether or not interest in politics affects patterns of brain activity when individuals think about political matters. Using functional magnetic resonance imaging (fMRI), we scanned individuals (either interested or uninterested in politics based on a self-report questionnaire) while they were expressing their agreement or disagreement with political opinions. After scanning, participants were asked to rate each political opinion presented in the scanner for emotional valence and emotional intensity. Behavioral results showed that those political opinions participants agreed with were perceived as more emotionally intense and more positive by individuals interested in politics relative to individuals uninterested in politics. In addition, individuals interested in politics showed greater activation in the amygdala and the ventral striatum (ventral putamen) relative to individuals uninterested in politics when reading political opinions in accordance with their own views. This study shows that having an interest in politics elicits activations in emotion- and reward-related brain areas even when simply agreeing with written political opinions.

Individualism, conservatism, and radicalism as criteria for processing political beliefs: a parametric fMRI study.

Politics is a manifestation of the uniquely human ability to debate, decide, and reach consensus on decisions affecting large groups over long durations of time. Recent neuroimaging studies on politics have focused on the association between brain regions and specific political behaviors by adopting party or ideological affiliation as a criterion to classify either experimental stimuli or subjects. However, it is unlikely that complex political beliefs (i.e., "the government should protect freedom of speech") are evaluated only on a liberal-to-conservative criterion. Here we used multidimensional scaling and parametric functional magnetic resonance imaging to identify which criteria/dimensions people use to structure complex political beliefs and which brain regions are concurrently activated. We found that three independent dimensions explained the variability of a set of statements expressing political beliefs and that each dimension was reflected in a distinctive pattern of neural activation: individualism (medial prefrontal cortex and temporoparietal junction), conservatism (dorsolateral prefrontal cortex), and radicalism (ventral striatum and posterior cingulate). The structures we identified are also known to be important in self-other processing, social decision-making in ambivalent situations, and reward prediction. Our results extend current knowledge on the neural correlates of the structure of political beliefs, a fundamental aspect of the human ability to coalesce into social entities.

Dissociable effects of prefrontal and anterior temporal cortical lesions on stereotypical gender attitudes.

Clinical observations of patients with ventral frontal and anterior temporal cortical lesions reveal marked abnormalities in social attitudes. A previous study in seven patients with ventral prefrontal lesions provided the first direct experimental evidence for abnormalities in social attitudes using a well-established measure of gender stereotypes, the Implicit Association Test (IAT). Here, we were able to test whether these first findings could be reproduced in a larger sample of 154 patients with penetrating head injuries, and to determine the differential effects of ventromedial prefrontal (vmPFC) and ventrolateral prefrontal (vlPFC) cortical lesions on IAT performance. In addition, we investigated the role of the superior anterior temporal lobe (aTL), recently shown to represent conceptual social knowledge. First, we used a linear regression model to identify the role of each of the three regions, while controlling for the extent of damage to other regions. We found that larger lesions in either the vmPFC or the superior aTL were associated with increased stereotypical attitudes, whereas larger lesions in the vlPFC were associated with decreased stereotypical attitudes. Second, in a confirmatory analysis, we grouped patients by lesion location and compared their performance on the IAT with that of healthy volunteers. Compared to controls, patients with lesions in either the vmPFC or the superior aTL showed increased stereotypical attitudes, whereas patients with lesions in the vlPFC showed decreased stereotypical attitudes. The functional contributions of these regions in social attitudes are discussed.

How grammar can cope with limited short-term memory: simultaneity and seriality in sign languages.

It is known that in American Sign Language (ASL) span is shorter than in English, but this discrepancy has never been systematically investigated using other pairs of signed and spoken languages. This finding is at odds with results showing that short-term memory (STM) for signs has an internal organization similar to STM for words. Moreover, some methodological questions remain open. Thus, we measured span of deaf and matched hearing participants for Italian Sign Language (LIS) and Italian, respectively, controlling for all the possible variables that might be responsible for the discrepancy: yet, a difference in span between deaf signers and hearing speakers was found. However, the advantage of hearing subjects was removed in a visuo-spatial STM task. We attribute the source of the lower span to the internal structure of signs: indeed, unlike English (or Italian) words, signs contain both simultaneous and sequential components. Nonetheless, sign languages are fully-fledged grammatical systems, probably because the overall architecture of the grammar of signed languages reduces the STM load. Our hypothesis is that the faculty of language is dependent on STM, being however flexible enough to develop even in a relatively hostile environment.

Is short-term memory involved in decision making? Evidence from a short-term memory patient.

It is reasonable to suggest that working memory (WM; Baddeley & Hitch, 1974) is involved in decision making, as decision making is dependent on the ability to remember and update past choices and outcomes. However, contradictory results have been reported in the literature concerning the role of two of its components, namely the central executive and the phonological loop. In order to investigate the role of these components in the decision-making process, we tested a patient with intact central executive but impaired phonological loop on a laboratory decision-making task involving hypothetical gambles (gambling task, GT). When tested in a no-load condition (simple keypress task), her performance was not significantly different from that of matched controls. We also verified whether her performance would be affected differently by memory-load when compared with control subjects. The memory task (holding a string of letters in memory) loaded WM without incurring number-number interference. When the memory-load was imposed during the GT, both the patient and the controls showed a decline in performance, but the strategy they adopted differed. Possible explanations are discussed. In conclusion, our results suggest that the phonological loop is not directly involved in decision making.