Alterations in Task-Related Brain Activation in Children, Adolescents and Young Adults at Familial High-Risk for Schizophrenia or Bipolar Disorder - A Systematic Review.

Children, adolescents, and young adults with at least one first-degree relative [familial high-risk (FHR)] with either schizophrenia (SZ) or bipolar disorder (BD) have a one-in-two risk of developing a psychiatric disorder. Here, we review functional magnetic resonance imaging (fMRI) studies which examined task-related brain activity in young individuals with FHR-SZ and FHR-BD. A systematic search identified all published task-related fMRI studies in children, adolescents, and young adults below an age of 27 years with a first-degree relative with SZ or BD, but without manifest psychotic or affective spectrum disorder themselves. The search identified 19 cross-sectional fMRI studies covering four main cognitive domains: 1) working memory (n = 3), 2) cognitive control (n = 4), 3) reward processing (n = 3), and 4) emotion processing (n = 9). Thirteen studies included FHR-BD, five studies included FHR-SZ, and one study included a pooled FHR group. In general, task performance did not differ between the respective FHR groups and healthy controls, but 18 out of the 19 fMRI studies revealed regional alterations in task-related activation. Brain regions showing group differences in peak activation were regions associated with the respective task domain and showed little overlap between FHR-SZ and FHR-BD. The low number of studies, together with the low number of subjects, and the substantial heterogeneity of employed methodological approaches within the domain of working memory, cognitive control, and reward processing impedes finite conclusions. Emotion processing was the most investigated task domain in FHR-BD. Four studies reported differences in activation of the amygdala, and two studies reported differences in activation of inferior frontal/middle gyrus. Together, these studies provide evidence for altered brain processing of emotions in children, adolescents, and young adults at FHR-BD. More studies of higher homogeneity, larger sample sizes and with a longitudinal study design are warranted to prove a shared or specific FHR-related endophenotypic brain activation in young first-degree relatives of individuals with SZ or BD, as well as to pinpoint specific alterations in brain activation during cognitive-, emotional-, and reward-related tasks

The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21

Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2H-pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is e.g. present in various bioactive natural products. Our investigations were focused on the compound MT-21 - a simplified structural analogue of the natural product epolactaene - which is known to have both neurotrophic activity and ability to trigger apoptotic cell death. We found that the central N-acyl hemiaminal group of MT-21 can function as an electrophilic centre enabling divergent reactivity with both amine- and thiokbased nucleophiles, which furthermore translated to reactivity with proteins in both cell lysates and live cells. We found that in live cells MT-21 strongly engaged the lipid transport protein fatty acid-binding protein 5 (FABP5) by direct binding to a cysteine residue in the bottom of the ligand binding pocket. Through preparation of a series of MT-21 derivatives, we probed the specificity of this interaction which was found to be strongly dependent on subtle structural changes. Our study suggests that MT-21 may be employed as a tool compound in future studies of the biology of FABP5, which remains incompletely understood. Furthermore, our study has also made dear that other natural products containing the AHPO-motif may likewise possess covalent reactivity and that this property may underlie their biological activity.Molecular Physiolog

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Molecular Mechanism of the Constitutive Activation of the L250Q Human Melanocortin-4 Receptor Polymorphism †

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65471/1/j.1747-0285.2006.00362.x.pd

Transverse momentum spectra of charged particles in proton-proton collisions at s=900\sqrt{s} = 900 GeV with ALICE at the LHC

The inclusive charged particle transverse momentum distribution is measured in proton-proton collisions at $\sqrt{s} = 900$ GeV at the LHC using the ALICE detector. The measurement is performed in the central pseudorapidity region $(|\eta|<0.8)$ over the transverse momentum range $0.15<p_{\rm T}<10$ GeV/$c$. The correlation between transverse momentum and particle multiplicity is also studied. Results are presented for inelastic (INEL) and non-single-diffractive (NSD) events. The average transverse momentum for $|\eta|<0.8$ is $\left<p_{\rm T}\right>_{\rm INEL}=0.483\pm0.001$ (stat.) $\pm0.007$ (syst.) GeV/$c$ and \left_{\rm NSD}=0.489\pm0.001 (stat.) $\pm0.007$ (syst.) GeV/$c$, respectively. The data exhibit a slightly larger $\left<p_{\rm T}\right>$ than measurements in wider pseudorapidity intervals. The results are compared to simulations with the Monte Carlo event generators PYTHIA and PHOJET.Comment: 20 pages, 8 figures, 2 tables, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/390