Recruitment of the default mode network during a demanding act of executive control.

In the human brain, a default mode or task-negative network shows reduced activity during many cognitive tasks and is often associated with internally-directed processes, such as mind wandering and thoughts about the self. In contrast to this task-negative pattern, we show increased activity during a large and demanding switch in task set. Furthermore, we employ multivoxel pattern analysis and find that regions of interest within default mode network are encoding task-relevant information during task performance. Activity in this network may be driven by major revisions of cognitive context, whether internally or externally focused

Task Encoding across the Multiple Demand Cortex Is Consistent with a Frontoparietal and Cingulo-Opercular Dual Networks Distinction.

UNLABELLED: Multiple-demand (MD) regions of the human brain show coactivation during many different kinds of task performance. Previous work based on resting-state functional magnetic resonance imaging (fMRI) has shown that MD regions may be divided into two closely coupled subnetworks centered around the lateral frontoparietal (FP) and cingulo-opercular cortex. Here, we used on-task fMRI to test whether this division is apparent during the performance of an executive task. Furthermore, we investigated whether there is a difference in the encoding of task between the two subnetworks. Using connectivity methods, we found that activity across the entire MD cortex is correlated during task performance. Meanwhile, however, there was significantly stronger connectivity within each of the subnetworks than between them. Using multivoxel pattern analysis, we also found that, although we were able to decode task-relevant information from all regions of the MD cortex, classification accuracy scores were significantly higher in the FP subnetwork. These results suggest a nested picture with MD regions as a whole showing coactivation and broad rule representation, but with significant functional distinctions between component subnetworks. SIGNIFICANCE STATEMENT: Multiple-demand (MD) regions of frontal and parietal cortex appear essential for the orchestration of goal-directed behavior and problem solving. Understanding the relative specialization of regions within the MD cortex is crucial to understanding how we can coordinate and execute complex action plans. By examining functional connectivity during task performance, we extend previous findings suggesting that the MD cortex can be divided into two subnetworks centered around the frontoparietal (FP) and cingulo-opercular (CO) cortex. Furthermore, using multivoxel pattern analysis, we show that, compared with the CO subnetwork, the FP subnetwork manifests more differentiated coding of specific task events

Caldag-Gefi Down-Regulation in the Striatum as a Neuroprotective Change in Huntington's Disease.

Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington’s disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (R01-HD28341)National Institute of Mental Health (U.S.) (F32-MH065815)Wellcome Trust (London, England)Cure Huntington’s Disease Initiative, Inc.MGH/MIT Morris Udall Center of Excellence in Parkinson Disease Research (P50-NS038372

A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets

Leukocyte and platelet integrins rapidly alter their affinity and adhesiveness in response to various activation (inside-out) signals. A rare leukocyte adhesion deficiency (LAD), LAD-III, is associated with severe defects in leukocyte and platelet integrin activation. We report two new LAD cases in which lymphocytes, neutrophils, and platelets share severe defects in β1, β2, and β3 integrin activation. Patients were both homozygous for a splice junction mutation in their CalDAG-GEFI gene, which is a key Rap-1/2 guanine exchange factor (GEF). Both mRNA and protein levels of the GEF were diminished in LAD lymphocytes, neutrophils, and platelets. Consequently, LAD-III platelets failed to aggregate because of an impaired αIIbβ3 activation by key agonists. β2 integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNFα-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil β2 integrin adhesiveness by surface-bound chemoattractants and of primary T lymphocyte LFA-1 by the CXCL12 chemokine was abolished. Chemokine inside-out signals also failed to stimulate lymphocyte LFA-1 extension and high affinity epitopes. Chemokine-triggered VLA-4 adhesiveness in T lymphocytes was partially defective as well. These studies identify CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets

Advances in Molecular Quantum Chemistry Contained in the Q-Chem 4 Program Package

A summary of the technical advances that are incorporated in the fourth major release of the Q-Chem quantum chemistry program is provided, covering approximately the last seven years. These include developments in density functional theory methods and algorithms, nuclear magnetic resonance (NMR) property evaluation, coupled cluster and perturbation theories, methods for electronically excited and open-shell species, tools for treating extended environments, algorithms for walking on potential surfaces, analysis tools, energy and electron transfer modelling, parallel computing capabilities, and graphical user interfaces. In addition, a selection of example case studies that illustrate these capabilities is given. These include extensive benchmarks of the comparative accuracy of modern density functionals for bonded and non-bonded interactions, tests of attenuated second order Møller–Plesset (MP2) methods for intermolecular interactions, a variety of parallel performance benchmarks, and tests of the accuracy of implicit solvation models. Some specific chemical examples include calculations on the strongly correlated Cr2 dimer, exploring zeolite-catalysed ethane dehydrogenation, energy decomposition analysis of a charged ter-molecular complex arising from glycerol photoionisation, and natural transition orbitals for a Frenkel exciton state in a nine-unit model of a self-assembling nanotube

10 Simple Rules for a Supportive Laboratory Environment

The transition to principal investigator (PI), or lab leader, can be challenging, partially due to the need to fulfil new managerial and leadership responsibilities. One key aspect of this role, which is often not explicitly discussed, is creating a supportive lab environment. Here, we present ten simple rules to guide the new PI in the development of their own positive and thriving lab atmosphere. These rules were written and voted on collaboratively, by the students and mentees of Professor Mark Stokes, who inspired this piece