Multivariate Associations of Fluid Intelligence and NAA.

Understanding the neural and metabolic correlates of fluid intelligence not only aids scientists in characterizing cognitive processes involved in intelligence, but it also offers insight into intervention methods to improve fluid intelligence. Here we use magnetic resonance spectroscopic imaging (MRSI) to measure N-acetyl aspartate (NAA), a biochemical marker of neural energy production and efficiency. We use principal components analysis (PCA) to examine how the distribution of NAA in the frontal and parietal lobes relates to fluid intelligence. We find that a left lateralized frontal-parietal component predicts fluid intelligence, and it does so independently of brain size, another significant predictor of fluid intelligence. These results suggest that the left motor regions play a key role in the visualization and planning necessary for spatial cognition and reasoning, and we discuss these findings in the context of the Parieto-Frontal Integration Theory of intelligence.

The discovery of potent and selective kynurenine 3-monooxygenase inhibitors for the treatment of acute pancreatitis.

A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.

CSAR 2014: A Benchmark Exercise Using Unpublished Data from Pharma.

The 2014 CSAR Benchmark Exercise was the last community-wide exercise that was conducted by the group at the University of Michigan, Ann Arbor. For this event, GlaxoSmithKline (GSK) donated unpublished crystal structures and affinity data from in-house projects. Three targets were used: tRNA (m1G37) methyltransferase (TrmD), Spleen Tyrosine Kinase (SYK), and Factor Xa (FXa). A particularly strong feature of the GSK data is its large size, which lends greater statistical significance to comparisons between different methods. In Phase 1 of the CSAR 2014 Exercise, participants were given several protein-ligand complexes and asked to identify the one near-native pose from among 200 decoys provided by CSAR. Though decoys were requested by the community, we found that they complicated our analysis. We could not discern whether poor predictions were failures of the chosen method or an incompatibility between the participant's method and the setup protocol we used. This problem is inherent to decoys, and we strongly advise against their use. In Phase 2, participants had to dock and rank/score a set of small molecules given only the SMILES strings of the ligands and a protein structure with a different ligand bound. Overall, docking was a success for most participants, much better in Phase 2 than in Phase 1. However, scoring was a greater challenge. No particular approach to docking and scoring had an edge, and successful methods included empirical, knowledge-based, machine-learning, shape-fitting, and even those with solvation and entropy terms. Several groups were successful in ranking TrmD and/or SYK, but ranking FXa ligands was intractable for all participants. Methods that were able to dock well across all submitted systems include MDock,1 Glide-XP,2 PLANTS,3 Wilma,4 Gold,5 SMINA,6 Glide-XP2/PELE,7 FlexX,8 and MedusaDock.9 In fact, the submission based on Glide-XP2/PELE7 cross-docked all ligands to many crystal structures, and it was particularly impressive to see success across an ensemble of protein structures for multiple targets. For scoring/ranking, submissions that showed statistically significant achievement include MDock1 using ITScore1,10 with a flexible-ligand term,11 SMINA6 using Autodock-Vina,12,13 FlexX8 using HYDE,14 and Glide-XP2 using XP DockScore2 with and without ROCS15 shape similarity.16 Of course, these results are for only three protein targets, and many more systems need to be investigated to truly identify which approaches are more successful than others. Furthermore, our exercise is not a competition.

Evaluation of aromatic amines with different purities and different solvent vehicles in the Ames test.

Of all the in vitro mutagenicity assays, the Ames test displays the best correlation with rodent carcinogenicity and therefore carries significant weight with the food and drug regulatory bodies. Aromatic amines (AA) are ubiquitous structural groups in food and drug molecules despite the well-documented mutagenic and carcinogenic propensity for many representatives. Furthermore, recent regulatory guidelines (that is ICH M7) requires the hazard assessment of actual and potential impurities by two complementary (Q)SAR prediction methodologies if no carcinogenicity or bacterial mutagenicity data is available. One methodology should be expert-rule-based and the second should be statistics-based. Having encountered numerous reports of contradictory Ames results for members of this chemotype, we undertook systematic Ames tests on a diverse set of 14 AAs of differing purities in different solvents, and as free bases and their salts. The aim of this work was to investigate the reliability of the Ames test for this chemotype leading to the creation of a reference set of AAs for use by medicinal chemists and in silico modelling. Contrary to previous experience, which led to the investigations reported in this publication, the anticipated transformation from an Ames-positive to an Ames-negative after purification only occurred for one compound. Furthermore, this result proved inconclusive after testing as the HCl salt in DMSO and in water. The anticipated change in class from mutagen to non-mutagen, did not occur and this can be read as evidence for the reliability of the Ames test for AAs.

Computer based visualization of clot structures in extracorporeal membrane oxygenation and histological clot investigations for understanding thrombosis in membrane lungs.

Extracorporeal membrane oxygenation (ECMO) was established as a treatment for severe cardiac or respiratory disease. Intra-device clot formation is a common risk. This is based on complex coagulation phenomena which are not yet sufficiently understood. The objective was the development and validation of a methodology to capture the key properties of clots deposed in membrane lungs (MLs), such as clot size, distribution, burden, and composition. One end-of-therapy PLS ML was examined. Clot detection was performed using multidetector computed tomography (MDCT), microcomputed tomography (µCT), and photography of fiber mats (fiber mat imaging, FMI). Histological staining was conducted for von Willebrand factor (vWF), platelets (CD42b, CD62P), fibrin, and nucleated cells (4', 6-diamidino-2-phenylindole, DAPI). The three imaging methods showed similar clot distribution inside the ML. Independent of the imaging method, clot loading was detected predominantly in the inlet chamber of the ML. The µCT had the highest accuracy. However, it was more expensive and time consuming than MDCT or FMI. The MDCT detected the clots with low scanning time. Due to its lower resolution, it only showed clotted areas but not the exact shape of clot structures. FMI represented the simplest variant, requiring little effort and resources. FMI allowed clot localization and calculation of clot volume. Histological evaluation indicated omnipresent immunological deposits throughout the ML. Visually clot-free areas were covered with leukocytes and platelets forming platelet-leukocyte aggregates (PLAs). Cells were embedded in vWF cobwebs, while vWF fibers were negligible. In conclusion, the presented methodology allowed adequate clot identification and histological classification of possible thrombosis markers such as PLAs.

Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.

Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.

Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.

Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration.

Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.

Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode.

A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co-crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring in previous PDE4 co-crystal structures, and even shifts helix-15 by 1-2A. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design.

Brain network modularity predicts cognitive training-related gains in young adults.

The brain operates via networked activity in separable groups of regions called modules. The quantification of modularity compares the number of connections within and between modules, with high modularity indicating greater segregation, or dense connections within sub-networks and sparse connections between sub-networks. Previous work has demonstrated that baseline brain network modularity predicts executive function outcomes in older adults and patients with traumatic brain injury after cognitive and exercise interventions. In healthy young adults, however, the functional significance of brain modularity in predicting training-related cognitive improvements is not fully understood. Here, we quantified brain network modularity in young adults who underwent cognitive training with casual video games that engaged working memory and reasoning processes. Network modularity assessed at baseline was positively correlated with training-related improvements on untrained tasks. The relationship between baseline modularity and training gain was especially evident in initially lower performing individuals and was not present in a group of control participants that did not show training-related gains. These results suggest that a more modular brain network organization may allow for greater training responsiveness. On a broader scale, these findings suggest that, particularly in low-performing individuals, global network properties can capture aspects of brain function that are important in understanding individual differences in learning.

Studies on the Bisoxazoline and (-)-Sparteine Mediated Enantioselective Addition of Organolithium Reagents to Imines.

The enantioselective addition of organolithium reagents to N-anisyl aldimines promoted by chiral bisoxazolines and (-)-sparteine as external ligands is described. This reaction proceeds readily with a wide range of aldimine substrates (aliphatic, aromatic, olefinic) and organolithium nucleophiles (Me, n-Bu, Ph, vinyl) in excellent yields (81-99%) and with high enantioselectivities (up to 95.5:4.5 er). The external ligands can be used in substoichiometric amounts albeit with slightly attenuated enantioselectivities. A systematic evaluation of the structural features of the bisoxazolines revealed a primary contribution from the substituent at C(4) and a secondary influence from the bridging substituents. A computational analysis (PM3) provided a clear rationalization for the origin of enantioselectivity.

The cortical structure of functional networks associated with age-related cognitive abilities in older adults.

Age and cortical structure are both associated with cognition, but characterizing this relationship remains a challenge. A popular approach is to use functional network organization of the cortex as an organizing principle for post-hoc interpretations of structural results. In the current study, we introduce two complimentary approaches to structural analyses that are guided by a-priori functional network maps. Specifically, we systematically investigated the relationship of cortical structure (thickness and surface area) of distinct functional networks to two cognitive domains sensitive to age-related decline thought to rely on both common and distinct processes (executive function and episodic memory) in older adults. We quantified the cortical structure of individual functional network's predictive ability and spatial extent (i.e., number of significant regions) with cognition and its mediating role in the age-cognition relationship. We found that cortical thickness, rather than surface area, predicted cognition across the majority of functional networks. The default mode and somatomotor network emerged as particularly important as they appeared to be the only two networks to mediate the age-cognition relationship for both cognitive domains. In contrast, thickness of the salience network predicted executive function and mediated the age-cognition relationship for executive function. These relationships remained significant even after accounting for global cortical thickness. Quantifying the number of regions related to cognition and mediating the age-cognition relationship yielded similar patterns of results. This study provides a potential approach to organize and describe the apparent widespread regional cortical structural relationships with cognition and age in older adults.

Examining the Roles of Reasoning and Working Memory in Predicting Casual Game Performance across Extended Gameplay.

The variety and availability of casual video games presents an exciting opportunity for applications such as cognitive training. Casual games have been associated with fluid abilities such as working memory (WM) and reasoning, but the importance of these cognitive constructs in predicting performance may change across extended gameplay and vary with game structure. The current investigation examined the relationship between cognitive abilities and casual game performance over time by analyzing first and final session performance over 4-5 weeks of game play. We focused on two groups of subjects who played different types of casual games previously shown to relate to WM and reasoning when played for a single session: (1) puzzle-based games played adaptively across sessions and (2) speeded switching games played non-adaptively across sessions. Reasoning uniquely predicted first session casual game scores for both groups and accounted for much of the relationship with WM. Furthermore, over time, WM became uniquely important for predicting casual game performance for the puzzle-based adaptive games but not for the speeded switching non-adaptive games. These results extend the burgeoning literature on cognitive abilities involved in video games by showing differential relationships of fluid abilities across different game types and extended play. More broadly, the current study illustrates the usefulness of using multiple cognitive measures in predicting performance, and provides potential directions for game-based cognitive training research.

Working Memory, Reasoning, and Task Switching Training: Transfer Effects, Limitations, and Great Expectations?

Although some studies have shown that cognitive training can produce improvements to untrained cognitive domains (far transfer), many others fail to show these effects, especially when it comes to improving fluid intelligence. The current study was designed to overcome several limitations of previous training studies by incorporating training expectancy assessments, an active control group, and "Mind Frontiers," a video game-based mobile program comprised of six adaptive, cognitively demanding training tasks that have been found to lead to increased scores in fluid intelligence (Gf) tests. We hypothesize that such integrated training may lead to broad improvements in cognitive abilities by targeting aspects of working memory, executive function, reasoning, and problem solving. Ninety participants completed 20 hour-and-a-half long training sessions over four to five weeks, 45 of whom played Mind Frontiers and 45 of whom completed visual search and change detection tasks (active control). After training, the Mind Frontiers group improved in working memory n-back tests, a composite measure of perceptual speed, and a composite measure of reaction time in reasoning tests. No training-related improvements were found in reasoning accuracy or other working memory tests, nor in composite measures of episodic memory, selective attention, divided attention, and multi-tasking. Perceived self-improvement in the tested abilities did not differ between groups. A general expectancy difference in problem-solving was observed between groups, but this perceived benefit did not correlate with training-related improvement. In summary, although these findings provide modest evidence regarding the efficacy of an integrated cognitive training program, more research is needed to determine the utility of Mind Frontiers as a cognitive training tool.

Cognitive training with casual video games: points to consider.

Brain training programs have proliferated in recent years, with claims that video games or computer-based tasks can broadly enhance cognitive function. However, benefits are commonly seen only in trained tasks. Assessing generalized improvement and practicality of laboratory exercises complicates interpretation and application of findings. In this study, we addressed these issues by using active control groups, training tasks that more closely resemble real-world demands and multiple tests to determine transfer of training. We examined whether casual video games can broadly improve cognition, and selected training games from a study of the relationship between game performance and cognitive abilities. A total of 209 young adults were randomized into a working memory-reasoning group, an adaptive working memory-reasoning group, an active control game group, and a no-contact control group. Before and after 15 h of training, participants completed tests of reasoning, working memory, attention, episodic memory, perceptual speed, and self-report measures of executive function, game experience, perceived improvement, knowledge of brain training research, and game play outside the laboratory. Participants improved on the training games, but transfer to untrained tasks was limited. No group showed gains in reasoning, working memory, episodic memory, or perceptual speed, but the working memory-reasoning groups improved in divided attention, with better performance in an attention-demanding game, a decreased attentional blink and smaller trail-making costs. Perceived improvements did not differ across training groups and those with low reasoning ability at baseline showed larger gains. Although there are important caveats, our study sheds light on the mixed effects in the training and transfer literature and offers a novel and potentially practical training approach. Still, more research is needed to determine the real-world benefits of computer programs such as casual games.

The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis.

A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.

Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance.

Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.

Solution, solid phase and computational structures of apicidin and its backbone-reduced analogs.

The recently isolated broad-spectrum antiparasitic apicidin (1) is one of the few naturally occurring cyclic tetrapeptides (CTP). Depending on the solvent, the backbone of 1 exhibits two gamma-turns (in CH(2)Cl(2)) or a beta-turn (in DMSO), differing solely in the rotation of the plane of one of the amide bonds. In the X-ray crystal structure, the peptidic C==Os and NHs are on opposite sides of the backbone plane, giving rise to infinite stacks of cyclotetrapeptides connected by three intermolecular hydrogen bonds between the backbones. Conformational searches (Amber force field) on a truncated model system of 1 confirm all three backbone conformations to be low-energy states. The previously synthesized analogs of 1 containing a reduced amide bond exhibit the same backbone conformation as 1 in DMSO, which is confirmed further by the X-ray crystal structure of a model system of the desoxy analogs of 1. This similarity helps in explaining why the desoxy analogs retain some of the antiprotozoal activities of apicidin. The backbone-reduction approach designed to facilitate the cyclization step of the acyclic precursors of the CTPs seems to retain the conformational preferences of the parent peptide backbone.