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In this paper we address the issue of separating reading disability from general intelligence in order to identify those cognitive processes which discriminate between poor and good readers when intelligence is covaried. Subjects were 140 Grade 5 and 6 students who were administered Lorge-Thorndike intelligence test (1964), a reading decoding test and cognitive tests which measure planning, attention-arousal and simultaneous-successive processing. The tests which emerged as discriminators between good and poor readers when Lorge-Thorndike full scale IQ was covaried, were three measures of successive processing (Sequence Repetition, Naming Time, Speech Rate) and a measure of selective attention, the familiar Stroop Color-Word test. Subsequently, a comparison of reading disabled high and low average IQ children confirmed that the four tests were performed poorly by both groups. All four tests involve the use of articulatory representation, confirming the important role speech-related processes play in reading (decoding). The results support the notion that deficient speech-related processes may be the central problem of the majority of poor readers, especially those of above-average intelligence. Future directions for research on phonological coding and articulation were suggested.

Theoretical investigation for the geometric and energetic properties, rotational constants, harmonic vibrational frequencies, and binding energies of nucleic acid base pair, cytosine dimer, are carried out by using the density functional theory method. The dimer structures resulting from both the keto and the enol (cis/trans) tautomers are investigated in the present study. Various isomers are considered to find the stable structures of the cytosine dimer. The planar cytosine dimer, K-K3 with C2h symmetry, resulting from nonplanar keto tautomers, is found to be thermodynamically most stable out of the four different stable isomers and having the highest binding energy value, 19.51 kcal/mol (including basis set superposition error correction). The vibrational frequency analysis also suggests a red shift of 367.97 cm(-1) for the hydrogen-bonding K-K3 symmetric dimer with two hydrogen bond lengths, each of length 1.913 angstroms. Moreover, charge distribution (ChelpG charges), Laplacian electronic density distribution, and the dimerization equilibrium for the most stable dimer, K-K3, have also been investigated using the same method and the basis set.

Prostate cancer (PCa) is the second highest cause of cancer death in United States males. If the metastatic movement of PCa cells could be inhibited, then mortality from PCa could be greatly reduced. Mitogen-activated protein kinase kinase 4 (MAP2K4) has previously been shown to activate pro-invasion signaling pathways in human PCa. Recognizing that MAP2K4 represents a novel and validated therapeutic target, we sought to develop and characterize an efficient process for the identification of small molecules that target MAP2K4. Using a fluorescence-based thermal shift assay (FTS) assay, we first evaluated an 80 compound library of known kinase inhibitors, thereby identifying 8 hits that thermally stabilized MAP2K4 in a concentration dependent manner. We then developed two in vitro MAP2K4 kinase assays to evaluate kinase inhibitory function, one a western-blot based assay employing the biologically relevant downstream substrates, JNK1 and p38 MAPK, and the other an Alphascreen based activity assay. In this manner, we validated the performance of our initial FTS screen. Finally, by coupling our structure-activity relationship data to MAP2K4's crystal structure, we constructed a model for inhibitor binding. It predicted binding of our identified inhibitors to MAP2K4's ATP pocket. We next applied this approach in a high-throughput fashion to over 2200 chemically diverse compounds and identified new inhibitors of MAP2K4. Herein we report the creation of a robust inhibitor-screening platform with the ability to inform the discovery and design of new and potent MAP2K4 inhibitors. Citation Format: Sankar Narayan Krishna, Chi-Hao Luan, Matthew R. Clutter, Rama K. Mishra, Karl A. Scheidt, Wayne F. Anderson, Raymond C. Bergan. A high-throughput screening platform for the identification of small molecule inhibitors of MAP2K4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5394. doi:10.1158/1538-7445.AM2014-5394

Quantitative structure-activity relationships are often based on standard multidimensional statistical analyses and sophisticated local and global molecular descriptors. Here, the aim is to develop a tool helpful to define a molecule or a class of molecules which fulfills pre-described properties, i.e., an Inverse QSAR approach. If highly sophisticated descriptors are used in QSAR, the structure and then the synthesis recipe may be hard to derive. Thus, descriptors, from which the synthesis recipe can be easily derived, seem appropriate to be included within this study. However, if descriptors simple enough to be useful for defining syntheses recipes of chemicals were used, the accuracy of a numeric expression may fail. This paper suggests a method, based on very simple elements of the theory of partially ordered sets, to find a qualitative basis for the relationship between such fairly simple descriptors on the one side and a series of ecotoxicological properties, on the other side. The partial order ranking method assumes neither linearity nor certain statistical distribution properties. Therefore the method may be more general compared to many standard statistical techniques. A series of chlorinated aliphatic compounds has been used as an illustrative example and a comparison with more sophisticated descriptors derived from quantum chemistry and graph theory is given. Among the results, it was disclosed that only for algae lethal concentration, as one of the four ecotoxicological properties, the synthesis specific predictors seem to be good estimators. For all other ecotoxicological properties quantum chemical descriptors appear as the more suitable estimators.

Linear discriminant analysis has been demonstrated to be a very useful tool in the selection and design of new drugs. Up to now we have used it through the search of a topological pattern of activity. In this work our goal is to calculate a complete set of physicochemical parameters using semiempirical (quantum chemical) calculations as well as topological indices (TIs) and try to find out any discriminant function for antibacterial activity through the combined use of both types of descriptors. The physicochemical parameters, such as heat of formation, HOMO, LUMO, dipole moment, polarizability, hyperpolarizability, PM3 generated IR vibrational frequencies, etc., were calculated using PM3 Hamiltonian implemented within the MOPAC97 package. Among the TIs, connectivity as well as topological charge indices stands as the most representatives. The obtained results suggest that one of the maxima and minima vibrational frequencies play an important role in the antibacterial activity. These frequencies are associated with the torsional molecular vibration (N3) and the stretching vibration (N5) of X-H groups (X = C, N, O). Furthermore, the differences between the maxima and minima values showed an even better discriminant ability than the values themselves. The additional use of the topological indices provided a clear improvement in the discriminant function and also provided a straightforward way to predict the values of such frequencies, so that the results can be applied to a large set of compounds searching for new candidates as antibacterials.

Page 4702. In Figure 2, the chemical structure of compound 19 (DG-051) was incorrectly drawn as the (R)-enantiomer. Compound 19 is the (S)-enantiomer and is properly shown in the three-dimensional crystal structure image at the right-hand side in the corrected figure below. Figure 2 Panels showing ligand binding to LTA4H for compounds described in the manuscript. Enzyme assay IC50 values are in μM, human whole blood cell assay IC50 values are in nM when reported, and ligand efficiency (LE) values are in kcal/(mol·heavy atom). Compound structures are displayed as yellow stick structures, and LTA4H is displayed in gray. Green mesh corresponds to the Fo − Fc (difference) electron density at the 3.0σ level of the crystal structure with the compound omitted from the model. Polar contacts with LTA4H and/or bound water molecules are shown as red dashed lines. PDB IDs for each structure are indicated. On page 4704, right hand column, first paragraph, line 19 and second paragraph line 22, (R)-prolinol should be changed to (S)-prolinol. Supporting Information Page S16. In Table 2, the chemical structure of compound 19 (DG-051) was incorrectly drawn as the (R)-enantiomer. The correct (S)-enantiomer has been included in the revised version of Supplemental Table 2 below. Supplemental Table 2. Comparative IC50 data for peptidase, hydrolase, and HWB assays. View it in a separate window Supplemental Table 2. Comparative IC50data for peptidase, hydrolase, and HWB assays. For all compound structures described in this work, inhibition assays were carried out using at least two independent methods, either the hydrolase assay, peptidase assay and/or a hydrolase assay in human whole blood. See Materials and Methods section for details. All results are given as IC50 values in μM, with the number of replicates and the standard error of the mean indicated where applicable.

Prostate cancer (PCa) is the second highest cause of cancer death in United States males. If the metastatic movement of PCa cells could be inhibited, then mortality from PCa could be greatly reduced. Mitogen-activated protein kinase kinase 4 (MAP2K4) has previously been shown to activate pro-invasion signaling pathways in human PCa. Recognizing that MAP2K4 represents a novel and validated therapeutic target, we sought to develop and characterize an efficient process for the identification of small molecules that target MAP2K4. Using a fluorescence-based thermal shift assay (FTS) assay, we first evaluated an 80 compound library of known kinase inhibitors, thereby identifying 8 hits that thermally stabilized MAP2K4 in a concentration dependent manner. We then developed an in vitro MAP2K4 kinase assay employing the biologically relevant downstream substrates, JNK1 and p38 MAPK, to evaluate kinase inhibitory function. In this manner, we validated the performance of our initial FTS screen. We next applied this approach to a 2000 compound chemically diverse library, identified 7 hits, and confirmed them in the in vitro kinase assay. Finally, by coupling our structure-activity relationship data to MAP2K4's crystal structure, we constructed a model for ligand binding. It predicts binding of our identified inhibitory compounds to the ATP binding pocket. Herein we report the creation of a robust inhibitor-screening platform with the ability to inform the discovery and design of new and potent MAP2K4 inhibitors.

Cognitive remediation of decoding deficit was attempted by following a theoretically based program. The theory identifies four major cognitive processes: Planning, Attention, Simultaneous, and Successive (PASS) processing. The PASS Remedial Program (PREP) provides 10 structured tasks that are aimed at developing internalized strategies for mainly successive processes (6 tasks) and simultaneous processes (4 tasks); deficits in either of the two may lead to poor decoding. Through its “global process” training and curriculum-related “bridging” training, PREP facilitates application of internalized strategies arrived at inductively for learning word decoding and spelling; it does not provide direct teaching of rules or exercises. To test the efficacy of PREP, we divided 51 children with decoding difficulties in Grade 4 into two groups: PREP (both global and bridging) and no treatment. In the second part of the study, children from the no-treatment group received either the global or the bridging part of PREP. The relative efficacy of training was tested by pre- and posttests of performance on a standard word-decoding test (the WRMT-R), as well as on some cognitive tests (e.g., the CAS). The largest improvement in word decoding occurred for the PREP combined global and bridging treatment. The mechanism through which PREP improves word reading is discussed, as is the use of PREP for children at risk of developing dyslexia.

We tested the hypothesis that children with dyslexia identified by word decoding deficit will be poor in specific cognitive processes that require successive processing and rapid articulation, irrespective of their high or average nonverbal IQ. Children with dyslexia and normally achieving children between 9 years and 11 years of age were divided into four groups comprising average-IQ and high-IQ children with dyslexia and normal readers. All children were administered measures of planning, attention-arousal, simultaneous and successive processes, phonemic segmentation, and nonverbal IQ. Results confirmed the hypothesis: The cognitive tasks that differentiated children with dyslexia from nondyslexic children irrespective of IQ were the successive tasks, as well as two tasks of attention that required articulation and/or phonological coding. Tasks that demanded both phonological coding and articulation correctly classified children with dyslexia and nondyslexic children up to 80%. The importance of remedial training appropriate for alleviating the cognitive and word decoding deficits is discussed.

The 1988 revised version of the Inquiry Mode Questionnaire by Harrison and Bramson was administered to 216 nursing students in the post-RN baccalaureate programs at two universities. The first purpose was to validate further this measure of relative preference in forced-choice format for five main ways of thinking, Synthesist, Idealist, Pragmatist, Analyst, and Realist. Significant differences among thinking styles on analysis of variance with repeated measures supported the tests's predictive validity. There were negative intercorrelations (≥ – 0.40) between opposing styles such as Synthesist/Pragmatist, Synthesist/Realist, Pragmatist/Analyst, and Idealist/Realist. Ninety percent (81 of 90 items) were significant in discriminating among the styles of thinking. The second purpose to ascertain whether nurses show a particular thinking-style preference was confirmed. Nurses in this study preferred the Idealist (37.5%), Realist (36.1%), and Analyst (31%) styles of thinking.

SummaryNeurotrophins are important for neuronal health and function. Here, statins, inhibitors of HMG-CoA reductase and cholesterol lowering drugs, were found to stimulate expression of neurotrophins in brain cells independent of the mevalonate pathway. Time-resolved fluorescence resonance energy transfer (FRET) analyses, computer-derived simulation, site-directed mutagenesis, thermal shift assay, and de novo binding followed by electrospray ionization tandem mass spectrometry (ESI-MS) demonstrates that statins serve as ligands of PPARα and that Leu331 and Tyr 334 residues of PPARα are important for statin binding. Upon binding, statins upregulate neurotrophins via PPARα-mediated transcriptional activation of cAMP-response element binding protein (CREB). Accordingly, simvastatin increases CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus of Ppara null mice receiving full-length lentiviral PPARα, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARα. This study identifies statins as ligands of PPARα, describes neurotrophic function of statins via the PPARα-CREB pathway, and analyzes the importance of PPARα in the therapeutic success of simvastatin in an animal model of Alzheimer’s disease.

The definition of topological resonance energy (TRE) has been modified and new TRE values have been calculated for closed-and open-shell configurations of heterocyclobutadienes. The quantum chemical parameters of these molecules and their dissected counterparts have been evaluated.