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The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3- c ]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12 demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo . Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22 , which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.

A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD., (Copyright © 2015 the authors 0270-6474/15/351199-12$15.00/0.)

Children 4 through 13 yr. of age performed on a haptic-to-visual form-identification task. The obtained curves showed that for both sexes, rate of improvement slowed down at approximately 9 yr. of age.

Many theorists suggest that eidetic imagery is important in early child development, but there have been few systematic attempts to test whether eidetic imagery varies inversely with age. A sample of 280 students, ranging in age from 5 to 18 years, was tested for eidetic imagery by methods designed to minimize the probability of confusion between eidetic imagery and visual memory imagery of any other type. As expected, the youngest age groups showed the highest frequency of eidetic imagery, and beyond age 7, the incidence did not vary systematically. The results are interpreted as indicating the plausibility of a theory which affords eidetic imagery a role in the early cognitive development of the child.

Gray and Gummerman (1975) contended that eidetic imagery differs from visual-memory imagery only in quantitative aspects. There is evidence to controvert that argument and to support a theory of eidetic imagery as a qualitatively distinct phenomenon. It is proposed that eidetic imagery plays an essential role in early development and that superimposition methods are adequate for measurement of eidetic imagery in young children. It is further suggested that eidetic imagery is the precursor of iconic storage. The persistence of eidetic imagery in older children appears to be associated with some but not all forms of brain damage and may be overshadowed by more advanced memory imagery.

Seventy-eight boys and 71 girls (ages eight to 18 years) were assigned to one of eight groups on the basis of scores on the Junior Esysenck Personality Inventory, the Children's Manifest Anxiety Scale, and sex of the S. The Ss were administered a simple and a complex verbal fluency task and the coding subtest of the WISC. It was found that extraverted children of both sexes did better than introverted children on both measures of verbal fluency and the nonverbal coding task. Anxiety influenced girl's performance on the more complex verbal fluency task, but did not alter boys' performance. The present findings were discussed in relation to the adult literature relating extraversion, anxiety, and verbal fluency.

The relation of field articulation to sensitivity to linguistic structures was explored. Subjects (23 males and 23 females) were given the rod-and-frame test and then made true-false judgments of sentences varying in grammatical and semantic complexity. While increased complexity did increase the difficulty of true-false judgments of sentences, the latencies of these judgments were unrelated to the scores on the rod-and-frame test. These results were discussed in terms of the generality of previous studies reporting a relationship between field articulation and linguistic abilities.