A simple method for determining compound affinity and chemical yield from DNA-encoded library selections.

DNA-encoded libraries (DELs) can contain billions of unique chemical species; selecting against such large inputs, it is typical to find more candidate binders than is reasonable to pursue for follow-up synthesis and testing. Given this wealth of choices, common practice is to limit synthesis to only those compounds estimated to have the greatest chance of being high-affinity binders; of the many potential factors contributing to this estimation, the strength of the selection signal of a candidate binder is always important. We define here methods and equations which relate the theoretical selection signal of a compound to its affinity and chemical yield. Tests using known binders of BRD4 and ROCK2 support the theory backing these equations and suggest they should be of use for prospectively determining affinity and chemical yield from primary DEL selection data.

Alterations of Intrinsic Connectivity Networks in Antipsychotic-Naïve First-Episode Schizophrenia.

Background: The investigation of large-scale intrinsic connectivity networks in antipsychotic-naïve first-episode schizophrenia increases our understanding of system-level cerebral dysfunction in schizophrenia while enabling control of confounding effects of medication and disease progression. Reports on functional connectivity in antipsychotic-naïve patients have been mixed and the relation between network alterations, psychopathology and cognition is unclear. Methods: A total number of 47 patients with first-episode schizophrenia who had never received antipsychotic medication and 47 healthy controls were scanned with functional magnetic resonance imaging under resting conditions. Main outcome measures were differences in functional connectivity between groups and the relationship between network alterations, psychopathology and cognition. Results: Altered connectivity was found between right central executive network (CEN) and right ventral attention network (VAN) (patients > controls, P = .001), left CEN and left VAN (P = .002), and between posterior default mode network and auditory network (P = .006). Association between network connectivity and clinical characteristics was found as interactions between the effects of group and sustained attention (P = .005) and between group and processing speed (P = .007) on the connectivity between right CEN and right VAN. Conclusions: Our findings suggest that the early phase of schizophrenia is characterized by increased connectivity between fronto-parietal networks suggested to be involved in the control of cognitive and sensory functions. Moreover, the present study suggests that the problem of not disengaging the VAN leads to difficulties with attention and possibly subjective awareness.

Pedestrian safety in patients with Parkinson's disease: A case-control study.

BACKGROUND: Patients with Parkinson's disease experience debilitating motor symptoms as well as nonmotor symptoms, such as cognitive dysfunction and sleep disorders. This constellation of symptoms has the potential to negatively influence pedestrian safety. The objective of this study was to investigate the association of motor symptoms, daytime sleepiness, impaired vigilance, and cognitive dysfunction with pedestrian behavior in patients with Parkinson's disease and healthy older adults. METHODS: Fifty Parkinson's disease and 25 control participants were evaluated within a virtual reality pedestrian environment and completed assessments of motor performance, daytime sleepiness (Epworth Sleepiness Scale), vigilance (psychomotor vigilance task), and visual processing speed (Useful Field of View) outside the virtual reality environment. The primary outcome measure was time to contact, defined as the time remaining until a participant would have been hit by an approaching vehicle while crossing the virtual street. RESULTS: The virtual reality pedestrian environment was feasible in all participants. Patients with Parkinson's disease demonstrated riskier pedestrian behavior compared with controls. Among Parkinson's disease participants, walking speed, objective measures of vigilance, and visual processing speed were correlated with pedestrian behavior, with walking speed the strongest predictor of time to contact, explaining 48% of the variance. Vigilance explained an additional 8% of the variance. In controls, vigilance was also important for street-crossing safety, but older age was the most robust predictor of pedestrian safety. CONCLUSIONS: Walking speed is associated with unsafe pedestrian behavior in patients with Parkinson's disease. In contrast, age was the strongest predictor of pedestrian safety in healthy older adults. © 2017 International Parkinson and Movement Disorder Society.