A Novel 7H-[1,2,4]Triazolo[3,4-b]thiadiazine-based Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Directed toward Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit marginal clinical benefit or detrimental effects or have a form of the disease not approved or unlikely to respond using CFTR modulation. We tested hit compounds from a 300,000-drug screen for their ability to augment CFTR transepithelial transport alone or in combination with the FDA-approved CFTR potentiator ivacaftor (VX-770). A subsequent SAR campaign led us to a class of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines that in combination with VX-770 rescued function of G551D mutant CFTR channels to approximately 400% above the activity of VX-770 alone and to nearly wild-type CFTR levels in the same Fischer rat thyroid model system.

Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes.

Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, "Variant Explorer Pipeline" (VExP). This reanalysis approach and results were compared with existing literature. Reanalysis of candidate variants from CES in 28 cases revealed 1 interpretation that needed to be reclassified. A confirmed or potential genetic diagnosis was identified in 24 of 75 CES-negative/reclassified cases (32.0%), including variants in known disease-causing genes (n = 6) or candidate genes (n = 18). This yield was higher compared with similar studies demonstrating the utility of this approach. In summary, reanalysis of negative CES in a research setting enhances diagnostic yield by about a third. This study suggests the need for comprehensive, continued reanalysis of exome data when molecular diagnosis is elusive.

Hand proximity effects are fragile: a useful null result.

Placing one's hands near an object has been reported to enhance visual processing in a number of ways. We explored whether hand proximity confers an advantage when applied to complex visual search. In one experiment, participants indicated the presence or absence of a target item in a baggage x-ray image by pressing response boxes located at the edge of a tablet computer screen, requiring them to grip the display between their hands. Alternatively, they responded using a mouse held within their lap. Contrary to expectations, hand position did not influence search performance. In a second experiment, participants used their finger to trace along the x-ray image while searching. In addition to any effect of hand proximity it was predicted that this strategy would encourage a more systematic search strategy. Participants inspected bags longer using this strategy, but this did not translate into improved target detection. A third experiment attempted to replicate the near-hands advantage in a change detection paradigm featuring simple stimuli (Tseng and Bridgeman, Experimental Brain Research 209:257-269, 2011), and the same equipment and hand positions as Experiment 1, but was unable to do so. One possibility is that the grip posture associated with holding a tablet is not conducive to producing a near-hands advantage. A final experiment tested this hypothesis with a direct replication of Tseng and Bridgeman, in which participants responded to stimuli presented on a CRT monitor using keys attached to the side of the monitor. Still, no near-hands advantage was observed. Our results suggest that the near-hands advantage may be sensitive to small differences in procedure, a finding that has important implications for harnessing the near-hands advantage to produce better performance in applied contexts.