On-Road Bicycle Facilities and Cyclist Injury in Bicycle-Motor Vehicle Crashes in Chicago

Bicycling has been increasing in North America, in particular for utilitarian trips and in urban areas. Infrastructure changes such as on- and off-road bicycle lanes, routes, and paths have been implemented in many cities to accommodate growing numbers of cyclists. Risk perceptions deter many more potential cyclists concerned about collisions with motor vehicles. This cross-sectional study examined road crashes between motor vehicles and bicycles from 2008–2010 in the city of Chicago using traffic crash report data. Geographic Information Systems files containing on-road bicycle facilities (i.e., designated bike lanes, marked shared lanes, or signed recommended bike routes) and bus stops were obtained from the city of Chicago and spatially matched to crash locations. Logistic regression was used to examine the relationship between presence of each type of bike facility and bus stop with occurrence of an incapacitating or fatal injury to the cyclist, a dichotomous variable, separately for intersection and non-intersection crashes. Nearly three-fifths of the crashes were intersection-related but severe injury prevalence did not vary between intersection and non-intersection crashes. There were significantly more intersection crashes on or near recommended bike routes, while greater percentages of non-intersection crashes occurred near bike lanes and marked shared lanes. There were no statistically significant bivariate associations between the presence of any bicycle facility or bus stop and severe cyclist injury. In multivariable models, only presence of a recommended bike route was significantly negatively associated with severe cyclist injury for intersection crashes, and a designated bike lane was marginally negatively associated with severe injury in non-intersection crashes. Presence of a marked shared lane was not associated with the injury measure. Bicycle facilities and posted signage may lead drivers to anticipate cyclist presence and bicycle lanes may allow for greater distance between motor vehicles and bicycles at non-intersection locations. This study lends limited support to previous research suggesting that roadways with bicycle facilities may be safer for cyclists than untreated roadways. However, caution should be taken when interpreting results from injury studies using traffic crash report data due to potentially poor reliability of police injury assessments

Dual Allosteric Inhibition of SHP2 Phosphatase

SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the <i>PTPN11</i> gene and is involved in cell proliferation, differentiation, and survival. Recently, we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (<b>1</b>) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies that enabled the identification of a second, distinct small molecule allosteric site. SHP244 (<b>2</b>) was identified as a weak inhibitor of SHP2 with modest thermal stabilization of the enzyme. X-ray crystallography revealed that <b>2</b> binds and stabilizes the inactive, closed conformation of SHP2, at a distinct, previously unexplored binding sitea cleft formed at the interface of the <i>N</i>-terminal SH2 and PTP domains. Derivatization of <b>2</b> using structure-based design resulted in an increase in SHP2 thermal stabilization, biochemical inhibition, and subsequent MAPK pathway modulation. Downregulation of DUSP6 mRNA, a downstream MAPK pathway marker, was observed in KYSE-520 cancer cells. Remarkably, simultaneous occupation of both allosteric sites by <b>1</b> and <b>2</b> was possible, as characterized by cooperative biochemical inhibition experiments and X-ray crystallography. Combining an allosteric site 1 inhibitor with an allosteric site 2 inhibitor led to enhanced pharmacological pathway inhibition in cells. This work illustrates a rare example of dual allosteric targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies