Longitudinal and Concurrent Effortful Control as Predictors of Risky Bicycling in Adolescence: Moderating Effects of Age and Gender.

OBJECTIVE: Collisions between bicycles and motor vehicles are one of the leading risk factors for injury and death in childhood and adolescence. We examined longitudinal and concurrent effortful control (EC) as predictors of risky bicycling behavior in early- to mid-adolescence, with age and gender as moderators. We also examined whether EC was associated with parent-reported real-world bicycling behavior and all lifetime unintentional injuries. METHODS: Parent-reported EC measures were collected when children (N = 85) were 4 years old and when they were either 10 years (N = 42) or 15 years (N = 43) old. We assessed risky bicycling behavior by asking the adolescents to bicycle across roads with high-density traffic in an immersive virtual environment. Parents also reported on children's real-world bicycling behavior and lifetime unintentional injuries at the time of the bicycling session. RESULTS: We found that both longitudinal and concurrent EC predicted adolescents' gap choices, though these effects were moderated by age and gender. Lower parent-reported early EC in younger and older girls predicted a greater willingness to take tight gaps (3.5 s). Lower parent-reported concurrent EC in older boys predicted a greater willingness to take gaps of any size. Children lower in early EC started bicycling earlier and were rated as less cautious bicyclists as adolescents. Adolescents lower in concurrent EC were also rated as less cautious bicyclists and had experienced more lifetime unintentional injuries requiring medical attention. CONCLUSION: Early measures of child temperament may help to identify at-risk populations who may benefit from parent-based interventions.

Do Simulated Augmented Reality Overlays Influence Street-Crossing Decisions for Non-Mobility-Impaired Older and Younger Adult Pedestrians?

OBJECTIVE: This study used a virtual environment to examine how older and younger pedestrians responded to simulated augmented reality (AR) overlays that indicated the crossability of gaps in a continuous stream of traffic. BACKGROUND: Older adults represent a vulnerable group of pedestrians. AR has the potential to make the task of street-crossing safer and easier for older adults. METHOD: We used an immersive virtual environment to conduct a study with age group and condition as between-subjects factors. In the control condition, older and younger participants crossed a continuous stream of traffic without simulated AR overlays. In the AR condition, older and younger participants crossed with simulated AR overlays signaling whether gaps between vehicles were safe or unsafe to cross. Participants were subsequently interviewed about their experience. RESULTS: We found that participants were more selective in their crossing decisions and took safer gaps in the AR condition as compared to the control condition. Older adult participants also reported reduced mental and physical demand in the AR condition compared to the control condition. CONCLUSION: AR overlays that display the crossability of gaps between vehicles have the potential to make street-crossing safer and easier for older adults. Additional research is needed in more complex real-world scenarios to further examine how AR overlays impact pedestrian behavior. APPLICATION: With rapid advances in autonomous vehicle and vehicle-to-pedestrian communication technologies, it is critical to study how pedestrians can be better supported. Our research provides key insights for ways to improve pedestrian safety applications using emerging technologies like AR.

Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria.

Leupeptin is a bacterial small molecule that is used worldwide as a protease inhibitor. However, its biosynthesis and genetic distribution remain unknown. We identified a family of leupeptins in gammaproteobacterial pathogens, including Photorhabdus, Xenorhabdus, and Klebsiella species, amongst others. Through genetic, metabolomic, and heterologous expression analyses, we established their construction by discretely expressed ligases and accessory enzymes. In Photorhabdus species, a hypothetical protein required for colonizing nematode hosts was established as a new class of proteases. This enzyme cleaved the tripeptide aldehyde protease inhibitors, leading to the formation of "pro-pyrazinones" featuring a hetero-tricyclic architecture. In Klebsiella oxytoca, the pathway was enriched in clinical isolates associated with respiratory tract infections. Thus, the bacterial production and proteolytic degradation of leupeptins can be associated with animal colonization phenotypes.

CXCR2 inhibition enhances sulindac-mediated suppression of colon cancer development.

Small chemical compound sulindac has been approved as a preventive approach against colon cancer for its effectiveness in treatment of precancerous adenoma. Due to its severe toxicities in the cardiovascular, gastrointestinal and renal systems, however, a combination of low-dose sulindac with other chemopreventive agents has been sought after as an alternative therapeutic strategy that could increase its effectiveness, while minimizing its adverse effects. To identify the promising alternative approach, we investigated the therapeutic potential of targeting the interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals. We found that deletion of CXCR2 gene and ectopic expression of IL-8 suppresses and enhances, respectively, intestinal tumor development caused by a mutation in the APC gene. Moreover, a single copy deletion of CXCR2 gene resulted in abrogation of COX-2 and Gro-α upregulation in intestinal tumors caused by the APC mutation. Moreover, a single copy (heterozygote) deletion of CXCR2 gene was sufficient to synergize with a low-dose sulindac treatment in suppressing APCmin-induced intestinal polyposis. Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention.

Opposing regulation of PROX1 by interleukin-3 receptor and NOTCH directs differential host cell fate reprogramming by Kaposi sarcoma herpes virus.

Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Rα) and NOTCH play integral roles in the host cell type-specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Rα and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Rα and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV.

Deciding when to cross in front of an autonomous vehicle: How child and adult pedestrians respond to eHMI timing and vehicle kinematics.

How autonomous vehicles (AVs) communicate their intentions to vulnerable road users (e.g., pedestrians) is a concern given the rapid growth and adoption of this technology. At present, little is known about how children respond to external Human Machine Interface (eHMI) signals from AVs. The current study examined how adults and children respond to the combination of explicit (eHMI signals) and implicit information (vehicle deceleration) to guide their road-crossing decisions. Children (8- to 12-year-olds) and adults made decisions about when to cross in front of a driverless car in an immersive virtual environment. The car sometimes stopped, either abruptly or gradually (manipulated within subjects), to allow participants to cross. When yielding, the car communicated its intent via a dome light that changed from red to green and varied in its timing onset (manipulated between subjects): early eHMI onset, late eHMI onset, or control (no eHMI). As expected, we found that both children and adults waited longer to enter the roadway when vehicles decelerated abruptly than gradually. However, adults responded to the early eHMI signal by crossing sooner when the cars decelerated either gradually or abruptly compared to the control condition. Children were heavily influenced by the late eHMI signal, crossing later when the eHMI signal appeared late and the vehicle decelerated either gradually or abruptly compared to the control condition. Unlike adults, children in the control condition behaved similarly to children in the early eHMI condition by crossing before the yielding vehicle came to a stop. Together, these findings suggest that early eHMI onset may lead to riskier behavior (initiating crossing well before a gradually decelerating vehicle comes to a stop), whereas late eHMI onset may lead to safer behavior (waiting for the eHMI signal to appear before initiating crossing). Without an eHMI signal, children show a concerning overreliance on gradual vehicle deceleration to judge yielding intent.

Lymphatic reprogramming by Kaposi sarcoma herpes virus promotes the oncogenic activity of the virus-encoded G-protein-coupled receptor.

Kaposi sarcoma, the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the Kaposi sarcoma herpes virus (KSHV)-encoded G-protein-coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BEC) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, Kaposi sarcoma tumors express numerous lymphatic endothelial cell (LEC) signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to Kaposi sarcoma formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression, and Akt activation and suppressed tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathologic impact of KSHV-induced reprogramming of host cell identity, and they offer biologic and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for Kaposi sarcoma tumorigenesis.