Structure and design of Langya virus glycoprotein antigens.

Langya virus (LayV) is a recently discovered henipavirus (HNV), isolated from febrile patients in China. HNV entry into host cells is mediated by the attachment (G) and fusion (F) glycoproteins which are the main targets of neutralizing antibodies. We show here that the LayV F and G glycoproteins promote membrane fusion with human, mouse, and hamster target cells using a different, yet unknown, receptor than Nipah virus (NiV) and Hendra virus (HeV) and that NiV- and HeV-elicited monoclonal and polyclonal antibodies do not cross-react with LayV F and G. We determined cryoelectron microscopy structures of LayV F, in the prefusion and postfusion states, and of LayV G, revealing their conformational landscape and distinct antigenicity relative to NiV and HeV. We computationally designed stabilized LayV G constructs and demonstrate the generalizability of an HNV F prefusion-stabilization strategy. Our data will support the development of vaccines and therapeutics against LayV and closely related HNVs.

Structure and design of Langya virus glycoprotein antigens.

Langya virus (LayV) is a recently discovered henipavirus (HNV), isolated from febrile patients in China. HNV entry into host cells is mediated by the attachment (G) and fusion (F) glycoproteins which are the main targets of neutralizing antibodies. We show here that the LayV F and G glycoproteins promote membrane fusion with human, mouse and hamster target cells using a different, yet unknown, receptor than NiV and HeV and that NiV- and HeV-elicited monoclonal and polyclonal antibodies do not cross-react with LayV F and G. We determined cryo-electron microscopy structures of LayV F, in the prefusion and postfusion states, and of LayV G, revealing previously unknown conformational landscapes and their distinct antigenicity relative to NiV and HeV. We computationally designed stabilized LayV G constructs and demonstrate the generalizability of an HNV F prefusion-stabilization strategy. Our data will support the development of vaccines and therapeutics against LayV and closely related HNVs.

Rational design of selective inhibitors of PARP4.

PARPs (PARP1-16 in humans) are a large family of ADP-ribosyltransferases (ARTs) that have diverse roles in cellular physiology and pathophysiology. Most PARP family members mediate mono-ADP-ribosylation (MARylation) of targets. The function of PARP-mediated MARylation in cells is poorly characterized, due in large part to the paucity of selective small molecule inhibitors of the catalytic activity of individual PARP enzymes. Herein we describe the rational design of selective small molecule inhibitors of PARP4 (also known as vPARP). These inhibitors are based on a quinazolin-4(3H)-one scaffold, and contain substituents at the C-8 position designed to exploit a unique threonine (Thr484, human PARP4 numbering) in the PARP4 nicotinamide sub-pocket. Our most potent analog, AEP07, which contains an iodine at the C-8 position, is at least 12-fold selective over other PARP family members. AEP07 will serve as a useful lead compound for the further development of PARP4 inhibitors that can be used to probe the cellular functions of PARP4 catalytic activity.

Barriers to participation in a worksite wellness program.

THE PURPOSE OF THIS RESEARCH WAS TO DETERMINE BARRIERS THAT PREVENT PARTICIPATION IN AN EMPLOYEE WELLNESS PROGRAM, WELLNESS WEDNESDAYS: "Eat & Meet" About Healthy Living, conducted at East Carolina University (ECU) in Greenville, North Carolina. All ECU ARAMARK employees (n = 481) over the age of 18 were eligible to participate in the wellness program. Weekly 30 minute classes, taught by a Registered Dietitian, on various nutrition- and health-related topics were conducted for 10-weeks. Five question knowledge quizzes were administered to participants at the end of each class to determine the comprehension of material presented. Qualitative interviews (n = 19) were conducted with employees (participants and non-participants) and the program organizer after the completion of the 10-week program to identify barriers to program participation. A total of 50 (10.4% of the total number of potential participants) ECU ARAMARK employees, managers, and leadership team directors attended Wellness Wednesdays at least once during the 10-week program. Employees, on average, scored 71-100% on the weekly knowledge quizzes administered at the end of each class. The most common barriers to participation reported included (most often to least often reported): insufficient incentives, inconvenient locations, time limitations, not interested in topics presented, undefined reasons, schedule, marketing, health beliefs, and not interested in the program. Results showed that employee wellness programs can be effective in increasing knowledge of employees on nutrition- and health-related topics. However, program planning that addresses identified barriers including insufficient incentives, inconvenient locations, and time limitations may facilitate higher participation in future worksite wellness opportunities.