Analysis of the health economics portfolio funded by the National Institutes of Health in response to published guidance.

Health services, economics, and outcomes research (referred to as health economics research hereinafter) is one of the interdisciplinary sciences that the National Institutes of Health (NIH) supports in order to pursue its overall mission to improve health. In 2015, NIH guidance was published to clarify the type of health economics research that NIH would continue to fund. This analysis aimed to determine if there were changes in the number of health economics applications received and funded by NIH after the release of the guidance. Health economics applications submitted to NIH both before and after publication of the guidance were identified using a machine learning approach with input from subject matter experts. Application and funding trends were examined by fiscal year, method of application (solicited vs. unsolicited), and activity code. This study found that application and funding rates of health economics research were decreasing prior to guidance. Following publication of this guidance, the application and funding rate of health economics applications increased.

Publication rates from biomedical and behavioral and social science R01s funded by the National Institutes of Health.

Prior research has shown a serious lack of research transparency resulting from the failure to publish study results in a timely manner. The National Institutes of Health (NIH) has increased its use of publication rate and time to publication as metrics for grant productivity. In this study, we analyze the publications associated with all R01 and U01 grants funded from 2008 through 2014, providing sufficient time for these grants to publish their findings, and identify predictors of time to publication based on a number of variables, including if a grant was coded as a behavioral and social sciences research (BSSR) grant or not. Overall, 2.4% of the 27,016 R01 and U01 grants did not have a publication associated with the grant within 60 months of the project start date, and this rate of zero publications was higher for BSSR grants (4.6%) than for non-BSSR grants (1.9%). Mean time in months to first publication was 15.2 months, longer for BSSR grants (22.4 months) than non-BSSR grants (13.6 months). Survival curves showed a more rapid reduction of risk to publish from non-BSSR vs BSSR grants. Cox regression models showed that human research (vs. animal, neither, or both) and clinical trials research (vs. not) are the strongest predictors of time to publication and failure to publish, but even after accounting for these and other predictors, BSSR grants continued to show longer times to first publication and greater risk of no publications than non-BSSR grants. These findings indicate that even with liberal criteria for publication (any publication associated with a grant), a small percentage of R01 and U01 grantees fail to publish in a timely manner, and that a number of factors, including human research, clinical trial research, child research, not being an early stage investigator, and conducting behavioral and social sciences research increase the risk of time to first publication.

Keratinocyte secretion of cyclophilin B via the constitutive pathway is regulated through its cyclosporin-binding site.

Cyclophilin B (CypB) is an endoplasmic reticulum (ER)-resident member of the cyclophilin family of proteins that bind cyclosporin A (CsA). We report that as in other cell types, CypB trafficked from the ER and was secreted by keratinocytes into the media in response to CsA. Concentrations as low as 1 pM of CsA induced secretion of CypB. Using brefeldin A, we showed that CypB is secreted from keratinocytes via the constitutive secretory pathway. We defined that substitution of tryptophan residue 128 in the CsA-binding site of CypB with alanine resulted in dissociation of CypB(W128A)-green fluorescent protein (GFP) from the ER. Photobleaching studies revealed a significant reduction in the diffusible mobility of CypB(W128A)-GFP compared with CypB(WT)-GFP, consistent with redistribution of CypB(W128A)-GFP into secretory vesicles disconnected from the ER/Golgi network. Furthermore, CsA significantly decreased the mobility of CypB(WT)-GFP but not CypB(W128A)-GFP. These studies demonstrate that therapeutically relevant concentrations of CsA regulate secretion of CypB by keratinocytes, and that a key residue within the CsA-binding site of CypB controls retention of CypB within the ER and regulates entry into the secretory pathway. As keratinocytes express CypB receptors (CD147) and CypB exhibits chemotactic properties, these data have implications for the therapeutic effects of CsA in inflammatory skin disease.

The endoplasmic reticulum takes center stage in cell cycle regulation.

Cell cycle progression is controlled by the action of cyclins and their partners, the cyclin-dependent kinases (CDKs). Although many of the cyclin/CDK targets are in the nucleus, some cyclins spend part of their time in the cytoplasm. Until recently, it was not clear what happens to these cyclins while they are in the cytoplasm; now, two different cyclins have been found to be associated with the endoplasmic reticulum. The question is why.