Sulfation is an important biological process that modulates the function of numerous molecules. It is directly mediated by cytosolic and Golgi sulfotransferases, which use 3-phosphoadenosine 5-phosphosulfate to produce sulfated acceptors and 3-phosphoadenosine 5-phosphate (PAP). Here, we identify a Golgi-resident PAP 3-phosphatase (gPAPP) and demonstrate that its activity is potently inhibited by lithium in vitro. The inactivation of gPAPP in mice led to neonatal lethality, lung abnormalities resembling atelectasis, and dwarfism characterized by aberrant cartilage morphology. The phenotypic similarities of gPAPP mutant mice to chondrodysplastic models harboring mutations within components of the sulfation pathway lead to the discovery of undersulfated chondroitin in the absence of functional enzyme. Additionally, we observed loss of gPAPP leads to perturbations in the levels of heparan sulfate species in lung tissue and whole embryos. Our data are consistent with a model that clearance of the nucleotide product of sulfotransferases within the Golgi plays an important role in glycosaminoglycan sulfation, provide a unique genetic basis for chondrodysplasia, and define a function for gPAPP in the formation of skeletal elements derived through endochondral ossification.chondrodysplasia ͉ glycosaminoglycan ͉ phosphatase ͉ chondroitin sulfate ͉ phosphoadenosine phosphate

The Patient-Centered Outcomes Research Institute (PCORI) uses a unique approach to Merit Review that includes patients and stakeholders as reviewers with scientists, and includes unique review criteria (patient-centeredness and active engagement of end users in the research).This study assessed the extent to which different reviewer types influence review scores and funding outcomes, the emphasis placed on technical merit compared to other criteria by a multistakeholder panel, and the impact of the in-person discussion on agreement among different reviewer types. Methods: Cross-sectional analysis of administrative data from PCORI online and in-person Merit Review (N ¼ 1312 applications from the five funding cycles from November 2013 to August 2015). Linear and logistic regression models were used to analyze the data. Results: For all reviewer types, final review scores were associated with at least one review criterion score from each of the three reviewer types. The strongest predictor of final overall scores for all reviewer types was scientists' prediscussion ratings of technical merit. All reviewers' prediscussion ratings of the potential to improve health care and outcomes, and scientists' ratings of technical merit and patient-centeredness, were associated with funding success. For each reviewer type, overall impact scores from the online scoring were changed on at least half of the applications at the inperson panel discussion. Score agreement across reviewer types was greater after panel discussion. Conclusions: Scientist, patient, and stakeholder views all contribute to PCORI Merit Review of applications for research funding. Technical merit is critical to funding success but patient and stakeholder ratings of other criteria also influence application disposition.

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Patient engagement often starts after research funding is secured with little or no involvement of patients in the proposal development phase. This paper compares three levels of patient engagement and describes patients’ early engagement in research proposal development process and its contemporary relevance to clinical and translational research. Authentic patient engagement is illustrated using an example of an ongoing pragmatic clinical trial. The paper also addresses key patient considerations and questions that have an impact on the proposal development. The final section presents strategies to overcome challenges to the patients’ early engagement in research proposal development approach from the perspectives of both patients and researchers. Although the examples are from comparative effectiveness research, strategies discussed can be applied to all clinical and translational research.

During development, the sympathetic neurons innervating sweat glands undergo a neurotransmitter switch from noradrenergic to cholinergic between postnatal day (P) 4, when the sympathetic neurons first contact the sweat glands, and P21. Several in vitro experiments suggest that norepinephrine (NE), produced by sympathetic neurons, stimulates sweat glands to produce a factor that then induces the phenotypic switch. We tested this hypothesis in vivo using dopamine ␤-hydroxylasedeficient mice (DBH Ϫ/Ϫ), which are unable to synthesize NE and epinephrine, and tyrosine hydroxylase-deficient mice (TH Ϫ/Ϫ), which are unable to synthesize any catecholamines. The cholinergic agonist pilocarpine and electrostimulation of the sciatic nerve both elicited a sweat response in adult DBH Ϫ/Ϫ mice that was indistinguishable from the response of controls, and the cholinergic antagonist atropine effectively blocked these responses. We did note, however, a 1-to 2-week delay in the acquisition of the sweat response in DBH Ϫ/Ϫ mice. Although diminished in magnitude, a sweat response to pilocarpine was also noted in TH Ϫ/Ϫ mice at P21. Immunohistochemistry demonstrated that TH and vasoactive intestinal peptide were detectable at P14 and increased to adult levels by P21 in DBH ϩ/Ϫ and DBH Ϫ/Ϫ mice. These observations indicate that NE is not essential for the acquisition of the cholinergic phenotype, but it may facilitate its postnatal development.