Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagenproducing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.

BackgroundEpidemiological evidence suggests that smoking has been associated with emergence of metabolic syndrome. However, data on this issue are inconsistent and controversial. We therefore conducted a meta-analysis to examine the association between smoking and metabolic syndrome.Methodology and Principal FindingsWe searched the Medline, Embase and the Cochrane Library database up to March 2012 to identify prospective cohort studies related to smoking and metabolic syndrome. Reference lists of retrieved articles were also reviewed. Summary effect estimates were derived using a random-effects model and stratified by gender, smoking dose, follow-up duration and geographical area. Primary analysis of 13 studies involving 56,691 participants and 8,688 cases detected a significant positive association between active smoking and risk of metabolic syndrome (pooled relative risk [RR] 1.26, 95% CI: 1.10–1.44). Estimates of effects were substantially consistent in the stratified analyses. In the dose-response analysis, risk of metabolic syndrome was stronger for active male smokers (pooled RR 1.34, 95% CI: 1.20–1.50) than it was for former male smokers (pooled RR 1.19, 95% CI: 1.00–1.42), and greater for heavy smokers (pooled RR 1.42, 95% CI: 1.27–1.59) compared with light smokers (pooled RR 1.10, 95% CI: 0.90–1.35). No evidence of statistical publication bias was found (Egger' s test P = 0.227, Begg' s test P = 0.113).ConclusionsActive smoking is associated with development of metabolic syndrome. Smoking cessation appears to reduce the risk of metabolic syndrome.

The present meta-analysis provides evidence that MSD improves outcomes of glycemic control, body weight and cardiovascular risk factors in T2D patients.

Golgi fragmentation is a common feature in multiple neurodegenerative diseases; however, the precise mechanism that causes fragmentation remains obscure. A potential link between Cdk5 and Golgi fragmentation in Alzheimer's disease (AD) was investigated in this study. Because Golgi is physiologically fragmented during mitosis by Cdc2 kinase and current Cdk5-specific chemical inhibitors target Cdc2 as well, development of novel tools to modulate Cdk5 activity was essential. These enzyme modulators, created by fusing TAT sequence to Cdk5 activators and an inhibitor peptide, enable specific activation and inhibition of Cdk5 activity with high temporal control. These genetic tools revealed a major role of Cdk5 in Golgi fragmentation upon beta-amyloid and glutamate stimulation in differentiated neuronal cells and primary neurons. A crucial role of Cdk5 was further confirmed when Cdk5 activation alone resulted in robust Golgi disassembly. The underlying mechanism was unraveled using a chemical genetic screen, which yielded cis-Golgi matrix protein GM130 as a novel substrate of Cdk5. Identification of the Cdk5 phosphorylation site on GM130 suggested a mechanism by which Cdk5 may cause Golgi fragmentation upon deregulation in AD. As Cdk5 is activated in several neurodegenerative diseases where Golgi disassembly also occurs, this may be a common mechanism among multiple disorders.