SUMMARY Tissue homeostasis in metazoans is regulated by transitions of cells between quiescence and proliferation. The hallmark of proliferating populations is progression through the cell cycle, which is driven by cyclin-dependent kinase (CDK) activity. Here, we introduce a live-cell sensor for CDK2 activity and unexpectedly found that proliferating cells bifurcate into two populations as they exit mitosis. Many cells immediately commit to the next cell cycle by building up CDK2 activity from an intermediate level, while other cells lack CDK2 activity and enter a transient state of quiescence. This bifurcation is directly controlled by the CDK inhibitor p21 and is regulated by mitogens during a restriction window at the end of the previous cell cycle. Thus, cells decide at the end of mitosis to either start the next cell cycle by immediately building up CDK2 activity or to enter a transient G0-like state by suppressing CDK2 activity.

Developmental signals such as Wnts are often presented to cells in an oriented manner. To examine the consequences of local Wnt signaling, we immobilized Wnt proteins on beads and introduced them to embryonic stem cells in culture. At the single-cell level, the Wnt-bead induced asymmetric distribution of Wnt–β-catenin signaling components, oriented the plane of mitotic division, and directed asymmetric inheritance of centrosomes. Before cytokinesis was completed, the Wnt-proximal daughter cell expressed high levels of nuclear β-catenin and pluripotency genes, whereas the distal daughter cell acquired hallmarks of differentiation. We suggest that a spatially restricted Wnt signal induces an oriented cell division that generates distinct cell fates at predictable positions relative to the Wnt source.

Pyogenic liver abscess has become a health problem in Taiwanese society. However, the extent of this problem has remained unclear because of the lack of a populationbased study. We therefore performed a nationwide analysis of pyogenic liver abscess in Taiwan from 1996 through 2004. We analyzed 29,703 cases from the Taiwan National Health Insurance database and 506 cases from National Taiwan University Hospital. Our analysis showed that the annual incidence of pyogenic liver abscess increased steadily from 11.15/100,000 population in 1996 to 17.59/100,000 in 2004. Diabetes, malignancy, renal disease, and pneumonia were associated with a higher risk for the disease. By contrast, death due to pyogenic liver abscess decreased over time, although population-based abscess-related death increased slightly. Renal disease, malignancy, pneumonia, and heart disease correlated with higher death rates; Klebsiella pneumoniae infection and therapeutic procedures were related to lower death rates. Diabetes did not signifi cantly change death rates for the 506 patients from the hospital.T he epidemiology of pyogenic liver abscess has changed dramatically in recent years (1). Previously, although incidence was considered rare, the condition was associated with high illness and death rates, usually due to underlying hepatobiliary diseases and polymicrobial infection (2), with Escherichia coli as the major pathogen (3). More recently, investigations in Taiwan suggest the role of cryptogenic or primary liver abscess, i.e., abscesses without underlying hepatobiliary diseases, in pyogenic liver abscess (4,5). These reports also indicate that diabetes is the major predisposing factor of liver abscess and that Klebsiella pneumoniae is the primary pathogen. However, these results were obtained from small-scale hospital-based surveys, which could not provide a panoramic view of the disease. To confi rm these observation-based results, we conducted a large-scale, unbiased investigation.In addition to epidemiology, the pathogenesis of liver abscess caused by Klebsiella spp. has also been extensively studied, but the mechanism is still not clear. MagA, an outermembrane protein contributing to capsular polysaccharide formation, coexists with serotype K1 and has been identifi ed as the major virulence factor of K. pneumoniae (6). MagApositive (or serotype K1) K. pneumoniae is accordingly recognized as the main pathogen of pyogenic liver abscess (7,8). Nevertheless, how diabetes increases the risk for Klebsiella spp. liver abscess is still not clear. Further research is needed on whether pyogenic liver abscess is affected by immunocompromised conditions, such as malignancy, renal failure, postorgan transplantation, or HIV infection.To clarify the epidemiology and pathogenesis of pyogenic liver abscess, we used information gathered by the Taiwan National Health Insurance (NHI) program, which was initiated in 1995 by the government to cover most Taiwanese citizens. In 2005, 91.25% of healthcare providers were enrolled in the program and 99% of Ta...

Ca2+ signals control cell migration by regulating forward movement and cell adhesion. However, it is not well understood how Ca2+-regulatory proteins and second messengers are spatially organized in migrating cells. Here we show that receptor tyrosine kinase and phospholipase C signaling are restricted to the front of migrating endothelial leader cells, triggering local Ca2+ pulses, local depletion of Ca2+ in the endoplasmic reticulum, and local activation of STIM1, supporting pulsatile front retraction and adhesion. At the same time, the mediator of store-operated Ca2+ influx STIM1 is transported by microtubule plus ends to the front. Furthermore, higher Ca2+ pump rates in the front relative to the back of the plasma membrane enable effective local Ca2+ signaling by locally decreasing basal Ca2+. Finally, polarized phospholipase C signaling generates a diacylglycerol gradient towards the front that promotes persistent forward migration. Thus, cells employ an integrated Ca2+ control system with polarized Ca2+ signaling proteins and second messengers to synergistically promote directed cell migration.