The primary cilium is an antenna-like organelle that is dynamically regulated during the cell cycle. Ciliogenesis is initiated as cells enter quiescence, while cilium resorption precedes mitosis. The mechanisms coordinating ciliogenesis with the cell cycle are unknown. Here we identify the centrosomal protein, Nde1, as a negative regulator of ciliary length. Nde1 is expressed at high levels in mitosis, low levels in quiescence and localizes at the mother centriole, which nucleates the primary cilium. Cells depleted of Nde1 show longer cilia and a delay in cell cycle re-entry that correlates with ciliary length. Knockdown of Nde1 in zebrafish embryos results in increased ciliary length, suppression of cell division, reduction of the number of cells forming the Kupffer’s vesicle, and left-right patterning defects. These data suggest that Nde1 is an integral component of a network coordinating ciliary length with cell cycle progression and have implications in the transition from quiescence to a proliferative state.

The Korean EQ-5D exhibits good validity and sensitivity in various rheumatic conditions. Although its reliability and responsiveness were not excellent, it seems acceptable if condition-specific measures are applied together.

Summary Many proteins are known to promote ciliogenesis, but mechanisms that promote primary cilia disassembly prior to mitosis are largely unknown. Here, we identify a mechanism that favors cilium disassembly and maintains the disassembled state. We show that co-localization of the S/G2 phase kinase, Nek2, and Kif24 triggers Kif24 phosphorylation, inhibiting cilia formation. We show that Kif24, a microtubule depolymerizing kinesin, is phosphorylated by Nek2, which stimulates its activity and prevents the outgrowth of cilia in proliferating cells, independent of Aurora A and HDAC6. Our data also suggest that cilium assembly and disassembly are in dynamic equilibrium, but Nek2 and Kif24 can shift the balance toward disassembly. Further, Nek2 and Kif24 are over-expressed in breast cancer cells, and ablation of these proteins restores ciliation in these cells, thereby reducing proliferation. Thus, Kif24 is a physiological substrate of Nek2, which regulates cilia disassembly through a concerted mechanism involving Kif24-mediated microtubule de-polymerization.

The results of this multicenter field test provide support for the reliability and validity of the LDQOL 1.0 as an HRQOL outcome measure for individuals with chronic liver disease.

Talpid3 and Cep290 promote proper ciliary vesicle formation by regulating centriolar satellite accretion and Rab8a localization.

Summary Cilia are evolutionarily conserved, membrane-bound, microtubular projections emanating from the cell surface. They are assembled on virtually all cell types in the human body, with very few exceptions, and several recent reviews have covered the topic in great detail [1–3]. The cilium is assembled from mature (mother) centrioles or basal bodies, which serve to nucleate growth of axonemes that give rise to two structurally distinct variants, motile and non-motile cilia. Whereas motile cilia are typically found in large bundles and beat synchronously to generate fluid flow, primary cilia (with the exception of those found at the embryonic node) are generally immotile and are found as solitary organelles [3, 4]. Remarkably, until recently, the primary cilium was considered a vestigial organelle without apparent biological function. However, research over the past decade has established that the primary cilium is capable of transducing essential signaling information from the extracellular milieu [1, 5]. Defects in the cilium, and the structure from which it arises, the basal body, have been shown to cause a spectrum of diseases, ranging from developmental defects to obesity, diabetes, and cancer [6]. Many of these diseases, or ciliopathies, are manifested as genetic syndromes, such as Joubert syndrome, Bardet-Biedel (BBS), Meckel-Gruber (MKS), and Nephronophthisis (NPHP) [6], illustrating the importance of understanding cilium structure and function and the mechanisms required for its assembly. This review focuses primarily on recent advances in our understanding of the regulatory controls governing the assembly and maintenance of the primary cilium.

Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. Centrosome duplication is controlled in part by CP110, a centriolar protein that positively regulates centriole duplication while restricting centriole elongation and ciliogenesis. Maintenance of normal CP110 levels is essential, since excessive CP110 drives centrosome over-duplication and suppresses ciliogenesis, whereas its depletion inhibits centriole amplification and leads to highly elongated centrioles and aberrant assembly of cilia in growing cells1,2. CP110 levels are tightly controlled in part through SCFcyclin F-mediated ubiquitylation during G2 and M phase of the cell cycle3. Here we report a new mechanism for regulation of centrosome duplication that requires USP33, a de-ubiquitylating enzyme (DUB) able to regulate CP110 levels. USP33 interacts with CP110 and localizes to centrioles primarily during S and G2/M phase, the period during which centrioles duplicate and elongate. USP33 potently and specifically de-ubiquitylates CP110, but not other cyclin F substrates. USP33 activity antagonizes SCFcyclin F-mediated ubiquitylation and promotes generation of supernumerary centriolar foci, whereas ablation of USP33 destabilizes CP110 and thereby inhibits centrosome amplification and mitotic defects. To our knowledge, these studies have identified the first centriolar de-ubiquitinating enzyme whose expression regulates centrosome homeostasis by countering cyclin F-mediated destruction of a key substrate and suggest potential therapeutic strategies for inhibiting tumorigenesis associated with centrosome amplification.

Objectives. We estimated the prevalence and determinants of delayed and unmet needs for medical care among patients in a restructured public health system. Methods. We conducted a stratified cross-sectional probability sample of primary care patients in the Los Angeles County Department of Health Services. Face-to-face interviews were conducted with 1819 adult patients in 6 languages. The response rate was 80%. The study sample was racially/ethnically diverse. Results. Thirty-three percent reported delaying needed medical care during the preceding 12 months; 25% reported an unmet need for care because of competing priorities; and 46% had either delayed or gone without care. Conclusions. Barriers to needed health care continue to exist among patients receiving care through a large safety net system. Competing priorities for basic necessities and lack of insurance contribute importantly to unmet health care needs.