RAD in the realm of next-generation sequencing technologies

The first North American RAD Sequencing and Genomics Symposium, sponsored by Floragenex (http://www.floragenex.com/radmeeting/), took place in Portland, Oregon (USA) on 19 April 2011. This symposium was convened to promote and discuss the use of restriction-site-associated DNA (RAD) sequencing technologies. RAD sequencing is one of several strategies recently developed to increase the power of data generated via short-read sequencing technologies by reducing their complexity (Baird et al. 2008; Huang et al. 2009; Andolfatto et al. 2011; Elshire et al. 2011). RAD sequencing, as a form of genotyping by sequencing, has been effectively applied in genetic mapping and quantitative trait loci (QTL) analyses in a range of organisms including nonmodel, genetically highly heterogeneous organisms (Table 1; Baird et al. 2008; Baxter et al. 2011; Chutimanitsakun et al. 2011; Pfender et al. 2011). RAD sequencing has recently found applications in phylogeography (Emerson et al. 2010) and population genomics (Hohenlohe et al. 2010). Considering the diversity of talks presented during this meeting, more developments are to be expected in the very near future.     

The ongoing saga of sirtuins and aging

Sirtuins are known to slow aging in simple eukaryotes; however, viewing mammalian sirtuins as antiaging proteins may be overly simplistic. In this issue of Cell Metabolism, Li et al. (2008) provide evidence that SirT1 has properties consistent with both pro- and antiaging functions in mice.     

Converted neural cells: induced to a cure?

Many neurodegenerative disorders such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and others often occur as a result of progressive loss of structure or function of neurons. Recently, many groups were able to generate neural cells, either differentiated from induced pluripotent stem cells (iPSCs) or converted from somatic cells. Advances in converted neural cells have opened a new era to ease applications for modeling diseases and screening drugs. In addition, the converted neural cells also hold the promise for cell replacement therapy (Kikuchi et al., 2011; Krencik et al., 2011; Kriks et al., 2011; Nori et al., 2011; Rhee et al., 2011; Schwartz et al., 2012). Here we will mainly discuss most recent progress on using converted functional neural cells to treat neurological diseases and highlight potential clinical challenges and future perspectives.     

Evicting the pneumococcus from its nasopharyngeal lodgings

Adenylylation of Rab proteins appears to be an intriguing mechanism that Legionella pneumophila uses to modulate their activity during infection. Now the reverse reaction (deadenylylation) (Neunuebel et?al., 2011; Tan and Luo, 2011) and a new posttranslational modification (phosphocholination) of Rab1 (Mukherjee et?al., 2011) have been reported.     

Converting human skin cells to neurons: a new tool to study and treat brain disorders?

Recent publications in Cell Stem Cell (Son et?al., 2011; Ambasudhan et?al., 2011), PNAS (Pfisterer et?al., 2011), and Nature (Caiazzo et?al., 2011; Pang et?al., 2011; Yoo et?al., 2011) report that functional neurons can be directly generated from human fibroblast cells without going through the pluripotent state.     

Tales from the crypt: the expanding role of slow cycling intestinal stem cells

Similar to other highly self-renewing tissues, the intestinal epithelium contains both slowly and rapidly cycling progenitor/stem cells, though their relationship has been largely unexplored. Two recent reports in Nature (Tian et al., 2011) and Science (Takeda et al., 2011) shed new light on their dynamic interplay.     

Early human dispersals into the Iberian Peninsula: a comment on Martínez et al.(2010) and Garcia et al. (2011)

Garcia et al. (2011) recently discussed early human dispersals into the Iberian Peninsula, describing several putative lithic artifacts (Martínez et al., 2010) recovered from layer 7 of the Vallpara díssection (Madurell-Malapeira et al., 2010) in Terrassa (Vallès-Penedès Basin, Catalonia, Spain). According to the authors' opinion, such evidence (1) fills a gap in the chronology of early human occupation in Iberia, (2) indicates that these populations had primary and early access to carcasses, and (3) confirms that early human populations were equipped with advanced cultural traits enabling them to survive in unfavourable climatic conditions. We argue below that the record of human activity at Vallparadís (Martínez et al., 2010;Garcia et al., 2011) is doubtful and even that if confirmed, a chronological gap would remain (contra Garcia et al., 2011). Additional remarks on assertions by these authors on the Vallparadís geology, taphonomy and paleonvironment are also provided.     

iPSCs: induced back to controversy

Several recent reports (Mayshar et?al., 2010; Laurent et?al., 2011; Lister et?al., 2011; Gore et?al., 2011; Hussein et?al., 2011) uncover genetic and epigenetic alterations in induced pluripotent stem cells, stimulating debate about their future. However, will these important findings really impact what we hope to gain?     

Recombining DNA by protein swivels

Two new reports on serine recombinases, one of a crystal snapshot in an alternate rotational conformer poised for DNA cleavage (Keenholtz et al., 2011), and a second employing single-DNA molecule approaches (Bai et al., 2011), provide strong support for the subunit rotation model for exchanging DNA strands.     

Breaking the cell cycle of HSCs by p57 and friends

The cell cycle regulators involved in maintaining the quiescence, and thereby the self-renewal capacity, of somatic stem cells have long been elusive. Two new Cell Stem Cell articles in this issue (Matsumoto et?al., 2011; Zou et?al., 2011) now show that the CDK inhibitor p57 is a crucial brake for cycling HSCs, and links self-renewal activity to cell cycle quiescence.     

DEPTOR ubiquitination and destruction by SCF(β-TrCP)

β-Transducin repeats-containing protein (β-TrCP) is the substrate recognition subunit of the SCF (SKP1, CUL1, and F-box protein)-type E3 ubiquitin ligase complex. SCF(β-TrCP) ubiquitinates specifically phosphorylated substrates to promote their subsequent destruction by the 26S proteasome and plays a critical role in various human diseases including tumorigenesis. We and others (Duan S et al. Mol Cell 44: 317-324, 2011; Gao D et al. Mol Cell 44: 290-303, 2011; Zhao Y et al. Mol Cell 44: 304-316, 2011) recently reported that SCF(β-TrCP) regulates cell growth and autophagy by controlling the ubiquitination and destruction of DEPTOR, an endogenous mammalian target of rapamycin inhibitor, in a phosphorylation-dependent manner. In this review, we discuss β-TrCP's new downstream substrate, DEPTOR, as well as summarize the novel functional aspects of β-TrCP in controlling cell growth and regulating autophagy, in part through governing the stability of DEPTOR.     

PP2A targets SAS-5 in centriole assembly

In this issue of Developmental Cell, Kitagawa et al. (2011a) and Song et al. (2011) show that the protein phosphatase PP2A regulates SAS-5 to control centriole duplication. Two paradigms are presented to explain how PP2A regulates SAS-5.     

Robust generation of hepatocyte-like cells from human embryonic stem cell populations

Despite progress in modelling human drug toxicity, many compounds fail during clinical trials due to unpredicted side effects. The cost of clinical studies are substantial, therefore it is essential that more predictive toxicology screens are developed and deployed early on in drug development (Greenhough et al 2010). Human hepatocytes represent the current gold standard model for evaluating drug toxicity, but are a limited resource that exhibit variable function. Therefore, the use of immortalised cell lines and animal tissue models are routinely employed due to their abundance. While both sources are informative, they are limited by poor function, species variability and/or instability in culture (Dalgetty et al 2009). Pluripotent stem cells (PSCs) are an attractive alternative source of human hepatocyte like cells (HLCs) (Medine et al 2010). PSCs are capable of self renewal and differentiation to all somatic cell types found in the adult and thereby represent a potentially inexhaustible source of differentiated cells. We have developed a procedure that is simple, highly efficient, amenable to automation and yields functional human HLCs (Hay et al 2008 ; Fletcher et al 2008 ; Hannoun et al 2010 ; Payne et al 2011 and Hay et al 2011). We believe our technology will lead to the scalable production of HLCs for drug discovery, disease modeling, the construction of extra-corporeal devices and possibly cell based transplantation therapies.     

Getting cells and tissues into shape

Cells of all shapes and sizes are able to calculate the location of their middles in order to divide into two during mitosis. Minc et?al. (2011) and Gibson et?al. (2011) now show that simple mechanical models accurately predict cleavage-plane positioning, and that geometrical interactions between neighboring cells are sufficient to generate ordered patterns of mitosis in growing epithelia.     

Revoking the cellular license to replicate: yet another AAA assignment

In this issue of Molecular Cell, Raman et al. (2011) and Franz et al. (2011) establish the AAA ATPase CDC-48/p97 as an essential regulator of eukaryotic DNA replication that coordinates the release of chromatin-bound CDT1 with its degradation by the proteasome.     

Unveiled α-neurexins take center stage

Neurexins are presynaptic transmembrane proteins that play an essential role in synapse function. The crystal structures of α-neurexin extracellular domains (Chen et?al., 2011; Miller et?al., 2011) provide important insights into their conformational freedom and their putative spatial arrangement with binding partners in the synaptic cleft.     

Clever leukemic stem cells branch out

Individual tumors harbor heterogeneous populations of genetically distinct subclones. Two recent papers in Nature by Notta et al. (2011) and Anderson et al. (2011) reveal genetic heterogeneity in functional leukemic stem cells, which has important implications for how both cancer and normal stem cell populations may adapt to selective pressure.