Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease

Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.     

Nowcasting quarterly GDP growth in a monthly coincident indicator model

This paper presents an extension of the Stock and Watson coincident indicator model that allows one to include variables available at different frequencies while taking care of missing observations at any time period. The proposed procedure provides estimates of the unobserved common coincident component, of the unobserved monthly series underlying any included quarterly indicator, and of any missing values in the series. An application to a coincident indicator model for the Portuguese economy is presented. We use monthly indicators from business surveys whose results are published with a very short delay. By using the available data for the monthly indicators and for quarterly real GDP, it becomes possible to produce simultaneously a monthly composite index of coincident indicators and an estimate of the latest quarter real GDP growth well ahead of the release of the first official figures. Copyright © 2005 John Wiley & Son, Ltd.     

Speciation by hybridization in Heliconius butterflies

Speciation is generally regarded to result from the splitting of a single lineage. An alternative is hybrid speciation, considered to be extremely rare, in which two distinct lineages contribute genes to a daughter species. Here we show that a hybrid trait in an animal species can directly cause reproductive isolation. The butterfly species Heliconius heurippa is known to have an intermediate morphology and a hybrid genome, and we have recreated its intermediate wing colour and pattern through laboratory crosses between H. melpomene, H. cydno and their F1 hybrids. We then used mate preference experiments to show that the phenotype of H. heurippa reproductively isolates it from both parental species. There is strong assortative mating between all three species, and in H. heurippa the wing pattern and colour elements derived from H. melpomene and H. cydno are both critical for mate recognition by males.     

Widespread amphibian extinctions from epidemic disease driven by global warming

As the Earth warms, many species are likely to disappear, often because of changing disease dynamics. Here we show that a recent mass extinction associated with pathogen outbreaks is tied to global warming. Seventeen years ago, in the mountains of Costa Rica, the Monteverde harlequin frog (Atelopus sp.) vanished along with the golden toad (Bufo periglenes). An estimated 67% of the 110 or so species of Atelopus, which are endemic to the American tropics, have met the same fate, and a pathogenic chytrid fungus (Batrachochytrium dendrobatidis) is implicated. Analysing the timing of losses in relation to changes in sea surface and air temperatures, we conclude with 'very high confidence' (> 99%, following the Intergovernmental Panel on Climate Change, IPCC) that large-scale warming is a key factor in the disappearances. We propose that temperatures at many highland localities are shifting towards the growth optimum of Batrachochytrium, thus encouraging outbreaks. With climate change promoting infectious disease and eroding biodiversity, the urgency of reducing greenhouse-gas concentrations is now undeniable.     

A restricted cell population propagates glioblastoma growth after chemotherapy

Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.     

Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation

c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function, the signals that mediate its antiapoptotic effect are largely unknown. Here we show that worms carrying an abl-1 deletion allele, abl-1(ok171), are specifically hypersensitive to radiation-induced apoptosis in the Caenorhabditis elegans germ line. Our findings delineate an apoptotic pathway antagonized by ABL-1, which requires sequentially the cell cycle checkpoint genes clk-2, hus-1 and mrt-2; the C. elegans p53 homolog, cep-1; and the genes encoding the components of the conserved apoptotic machinery, ced-3, ced-9 and egl-1. ABL-1 does not antagonize germline apoptosis induced by the DNA-alkylating agent ethylnitrosourea. Furthermore, worms treated with the c-Abl inhibitor STI-571 (Gleevec; used in human cancer therapy), two newly synthesized STI-571 variants or PD166326 had a phenotype similar to that generated by abl-1(ok171). These studies indicate that ABL-1 distinguishes proapoptotic signals triggered by two different DNA-damaging agents and suggest that C. elegans might provide tissue models for development of anticancer drugs.     

Chaos-based communications at high bit rates using commercial fibre-optic links

Chaotic signals have been proposed as broadband information carriers with the potential of providing a high level of robustness and privacy in data transmission. Laboratory demonstrations of chaos-based optical communications have already shown the potential of this technology, but a field experiment using commercial optical networks has not been undertaken so far. Here we demonstrate high-speed long-distance communication based on chaos synchronization over a commercial fibre-optic channel. An optical carrier wave generated by a chaotic laser is used to encode a message for transmission over 120 km of optical fibre in the metropolitan area network of Athens, Greece. The message is decoded using an appropriate second laser which, by synchronizing with the chaotic carrier, allows for the separation of the carrier and the message. Transmission rates in the gigabit per second range are achieved, with corresponding bit-error rates below 10(-7). The system uses matched pairs of semiconductor lasers as chaotic emitters and receivers, and off-the-shelf fibre-optic telecommunication components. Our results show that information can be transmitted at high bit rates using deterministic chaos in a manner that is robust to perturbations and channel disturbances unavoidable under real-world conditions.     

An array of possibilities for the study of autoimmunity

Since the completion of the sequencing of the human genome, scientific focus has shifted from studying genes to analysing the much larger number of proteins encoded by them. Several proteins can be generated from a single gene depending on how the genetic information is read (transcribed) and how the resultant protein is modified following translation (post-translational modification). Genomic and proteomic technologies are already providing useful information about autoimmune disease, and they are likely to lead to important discoveries within the next decade.