Free amino acid composition of the hemolymph of the larval blackflySimulium venustum (Diptera: Simuliidae)

Zusammenfassung Nachweis, dass die Aminosäure-Zusammensetzung der Hämolymphe vonSimuliumvenustum-Larven total 39.3±1.3 mg Amino N pro 100 ml enthält, wobei als hauptsächliche Ninhydrinpositive Bestandteile der Hämolymphe Alanin, Asparagin, Asparaginsäure, Dioxyphenylalanin, Äthanolanin, Glutaminsäure, Glutamin, Glycin, Histidin, Phenylalanin und Serin gefunden wurden, während nur kleine Mengen von Tyrosin, Halb-Cystin und Cystathion festgestellt wurden.     

WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion

A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal NaCl and K+ handling. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.     

A fractal forecasting model for financial time series

Financial market time series exhibit high degrees of non‐linear variability, and frequently have fractal properties. When the fractal dimension of a time series is non‐integer, this is associated with two features: (1) inhomogeneity—extreme fluctuations at irregular intervals, and (2) scaling symmetries—proportionality relationships between fluctuations over different separation distances. In multivariate systems such as financial markets, fractality is stochastic rather than deterministic, and generally originates as a result of multiplicative interactions. Volatility diffusion models with multiple stochastic factors can generate fractal structures. In some cases, such as exchange rates, the underlying structural equation also gives rise to fractality. Fractal principles can be used to develop forecasting algorithms. The forecasting method that yields the best results here is the state transition‐fitted residual scale ratio (ST‐FRSR) model. A state transition model is used to predict the conditional probability of extreme events. Ratios of rates of change at proximate separation distances are used to parameterize the scaling symmetries. Forecasting experiments are run using intraday exchange rate futures contracts measured at 15‐minute intervals. The overall forecast error is reduced on average by up to 7% and in one instance by nearly a quarter. However, the forecast error during the outlying events is reduced by 39% to 57%. The ST‐FRSR reduces the predictive error primarily by capturing extreme fluctuations more accurately. Copyright © 2004 John Wiley & Sons, Ltd.     

Oligocene mammals from Ethiopia and faunal exchange between Afro-Arabia and Eurasia

Afro-Arabian mammalian communities underwent a marked transition near the Oligocene/Miocene boundary at approximately 24 million years (Myr) ago. Although it is well documented that the endemic paenungulate taxa were replaced by migrants from the Northern Hemisphere, the timing and evolutionary dynamics of this transition have long been a mystery because faunas from about 32 to 24 Myr ago are largely unknown. Here we report a late Oligocene fossil assemblage from Ethiopia, which constrains the migration to postdate 27 Myr ago, and yields new insight into the indigenous faunal dynamics that preceded this event. The fauna is composed of large paenungulate herbivores and reveals not only which earlier taxa persisted into the late Oligocene epoch but also demonstrates that one group, the Proboscidea, underwent a marked diversification. When Eurasian immigrants entered Afro-Arabia, a pattern of winners and losers among the endemics emerged: less diverse taxa such as arsinoitheres became extinct, moderately species-rich groups such as hyracoids continued into the Miocene with reduced diversity, whereas the proboscideans successfully carried their adaptive radiation out of Afro-Arabia and across the world.     

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.