TGF-beta2 neutralization inhibits proliferation and activates apoptosis of cerebellar granule cell precurors in the developing cerebellum

Transforming growth factor beta 2 (TGF-beta2) plays a critical role in growth, differentiation and cell death, but its function in the developing cerebellum is still uncertain. In this study we analyzed the effects of TGF-beta2 on ex vivo developing cerebellar slice cultures. Proliferation of granule cell precursors peaked ex vivo in the same developmental window as in vivo (P8-P14). Addition of recombinant TGF-beta2 could extent the proliferation of granule cell precursors and induced a second late proliferation wave. In contrast, antibody neutralization of TGF-beta2 strongly reduced proliferation and induced neurodegeneration. TGF-beta2 neutralization resulted in apoptotic cells, which showed caspase 3 activation. Taken together our results demonstrate that TGF-beta2 is a novel growth and survival factor for granule cells precursors in the developing cerebellum.     

Game-theoretical approaches to studying the evolution of biochemical systems

Evolutionary optimization has been successfully used to increase our understanding of key properties of biochemical systems. Traditional optimization is, however, often insufficient for gaining deeper insights into the evolution of such systems because usually there is a mutual relationship between the properties optimized by evolution and the properties of the environment. Thus, by evolving towards optimal properties, organisms change their environment, which in turn alters the optimum. Evolutionary game theory provides an appropriate framework for analyzing evolution in such 'dynamic fitness landscapes'. We therefore argue that it is a promising approach to studying the evolution of biochemical systems. Indeed, recent studies have applied evolutionary game theory to key issues in the evolution of energy metabolism.     

On criteria for evaluating models of absolute risk

Absolute risk is the probability that an individual who is free of a given disease at an initial age, a, will develop that disease in the subsequent interval (a, t]. Absolute risk is reduced by mortality from competing risks. Models of absolute risk that depend on covariates have been used to design intervention studies, to counsel patients regarding their risks of disease and to inform clinical decisions, such as whether or not to take tamoxifen to prevent breast cancer. Several general criteria have been used to evaluate models of absolute risk, including how well the model predicts the observed numbers of events in subsets of the population ("calibration"), and "discriminatory power," measured by the concordance statistic. In this paper we review some general criteria and develop specific loss function-based criteria for two applications, namely whether or not to screen a population to select subjects for further evaluation or treatment and whether or not to use a preventive intervention that has both beneficial and adverse effects. We find that high discriminatory power is much more crucial in the screening application than in the preventive intervention application. These examples indicate that the usefulness of a general criterion such as concordance depends on the application, and that using specific loss functions can lead to more appropriate assessments.     

The membrane proteome of Halobacterium salinarum

The identification of 114 integral membrane proteins from Halobacterium salinarum was achieved using liquid chromatography/tandem mass spectrometric (LC/MS/MS) techniques, representing 20% of the predicted alpha-helical transmembrane proteins of the genome. For this experiment, a membrane preparation with only minor contamination by soluble proteins was prepared. From this membrane preparation a number of peripheral membrane proteins were identified by the classical two dimensional gel electrophoresis (2-DE) approach, but identification of integral membrane proteins largely failed with only a very few being identified. By use of a fluorescently labeled membrane preparation, we document that this is caused by an irreversible precipitation of the membrane proteins upon isoelectric focusing (IEF). Attempts to overcome this problem by using alternative IEF methods and IEF strip solubilisation techniques were not successful, and we conclude that the classical 2-DE approach is not suited for the identification of integral membrane proteins. Computational analysis showed that the identification of integral membrane proteins is further complicated by the generation of tryptic peptides, which are unfavorable for matrix assisted laser desorption/ionization time of flight mass spectrometric peptide mass fingerprint analysis. Together with the result from the analysis of the cytosolic proteome (see preceding paper), we could identify 34% (943) of all gene products in H. salinarum which can be theoretically expressed. This is a cautious estimate as very stringent criteria were applied for identification. These results are available under www.halolex.mpg.de.     

F-81 skeleton from Wadi Mataha, Jordan, and its bearing on human variability in the Epipaleolithic of the Levant

The discovery of a Middle Epipaleolithic adult skeleton (F-81) at the site of Wadi Mataha in southern Jordan provides new insights into human variability in the Epipaleolithic of the Levant. This paper analyzes the skeletal morphology of Wadi Mataha F-81 in the context of other Epipaleolithic remains from Jordan and Israel to assess the current evidence for morphological variability throughout this period. The F-81 skeleton shares morphological features with earlier Epipaleolithic skeletons from Ohalo and Nahal Ein Gev, and later Natufian populations. Despite the morphological similarities, F-81 extends the range of known variability prior to the Natufian with its unusually small stature and unique combination of morphological characteristics. High levels of cranial and postcranial robusticity suggest that the F-81 individual was physically active and terrestrially mobile. Pronounced bilateral asymmetry in the upper limb suggests significant lateralization of habitual activity. In the context of Epipaleolithic remains, the F-81 skeleton provides preliminary evidence for greater morphological variability, terrestrial mobility, and lateralized habitual behavior prior to the Natufian, and skeletal gracilization between the Middle and Late Epipaleolithic in the Levant.     

A model to estimate risk of infection with human herpesvirus 8 associated with transfusion from cross-sectional data

In cross-sectional studies of infectious diseases, the data typically consist of: age at the time of study, status (presence or absence) of infection, and a chronology of events possibly associated with the disease. Motivated by a study of how human herpesvirus 8 (HHV-8) is transmitted among children with sickle cell anemia in Uganda, we have developed a flexible parametric approach for combining current-status data with a history of blood transfusions. We model heterogeneity in transfusion-associated risk by a child-specific random effect. We present an extension of the model to accommodate the fact that there is no gold standard for HHV-8 infection and infection status was assessed by a serological assay. The parameters are estimated via maximum likelihood. Finally, we present results from applying various parameterizations of the model to the Ugandan study.     

An ill child among mid-Holocene foragers of Southern Africa

The skeletal remains of an infant from a southwest South African rock shelter at Byneskranskop show pervasive abnormalities that are consistent with the effects of hypertrophic (hyperplastic) rickets. Diagnostic features include beading of the costochondral junctions of the ribs, flaring and tilting of the metaphyses, and cupping of the distal ulna, as well as general skeletal hypertrophy. With an uncalibrated accelerator mass spectrometry (AMS) radiocarbon date of 4820 +/- 90 BP (TO-9531), this is a very early instance of the condition, among foragers whose environment and diet make dietary shortages of active vitamin D or dietary calcium improbable. Carbon and nitrogen stable isotope ratios indicate a mixed diet, including marine as well as terrestrial protein. Solicitous care maintained the sick infant to an estimated age of 3.5-5 months; it was buried in a manner like that of other deceased group members. This case suggests that if infanticide was practiced, it was an option only during the immediate perinatal period, when this infant would have appeared normal. This is consistent with documentation of infanticide practices among historic foragers from southern Africa.     

Cortical migration defects in mice expressing A-RAF from the B-RAF locus

We have previously shown that mice lacking the protein kinase B-RAF have defects in both neural and endothelial cell lineages and die around embryonic day 12 (E12). To delineate the function of B-RAF in the brain, B-RAF KIN/KIN mice lacking B-RAF and expressing A-RAF under the control of the B-RAF locus were created. B-RAF KIN/KIN embryos displayed no vascular defects, no endothelial and neuronal apoptosis, or gross developmental abnormalities, and a significant proportion of these animals survived for up to 8 weeks. Cell proliferation in the neocortex was reduced from E14.5 onwards. Newborn cortical neurons were impaired in their migration toward the cortical plate, causing a depletion of Brn-2-expressing pyramidal neurons in layers II, III, and V of the postnatal cortex. Our data reveal that B-RAF is an important mediator of neuronal survival, migration, and dendrite formation and that A-RAF cannot fully compensate for these functions.