Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.     

Crystal structure of the transfer-RNA domain of transfer-messenger RNA in complex with SmpB

Accurate translation of genetic information into protein sequence depends on complete messenger RNA molecules. Truncated mRNAs cause synthesis of defective proteins, and arrest ribosomes at the end of their incomplete message. In bacteria, a hybrid RNA molecule that combines the functions of both transfer and messenger RNAs (called tmRNA) rescues stalled ribosomes, and targets aberrant, partially synthesized, proteins for proteolytic degradation. Here we report the 3.2-A-resolution structure of the tRNA-like domain of tmRNA (tmRNA(Delta)) in complex with small protein B (SmpB), a protein essential for biological functions of tmRNA. We find that the flexible RNA molecule adopts an open L-shaped conformation and SmpB binds to its elbow region, stabilizing the single-stranded D-loop in an extended conformation. The most striking feature of the structure of tmRNA(Delta) is a 90 degrees rotation of the TPsiC-arm around the helical axis. Owing to this unusual conformation, the SmpB-tmRNA(Delta) complex positioned into the A-site of the ribosome orients SmpB towards the small ribosomal subunit, and directs tmRNA towards the elongation-factor binding region of the ribosome. On the basis of this structure, we propose a model for the binding of tmRNA on the ribosome.     

Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin

We have identified nonsense mutations in the gene CDSN (encoding corneodesmosin) in three families suffering from hypotrichosis simplex of the scalp (HSS; OMIM 146520). CDSN, a glycoprotein expressed in the epidermis and inner root sheath (IRS) of hair follicles, is a keratinocyte adhesion molecule. Truncated CDSN aggregates were detected in the superficial dermis and at the periphery of hair follicles. Our findings suggest that CDSN is important in normal scalp hair physiology.     

Anaerobic ammonium oxidation by anammox bacteria in the Black Sea

The availability of fixed inorganic nitrogen (nitrate, nitrite and ammonium) limits primary productivity in many oceanic regions. The conversion of nitrate to N2 by heterotrophic bacteria (denitrification) is believed to be the only important sink for fixed inorganic nitrogen in the ocean. Here we provide evidence for bacteria that anaerobically oxidize ammonium with nitrite to N2 in the world's largest anoxic basin, the Black Sea. Phylogenetic analysis of 16S ribosomal RNA gene sequences shows that these bacteria are related to members of the order Planctomycetales performing the anammox (anaerobic ammonium oxidation) process in ammonium-removing bioreactors. Nutrient profiles, fluorescently labelled RNA probes, 15N tracer experiments and the distribution of specific 'ladderane' membrane lipids indicate that ammonium diffusing upwards from the anoxic deep water is consumed by anammox bacteria below the oxic zone. This is the first time that anammox bacteria have been identified and directly linked to the removal of fixed inorganic nitrogen in the environment. The widespread occurrence of ammonium consumption in suboxic marine settings indicates that anammox might be important in the oceanic nitrogen cycle.     

Segregation of object and background motion in the retina

An important task in vision is to detect objects moving within a stationary scene. During normal viewing this is complicated by the presence of eye movements that continually scan the image across the retina, even during fixation. To detect moving objects, the brain must distinguish local motion within the scene from the global retinal image drift due to fixational eye movements. We have found that this process begins in the retina: a subset of retinal ganglion cells responds to motion in the receptive field centre, but only if the wider surround moves with a different trajectory. This selectivity for differential motion is independent of direction, and can be explained by a model of retinal circuitry that invokes pooling over nonlinear interneurons. The suppression by global image motion is probably mediated by polyaxonal, wide-field amacrine cells with transient responses. We show how a population of ganglion cells selective for differential motion can rapidly flag moving objects, and even segregate multiple moving objects.     

Synthese von Vitamin-A-Methyläther

Summary Preliminary report on the synthesis of vitamin A methyl ether starting from 4-trimethylcyclohexenyl-2-methyl-butenal and 1-methoxy-3-methyl-pentenin.     

Embodiments of organizational fitness: The Viable System Model (VSM) as a guide

Managers are facing new problems in their quest for organizational fitness. With environments of growing complexity, foresight, adaptability, and learning become critical features for a social system to survive and develop. Established models of organizational control are insufficient to cope with this proliferating complexity. The science of cybernetics provides powerful models to master this key challenge to management. The present article offers a synthesis of Beer's Viable System Model (VSM) and a multilevel concept of organizational fitness, based on recent progress made in the field of planning theory.     

Ethical principles and guidelines for scientific experiments on animals

Ethical principles and guidelines for scientific experiments on animals     

The influence of chelating agents on the prooxidative effect of a hydrogen peroxide producing methylhydrazine compound

Zusammenfassung Es wird gezeigt, dass die Chelatbildner für Eisen, Desferrioxamin B und Äthylendiamintetraacetat (EDTA), den Abbau von Desoxyribonucleinsäure (DNS) durch Wasserstoffperoxid stark hemmen. Dagegen wird der durch eine Wasserstoffperoxid liefernde Methylhydrazinverbindung bewirkte DNS-Abbau vom ersteren Chelatbildner viel weniger gehemmt und vom letzteren sogar verstärkt. Diese Unterschiede zwischen dem Effekt des Wasserstoffperoxids und dem des Wasserstoffperoxid-Bildners können auf das Reduktionsvermögen der Wasserstoffperoxid liefernden Verbindung zurückgeführt werden.     

Synergism between ionizing radiation and a cytotoxic methylhydrazine derivative: Effect on DNA-degradation

Zusammenfassung Die kombinierte Einwirkung von ionisierender Strahlung und N-Isopropyl-p-(2-methyl-hydrazinomethyl)benzamid hydrochlorid (Natulan®) führt zu einem wesentlich stärkeren Abbau von Desoxyribonucleinsäure (DNS) als auf Grund der linearen Superposition zu erwarten wäre. Der Synergismus ist am ausgeprägtesten, wenn der Zusatz von Natulan unmittelbar nach der Bestrahlung erfolgt. Dieser Effekt kann als Folge der Bildung instabiler Peroxide während der Bestrahlung erklärt werden. Bekanntlich zerfallen die bei der Bestrahlung entstandenen organischen Peroxide zum grössten Teil innerhalb der ersten zwei bis drei Stunden nach der Bestrahlung unter Bildung freier Radikale. Diese können als Startradikale bei der Autoxydation von Natulan wirken und daher den Abbau von DNS beschleunigen.