C-terminal domain of the Epstein-Barr virus LMP2A membrane protein contains a clustering signal

The latency-regulated transmembrane protein LMP2A interferes with signaling from the B-cell antigen receptor by recruiting the tyrosine kinases Lyn and Syk and by targeting them for degradation by binding the cellular E3 ubiquitin ligase AIP4. It has been hypothesized that this constitutive activity of LMP2A requires clustering in the membrane, but molecular evidence for this has been lacking. In the present study we show that LMP2A coclusters with chimeric rat CD2 transmembrane molecules carrying the 27-amino-acid (aa) intracellular C terminus of LMP2A and that this C-terminal domain fused to the glutathione-S-transferase protein associates with LMP2A in cell lysates. This molecular association requires neither the cysteine-rich region between aa 471 and 480 nor the terminal three aa 495 to 497. We also show that the juxtamembrane cysteine repeats in the LMP2A C terminus are the major targets for palmitoylation but that this acylation is not required for targeting of LMP2A to detergent-insoluble glycolipid-enriched membrane microdomains.     

Upstream migratory behaviour in landlocked Arctic charr

Synopsis Extensive upstream migration of landlocked Arctic charr during spring floods was recorded in several tributaries of an oligotrophic lake in north-west Sweden. Migration was confined to a period of about two weeks and residence in most creeks was of short duration. Only fish migrating to two small productive lakes remained in the new habitat over the summer. Repeated annual migrations were only recorded in the creek leading to these lakes and no straying was observed among repeat migrants. Water temperatures provided the primary cues for initiation and direction of migration, although an ability to detect productive habitats by odour was indicated. Creek size, feeding opportunities during migration and conspeeific odour were subordinate guiding factors.     

Microplate based biosensing with a computer screen aided technique

Melanophores, dark pigment cells from the frog Xenopus laevis, have the ability to change light absorbance upon stimulation by different biological agents. Hormone exposure (e.g. melatonin or alpha-melanocyte stimulating hormone) has been used here as a reversible stimulus to test a new compact microplate reading platform. As an application, the detection of the asthma drug formoterol in blood plasma samples is demonstrated. The present system utilizes a computer screen as a (programmable) large area light source, and a standard web camera as recording media enabling even kinetic microplate reading with a versatile and broadly available platform, which suffices to evaluate numerous bioassays. Especially in the context of point of care testing or self testing applications these possibilities become advantageous compared with highly dedicated comparatively expensive commercial systems.     

Oxysterols and neurodegenerative diseases

In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood–brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of 27-hydroxycholesterol (27-OHC) from the circulation into the brain may regulate a number of key enzymes within the brain. In vitro experiments suggest that the balance between the levels of these two molecules may be of importance for the generation of β-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cytoskeleton-associated protein (Arc), a protein important in memory consolidation which is reduced in patients with Alzheimer’s disease (AD). In the present work we explore the possibility that the flux of 27-OHC from the circulation into the brain represents the missing link between AD and hypercholesterolemia, and discuss the possibility that modification of this flux may be a therapeutic strategy. Lastly, we discuss the use of oxysterols as diagnostic markers in neurodegenerative disease.     

Cancer attractors: A systems view of tumors from a gene network dynamics and developmental perspective

Cell lineage commitment and differentiation are governed by a complex gene regulatory network. Disruption of these processes by inappropriate regulatory signals and by mutational rewiring of the network can lead to tumorigenesis. Cancer cells often exhibit immature or embryonic traits and dysregulated developmental genes can act as oncogenes. However, the prevailing paradigm of somatic evolution and multi-step tumorigenesis, while useful in many instances, offers no logically coherent reason for why oncogenesis recapitulates ontogenesis. The formal concept of “cancer attractors”, derived from an integrative, complex systems approach to gene regulatory network may provide a natural explanation. Here we present the theory of attractors in gene network dynamics and review the concept of cell types as attractors. We argue that cancer cells are trapped in abnormal attractors and discuss this concept in the light of recent ideas in cancer biology, including cancer genomics and cancer stem cells, as well as the implications for differentiation therapy.     

Phenolic P2/P3 core motif as thrombin inhibitors--design, synthesis, and X-ray co-crystal structure

Prototypical thrombin inhibitors were synthesized based on a trisubstituted phenol as a core motif. A naphthylsulfonamide analogue showed excellent antithrombin activity. An X-ray co-crystal structure showed the expected interactions.     

Stressful life events preceding the acute onset of schizophrenia: A cross-national study from the World Health Organization

This study reports on the findings from a WHO sponsored cross-national investigation of life events and schizophrenia. Data are presented from a series of 386 acutely ill schizophrenic patients selected from nine field research centers located in developing and developed countries (Aarhus, Denmark; Agra, India; Cali, Colombia; Chandigarh, India; Honolulu, USA; Ibadan, Nigeria; Nagasaki, Japan; Prague, Czechoslovakia; Rochester, USA). On a methodological level, the study demonstrates that life event methodologies originating in the developed countries can be adapted for international studies and may be used to collect reasonably reliable and comparable cross-cultural data on psychosocial factors affecting the course of schizophrenic disorders. Substantive findings replicate the results of prior studies which conclude that socioenvironmental stressors may precipitate schizophrenic attacks and such events tend to cluster in the two to three week period immediately preceding illness onset.The paper was prepared by these authors on behalf of the collaborating investigators listed on page 196.