Role of the tubulin-microtubule system in lymphocyte activation

The role of the tubulin-microtubule system was examined in human peripheral blood leukocytes after activation with phytohemagglutinin (PHA). Soluble tubulin and microtubules were measured with a [(3)H]colchicine-binding assay. It was found that the tubulin content of PHA-activated lymphocytes was consistently increased relative to total protein content after 36 h of culture. There was no increase in the proportion of total tubulin synthesis which was present as microtubules at 36 h. Nevertheless, as a result of increased tubulin synthesis, there was a two-to three-fold increase in total microtubular mass. Colchicine, which disrupts microtubles, was used to assess the role of microtubule assembly in the sequence of events which follow lymphocyte activation, namely lymphokine release, protein synthesis, RNA synthesis, and DNA synthesis. Colchicine consistently inhibited DNA synthesis but did not inhibit release of the lymphokine, osteoclast activating factor (OAF). Protein and RNA syntheses were inhibited much less than DNA synthesis. The fact that some effects of PHA on lymphocytes appear to require intact microtubules and at least one does not suggest that the microtubule dependent step in PHA-stimulated lymphocyte activation occurs at a stage after propagation of the signal from the membrane to the cell interior.     

Efficient use of a 'dead-end' GA 5' splice site in the human fibroblast growth factor receptor genes

We have investigated use of a conserved non-canonical GA 5' splice site present in vertebrate fibroblast growth factor receptor (FGFR) genes. Despite previous studies suggesting that GA at the beginning of an intron is incompatible with splicing, we observe efficient utilization of this splice site for human FGFR1 gene constructs. We show that use of the GA splice site is dependent on both a conventional splice site six nucleotides upstream and sequence elements within the downstream intron. Furthermore, our results are consistent with competition between the tandem 5' splice sites being mediated by U6 snRNP, rather than U1 snRNP. Thus the GA 5' splice site represents an extension of the adjacent conventional 5' splice site, the first natural example of such a composite 5' splice site.     

Simulated brain tumor growth dynamics using a three-dimensional cellular automaton

We have developed a novel and versatile three-dimensional cellular automaton model of brain tumor growth. We show that macroscopic tumor behavior can be realistically modeled using microscopic parameters. Using only four parameters, this model simulates Gompertzian growth for a tumor growing over nearly three orders of magnitude in radius. It also predicts the composition and dynamics of the tumor at selected time points in agreement with medical literature. We also demonstrate the flexibility of the model by showing the emergence, and eventual dominance, of a second tumor clone with a different genotype. The model incorporates several important and novel features, both in the rules governing the model and in the underlying structure of the model. Among these are a new definition of how to model proliferative and non-proliferative cells, an isotropic lattice, and an adaptive grid lattice.     

A revision of Aceratherium blanfordi Lydekker, 1884 (Mammalia: Rhinocerotidae) from the Early Miocene of Pakistan: postcranials as a key

Rhinocerotids are particularly abundant and diversified in Neogene deposits of the Indian subcontinent, but their systematics is far from being well defined. Based on the revision of old collections and new findings from the Early Miocene of the Bugti Hills and Zinda Pir, Pakistan, ‘Aceratherium blanfordi Lydekker, 1884’ is a chimera, consisting of two dentally convergent but postcranially distinct rhinocerotid taxa: Pleuroceros blanfordi and Mesaceratherium welcommi sp. nov. Postcranial features appear to be much more diagnostic than craniodental morphology in this case. A phylogenetic analysis based on 282 morphological characters scored for 28 taxa (four outgroups and ingroup including both taxa of interest and a ‘branching group’) strengthens this statement and supports Pleuroceros and Mesaceratherium as monophyletic genera within Rhinocerotinae. Both genera are recognized for the first time outside Europe. In the Bugti Hills, P. blanfordi and M. welcommi are part of an exceptionally diversified rhinocerotid fauna, with up to nine species associated in the same locality (Kumbi 4f). This rhinocerotid assemblage confirms the earliest Miocene age (Agenian/Aquitanian) of the upper member of the Chitarwata Formation as a whole. Coeval homotaxic rhinocerotid faunas from Europe (France, Czech Republic) and East Africa (Uganda, Kenya) support broad and sustainable rhinocerotid interchanges amongst South Asia, Europe, and Africa under compatible environmental conditions throughout earliest Miocene times. © 2010 The Linnean Society of London, Zoological Journal of the Linnean Society, 2010, 160 , 139–194.     

Future climate‐driven shifts in distribution of Calanus finmarchicus

Calanus finmarchicus is a key‐structural species of the North Atlantic polar biome. The species plays an important trophic role in subpolar and polar ecosystems as a grazer of phytoplankton and as a prey for higher trophic levels such as the larval stages of many fish species. Here, we used a recently developed ecological niche model to assess the ecological niche (sensu Hutchinson) of C. finmarchicus and characterize its spatial distribution. This model explained about 65% of the total variance of the observed spatial distribution inferred from an independent dataset (data of the continuous plankton recorder survey). Comparisons with other types of models (structured population and ecophysiological models) revealed a clear similarity between modeled spatial distributions at the scale of the North Atlantic. Contemporary models coupled with future projections indicated a progressive reduction of the spatial habitat of the species at the southern edge and a more pronounced one in the Georges Bank, the Scotian Shelf and the North Sea and a potential increase in abundance at the northern edge of its spatial distribution, especially in the Barents Sea. These major changes will probably lead to a major alteration of the trophodynamics of North Atlantic ecosystems affecting the trophodynamics and the biological carbon pump.     

T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal?

Dengue virus infection poses a growing public health and economic burden in a number of tropical and subtropical countries. Dengue circulates as a number of quasispecies, which can be divided by serology into four groups or serotypes. An interesting feature of Dengue, recognized over five decades ago, is that most severe cases that show hemorrhagic fever are not suffering from a primary infection. Instead, they are reinfected with a virus of different serotype. This observation poses considerable problems in vaccine design, and it is therefore imperative to gain a full understanding of the mechanisms underlying this immunological enhancement of disease. In this study, we examined a T cell epitope restricted by HLA-A*24, a major MHC class I allele, in Southeast Asia in a cohort of children admitted to a hospital with acute Dengue infection. The cytokine profiles and the degranulation capacity of T cells generated to this epitope are defined and compared across different viral serotypes. Cross-reactive Dengue-specific T cells seem to show suboptimal degranulation but high cytokine production, which may contribute to the development of the vascular leak characteristic of Dengue hemorrhagic fever.     

Serine-arginine (SR) protein-like factors that antagonize authentic SR proteins and regulate alternative splicing.

We have characterized two RNA-binding proteins, of apparent molecular masses of approximately 40 and 35 kDa, which possess a single N-terminal RNA-recognition motif (RRM) followed by a C-terminal domain rich in serine-arginine dipeptides. Their primary structures resemble the single-RRM serine-arginine (SR) protein, SC35; however their functional effects are quite distinctive. The 40-kDa protein cannot complement SR protein-deficient HeLa cell S100 extract and showed a dominant negative effect in vitro against the authentic SR proteins, SF2/ASF and SC35. Interestingly, the 40- and 35-kDa proteins antagonize SR proteins and activate the most distal alternative 5' splice site of adenovirus E1A pre-mRNA in vivo, an activity that is similar to that characterized previously for the heterogeneous nuclear ribonucleoprotein particles A/B group of proteins. A series of recombinant chimeric proteins consisting of domains from these proteins and SC35 in various combinations showed that the RRM, but not the C-terminal domain rich in serine-arginine dipeptides, has a dominant role in this activity. Because of the similarity to SR proteins we have named these proteins SRrp40 and SRrp35, respectively, for SR-repressor proteins of approximately 40 and approximately 35 kDa. Both factors show tissue- and cell type-specific patterns of expression. We propose that these two proteins are SR protein-like alternative splicing regulators that antagonize authentic SR proteins in the modulation of alternative 5' splice site choice.     

The antigenic anatomy of SARS-CoV-2 receptor binding domain

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