Modular organization of motor behavior

The issue of translating the planning of arm movements into muscle forces is discussed in relation to the recent discovery of structures in the spinal cord. These structures contain circuitry that, when activated, produce precisely balanced contractions in groups of muscles. These synergistic contractions generate forces that direct the limb toward an equilibrium point in space. Remarkably, the force outputs, produced by activating different spinal-cord structures, sum vectorially. This vectorial combination of motor outputs might be a mechanism for producing a vast repertoire of motor behaviors in a simple manner.     

Genomic organization, sequence, and transcriptional regulation of the human eotaxin gene

Our previous studies showed that early, stage I preneoplastic cells (sup+ I) are highly susceptible to apoptosis, whereas the later, stage II preneoplastic cells (sup- II) are relatively resistant. To examine possible mechanisms that might explain these differences in the regulation of apoptosis, Ca2+ homeostasis was analyzed and comparisons were made between these two Syrian hamster embryo cell lines. The Ca2+ indicator, fura-2, and fluorescent microscopy were used to measure intracellular free calcium concentrations, [Ca2+]i. The results indicated that the [Ca2+]i level in logarithmically growing sup+ I cells (approximately 100 nM) was considerably lower than that observed in sup- II cells (approximately 260 nM). Serum removal resulted in a reduction of [Ca2+]i in the sup+ I cells (approximately 82 nM), whereas the [Ca2+]i level in sup- II cells did not change. Endoplasmic reticulum (ER) calcium levels were determined by measuring thapsigargin-releasable Ca2+. Reduced ER calcium was consistently observed in cells induced to undergo apoptosis. Specifically, thapsigargin-releasable Ca2+ was greatly reduced in sup+ I cells (45 nM) as compared to sup- II cells (190 nNM) after 4 h in low serum. When sup- II cells were placed under conditions that resulted in apoptosis (thapsigargin or okadaic acid), decreased ER calcium was observed. To determine whether reduced ER calcium had a causative effect in apoptosis, ER calcium levels were exogenously increased in sup+ I cells by raising extracellular Ca2+ to 3 mM; ER calcium levels were maintained, and apoptosis was blocked. Studies were performed to determined whether the decrease in ER calcium could be attributed to reduced Ca2+ influx at the plasma membrane. To measure directly whether Ca2+ entry was decreased in sup+ I cells in 0.2% serum, Mn2+ uptake was used to monitor Ca2+ influx. The data show that in low serum, the rate of thapsigargin-induced Mn2+ entry in sup+ I cells was approximately 50% lower than that of sup- II cells, demonstrating that capacitative entry is reduced in sup+ I cells. In further support of this hypothesis, thapsigargin-treated sup+ I cells (0.2% serum) showed decreased Ca2+ entry upon raising extracellular Ca2+ from 0 to 2 mM. We report the novel finding that early preneoplastic cells, which exhibit a high propensity to undergo apoptosis, have decreased calcium entry at the plasma membrane, resulting in decreased ER calcium pools. This study provides new insight into mechanisms that can be involved in the regulation/dysregulation of apoptosis during neoplastic progression. Furthermore, the data imply that preneoplastic cells, which have developed a mechanism to maintain ER calcium, would be less susceptible to apoptosis and would thus have an increased potential for becoming transformed.     

CCAAT/enhancer binding proteins are critical components of the transcriptional regulation of hematopoiesis (Review)

Antineutrophil cytoplasmic antibodies (ANCA) are generally believed to be strongly associated with some primary systemic vasculitides (PSV), such as Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS), which have some clinical manifestations in common and are 'pauci-immune' by immunohistology. This group of PSV has thus been termed 'ANCA-associated vasculitis' (AAV). By contrast, essential mixed cryoglobulinaemic vasculitides (EMC) are clinically heterogeneous and characterized immunologically by complement consumption and by immunocomplex depositions; they are also characteristically ANCA-negative. We report here on two SV-patients in whom the detection of cANCA (proteinase 3-ANCA in one case) in conjunction with glomerulonephritis and various extrarenal vasculitic lesions was suggestive of an AAV. However, demonstration of type II cryoglobulinaemia in conjunction with hypocomplementaemia, and histological proof of immunocomplexes in the glomerulus led to the diagnosis of an EMC, which was associated with hepatitis C virus (HCV) infection in one of the cases. Against the setting of 'false positive' cANCA in EMC, we discuss the differential diagnostic steps as well as current differential therapeutic approaches.     

High resolution crystal structure of a paired (Pax) class cooperative homeodomain dimer on DNA

The crystal structure of the paired homeodomain bound to DNA as a cooperative dimer has been determined to 2.0 A resolution. Direct contacts between each homeodomain and the DNA are similar to those described previously. In addition, an extensive network of water molecules mediates contacts between the recognition helix and the DNA major groove. Several symmetrical contacts between the two homeodomains underlie the cooperative interaction, and deformations in the DNA structure are necessary for the establishment of these contacts. Comparison with structures of homeodomains bound monomerically to DNA suggests that the binding of a single paired homeodomain can introduce these DNA distortions, thus preparing a template for the cooperative interaction with a second homeodomain. This study shows how the paired (Pax) class homeodomains have achieved cooperativity in DNA binding without the assistance of other domains, thereby enabling the recognition of target sequences that are long enough to ensure specificity.     

Involvement of protein tyrosine kinases in regulation of endothelial cell organization by basement membrane proteins

A complete understanding of the biological mechanisms that take part in the hyperacute vascular rejection is necessary to prevent its development. Nitric Oxide (NO) release by the graft could be one of those mechanisms as cytokine induction of NO synthase in reticuloendothelial cells produces NO with cytotoxic activity. We have performed 20 heterotopic pig-to-dog kidney xenotransplantations in order to determine if cytotoxic NO is released during the hyperacute rejection. Nitrites and cGMP levels were determined in plasma samples taken from the graft artery and vein until vessel thromboses. NO synthase activity was measured in pieces from renal artery and renal tissue. The results show that after discordant xenotransplantation, inducible NO synthase is activated in the transplanted organ, indicating that NO can mediate host tissue damage during the hyperacute rejection.     

Modular organization of cognitive systems masked by interhemispheric integration

After resection of the corpus callosum, V.J., a left-handed woman with left-hemisphere dominance for spoken language, demonstrated a dissociation between spoken and written language. In the key experiment, words flashed to V.J.'s dominant left hemisphere were easily spoken out loud, but could not be written. However, when the words were flashed to her right hemisphere, she could not speak them out loud, but could write them with her left hand. This marked dissociation supports the view that spoken and written language output can be controlled by independent hemispheres, even though before her hemispheric disconnection, they appeared as inseparable cognitive entities.     

DNA binding specificity of two homeodomain proteins in vitro and in Drosophila embryos

In previous experiments, the homeodomain proteins even-skipped and fushi-tarazu were found to UV cross-link to a surprisingly wide array of DNA sites in living Drosophila embryos. We now show that UV cross-linking gives a highly accurate measure of DNA binding by these proteins. In addition, the binding of even-skipped and fushi-tarazu proteins has been measured in vitro to the same DNA fragments that were examined in vivo. This analysis shows that these proteins have broad DNA recognition properties in vitro that are likely to be important determinants of their distribution on DNA in vivo, but it also shows that in vitro DNA binding specificity alone is not sufficient to explain the distribution of these proteins in embryos.