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Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures.

Single neurons in spinal laminae I and II of cats were recorded intracellularly while stimulating in nucleus raphe magnus (NRM) and periaqueductal gray (PAG) with monopolar tungsten microelectrodes. Brain stem stimulation inhibited about one-half of the nociceptive-specific neurons, whereas the other half was unaffected. Brain stem stimulation inhibited about one-half of the multireceptive neurons, but the other half was excited and then inhibited. Brain stem stimulation inhibited about one-third of the low-threshold neurons, one-half was excited then inhibited, and one-fifth showed no effect. In all classes of neurons, the inhibition was produced by an inhibitory postsynaptic potential (IPSP) that began with a latency of approximately 25 ms and lasted approximately 400 ms following a single stimulus. The IPSP occurred with a small conductance increase and was reversed by hyperpolarizing currents applied to the cell. These data indicate that NRM and PAG modulated laminae I and II neurons via a postsynaptic mechanism. The conduction velocity of this descending pathway was calculated to range from 6.1 to 66.6 m/s with an average of 13.8 m/s. These data also indicate heterogeneity in the pathway, since some neurons were inhibited, whereas other neurons were excited then inhibited by descending stimulation. Finally, these data indicate specificity in these descending pathways since nearly one-half of neurons that had low-threshold inputs were excited by brain stem stimulation, whereas nearly all nociceptive-specific neurons were either inhibited or unaffected.

The three-dimensional structure of a human monoclonal antibody (Fab), which binds specifically to a major epitope of the transmembrane protein gp41 of the human immunodeficiency virus type 1, has been determined by crystallographic methods to a resolution of 2.7 A. It has been previously determined that this antibody recognizes the epitope SGKLICTTAVPWNAS, belongs to the subclass IgG1 (kappa), and exhibits antibody-dependent cellular cytotoxicity. The quaternary structure of the Fab is in an extended conformation with an elbow bend angle between the constant and variable domains of 175 degrees. Structurally, four of the hypervariable loops can be classified according to previously recognized canonical structures. The third hypervariable loops of the heavy (H3) and light chain (L3) are structurally distinct. Hypervariable loop H3, residues 102H-109H, is unusually extended from the surface. The complementarity-determining region forms a hydrophobic binding pocket that is created primarily from hypervariable loops L3, H3, and H2.

The investigation of problems of heat transmission in laser-irradiated samples and the relative modelistic approaches acquire particular significance when whole biological specimens are considered. The possibility of employing a theoretical model, generally utilized in laser irradiation of solid materials, is here analyzed in the irradiation of biological samples. Also, experimental modifications of the thermal diffusivity values are related to the energy level of the single optical pulse obtained from a cw Ar^+ laser.

1. Two hundred and twelve corticospinal axons were identified by stimulation in the hindlimb representation in area 3b of the somatosensory cortex and were recorded in the left dorsolateral funiculus of the spinal cord of the cat. The mean conduction velocity was 38 m/s, range 9-113 m/s. 2. Electrical stimulation of the receptive field evoked discharge in corticospinal axons with a mean latency of 36 ms (range 9-100 ms). 3. One hundred nine of the 212 recorded axons were successfully intra-axonally labeled by iontophoretic injection of horseradish peroxidase, with the mean length of labeled axon being 4.8 mm. Seventy-three of the labeled axons issued no collaterals, and 36 issued at least one labeled collateral into the spinal gray matter along the labeled portion of the parent axon. 4. Most labeled axons issued only one labeled collateral per spinal cord segment. Fourteen collaterals from 10 units were labeled well enough to permit reconstruction of their terminal arborizations. 5. Most terminal collaterals were oriented rostrocaudally and terminated in laminae V, VI, and VII. Most collaterals terminated within large mediolateral extents of the gray matter with no apparent topographic organization. 6. No collaterals terminated in laminae I or II or within the motoneuron pools, and no apparent correlation was found between their anatomic and physiological characteristics.

Temperature measurements related to the interaction of the 5145-Å line of a cw argon laser with in vivo whole biological specimens are presented, both in TEM_00, single frequency, and multimode, multifrequency operating conditions. A simple mathematical model for the evaluation of the temperature trends in a region outside the direct impact of the laser beam is also proposed.