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The RASopathies constitute a family of autosomal dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering son of sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its auto-inhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the Dbl homology domain.

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Fumonisin B1 (FB1) was reacted with fructose in an attempt to detoxify this mycotoxin. Fischer 344/N rats were initiated with diethylnitrosamine (15 mg/kg body weight) and then fed 69.3 μmol FB1/kg diet or 69.3 μmol FB1 reacted with fructose (FB1−fructose)/kg diet for 4 weeks. In comparison with the rats fed basal diet or FB1−fructose, the FB1-fed rats had significantly increased plasma cholesterol (P < 0.01), plasma alanine aminotransferase activity (P < 0.05), and endogenous hepatic prostaglandin production (P < 0.05). Placental glutathione S-transferase-positive and γ-glutamyl transferase-positive altered hepatic foci occurred only in the FB1-fed rats. Liver-associated natural killer (NK) cell activity was significantly decreased in the FB1-fed rats and increased in the group fed FB1-fructose, as compared with the basal group (P < 0.03). Therefore, modifying FB1 with fructose seems to prevent FB1-induced hepatotoxicity and promotion of hepatocarcinogenesis while stimulating liver-associated NK cell activity in rats. Fumonisin B 1 (FB 1 ) was reacted with fructose in an attempt to detoxify this mycotoxin. Fischer 344/N rats were initiated with diethylnitrosamine (15 mg/kg body weight) and then fed 69.3 µmol FB 1 /kg diet or 69.3 µmol FB 1 reacted with fructose (FB 1 -fructose)/kg diet for 4 weeks. In comparison with the rats fed basal diet or FB 1 -fructose, the FB 1 -fed rats had significantly increased plasma cholesterol (P < 0.01), plasma alanine aminotransferase activity (P < 0.05), and endogenous hepatic prostaglandin production (P < 0.05). Placental glutathione S-transferase-positive and γ-glutamyl transferase-positive altered hepatic foci occurred only in the FB 1 -fed rats. Liver-associated natural killer (NK) cell activity was significantly decreased in the FB 1 -fed rats and increased in the group fed FB 1 -fructose, as compared with the basal group (P < 0.03). Therefore, modifying FB 1 with fructose seems to prevent FB 1 -induced hepatotoxicity and promotion of hepatocarcinogenesis while stimulating liver-associated NK cell activity in rats.

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DBP polyurethane possesses physical (water absorption) and biomechanical properties comparable to unmodified polyurethane and can resist intrinsic heart-valve leaflet calcification in blood-stream implants.

Key Points Scaffolding adaptor protein GAB2 is required for BCR-ABL1–evoked myeloid and lymphoid leukemogenesis. SHP2 and p85 binding to GAB2 activate distinct signaling pathways and are required differentially for myeloid and lymphoid leukemogenesis.

Topological scores, measures of sequence-structure compatibility, are calculated for all 1,881 single point mutants of the human immunodeficiency virus (HIV)-1 protease using a four-body statistical potential function based on Delaunay tessellation of protein structure. Comparison of the mutant topological score data with experimental data from alanine scan studies specifically on the dimer interface residues supports previous findings that 1) L97 and F99 contribute greatly to the Gibbs energy of HIV-1 protease dimerization, 2) Q2 and T4 contribute the least toward the Gibbs energy, and 3) C-terminal residues are more sensitive to mutations than those at the N-terminus. For a more comprehensive treatment of the relationship between protease structure and function, mutant topological scores are compared with the activity levels for a set of 536 experimentally synthesized protease mutants, and a significant correlation is observed. Finally, this structure-function correlation is similarly identified by examining model systems consisting of 2,015 single point mutants of bacteriophage T4 lysozyme as well as 366 single point mutants of HIV-1 reverse transcriptase and is hypothesized to be a property generally applicable to all proteins.