CATH--a hierarchic classification of protein domain structures

BACKGROUND: Protein evolution gives rise to families of structurally related proteins, within which sequence identities can be extremely low. As a result, structure-based classifications can be effective at identifying unanticipated relationships in known structures and in optimal cases function can also be assigned. The ever increasing number of known protein structures is too large to classify all proteins manually, therefore, automatic methods are needed for fast evaluation of protein structures. RESULTS: We present a semi-automatic procedure for deriving a novel hierarchical classification of protein domain structures (CATH). The four main levels of our classification are protein class (C), architecture (A), topology (T) and homologous superfamily (H). Class is the simplest level, and it essentially describes the secondary structure composition of each domain. In contrast, architecture summarises the shape revealed by the orientations of the secondary structure units, such as barrels and sandwiches. At the topology level, sequential connectivity is considered, such that members of the same architecture might have quite different topologies. When structures belonging to the same T-level have suitably high similarities combined with similar functions, the proteins are assumed to be evolutionarily related and put into the same homologous superfamily. CONCLUSIONS: Analysis of the structural families generated by CATH reveals the prominent features of protein structure space. We find that nearly a third of the homologous superfamilies (H-levels) belong to ten major T-levels, which we call superfolds, and furthermore that nearly two-thirds of these H-levels cluster into nine simple architectures. A database of well-characterised protein structure families, such as CATH, will facilitate the assignment of structure-function/evolution relationships to both known and newly determined protein structures.     

The L5178Y/tk+/- mouse lymphoma specific gene and chromosomal mutation assay a phase III report of the U.S. Environmental Protection Agency Gene-Tox Program

The L5178Y/tk+/- (-)3.7.2C mouse lymphoma assay (MLA) which detects mutations affecting the heterozygous thymidine kinase (tk) locus is capable of responding to chemicals acting as clastogens as well as point mutagens. Improvements in the assay to enhance detection of this spectrum of genetic events are summarized, and criteria for evaluating the data are defined. Using these criteria, the Phase III Work Group reviewed and evaluated literature containing MLA results published from 1976 through 1993. The data base included 602 chemicals of which 343 were evaluated as positive, 44 negative, 18 equivocal, 54 apparently inappropriate for evaluation in this test system with the published protocols, and 142 that were inadequately tested, and thus a definitive call could not be made. The overall performance of the assay is summarized by chemical class, and the outcome of testing 260 chemicals in the MLA is compared with Gene-Tox and National Toxicology Program evaluations of rodent carcinogenesis bioassay results for the same chemicals. Based on the Work Group's evaluation of published MLA data for chemicals that were considered adequately tested, it is concluded that for most chemicals the L5178Y/tk+/- mouse lymphoma assay is eminently well suited for genotoxicity testing and for predicting the potential for carcinogenicity.     

Smoking and nicotine addiction: a pediatric epidemic with sequelae in adulthood

Pediatric addiction to nicotine from cigarette smoking is a major public health problem, extracting a tremendous societal toll in terms of human suffering, a loss of future productivity, and the consumption of scarce health care resources. Teenagers smoke 1.1 billion packs of cigarettes yearly and will account for more than $200 billion in future health care costs. Recent behavioral studies confirm nicotine's ability to induce in adolescents both the tolerance and abstinence phenomena typical of other addicting substances. A range of adverse health effects, first detectable in adolescent cigarette smokers, extend into adulthood. Through the effects of environmental smoke or smoking during pregnancy, adolescent smokers affect not only their own health, but that of friends, family members, and even their own fetuses and children. Additional research into effective prevention and smoking cessation programs is urgently needed to forestall the ravaging of yet another generation by this preventable and deadly habit.     

Relation of endothelium, thrombogenesis, and hemorheology in systemic hypertension to ethnicity and left ventricular hypertrophy

Although the arterial tree is exposed to increased pressure in hypertensive patients, paradoxically, the complications of hypertension (heart attacks, stroke) are mainly thrombotic rather than hemorrhagic. Patients with left ventricular (LV) hypertrophy are at high risk of the complications of hypertension. We performed a cross-sectional study of 178 patients attending a hypertension clinic in a city center teaching hospital, and measured plasma levels of the soluble adhesion molecule P-selectin (associated with platelet activity/function and atherosclerosis), the von Willebrand factor (vWf; a marker of endothelial dysfunction), fibrin D-dimer (an index of thrombogenesis), plasminogen activator inhibitor (PAI, an index of fibrinolysis), lipoprotein(a) (Lp(a), associated with thrombogenesis and atherogenesis) and hemorheological indexes (fibrinogen, hematocrit, plasma viscosity, hemoglobin) in patients with essential hypertension, in whom the LV mass and LV mass index were determined using echocardiography. The 178 patients (86 men, mean age 54 +/- 15 years) were compared with 47 normotensive healthy controls (aged 56 +/- 20 years). Hypertensive patients had higher P-selectin, PAI, vWf, fibrin D-dimer, Lp(a), plasma fibrinogen, and plasma viscosity when compared with controls. Black hypertensive patients had higher Lp(a) levels and LV septal and posterior wall thickness on echocardiography, but lower plasma PAI levels. Patients with LV hypertrophy (defined as a LV mass index > 134 g/m2 in men or > 110 g/m2 in women) had higher plasma fibrinogen compared with those without LV hypertrophy. Systolic blood pressures were significantly correlated to age, plasma viscosity, plasma fibrinogen, and vWf. Diastolic blood pressures were significantly correlated with age and plasma fibrinogen. Fibrinogen levels were correlated with LV mass, LV mass index, left atrial size, plasma viscosity, and vWf. Fibrin D-dimer levels were significantly correlated with vWf and fibrinogen levels. Thus, hypertensive patients have high plasma fibrinogen levels, thrombogenesis, and impaired fibrinolysis (as indicated by high D-dimer and PAI levels, respectively), platelet activation (raised soluble P-selectin), and endothelial dysfunction (high vWF). The high plasma fibrinogen levels were related to blood pressures, LV mass index (and LV hypertrophy), and left atrial size. These abnormalities in hemorheologic factors and markers of thrombogenesis and endothelial function may act synergistically to increase the risk of thrombogenesis and atherosclerosis in hypertensive patients.