Natural killer activating receptors trigger interferon gamma secretion from T cells and natural killer cells

Proliferation of human CD4+ alphabeta T cells expressing a natural killer cell activating receptor (NKAR) has been shown to be enhanced, particularly in response to low doses of antigen, if the target cells present appropriate human class I major histocompatibility complex (MHC) molecules. Here, we show that NKAR also enhance proliferation and killing of target cells by subsets of CD8+ alphabeta and CD8+ gammadelta T cells, as well as by NK cells. Strikingly, interferon gamma secretion from all of these types of lymphocytes was markedly increased by interaction of the NKAR with their MHC class I ligands, independently of enhancement of proliferation. Thus, the recognition of class I MHC molecules by NKAR on both T cells and NK cells may provide a regulatory mechanism that affects immune responses through the secretion of interferon gamma and possibly other cytokines. It represents a signal for cytokine secretion alternative and/or augmentative to that through the T cell receptor.     

The spectrum of respiratory disease associated with exposure to metal working fluids

Occupational respiratory diseases have been reported following exposure to metal working fluids. We report a spectrum of respiratory illnesses occurring in an outbreak in 30 workers of an automobile parts engine manufacturing plant. Workers presented with respiratory complaints and, after clinical and laboratory evaluations, were classified as those having hypersensitivity pneumonitis, occupational asthma, or industrial bronchitis, or those without occupational lung disease. Hypersensitivity pneumonitis affected seven workers, with six exhibiting serum precipitins to Acinetobacter Iwoffii. Occupational asthma and industrial bronchitis affected 12 and six workers, respectively. Oil-mist exposures were below current recommendations. Gram-negative bacteria, but no fungi, Thermophiles, or Legionella, were identified. Although specific agents responsible for each individual case could not be identified, probably both specific sensitizing agents and non-specific irritants from metal working fluids, additives, or contaminants contributed to this spectrum of occupational respiratory illness.     

Crystal structure of Taq DNA polymerase in complex with an inhibitory Fab: the Fab is directed against an intermediate in the helix-coil dynamics of the enzyme

We report the crystal structure of Thermus aquaticus DNA polymerase I in complex with an inhibitory Fab, TP7, directed against the native enzyme. Some of the residues present in a helical conformation in the native enzyme have adopted a gamma turn conformation in the complex. Taken together, structural information that describes alteration of helical structure and solution studies that demonstrate the ability of TP7 to inhibit 100% of the polymerase activity of the enzyme suggest that the change in conformation is probably caused by trapping of an intermediate in the helix-coil dynamics of this helix by the Fab. Antibodies directed against modified helices in proteins have long been anticipated. The present structure provides direct crystallographic evidence. The Fab binds within the DNA binding cleft of the polymerase domain, interacting with several residues that are used by the enzyme in binding the primer:template complex. This result unequivocally corroborates inferences drawn from binding experiments and modeling calculations that the inhibitory activity of this Fab is directly attributable to its interference with DNA binding by the polymerase domain of the enzyme. The combination of interactions made by the Fab residues in both the polymerase and the vestigial editing nuclease domain of the enzyme reveal the structural basis of its preference for binding to DNA polymerases of the Thermus species. The orientation of the structure-specific nuclease domain with respect to the polymerase domain is significantly different from that seen in other structures of this polymerase. This reorientation does not appear to be antibody-induced and implies remarkably high relative mobility between these two domains.     

Ontogeny of humoral immunity in northern elephant seal (Mirounga angustirostris) neonates

OBJECTIVE: To assess relations of left ventricular (LV) geometry and function to insulin resistance in obesity-a condition associated with volume overload and abnormal LV relaxation. DESIGN: Cross-sectional relational study. SUBJECTS: 27 healthy overweight-obese subjects (18 women, body mass index (BMI) = 35.0+/-4.0 kg/m2) and 31 age-matched normal-weight controls (21 women, BMI = 22.6+/-2.4 kg/m2). MEASUREMENTS: Subjects were studied by Doppler-echocardiography the same day and hour (08.00 h) as measurements of fasting insulin and blood glucose were made. Insulin resistance was determined by the 'Homeostasis Assessment Model'. RESULTS: Twelve obese subjects with insulin resistance (IR) had higher body size than 15 patients without IR and higher blood pressure than normal-weight controls (all P < 0.01). Relative IR was related to isovolumic relaxation time. This relation was not maintained after controlling for age, blood pressure, weight and height. Isovolumic relaxation time was, however, positively related to diastolic blood pressure, a measure of load, in normal controls (r=0.44) and obese without IR (r=0.62) but not in insulin resistant subjects (r=0.14). CONCLUSION: IR does not independently influence myocardial relaxation in uncomplicated obesity, but modulates the effect of load on active diastole.     

Squamotacin: an annonaceous acetogenin with cytotoxic selectivity for the human prostate tumor cell line (PC-3)

A 12-year-old child with tricuspid atresia and acquired hypoplasia of the left pulmonary artery was successfully treated with unilateral Fontan operation. Angiography at age 2 months had shown a normal left pulmonary artery, and a modified Potts shunt was performed. An emergency central shunt was required a year later. Reinvestigation 5 years after the initial operation revealed severe hypoplasia of the left pulmonary artery.     

Altered trafficking of mutant connexin32

We examined the cellular localization of nine different connexin32 (Cx32) mutants associated with X-linked Charcot-Marie-Tooth disease (CMTX) in communication-incompetent mammalian cells. Cx32 mRNA was made, but little or no protein was detected in one class of mutants. In another class of mutants, Cx32 protein was detectable in the cytoplasm and at the cell surface, where it appeared as plaques and punctate staining. Cx32 immunoreactivity in a third class of mutants was restricted to the cytoplasm, where it often colocalized with the Golgi apparatus. Our studies suggest that CMTX mutations have a predominant effect on the trafficking of Cx32 protein, resulting in a potentially toxic cytoplasmic accumulation of Cx32 in these cells. These results and evidence of cytoplasmic accumulation of other mutated myelin proteins suggest that diseases affecting myelinating cells may share a common pathophysiology.