Autoantibodies to the insulin receptor. Effect on the insulin-receptor interaction in IM-9 lymphocytes

The serum of some patients with insulin-resistant "diabetes" contains antibodies that bind to and block the cell membrane receptors for insulin. In this report, we have characterized the effects of the antireceptor antibodies on the interaction of (125)I-insulin with its receptor on the human lymphoblastoid cell line IM-9. Up to 95% of specific insulin binding can be inhibited by pretreatment of the cells with these immunoglobulins. The onset of the inhibitory effect is time- and temperature-dependent, and the effect is reversed extremely slowly if the cells are suspended in a large excess of antibody-free buffer. These features of antibody binding can be easily distinguished from those for insulin binding to its receptor. The inhibitory effect of the antibodies can be reversed by exposure of the cells to conditions known to elute surface immunoglobulins. The three antireceptor sera studied appear to alter the insulin-receptor interaction in different ways. Two antisera markedly reduce receptor affinity through combined effects on the insulin association and dissociation rates, and, additionally, have smaller effects on available receptor number. A third antiserum primarily affects available receptor number and has little effect on receptor affinity. All three antisera inhibit the capacity of insulin to promote negatively cooperative site-site interactions among insulin receptors. The data suggest that these autoantibodies to the insulin receptor bind to different determinants on the receptor and may therefore be useful as unique probes of insulin receptor structure and function.     

Uncouplers can shuttle between localized energy-coupling sites during photophosphorylation by chromatophores of Rhodopseudomonas capsulata N22

Two models of the action of uncoupler molecules in inhibiting photophosphorylation in bacterial chromatophores are considered: either uncoupler molecules shuttle rapidly between energy-coupling sites, or uncoupler molecules that are bound to particular sites in the chromatophores for a time that is comparable with the turnover time of the photophosphorylation apparatus may uncouple by a co-operative "substoichiometric' mechanism. It is found that the titre of uncoupler necessary to cause complete uncoupling is lowered if the rate of photophosphorylation is initially decreased by partially restricting electron flow with an appropriate titre of antimycin A. This result indicates that uncoupler molecules shuttle rapidly between energy coupling in which the energized intermediate between electron transport and phosphorylation is delocalized over the entire chromatophore membrane and those in which it is not. If the rate of photophosphorylation is partially restricted with the covalent H+-translocating ATP synthase inhibitor dicyclohexylcarbodi-imide, the titre of uncoupler necessary to effect complete inhibition of photophosphorylation is also decreased relative to that in which the covalent H+-ATP synthase inhibitor is absent. This important result appears to be inconsistent with models of electron-transport phosphorylation in which the "energized state' of the chromatophore membrane that is set up by electron transport and utilized in photophosphorylation is delocalized over the entire chromatophore membrane.     

Drinking patterns as predictors of alcohol withdrawal reactions in DBA/2J mice

Individually housed DBA/2J mice were fed a liquid diet in which ethanol supplied 33% of the calories. The level of physical dependence that developed was estimated by scoring convulsions, elicited by handling the mice, after discontinuing the alcohol diet. The severity of the withdrawal reaction increased progressively with duration (5-12 days) of alcohol administration. A 2-day period on the diet produced no withdrawal reaction. Pretreatment of the mice with alcohol in their drinking water slightly increased the subsequent intake of the liquid diet. "Effective" alcohol intake was defined as uninterrupted alcohol consumption above 10 g/kg/day. Withdrawal scores correlated better with effective intake than with total intake under a variety of conditions. We interpret this to mean that brief interruptions in drinking (1 day) may allow the accrued physical dependence to disappear. On the basis of their effective alcohol intake, mice could be assigned to nondependent, moderately dependent or severely dependent groups for further study of the nature of physical dependence.     

Detection of cross-channel anomalies

The data deluge has created a great challenge for data mining applications wherein the rare topics of interest are often buried in the flood of major headlines. We identify and formulate a novel problem: cross-channel anomaly detection from multiple data channels. Cross-channel anomalies are common among the individual channel anomalies and are often portent of significant events. Central to this new problem is a development of theoretical foundation and methodology. Using the spectral approach, we propose a two-stage detection method: anomaly detection at a single-channel level, followed by the detection of cross-channel anomalies from the amalgamation of single-channel anomalies. We also derive the extension of the proposed detection method to an online settings, which automatically adapts to changes in the data over time at low computational complexity using incremental algorithms. Our mathematical analysis shows that our method is likely to reduce the false alarm rate by establishing theoretical results on the reduction of an impurity index. We demonstrate our method in two applications: document understanding with multiple text corpora and detection of repeated anomalies in large-scale video surveillance. The experimental results consistently demonstrate the superior performance of our method compared with related state-of-art methods, including the one-class SVM and principal component pursuit. In addition, our framework can be deployed in a decentralized manner, lending itself for large-scale data stream analysis.     

Regularized nonnegative shared subspace learning

Joint modeling of related data sources has the potential to improve various data mining tasks such as transfer learning, multitask clustering, information retrieval etc. However, diversity among various data sources might outweigh the advantages of the joint modeling, and thus may result in performance degradations. To this end, we propose a regularized shared subspace learning framework, which can exploit the mutual strengths of related data sources while being immune to the effects of the variabilities of each source. This is achieved by further imposing a mutual orthogonality constraint on the constituent subspaces which segregates the common patterns from the source specific patterns, and thus, avoids performance degradations. Our approach is rooted in nonnegative matrix factorization and extends it further to enable joint analysis of related data sources. Experiments performed using three real world data sets for both retrieval and clustering applications demonstrate the benefits of regularization and validate the effectiveness of the model. Our proposed solution provides a formal framework appropriate for jointly analyzing related data sources and therefore, it is applicable to a wider context in data mining.     

Independent components of magnetoencephalography: localization

We applied second-order blind identification (SOBI), an independent component analysis method, to MEG data collected during cognitive tasks. We explored SOBI's ability to help isolate underlying neuronal sources with relatively poor signal-to-noise ratios, allowing their identification and localization. We compare localization of the SOBI-separated components to localization from unprocessed sensor signals, using an equivalent current dipole modeling method. For visual and somatosensory modalities, SOBI preprocessing resulted in components that can be localized to physiologically and anatomically meaningful locations. Furthermore, this preprocessing allowed the detection of neuronal source activations that were otherwise undetectable. This increased probability of neuronal source detection and localization can be particularly beneficial for MEG studies of higher-level cognitive functions, which often have greater signal variability and degraded signal-to-noise ratios than sensory activation tasks.     

The effect of converting from pravastatin to simvastatin on the pharmacodynamics of warfarin

Glycosylated amino acids and glycosylated human serum albumin reduce nitrite to nitric oxide under anaerobic conditions. The amount of nitric oxide produced was recorded by generation of nitrosoHb from deoxyHb. Without preincubation after the addition of sodium nitrite, glucose or a mixture of glucose with amino acid or serum albumin did not cause spectrophotometrically detectible transformation of deoxyHb into nitrosoHb. The generation of NO increased with an increase in content of colored "final" products of amino acid and serum albumin glycosylation in the incubation mixture. The incubation of blood plasma of patients with diabetes mellitus with nitrite also resulted in the increased production of NO as compared to blood plasma of healthy subjects. During the incubation of healthy subjects' blood plasma with nitrite a small amount of NO was produced. The removal of low-molecular-weight compounds was accompanied by a significantly decreased generation of NO by blood plasma.     

Isolation and characterization of the Saccharomyces cerevisiae DPP1 gene encoding diacylglycerol pyrophosphate phosphatase

Diacylglycerol pyrophosphate (DGPP) is involved in a putative novel lipid signaling pathway. DGPP phosphatase (DGPP phosphohydrolase) is a membrane-associated 34-kDa enzyme from Saccharomyces cerevisiae which catalyzes the dephosphorylation of DGPP to yield phosphatidate (PA) and then catalyzes the dephosphorylation of PA to yield diacylglycerol. Amino acid sequence information derived from DGPP phosphatase was used to identify and isolate the DPP1 (diacylglycerol pyrophosphate phosphatase) gene encoding the enzyme. Multicopy plasmids containing the DPP1 gene directed a 10-fold overexpression of DGPP phosphatase activity in S. cerevisiae. The heterologous expression of the S. cerevisiae DPP1 gene in Sf-9 insect cells resulted in a 500-fold overexpression of DGPP phosphatase activity over that expressed in wild-type S. cerevisiae. DGPP phosphatase possesses a Mg2+-independent PA phosphatase activity, and its expression correlated with the overexpression of DGPP phosphatase activity in S. cerevisiae and in insect cells. DGPP phosphatase was predicted to be an integral membrane protein with six transmembrane-spanning domains. The enzyme contains a novel phosphatase sequence motif found in a superfamily of phosphatases. A dpp1Delta mutant was constructed by deletion of the chromosomal copy of the DPP1 gene. The dpp1Delta mutant was viable and did not exhibit any obvious growth defects. The mutant was devoid of DGPP phosphatase activity and accumulated (4-fold) DGPP. Analysis of the mutant showed that the DPP1 gene was not responsible for all of the Mg2+-independent PA phosphatase activity in S. cerevisiae.