ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progression.

The interaction between stromal cells and tumor cells is emerging as a critical aspect of tumor progression. Yet there is a paucity of molecular markers for cells participating in such interactions, and only few genes are known to play a critical role in this process. Here, we describe the identification of ADAM12 (a disintegrin and metalloprotease 12) as a novel marker for a subpopulation of stromal cells that are adjacent to epithelial tumor cells in three mouse carcinoma models (models for prostate, breast and colon cancer). Moreover, we show that ADAM12 is essential for tumor development and progression in the W10 mouse model for prostate cancer. These results suggest that ADAM12 might be a useful marker for stromal cells in mouse tumors that are likely to participate in stromal/tumor cell crosstalk, and that ADAM12 is a potential target for design of drugs that prevent carcinoma growth.

On finding for defendants who plead insanity: the crucial impact of dispositional instructions and opportunity to deliberate.

One hundred twenty participants functioned as mock-jurors and as members of deliberating juries in an experiment designed to assess the impact of dispositional instruction on verdicts rendered in an insanity trial. Consistent with prior research (K. E. Whittemore & J. R. Ogloff, 1995), dispositional instruction had no effect on the verdict preferences of individual jurors prior to deliberating. Yet, as expected, the instruction manipulation had a major impact on postdeliberative decisions (i.e., group verdicts; individual juror verdict preferences). Content analyses of jury deliberations revealed that postdeliberative shifts toward harsh verdicts in uninstructed juries and toward lenient verdicts in instructed juries were mediated by the impact of the Instruction manipulation on the content of jury deliberations: uninstructed juries feared that an acquitted-insane defendant would be freed to act again, whereas instructed juries recognized that finding for an insane defendant implied his retention and treatment. Implications of these results for both legal policy and the conduct of mock-trial research are discussed.

Relationship quality and potentially harmful behaviors by spousal caregivers: how we were then, how we are now. The Family Relationships in Late Life Project.

Structured interview data from 142 caregivers (98 wives, 44 husbands) indicate that more depressed caregivers are more likely to treat their spouses in potentially harmful ways. However, consistent with hypotheses derived from communal relationships theory, when the preillness relationship between caregiver and care recipient was characterized by mutual responsiveness to each other's needs (i.e., was more communal), caregivers were less depressed and less frequently engaged in potentially harmful behaviors. These effects were not attributable to demographic factors, amount of care provided, care recipient dementia status, or length of time in the caregiving role. Rather, multivariate analyses suggest that the extent to which premorbid relationships were communal in nature determines whether caregivers perceive their current relationships as rewarding, which, in turn, predicts caregiver depression and potentially harmful behaviors.

Activity restriction and prior relationship history as contributors to mental health outcomes among middle-aged and older spousal caregivers.

In a sample of cancer patients (n = 75) and spousal caregivers (24 men and 51 women), restriction in caregiver routine activities mediated associations between caregiving stress (patient symptom severity) and caregiver depressed affect and resentment. Moreover, the antecedents and affective consequences of caregiver activity restriction were consistent with the theory of communal relationships (e.g., M. S. Clark & J. Mills, 1979, 1993). If a relationship had been communal in the past (i.e., characterized by mutual concern for and responsiveness to one another's needs), activity restriction was predicted by intimacy and affectional loss (rather than by the severity of patient symptoms) and in turn predicted caregiver depressed affect. Among caregivers in less communal relationships, activity restriction was predicted by severity of patient symptoms (rather than by intimacy and affectional loss) and in turn predicted resentment of care recipients and the caregiving role.

Gender and situational context moderate the relationship between self-monitoring and induction of self-disclosure.

Male and female undergraduates who differed in degree of self-monitoring interviewed same-sex strangers to test the hypothesis that interviewer self-monitoring propensities foster self-disclosure only in disclosure-conducive contexts (i.e., collaborative contexts for men and social-expressive contexts for women). Results indicated that high self-monitoring (but not low self-monitoring) interviewers of each gender were notably more successful at eliciting personal information in the contexts generally considered amenable to male and female self-disclosure than in disclosure-nonconducive contexts. Moreover, male high self-monitoring interviewers reliably elicited more information than their low self-monitoring counterparts only in the disclosure-conducive (for men) collaborative context. However, high self-monitoring female interviewers did not elicit more information than their dispositional counterparts in disclosure-conducive, social-expressive contexts, although they reliably induced less disclosure than low self-monitors in the disclosure-nonconducive (for women) collaborative context.

Temperature-sensitive hepatitis A virus mutants with deletions downstream of the first pyrimidine-rich tract of the 5' nontranslated RNA are impaired in RNA synthesis.

Hepatitis A virus (HAV) mutants containing large deletions within the first pyrimidine-rich tract (pY1; nucleotides [nt] 99 to 138) of the 5' nontranslated RNA (5'NTR) replicate well in cultured cells, while those with pY1 deletions which extend in a 3' direction to include nt 140 to 144 (CUUGU) have a temperature-sensitive (ts) replication phenotype (D.R. Shaffer, E.A. Brown, and S.M. Lemon, J. Virol. 68:5568-5578, 1994). To characterize this replication defect, the ts mutant delta 131-144 was grown under one-step conditions at the nonpermissive temperature (37 degrees C). A shift to the permissive temperature (31 degrees C) for the first 18 h of the viral replication cycle did not enhance virus yields, indicating that temperature sensitivity is not due to a defect in viral entry or uncoating. Similarly, absence of increased yield with a late shift to 31 degrees C between 54 and 72 h suggested that the ts defect does not involve viral assembly. Although monocistronic RNA transcripts containing the delta 99-144 deletion directed translation 22 to 58% less efficiently than the standard 5'NTR in transfected BS-C-1 cells, this difference was present at both 31 and 37 degrees C. In addition, there were no temperature-dependent differences in the abilities of bicistronic transcripts containing either ts or non-ts 5'NTR sequences within the intercistronic space to direct translation of a downstream reporter gene. Thus, ts mutations do not confer a demonstrable temperature-related defect in cap-independent translation. In contrast, an RNase protection assay showed that synthesis of viral plus-strand RNA was markedly delayed in BS-C-1 cells infected with ts virus at 37 degrees C. Analysis of the nucleotide sequence surrounding the deletion in a non-ts revertant derived from delta 116-144 virus revealed that a single U-to-G transversion at nt 114 (CUUUU-->CUUGU) had restored the sequence normally present between nt 140 and 144. These results indicate that ts mutants of HAV with deletions extending downstream from the pY1 domain to nt 140 to 144 are defective in RNA synthesis and that the single-stranded RNA segment containing nt 140 to 144 plays a critical role in replication of HAV RNA.

A hepatitis A virus deletion mutant which lacks the first pyrimidine-rich tract of the 5' nontranslated RNA remains virulent in primates after direct intrahepatic nucleic acid transfection.

Cell culture-adapted variants of hepatitis A virus (HAV) in which the first pyrimidine-rich tract (pY1; nucleotides 99 to 138) of the 5' nontranslated region has been deleted (delta 96-137 or delta 96-139) replicate as well as parental virus in cultured cells (D.R. Shaffer, E.A. Brown, and S.M. Lemon, J. Virol. 68:5568-5578, 1994). To determine whether viruses with such large deletion mutations are able to replicate and to produce acute hepatitis in primates, we reconstructed the delta 96-137 deletion in the genetic background of a virulent virus which differs from the wild type by only one mutation in the 2B-coding region (HM175/8Y). Full-length synthetic delta 96-137/8Y RNA was injected into the livers of two HAV-seronegative marmosets (Saguinus mystax). Both animals developed serum liver enzyme elevations and inflammatory changes in serial liver biopsies within 3 to 4 weeks of inoculation which were comparable in magnitude to those observed previously following intrahepatic inoculation of marmosets with HM175/8Y RNA. Sequencing of RNA from virus shed in feces demonstrated the presence of the delta 96-137 deletion. These results indicate that the pY1 sequence of HAV is not required for efficient viral replication in hepatocytes in situ or for production of acute hepatic injury following intrahepatic RNA transfection in primates.

Large deletion mutations involving the first pyrimidine-rich tract of the 5' nontranslated RNA of human hepatitis A virus define two adjacent domains associated with distinct replication phenotypes.

The 5' nontranslated RNA (5'NTR) of the HM175 strain of human hepatitis A virus contains several pyrimidine-rich regions, the largest and most 5' of which (pY1) is an almost pure polypyrimidine tract located between nucleotides (nt) 99 and 138, which includes five tandem repeats of the sequence motif (U)UUCC(C). Previous modeling of the RNA secondary structure suggested that this region was likely to be single-stranded, but repetitive RNase V1 cleavage sites within these (U)UUCC(C) motifs indicated that pY1 possesses an ordered structure. To assess the role of this domain in replication of the virus, a series of large deletion mutations were created which involved the pY1 domain of an infectious cDNA clone. Deletion of 44 nt between nt 96 and 139, including the entire pY1 domain, did not reduce the capacity of the virus to replicate in BS-C-1 or FRhK-4 cells, as assessed by the size of replication foci in radioimmunofocus assays or by virus yields under one-step growth conditions. In contrast, viable virus could not be recovered from transfected RNAs in which the deletion was extended in a 5' direction by an additional 3 nt (delta 93-134), most likely because of the destabilization of a predicted stem-loop structure upstream of pY1. Deletion mutations extending in a 3' fashion to nt 140, 141, or 144 resulted in moderately (delta 96-140 and delta 96-141) or strongly (delta 99-144, delta 116-144, and delta 131-144) temperature-sensitive replication phenotypes. Although deletion of the pY1 domain did not by itself affect the replication phenotype of virus, the additional deletion of sequence elements within the pY1 domain (nt 99 to 130) substantially enhanced the temperature-sensitive phenotype of delta 131-144 virus. These data suggest that the (U)UUCC(C) motifs within the pY1 domain are conserved among wild-type viruses in order to serve a function required during infection in vivo but not in cell culture. In contrast, the single-stranded region located immediately downstream of pY1 (nt 140 to 144) is essential for efficient replication in cultured cells at physiological temperature. Viruses with deletion mutations involving nt 140 to 144 and viruses with large pY1 deletions but normal replication phenotypes in cell culture may have attenuation properties which could be exploited for vaccine development.

Gender and self-disclosure revisited: personal and contextual variations in self-disclosure to same-sex acquaintances.

Male and female American students who differed in masculinity and in femininity self-disclosed to a same-sex stranger in contexts that made either social/expressive motives or instrumental motives salient. The results were consistent with the primary assertion that measures of sex role identity are better predictors of contextual variations in self-disclosure than is sex per se. Sex consistently failed to predict subjects' willingness to self-disclose, both within and across contexts, whereas femininity promoted self-disclosure in the context that was clearly social and expressive in character. Although masculinity failed to exert the expected facilitative impact on self-disclosure within the instrumental context, it nonetheless influenced the results; androgynous subjects, who scored high in both masculinity and femininity, were more self-revealing across contexts than was any other group.

Interaction of low density lipoproteins with human aortic elastin.

Interaction between lipoproteins and elastin in the arterial wall may play an important role in atherosclerotic lipid deposition, but binding affinities and other characteristics of the interaction have not been determined previously. Elastin was isolated by hot alkali treatment of human aortic tissue. At 4 degrees C, radioiodinated human low density lipoprotein (LDL) bound to more than one class of binding sites on elastin. Sites of highest affinity had an apparent dissociation constant of 3.6 x 10(-8) M. Total binding at an LDL concentration of 50 micrograms/ml ranged from 4 to 50 ng LDL protein/mg elastin. The binding was relatively specific, since binding was competitively inhibited by LDL and apo E-containing high density lipoprotein (HDL) but only modestly by HDL3. Atherosclerotic elastin exhibited a twofold to fourfold higher capacity for binding LDL, but a reduced affinity. At 37 degrees C, normal elastin exhibited an initial rapid binding of LDL, with a slower linear phase of binding over a 15-hour period, indicating an additional complex process at this temperature. Consideration of the expected LDL concentrations in the arterial intima, in comparison with binding affinities, suggests that LDL binding to elastin probably occurs in the intima and may foster atherosclerotic lipid deposition.

Stress fibers in endothelial cells overlying atherosclerotic lesions in rabbit aorta.

Endothelial injury or dysfunction has long been postulated to promote atherogenesis, but structural alterations of endothelium in atherosclerosis have remained obscure. We report the common occurrence of actin-containing stress fibers, stainable by rhodamine-phalloidin, in endothelium overlying atherosclerotic lesions in cholesterol-fed rabbits. Nonlesioned areas in the same aortas showed normal endothelium with minimal development of stress fibers, which was no different from the appearance of endothelium in chow-fed rabbits. Microtubule organization revealed by immunofluorescence appeared normal in all areas. The development of stress fibers may be related to an altered substratum for endothelial attachment. This study provided no evidence to relate stress fiber formation with lesion initiation, but an association with well-developed foam cell lesions was evident.