Showing papers by "Vanderbilt University published in 1995"

Stress, coping, and social support processes: where are we? What next?

Abstract: I review existing knowledge, unanswered questions, and new directions in research on stress, coping resource, coping strategies, and social support processes. New directions in research on stressors include examining the differing impacts of stress across a range of physical and mental health outcomes, the "carry-overs" of stress from one role domain or stage of life into another, the benefits derived from negative experiences, and the determinants of the meaning of stressors. Although a sense of personal control and perceived social support influence health and mental health both directly and as stress buffers, the theoretical mechanisms through which they do so still require elaboration and testing. New work suggests that coping flexibility and structural constraints on individuals' coping efforts may be important to pursue. Promising new directions in social support research include studies of the negative effects of social relationships and of support giving, mutual coping and support-giving dynamics, optimal "matches" between individuals' needs and support received, and properties of groups which can provide a sense of social support. Qualitative comparative analysis, optimal matching analysis, and event-structure analysis are new techniques which may help advance research in these broad topic areas. To enhance the effectiveness of coping and social support interventions, intervening mechanisms need to be better understood. Nevertheless, the policy implications of stress research are clear and are important given current interest in health care reform in the United States.

Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification.

Abstract: The eukaryotic protein kinases make up a large superfamily of homologous proteins. They are related by virtue of their kinase domains (also known as catalytic domains), which consist of approximately 250-300 amino acid residues. The kinase domains that define this group of enzymes contain 12 conserved subdomains that fold into a common catalytic core structure, as revealed by the 3-dimensional structures of several protein-serine kinases. There are two main subdivisions within the superfamily: the protein-serine/threonine kinases and the protein-tyrosine kinases. A classification scheme can be founded on a kinase domain phylogeny, which reveals families of enzymes that have related substrate specificities and modes of regulation.

Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse.

Abstract: Bone morphogenetic protein-4 (BMP-4) is a member of the TGF-beta superfamily of polypeptide signaling molecules, closely related to BMP-2 and to Drosophila decapentaplegic (DPP). To elucidate the role of BMP-4 in mouse development the gene has been inactivated by homologous recombination in ES cells. Homozygous mutant Bmp-4tm1blh embryos die between 6.5 and 9.5 days p.c., with a variable phenotype. Most Bmp-4tm1blh embryos do not proceed beyond the egg cylinder stage, do not express the mesodermal marker T(Brachyury), and show little or no mesodermal differentiation. Some homozygous mutants develop to the head fold or beating heart/early somite stage or beyond. However, they are developmentally retarded and have truncated or disorganized posterior structures and a reduction in extraembryonic mesoderm, including blood islands. These results provide direct genetic evidence that BMP-4 is essential for several different processes in early mouse development, beginning with gastrulation and mesoderm formation. Moreover, in the presumed absence of zygotic ligand, it appears that homozygous mutants can be rescued partially by related proteins or by maternal BMP-4.

Infection with Helicobacter pylori Strains Possessing cagA Is Associated with an Increased Risk of Developing Adenocarcinoma of the Stomach

Abstract: To determine whether infection with a Helicobacter pylori strain possessing cagA is associated with an increased risk of development of adenocarcinoma of the stomach, we used a nested case-control study based on a cohort of 5443 Japanese-American men in Oahu, Hawaii, who had a physical examination and a phlebotomy during 1967 to 1970 We matched 103 H pylori -infected men who developed gastric cancer during a 21-year surveillence period with 103 H pylori -infected men who did not develop gastric cancer and tested stored serum specimens from patients and controls for the presence of serum IgG to the cagA product of H pylori using an ELISA The serum IgG assay using a recombinant CagA fragment had a sensitivity of 944% and a specificity of 925% when used in a clinically defined population; serological results were stable for more than 7 years For men with antibodies to CagA, the odds ratio of developing gastric cancer was 19 (95% confidence interval, 09–40); for intestinal type cancer of the distal stomach, the odds ratio was 23 (95% confidence interval, 10–52) Age cagA -positive H pylori strain in comparison with a cagA -negative strain somewhat increases the risk for development of gastric cancer, especially intestinal type affecting the distal stomach

Return on quality (ROQ): Making service quality financially accountable

Abstract: Many companies have been disappointed by a lack of results from their quality efforts. The financial benefits of quality, which had been assumed as a matter of faith in the “religion of quality,” are now being seriously questioned by cost-cutting executives, who cite the highly publicized financial failures of some companies prominent in the quality movement. In this increasingly results-oriented environment, managers must now justify their quality improvement efforts financially. The authors present the “return on quality” approach, which is based on the assumptions that (1) quality is an investment, (2) quality efforts must be financially accountable, (3) it is possible to spend too much on quality, and (4) not all quality expenditures are equally valid. The authors then provide a managerial framework that can be used to guide quality improvement efforts. This framework has several attractive features, including ensured managerial relevance and financial accountability.

Targeted Disruption of Mouse EGF Receptor: Effect of Genetic Background on Mutant Phenotype

Abstract: Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.

Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage.

Abstract: Background It has been hypothesized that the pathogenesis of diseases induced by cigarette smoking involves oxidative damage by free radicals However, definitive evidence that smoking causes the oxidative modification of target molecules in vivo is lacking We conducted a study to determine whether the production of F2-isoprostanes, which are novel products of lipid peroxidation, is enhanced in persons who smoke Methods We measured the levels of free F2-isoprostanes in plasma, the levels of F2-isoprostanes esterified to plasma lipids, and the urinary excretion of metabolites of F2-isoprostanes in 10 smokers and 10 nonsmokers matched for age and sex The short-term effects of smoking (three cigarettes smoked over 30 minutes) and the effects of two weeks of abstinence from smoking on levels of F2-isoprostanes in the circulation were also determined in the smokers Results Plasma levels of free and esterified F2-isoprostanes were significantly higher in the smokers (mean ±SD, 242±147 and 574±217 pmol per l

Parental Involvement in Children's Education: Why Does It Make a Difference?.

Abstract: We assert that the most important questions concerning parental involvement in children's education address why parents choose to become involved and why their involvement, once underway, often positively influences educational outcomes. We present a model suggesting that parents become involved primarily because (a) they develop a personal construction of the parental role that includes participation in their children's education, (b) they have developed a positive sense of efficacy for helping their children succeed in school, and (c) they perceive opportunities or demands for involvement from children and the school. Parents then choose specific forms of involvement in response to the specific domains of skill and knowledge they possess, the total demands on their time and energy, and specific requests for involvement from children and the school. The model suggests that parental involvement then influences children's developmental and educational outcomes through such mechanisms as modeling, reinforcement, and instruction, as mediated by the parent's use of developmentally appropriate activities and the fit between parental activities and the school's expectations. The major educational outcomes of the involvement process are children's development of skills and knowledge, as well as a personal sense of efficacy for succeeding in school. Major implications of the model for research and practice are discussed.

Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases.

Abstract: Focal adhesion kinase (FAK) is a widely expressed nonreceptor protein-tyrosine kinase implicated in integrin-mediated signal transduction pathways and in the process of oncogenic transformation by v-Src. Elevation of FAK's phosphotyrosine content, following both cell adhesion to extracellular matrix substrata and cell transformation by Rous sarcoma virus, correlates directly with an increased kinase activity. To help elucidate the role of FAK phosphorylation in signal transduction events, we used a tryptic phosphopeptide mapping approach to identify tyrosine sites of phosphorylation responsive to both cell adhesion and Src transformation. We have identified four tyrosines, 397, 407, 576, and 577, which are phosphorylated in mouse BALB/3T3 fibroblasts in an adhesion-dependent manner. Tyrosine 397 has been previously recognized as the major site of FAK autophosphorylation. Phosphorylation of tyrosines 407, 576, and 577, which are previously unrecognized sites, is significantly elevated in the presence of c-Src in vitro and v-Src in vivo. Tyrosines 576 and 577 lie within catalytic subdomain VIII--a region recognized as a target for phosphorylation-mediated regulation of protein kinase activity. We found that maximal kinase activity of FAK immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of FAK by Src (or other Src family kinases) is an important step in the formation of an active signaling complex.

Guidelines for the medical management of osteoarthritis

Abstract: Treatment of patients with OA of the knee should be individualized and tailored to the severity of the symptoms. In individuals with mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other nonpharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this treatment regimen, the use of NSAIDs in addition to nonpharmacologic therapy is appropriate unless medically contraindicated. Judicious use of intraarticular steroid injections has a role either as monotherapy or an adjunct to systemic therapy in patients with knee OA who have symptomatic effusions. The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time. Patients with severe symptomatic OA of the knee require an aggressive approach to decreasing pain, increasing mobility, and decreasing functional impairment; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.

Following the Pied Piper: Do Individual Returns Herd around the Market?

Abstract: Do equity returns indicate the presence of herd behavior on the part of investors during periods of market stress? To test this proposition, the cross-sectional standard deviation of returns, or dispersion, is used to capture herd behavior. When individual returns herd around the market consensus, dispersions are predicted to be relatively low. In contrast, rational asset pricing models predict an increase in dispersion because individual returns are repelled away from the market return when stocks differ in their sensitivity to market movements. The results for both daily and monthly returns are inconsistent with the presence of herding during periods of large price movements. For example, during extreme down markets, when herding is expected to be most prevalent, the magnitude of the increase in the dispersion of actual returns is mirrored by the increase in the dispersion of predicted returns that are estimated from a rational asset pricing model.

Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor

Abstract: There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.

Effects of psychotherapy with children and adolescents revisited: a meta-analysis of treatment outcome studies.

Abstract: A meta-analysis of child and adolescent psychotherapy outcome research tested previous findings using a new sample of 150 outcome studies and weighted least squares methods. The overall mean effect of therapy was positive and highly significant. Effects were more positive for behavioral than for nonbehavioral treatments, and samples of adolescent girls showed better outcomes than other Age X Gender groups. Paraprofessionals produced larger overall treatment effects than professional therapists or students, but professionals produced larger effects than paraprofessionals in treating overcontrolled problems (e.g., anxiety and depression). Results supported the specificity of treatment effects: Outcomes were stronger for the particular problems targeted in treatment than for problems not targeted. The findings shed new light on previous results and raise significant issues for future study. Over the past decade, applications of the technique known as meta-analysis (see Cooper & Hedges, 1994; Mann, 1990; Smith, Glass, & Miller, 1980) have enriched our understanding of the impact of psychotherapy with children and adolescents (herein referred to collectively as "children"). At least three general meta-analyses encompassing diverse treatment methods and diverse child problems have indicated that the overall impact of child psychotherapy is positive, with effect sizes averaging not far below Cohen's (1988) threshold of 0.80 for a "large" effect. Casey and Herman (1985) reported a mean effect size of 0.71 for a collection of treatment outcome studies with children 12 years of age and younger (studies published from 19521983). Weisz, Weiss, Alicke, and Klotz (1987) reported a mean effect size of 0.79 for a collection of studies with youth 4-18 years old (studies published from 1958-1984). Kazdin, Bass,

Social information-processing patterns partially mediate the effect of early physical abuse on later conduct problems.

Abstract: The authors tested the hypothesis that early physical abuse is associated with later externalizing behavior outcomes and that this relation is mediated by the intervening development of biased social information-processing patterns. They assessed 584 randomly selected boys and girls from European American and African American backgrounds for the lifetime experience of physical abuse through clinical interviews with mothers prior to the child's matriculation in kindergarten. Early abuse increased the risk of teacher-rated externalizing outcomes in Grades 3 and 4 by fourfold, and this effect could not be accounted for by confounded ecological or child factors. Abuse was associated with later processing patterns (encoding errors, hostile attributional biases, accessing of aggressive responses, and positive evaluations of aggression), which, in turn, predicted later externalizing outcomes.

Human Cytochrome P450 Enzymes

Abstract: In the past decade there has been considerable progress in the characterization of individual human P450 enzymes. These advances were initiated by early work on the purification of individual enzymes from human liver and other sources. The early work in the area was guided by a focus on the most abundant and easily purified enzymes.1–4It is now apparent, in retrospect, that these proteins were in the 2C and 3A families. Efforts were shifted to attempts to purify individual P450s on the basis of catalytic activities with the evidence that in some cases a single P450 could be identified in this way; e.g., the P450 now known as P450 2D6 was found to be under monogenic control. 5 The approach is technically demanding because of the need to do separations in the presence of detergents and then remove them before analysis of catalytic activity. Nevertheless, human P450s 1A1,6 1A2,7 2A6,8 2C8,9 2C9,9,10 2D67,11,12 2E1 13,14 3A4,15 3A5,16 4A11,17 and lanosterol 14α-demethylase18 were isolated in this general manner. Another approach that has been used, sometimes in a mode complementary to catalytic specificity, is purification on the basis of immunochemical similarity to animal P450s. 7,11,19,20

Guillain-Barré syndrome in northern China Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies

Abstract: Guillain-Barre syndrome has been considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP). Our experience with Guillain-Barre syndrome in northern China differs from the traditional concept. Electrophysiologically and pathologically, most of our patients have motor axonal degeneration with minimal cellular inflammation, which we have termed 'acute motor axonal neuropathy' (AMAN). The current studies were undertaken to characterize prospectively the clinical, electrophysiological, and serological features of Guillain-Barre syndrome, defined clinically, in northern China. In 1991 and 1992, we characterized by electrodiagnostic criteria 129 Chinese patients with Guillain-Barre syndrome. The AMAN form was present in 65% of patients, the AIDP form in 24% and 11% were unclassifiable. For the 38 patients who presented from January to October, 1992, we performed serological assays for antibodies to Campylobacter jejuni and to glycolipids. Of these 38 patients, 55% had AMAN, 32% had AIDP and 13% were unclassifiable. Sixty-six percent of the 38 had serological evidence of recent C. jejuni infection as compared with 16% of village controls (P = 0.001). Seventy-six percent of AMAN patients and 42% of AIDP patients were seropositive. IgG anti-GM1 antibodies were more frequent in Guillain-Barre syndrome patients compared with village controls (42% versus 6%; P < 0.01). However, no statistically significant correlations were found between the pattern of disease, AMAN or AIDP, anti-glycolipid antibodies, or C. jejuni antibodies. Based on electrophysiological criteria, Guillain-Barre syndrome in northern China can be divided into two predominant forms: AIDP and AMAN. The AMAN form is more common and predominates in the yearly summer outbreaks of Guillain-Barre syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation.

Abstract: The eukaryotic transcription factor NF-kappa B plays a central role in the induced expression of human immunodeficiency virus type 1 and in many aspects of the genetic program mediating normal T-cell activation and growth. The nuclear activity of NF-kappa B is tightly regulated from the cytoplasmic compartment by an inhibitory subunit called I kappa B alpha. This cytoplasmic inhibitor is rapidly phosphorylated and degraded in response to a diverse set of NF-kappa B-inducing agents, including T-cell mitogens, proinflammatory cytokines, and viral transactivators such as the Tax protein of human T-cell leukemia virus type 1. To explore these I kappa B alpha-dependent mechanisms for NF-kappa B induction, we identified novel mutants of I kappa B alpha that uncouple its inhibitory and signal-transducing functions in human T lymphocytes. Specifically, removal of the N-terminal 36 amino acids of I kappa B alpha failed to disrupt its ability to form latent complexes with NF-kappa B in the cytoplasm. However, this deletion mutation prevented the induced phosphorylation, degradative loss, and functional release of I kappa B alpha from NF-kappa B in Tax-expressing cells. Alanine substitutions introduced at two serine residues positioned within this N-terminal regulatory region of I kappa B alpha also yielded constitutive repressors that escaped from Tax-induced turnover and that potently inhibited immune activation pathways for NF-kappa B induction, including those initiated from antigen and cytokine receptors. In contrast, introduction of a phosphoserine mimetic at these sites rectified this functional defect, a finding consistent with a causal linkage between the phosphorylation status and proteolytic stability of this cytoplasmic inhibitor. Together, these in vivo studies define a critical signal response domain in I kappa B alpha that coordinately controls the biologic activities of I kappa B alpha and NF-kappa B in response to viral and immune stimuli.

Radiation Therapy Oncology Group (RTOG) 88–08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary Results of a Phase III Trial in Regionally Advanced, Unresectable Non-Small-Cell Lung Cancer

Abstract: Background: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. Purpose: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. Methods: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m 2 ) on days 1 and 29 and 5 mg/m 2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). Results: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy-46%, 11.4 months; chemotherapy plus radiotherapy-60%, 13.8 months; and hyperfractionated radiation therapy-51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P=.03). Conclusions: In «good-risk» patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage

Do rats have prefrontal cortex? the rose-woolsey-akert program reconsidered

Abstract: Primates are unique among mammals in possessing a region of dorsolateral prefrontal cortex with a well-developed internal granular layer. This region is commonly implicated in higher cognitive functions. Despite the histological distinctiveness of primate dorsolateral prefrontal cortex, the work of Rose, Woolsey, and Akert produced a broad consensus among neuroscientists that homologues of primate granular frontal cortex exist in nonprimates and can be recognized by their dense innervation from the mediodorsal thalamic nucleus (MD). Additional characteristics have come to be identified with dorsolateral prefrontal cortex, including rich dopaminergic innervation and involvement in spatial delayed-reaction tasks. However, recent studies reveal that these characteristics are not distinctive of the dorsolateral prefrontal region in primates: MD and dopaminergic projections are widespread in the frontal lobe, and medial and orbital frontal areas may play a role in delay tasks. A reevaluation of rat frontal cortex suggests that the medial frontal cortex, usually considered to be homologous to the dorsolateral prefrontal cortex of primates, actually consists of cortex homologous to primate premotor and anterior cin-date cortex. The lateral MD-projection cortex of rats resembles portions of primate orbital cortex. If prefrontal cortex is construed broadly enough to include orbital and cingulate cortex, rats can be said to have prefrontal cortex. However, they evidently lack homologues of the dorsolateral prefrontal areas of primates. This assessment suggests that rats probably do not provide useful models of human dorsolateral frontal lobe function and dysfunction, although they might prove valuable for understanding other regions of frontal cortex.

Historical Syntax in Cross-Linguistic Perspective

Abstract: In this major new work Alice Harris and Lyle Campbell set out to establish a general framework for the investigation of linguistic change. Systematic cross-linguistic comparison of syntactic change across a wide variety of languages is used to construct hypotheses about the universals and limits of language change more generally. In particular, the authors seek to move closer towards describing the range of causes of syntactic change to develop an understanding of the mechanisms of syntactic change, and to provide an understanding of why some languages undergo certain changes and not others. The authors draw on languages as diverse as Pipil and French, Georgian and Estonian, and the data presented is one of the book's great strengths. Rigor and precision are combined here with a great breadth of scholarship to produce a unique resource for the study of linguistic change, which will be of use to scholars and students alike.

Topography of visual cortex connections with frontal eye field in macaque: convergence and segregation of processing streams

Abstract: The primate visual system consists of at least two processing streams, one passing ventrally into temporal cortex that is responsible for object vision, and the other running dorsally into parietal cortex that is responsible for spatial vision How information from these two streams is combined for perception and action is not understood Visually guided eye movements require information about both feature identity and location, so we investigated the topographic organization of visual cortex connections with frontal eye field (FEF), the final stage of cortical processing for saccadic eye movements Multiple anatomical tracers were placed either in parietal and temporal cortex or in different parts of FEF in individual macaque monkeys Convergence from the dorsal and ventral processing streams occurred in lateral FEF but not in medial FEF Certain extrastriate areas with retinotopic visual field organizations projected topographically onto FEF The dorsal bank of the superior temporal sulcus projected to medial FEF; the ventral bank, to lateral FEF, and the fundus, throughout FEF Thus, lateral FEF, which is responsible for generating short saccades, receives visual afferents from the foveal representation in retinotopically organized areas, from areas that represent central vision in inferotemporal cortex and from other areas having no retinotopic order In contrast, medial FEF, which is responsible for generating longer saccades, is innervated by the peripheral representation of retinotopically organized areas, from areas that emphasize peripheral vision or are multimodal and from other areas that have no retinotopic order or are auditory

Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression

Abstract: We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells. BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells. These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression.

Toward a theoretical model of voluntary overcompliance

Abstract: We explain why some firms voluntarily overcomply with environmental regulation. In our model all consumers value environmental quality but differ in their willingness to pay which depends on their income levels. Publicly available information on environmental performance of firms enables consumers to identify clean firms. Firms participate in a two-stage duopoly game where they first choose their levels of cleaning technology and next engage in price competition. The market gets segmented by income levels. A minimum standard binding on the dirty firm has the effect of improving the performance of the cleaner firm. A subsidy obtains the same competitive outcome.

Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination.

Abstract: The inhibitor protein I kappa B alpha controls the nuclear import of the transcription factor NF-kappa B. The inhibitory activity of I kappa B alpha is regulated from the cytoplasmic compartment by signal-induced proteolysis. Previous studies have shown that signal-dependent phosphorylation of serine residues 32 and 36 targets I kappa B alpha to the ubiquitin-proteasome pathway. Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of I kappa B alpha. Conservative Lys-->Arg substitutions at both Lys-21 and Lys-22 produce dominant-negative mutants of I kappa B alpha in vivo. These constitutive inhibitors are appropriately phosphorylated but fail to release NF-kappa B in response to multiple inducers, including viral proteins, cytokines, and agents that mimic antigenic stimulation through the T-cell receptor. Moreover, these Lys-->Arg mutations prevent signal-dependent degradation of I kappa B alpha in vivo and ubiquitin conjugation in vitro. We conclude that site-specific ubiquitination of phosphorylated I kappa B alpha at Lys-21 and/or Lys-22 is an obligatory step in the activation of NF-kappa B.

Machine learning approaches to estimating software development effort

Abstract: Accurate estimation of software development effort is critical in software engineering. Underestimates lead to time pressures that may compromise full functional development and thorough testing of software. In contrast, overestimates can result in noncompetitive contract bids and/or over allocation of development resources and personnel. As a result, many models for estimating software development effort have been proposed. This article describes two methods of machine learning, which we use to build estimators of software development effort from historical data. Our experiments indicate that these techniques are competitive with traditional estimators on one dataset, but also illustrate that these methods are sensitive to the data on which they are trained. This cautionary note applies to any model-construction strategy that relies on historical data. All such models for software effort estimation should be evaluated by exploring model sensitivity on a variety of historical data. >