bluuebunny/crossref_metadata_2025 huggingface dataset:
MotifPrototyper: A Bayesian profile model for motif families
Authors: Xing Eric P. , Karp Richard M.
Published: July 2004

In this article, we address the problem of modeling generic features ofstructurallybut nottextuallyrelated DNA motifs, that is, motifs whose consensus sequences are entirely different but nevertheless share “metasequence features” reflecting similarities in the DNA-binding domains of their associated protein recognizers. We present MotifPrototyper, a profile Bayesian model that can capture structural properties typical of particular families of motifs. Each family corresponds to transcription regulatory proteins with similar types of structural signatures in their DNA-binding domains. We show how to train MotifPrototypers from biologically identified motifs categorized according to the TRANSFAC categorization of transcription factors and present empirical results of motif classification, motif parameter estimation, andde novomotif detection by using the learned profile models.
Origin of the neighboring residue effect on peptide backbone conformation
Authors: Avbelj Franc , Baldwin Robert L.
Published: July 2004

Unfolded peptides in water have some residual structure that may be important in the folding process, and the nature of the residual structure is currently of much interest. There is a neighboring residue effect on backbone conformation, discovered in 1997 from measurements of
3
J
HNα
coupling constants. The neighboring residue effect appears also in the “coil library” of Protein Data Bank structures of residues not in α-helix and not in β-structure. When a neighboring residue (
i
– 1 or
i
+ 1) belongs to class L (aromatic and β-branched amino acids, FHITVWY) rather than class S (all others, G and P excluded), then the backbone angle φ of residue
i
is more negative for essentially all amino acids. Calculated values of peptide solvation (electrostatic solvation free energy, ESF) predict basic properties of the neighboring residue effect. We show that L amino acids reduce the solvation of neighboring peptide groups more than S amino acids. When tripeptides from the coil library are excised to allow solvation, the central residues have more negative values of 〈φ〉 but less negative values of 〈ESF〉 with L than with S neighbors. The coil library values of 〈
3
J
HNα
〉, which vary strikingly among the amino acids, are correlated with the neighboring residue effect seen by ESF. Moreover, values for the “blocking effect” of side chains on the hydrogen exchange rates of peptide NH protons are correlated with ESF values.
Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity
Authors: Yao Dongdong , Gu Zezong , Nakamura Tomohiro , Shi Zhong-Qing , Ma Yuliang , Gaston Benjamin , Palmer Lisa A. , Rockenstein Edward M. , Zhang Zhuohua , Masliah Eliezer , Uehara Takashi , Lipton Stuart A.
Published: July 2004

Many hereditary and sporadic neurodegenerative disorders are characterized by the accumulation of aberrant proteins. In sporadic Parkinson's disease, representing the most prevalent movement disorder, oxidative and nitrosative stress are believed to contribute to disease pathogenesis, but the exact molecular basis for protein aggregation remains unclear. In the case of autosomal recessive-juvenile Parkinsonism, mutation in the E3 ubiquitin ligase protein parkin is linked to death of dopaminergic neurons. Here we show both
in vitro
and
in vivo
that nitrosative stress leads to
S
-nitrosylation of wild-type parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in parkin's E3 ubiquitin ligase activity leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease.
Competencies for effective public health nutrition practice: a developing consensus
Authors: Hughes Roger
Published: July 2004

Objectives:

To assess the level of consensus amongst an international panel of public health nutrition leaders regarding the essential competencies required for effective public health nutrition practice.

Design:

A modified Delphi study involving three rounds of questionnaires.

Subjects:

A panel of 20 public health nutrition experts from seven countries in the European Union, the USA and Australia.

Results:

Expert panellists completed three rounds of the study relating to competencies. A literature review conducted as a prelude to the expert panel survey identified common competency units from the fields of public health, health promotion, nutrition and dietetics, and health education. These were categorised into seven competency areas including analytical, socio-cultural and political, public health service, communication, management and leadership, nutrition science and professional competency categories. There was strong initial agreement (≥90% of panellists at Round 1) that developing internationally recognised competencies for public health nutrition specialists was a priority. Twenty-six of an initial listing of 52 competency units were rated as essential competencies by ≥80% of the panellists after Round 1. Iteration rounds resulted in the addition of five extra competency units suggested by panellists after Round 1 and an increase by 13 in the number of competencies rated as essential to consensus levels. From a total of 57 competency units rated after the final survey round, 41 competency units were rated as essential competencies by ≥80% of the panellists (consensus), with 21 of these unanimously rated as essential competencies.

Conclusions:

There is strong international agreement amongst public health nutrition leaders in Europe, the USA and Australia about a range of competencies required for effective public health nutrition practice. Essential competency units identified can be used to develop and review competency standards for public health nutrition.
Public health nutrition and food policy
Authors: Caraher Martin , Coveney John
Published: July 2004

Food in its many manifestations allows us to explore the global control of health and to examine the ways in which food choice is moulded by many interests. The global food market is controlled by a small number of companies who operate a system that delivers ‘cheap’ food to the countries of the developed world. This ‘cheap’ food comes at a price, which externalises costs to the nation state in terms of health consequences (diabetes, coronary heart disease and other food-related diseases) and to the environment in terms of pollution and the associated clean-up strategies. Food policy has not to any great extent dealt with these issues, opting instead for an approach based on nutrition, food choice and biomedical health. Ignoring wider elements of the food system including issues of ecology and sustainability constrains a broader understanding within public health nutrition. Here we argue that public health nutrition, through the medium of health promotion, needs to address these wider issues of who controls the food supply, and thus the influences on the food chain and the food choices of the individual and communities. Such an upstream approach to food policy (one that has been learned from work on tobacco) is necessary if we are seriously to influence food choice.
Secular trends in diet among elderly Swedes – cohort comparisons over three decades
Authors: Eiben G , Andersson CS , Rothenberg E , Sundh V , Steen B , Lissner L
Published: July 2004

Objective:

The purpose of this study was to compare dietary practices among different birth cohorts of 70-year-old Swedes, who were examined between 1971 and 2000.

Setting:

Göteborg, Sweden.

Design:

Four population-based samples of 1360 70-year-olds, born in 1901, 1911, 1922 and 1930, have undergone health examinations and dietary assessments over a period of almost three decades. One-hour diet history (DH) interviews were conducted in 1971, 1981, 1992 and 2000 with a total of 758 women and 602 women. The formats and contents of the dietary examinations were similar over the years. Statistical analysis of linear trends was conducted, using year of examination as the independent variable, to detect secular trends in food and nutrient intakes across cohorts.

Results:

At the 2000 examination, the majority of 70-year-olds consumed nutritionally adequate diets. Later-born cohorts consumed more yoghurt, breakfast cereals, fruit, vegetables, chicken, rice and pasta than earlier-born cohorts. Consumption of low-fat spread and milk also increased, along with that of wine, light beer and candy. In contrast, potatoes, cakes and sugar were consumed less in 2000 than in 1971. The ratio of reported energy intake to estimated basal metabolic rate did not show any systematic trend over time in women, but showed a significant upward trend in men.

Conclusions:

The diet history method has captured changes in food selections in the elderly without changing in general format over three decades. Dietary quality has improved in a number of ways, and these findings in the elderly are consistent with national food consumption trends in the general population.
The relationship between education and food consumption in the 1995 Australian National Nutrition Survey
Authors: Worsley Anthony , Blaschea Roswitha , Ball Kylie , Crawford David
Published: July 2004

Objective:

To assess the relationship between education and the intake of a variety of individual foods, as well as groups of foods, for Australian men and women in different age groups.

Design:

Cross-sectional national survey of free-living men and women.

Subjects:

A sample of 2501 men and 2739 women aged 18 years and over who completed the National Nutrition Survey (NNS) 1995.

Methods:

Information about the frequency of consumption of 88 food items was obtained using a food-frequency questionnaire in a nation-wide nutrition survey. Irregular and regular consumers of foods were identified according to whether they consumed individual foods less than or more than once per month. The relationship between single foods and an index of education (no post-school qualifications, vocational, university) was analysed via contingency table chi-square statistics for men and women. Food group variety scores were derived by assigning individual foods to conventional food group taxonomies, and then summing the dichotomised intake scores for individual foods within each food group. Two-way analyses of variance (education by age groups) were performed on food variety scores for men and women, separately.

Results:

While university-educated men and women consumed many individual foods more regularly than less-educated people, they were less likely to be regular consumers of several meat products. The relationship between education and food consumption was less apparent when individual food scores were aggregated into food group scores. University-educated men and women exhibited higher scores on total food group variety than the other educational groups.

Conclusions:

Higher education is associated with the regular consumption of a wider variety of foods. Aggregation of individual food consumption indices into food variety scores may mask the apparent effects of educational background on food consumption.
Prevalence of overweight and obesity in adolescent Tehrani students, 2000–2001: an epidemic health problem
Authors: Mohammadpour-Ahranjani B , Rashidi A , Karandish M , Eshraghian MR , Kalantari N
Published: July 2004

Objective:

Overweight has become a public health problem in most developing countries. Evidence suggests that adolescence is a critical period in determining adulthood obesity and its complications. The present study was carried out to assess the prevalence of overweight and obesity among secondary school students.

Design and setting:

This descriptive study was conducted in Tehran city, 2000–2001. Body weight and height were measured and body mass index (BMI) values were calculated. Underweight, overweight and obesity were defined as <5th, ≥85th and ≥95th percentile, respectively, of age- and sex-specific BMI values from the National Center for Health Statistics/Centers for Disease Control and Prevention (2000).

Subjects:

Using a multistage sampling method, 2321 students (1068 males and 1253 females) aged 11–16 years were assessed in Tehran, the capital city of Iran.

Results:

The overall prevalences of overweight and obesity were 21.1 and 7.8%, respectively. The prevalence of overweight among girl students (i.e. 23.1%; 95% confidence interval (CI) 20.8–25.4) was significantly higher than that among boys (i.e. 18.8%; 95% CI 16.5–21.1, P = 0.01) even after adjustment for age (odds ratio 1.26, 95% CI 1.03–1.55, P = 0.02). No significant risk of obesity associated with age was found in girls or boys. In both sexes, median values of age-specific BMI in this study were statistically higher than corresponding values collected in Tehrani adolescents 10 years ago (P = 0.03). Similarly, a significant difference was seen between girl students in this study and the reference population (P = 0.03).

Conclusion:

According to this study, overweight, especially in girls, should be considered an epidemic health problem among adolescent students in Tehran.
Promotions to increase lower-fat food choices among students in secondary schools: description and outcomes of TACOS (Trying Alternative Cafeteria Options in Schools)
Authors: Fulkerson Jayne A , French Simone A , Story Mary , Nelson Helen , Hannan Peter J
Published: July 2004

Objectives:

(1) To describe promotional activities, particularly student-led, targeting lower-fat à la carte foods that were conducted in secondary schools; and (2) to describe the relationships between the number and duration of total promotional activities for lower-fat à la carte foods and cafeteria sales of such foods over two years.

Design:

Promotional activities were implemented in schools that were randomised to the intervention condition of a larger, two-year, school-based, randomised, controlled nutrition intervention trial.

Setting:

Ten Minnesota secondary schools.

Subjects:

Students and school faculty, school food-service and research staff (measured at the school level).

Results:

Over two years, 181 promotions were implemented (n= 49 in Year 1 andn= 132 in Year 2). In Year 1, the number of promotions conducted in schools was significantly associated with percentage lower-fat food sales. In Year 2, the duration of promotions was significantly associated with percentage lower-fat food sales.

Conclusions:

Collaborative efforts among students, school food-service staff and research staff can be successful in implementing a large number of nutrition-related, school-wide promotional activities. These efforts can increase the sales of lower-fat foods in à la carte areas of school cafeterias.
A review of the effectiveness of agriculture interventions in improving nutrition outcomes
Authors: Berti Peter R , Krasevec Julia , FitzGerald Sian
Published: July 2004

Objectives:

To review the impact of agriculture interventions on nutritional status in participating households, and to analyse the characteristics of interventions that improved nutrition outcomes.

Design:

We identified and reviewed reports describing 30 agriculture interventions that measured impact on nutritional status. The interventions reviewed included home gardening, livestock, mixed garden and livestock, cash cropping, and irrigation. We examined the reports for the scientific quality of the research design and treatment of the data. We also assessed whether the projects invested in five types of ‘capital’ (physical, natural, financial, human and social) as defined in the Sustainable Livelihoods Framework, a conceptual map of major factors that affect people's livelihoods.

Results:

Most agriculture interventions increased food production, but did not necessarily improve nutrition or health within participating households. Nutrition was improved in 11 of 13 home gardening interventions, and in 11 of 17 other types of intervention. Of the 19 interventions that had a positive effect on nutrition, 14 of them invested in four or five types of capital in addition to the agriculture intervention. Of the nine interventions that had a negative or no effect on nutrition, only one invested in four or five types of capital.

Conclusions:

Those agriculture interventions that invested broadly in different types of capital were more likely to improve nutrition outcomes. Those projects which invested in human capital (especially nutrition education and consideration of gender issues), and other types of capital, had a greater likelihood of effecting positive nutritional change, but such investment is neither sufficient nor always necessary to effect change.
Are infant feeding options that are recommended for mothers with HIV acceptable, feasible, affordable, sustainable and safe? Pregnant women's perspectives
Authors: Manuela de Paoli Marina , Manongi Rachel , Klepp Knut-Inge
Published: July 2004

Objective:

To investigate pregnant women's views on infant feeding options recommended for HIV-infected women.

Design:

A structured interview survey complemented with focus group discussions.

Setting:

Antenatal clinics in Moshi urban and rural districts of Tanzania.

Subjects:

Five hundred pregnant women participated in the interview survey and 46 pregnant women participated in six focus group discussions.

Results:

Participating women reported that they would change to an alternative infant feeding method if they were found to be HIV-infected and were advised to do so. Cow's milk was regarded as the most feasible infant feeding method for local HIV-infected mothers. Infant feeding formula was regarded as too costly, but if recommended by health workers and distributed free of charge, the majority of the women (82%) were confident that they would then choose this option. In the focus group discussions, women were less optimistic and expressed great concern for the social consequences of not breast-feeding. The safety of exclusive breast-feeding was questioned. Less common infant feeding methods, such as expressed heat-treated breast milk and wet-nursing, were not regarded as viable options. Several social barriers to replacement feeding were identified in the focus group discussions, including possible lack of support from partner and potential negative reactions from the community.

Conclusion:

Future research on infant feeding options should include the broader cultural context and the psychological stress that HIV-infected women face when choosing infant feeding methods.
Are children able to distinguish among the concepts of aloneness, loneliness, and solitude?
Authors: Galanaki Evangelia
Published: July 2004

School-age children’s ability to distinguish among the concepts of aloneness, loneliness, and solitude was the focus of this study. This ability has been largely neglected by researchers. Also, the relation of this ability with self-reported loneliness was examined. Individual interviews were conducted with 180 second, fourth, and sixth graders from Athens, Greece. Their responses were qualitatively and quantitatively analysed. Results showed that school-age children were able to perceive the differences between aloneness and loneliness, although they frequently associated being alone with feeling lonely. Nearly half of them perceived the motivational dimension, which distinguishes voluntary from involuntary aloneness. The ability to recognise the existence of beneficial aloneness, that is, solitude, was extremely limited among second graders, but increased dramatically up to the beginning of adolescence. About two thirds of the total sample acknowledged the human desire to be alone. Girls were significantly more able than boys to perceive the differences between aloneness and loneliness, the motivational dimension, and the desire to be alone. More than two-thirds of the total sample had experienced loneliness, but this experience appeared to be unrelated to their understanding of the various aloneness concepts. Age and gender differences, as well as children’s various justifications of their responses, are discussed in the framework of the existing theoretical and research literature on children’s aloneness, loneliness, and solitude.
Controlling relationships in preschool children
Authors: Muñoz José Manuel , Braza Francisco , Carreras Rosario
Published: July 2004

In order to facilitate the comprehension of social structure in preschool children, our research has two foci: first, to define controlling behaviours (nonaggressive group organisation) and to determine their organisational principles, and second, to analyse the relation of the controlling behaviours with aggressive behaviours. Through direct observation, the behaviour of 90 preschoolers aged 4–5 years old during free playtime was registered. A correspondence analysis revealed that two organisational principles structure controlling relationships, one related to authority and another to acquiescence. The independence of these two dimensions suggests the existence of a social hierarchy in preschoolers’ playgroups based on controlling behaviour. No significant relation between authoritative and aggressive behaviours in 4-year-old children was detected, while 5-year-old children with high levels of authoritative behaviour were less aggressive than individuals with low levels. Our results point out that controlling activity is relevant in the organisation of preschool children’s social groups. Children’s goal development probably determines the change of the behavioural strategies that facilitate the evolution of social structure from aggressive to controlling hierarchies. We judge it necessary for research to focus on controlling interactions.
Internalising and externalising problems in middle childhood: A study of Indian (ethnic minority) and English (ethnic majority) children living in Britain
Authors: Atzaba-Poria Naama , Pike Alison , Barrett Martyn
Published: July 2004

The psychological adjustment of ethnic minority children has received little research attention, particularly in Britain. The present study set out to investigate the adjustment of Indian children living in Britain as well as the adjustment of their English peers. The sample consisted of 125 children (66 Indian and 59 English) between the ages of 7 and 9 years ( M = 8.51, SD = 0.62) and their parents and teachers. Mothers, fathers, and teachers reported about the children’s problem behaviour, and parents also reported on their acculturation strategy and use of their Indian language. Analyses revealed that overall Indian children seem to be well adjusted in Britain. Nevertheless, according to parental reports, they exhibited more internalising problems than did their English peers. No significant differences, however, were found for externalising or total problem behaviour. Furthermore, within the Indian group, it was found that children whose mothers and fathers were more traditional in their acculturation style displayed lower levels of externalising, internalising and total problem behaviour, according to their teachers. In addition, children whose mothers and fathers utilised their Indian language to a greater extent displayed lower levels of externalising and total problem behaviour (teachers’ reports). These findings highlight the importance of examining the adjustment of ethnic minority children in multiple contexts.
Metaethical cognition and epistemic reasoning development in adolescence
Authors: Krettenauer Tobias
Published: July 2004

The present study investigates whether epistemic cognition in moral domain (dubbed metaethical cognition) develops analogously to epistemic reasoning regarding empirical knowledge. The study’s conceptual framework distinguishes two main areas of metaethical cognition (beliefs about the nature of moral judgments and conceptions of the process of moral judgment formation), and three metaethical stances (intuitionism, subjectivism, and transsubjectivism). In a sample of 200 adolescents ( M 1/4 16.18 years, SD 1/4 2.41), these metaethical stances could be reliably identified by means of a semistructured interview procedure. Adolescents’ metaethical stance was related to age, cross-sectionally as well as longitudinally. Furthermore, significant differences in metaethical cognition were found between high school students and an expert group of university students with special training in moral philosophy. Overall, metaethical and epistemic stances were correlated substantially. Findings demonstrate that metaethical reasoning development is a structural analogue of epistemic development regarding factual knowledge. Implications for studies on moral development and for research addressing the domain specificity of epistemic reasoning development are discussed.
Peroxisome Proliferators and Receptor-Mediated Hepatic Carcinogenesis
Authors: Cattley Russell C.
Published: July 2004

The peroxisome proliferators represent an important group of hepatic carcinogens in rodents that act via the nuclear receptor PPARα. The primary role of PPARα in mediating this response had led to the further characterization of potential events downstream that likely enable the carcinogenic response, including increased peroxisomal fatty acid beta oxidation and the modulation of hepatocellular replication and death, either generally or in preneoplastic lesions. A cooperative role of Kupffer cell activation has been proposed to function in the modulation of hepatocellular proliferation in rodent liver by peroxisome proliferators, but data that confirm or refute this proposal are mixed. Presently there is no evidence that links the Kupffer cell activation by peroxisome proliferators directly to the development of liver tumors. There are marked species differences in susceptibility to peroxisomal proliferation, and active investigation concerning the molecular basis of these differences continues.
Microvesicular Steatosis Induced by a Short Chain Fatty Acid: Effects on Mitochondrial Function and Correlation with Gene Expression
Authors: Jolly Robert A. , Ciurlionis Rita , Morfitt David , Helgren Mary , Patterson Reid , Ulrich Roger G. , Waring Jeffrey F.
Published: July 2004

Hepatotoxicity characterized by microvesicular steatosis (MVS) is characterized by an abnormal accumulation of numerous small cytoplasmic lipid droplets in hepatocytes. Fulminant or progressive cases of microvesicular steatosis may lead to liver failure and death. Experimentally, short-chain carboxylic acids are known to induce microvesicular steatosis. The identification of gene changes that correlate with MVS concomitant with biochemical and histological indices could provide a better understanding of how this toxicity occurs as well as biomarkers that could be used to avoid this toxicity in the future. Sprague—Dawley rats were dosed days with cyclopropane carboxylic acid (CPCA) a short-chain fatty acid that can induce microvesicular steatosis, and with butyrate, a short chain fatty acid that served as a negative control. CPCA initiated microvesicular steatosis while butyrate did not. In addition, CPCA inhibited beta-oxidation in a concentration-dependent manner in vitro and caused a reduction in mitochondrial respiration ex vivo; no inhibition was evident with butyrate. Microarray results showed that gene expression changes with CPCA resulted in regulation of genes involved in beta-oxidation, as well as other genes associated with mitochondrial function. Overall, these results support altered hepatic mitochondrial function as a mechanism of the toxicity induced by a short-chain fatty acid and may provide potential biomarkers for this toxicity.
Mechanism of Benzene-Induced Hematotoxicity and Leukemogenicity: Current Review with Implication of Microarray Analyses
Authors: Hirabayashi Yoko , Yoon Byung-Il , Li Guang-Xun , Kanno Jun , Inoue Tohru
Published: July 2004

Benzene is a potent human leukemogen but the mechanism underlying benzene-induced leukemia remains an enigma due to a number of questions regarding the requirement of extraordinarily long exposure, a relatively low incidence of leukemia for genotoxicity of metabolites and a narrow dose range for leukemogenicity over marrow aplasia (overdoses tend to result in marrow aplasia). Moreover, there were previous controversies as to whether the cell cycle is upregulated or suppressed by the benzene exposure. Subsequently, it was found that the cell cycle is suppressed, but how leukemia develops under such suppression of hemopoiesis remains to be clarified. These questions were fortunately resolved with much effort. Benzene exposure was found to induce the expression of p21, an interlocking counterdevice for cell cycle: due to p53 upregulation, thereby inducing the immediate suppression of the kinetics of hemopoietic progenitors followed by the prominent suppression of hemopoiesis. Intermittent benzene exposure (i.e., cessation of exposure during weekends, for example) allowed an immediate recovery from marrow suppression after terminating exposure, which induced continuous oscillatory changes in marrow hemopoiesis. Benzene-induced leukemia was chiefly due to such an oscillatory change in hemopoiesis, which epigenetically developed leukemia more than 1 year later. The mechanisms of benzene-induced leukemogenicity seem to differ between wild-type mice and mice lacking p53. For p53 knockout mice, DNA damage such as weak mutagenicity or chromosomal damage was retained, and such damage induced consequent activation of proto-oncogenes and related genes, which led cells to undergo further neoplastic changes. In contrast, for wild-type mice carrying the p53 gene, a marked oscillatory change in the cell cycle of the stem cell compartment seems to be important. Compatible and discriminative gene expression profiling between the p53 knockout mice and wild-type mice was observed after benzene exposure by microarray analyses.
Digital Microscopy Imaging and New Approaches in Toxicologic Pathology
Authors: Mccullough Bruce , Xiaoyou Ying  , Monticello Thomas , Bonnefoi Marc
Published: July 2004

Digital microscopy, a comprehensive integration of digital imaging and light microscopy, can assist the pathologist to observe, acquire, record, share, analyze, and manage pathology image data. To lead the activity for establishing new generation digital microscopy capacity, novel concepts and strategies of digital pathology information flow and digital pathology platform were designed to integrate personal digital pathology microscopy workstations and other pathology imaging modalities with centralized data storage/management. In addition, a strategy for Web-enabled interactive telepathology that would permit global capacity was designed. A novel concept of high content pathology was also created to develop an automated tissue microscopy imaging and screening approach. These new concepts, strategies, and approaches guided the development and implementation of a digital pathology platform, a telepathology platform, and automated tissue slide imaging capacity. Digital microscopy photography is now able to replace photographic film in toxicologic pathology. Digital pathology and telepathology platforms can provide a networked environment for multisite, global team participation. Our practice also ascertained the central value of digital microscopy which can provide innovative quantitative pathology information and data mining capability with various imaging biomarkers via advanced digital image processing and pathology informatics; these are now the focus of ongoing development.
Chemical-Induced Nephropathy: A Review of the Renal Tubulointerstitial Lesions in Humans
Authors: Silva Fred G.
Published: July 2004

It is almost ironic that one of the major organs that serves to maintain the “internal milieux” by secretion of various toxic agents, can itself become injured in the process. The pattern of morphologic renal injury is nonspecific and can involve any of the components of the kidney, although the injury and subsequent morphologic changes are most commonly noted in the tubules and/or interstitium. Of course, unless the drug/toxin is commonly or regularly noted to be associated with tubular and/or interstitial injury, the association of the drug with the renal changes may be missed and the correlation may not necessarily identify causation. For example, if a drug is associated with a renal injury in a given individual, it may be quite difficult to prove that the drug is the cause of the injury. This scenario is somewhat reminiscent of the test question—is it “true-true-related,” or “true-true-unrelated”? Sometimes it is only by the accrual of a great many examples or correlations, and or dissection of the pathophysiology, can it be shown that the drug is directly related to the observed morphologic (and subsequent clinical) injury. Renal changes induced by chemicals can affect the tubules, interstitium or both. This review of chemically induced nephropathy in humans considers acute tubular necrosis, interstitial nephritis , and tubulointerstitial nephritis or nephropathy. Because the tubules and the interstitium are so intimately related, injury to 1 of these 2 components may eventually lead to injury of the other, resulting in tubulointerstitial disease.
Mechanisms of Hormone-Mediated Carcinogenesis of the Ovary
Authors: Capen Charles C.
Published: July 2004

Experimental ovarian carcinogenesis has been investigated in inbred and hybrid strains of mice and induced by a diversity of mechanisms including X-irradiation, oocytotoxic xenobiotic chemicals, ovarian grafting to ectopic or orthotopic sites, neonatal thymectomy, mutant genes reducing germ cell populations, and aging. Disruptions in the function of graafian follicles by a variety of mechanisms results in a spectrum of ovarian proliferative lesions, including tumors. The findings in mutant and genetically engineered mice support the concept of a secondary (hormonally mediated) mechanism of ovarian tumorigenesis in mice associated with sterility. Multiple pathogenic factors that either destroy or diminish the numbers of graafian follicles in the ovary result in decreased sex hormone secretion, especially estradiol-17 β, leading to a compensatory overproduction of pituitary gonadotrophins, particularly LH, which places the mouse ovary at an increased risk for developing tumors in chronic studies. The intense proliferation of ovarian surface epithelium and stromal (interstitial) cells with the development of unique tubular adenomas in response to sterility does not appear to have a counterpart in the ovaries of adult human females.
Toxicogenomic Approach to Endocrine Disrupters: Identification of a Transcript Profile Characteristic of Chemicals with Estrogenic Activity
Authors: Naciff Jorge M. , Daston George P.
Published: July 2004

Public concerns have been raised in recent years over the possible adverse effects that may result from exposure to chemicals in the environment that have the potential to interfere with the normal function of the endocrine system in wildlife and humans (“endocrine disrupters”). Regulations have been established that require the testing of pesticides used in food crops and drinking water contaminants, for estrogenicity and other hormonal activities. In the United States, the U.S. EPA proposed the Endocrine Disrupter Screening Program, which consists of a Tier 1 screening battery of tests that is designed to identify chemicals capable of interacting with various hormonal systems, and different Tier 2 testing assays that are designed to verify and broaden the Tier 1 results. We identify 2 main problems with this approach: (1) the fact that the developmental stages that are the most susceptible to endocrine disruption are not represented in the screening tier, mainly because developmental effects tend to be latent, and there is no way to economically screen in developing models; and (2) the expense to screen each chemical to be included in this program. Thus, the need arises for an accurate, rapid, and cost effective method for assessing the potential endocrine activity of multiple chemicals during development. We hypothesize that the largely latent developmental effects of some endocrine disruptors are preceded by immediate changes in gene expression in the embryo and fetus. Therefore, an approach to assess the potential estrogenic (and other steroid hormonal) activity of different compounds is to identify those patterns of gene expression elicited in a tissue/organ exposed to these particular classes of chemicals. In this paper, the potential utility of such an approach for screening and better understanding of mechanism of action for specific chemicals with endocrine disrupter activities is presented, using as an example chemicals with estrogenic activity.
CDER Photosafety Guidance for Industry
Authors: Jacobs Abigail C. , Brown Paul C. , Chen Conrad , Ellis Amy , Farrelly James , Osterberg Robert
Published: July 2004

In the Federal Register of January 10, 2000 (65 FR 1399), FDA published a draft guidance entitled “Photosafety Testing.” The notice gave interested persons an opportunity to submit comments. As a result of the comments, certain sections of the guidance were reworded to improve clarity. A final guidance was published in May 2003. The final guidance further emphasizes that a flexible approach can be used to address adverse photoeffects and that specific assays are not required. Moreover, it encourages the development of methods that can efficiently be used to evaluate human safety. The guidance describes a consistent, science-based approach for testing of topically and systemically administered drug products.
The MID3 Data Set, 1993—2001: Procedures, Coding Rules, and Description
Authors: Ghosn Faten , Palmer Glenn , Bremer Stuart A.
Published: July 2004

Dealing with questions of war and peace and understanding the causes of interstate conflict is a primary goal of the field of international relations. In order to study interstate conflict in a rigorous manner, scholars have relied on established rules and procedures for gathering information into coherent data sets. Among those data sets is the Militarized Interstate Dispute (MID) data. In this paper we first outline the data-collection process for the MID3 data. Second, we introduce two new data sets emerging from the project, “MID-I” and “MID-IP.” Third, we present relatively small changes in coding rules for the new MID3 data and some descriptive statistics. The statistics indicate that the MID3 data are remarkably similar to the MID2.1 version, varying in some minor and predictable ways.
Multiparty Disputes and the Probability of War, 1816—1992
Authors: Petersen Karen K. , Vasquez John A. , Yijia Wang
Published: July 2004

Previous theory and research have suggested that multiparty disputes might be significantly more likely to escalate to war than bilateral disputes, because of the difficulty of reaching a mutually acceptable agreement as the number of parties increases. This study presents a systematic test of this hypothesis. Efforts to provide such a test have been hampered by the absence of data that distinguish the number of participants in a militarized interstate dispute prior to the outbreak of war from the number of participants after the war breaks out. We find that multiparty disputes do have an increased probability to escalate to war. In addition, we find that the issue over which the disputants contend has an important effect on the probability that the dispute will escalate to war; multiparty disputes that are over territory have a higher probability of escalating to war than multiparty disputes in general. Lastly, it is found that the effects related to the number of parties in a dispute and to whether the dispute is over territory are independent, and one does not eliminate the effect of the other. In order to contribute to future scholarship on this topic, the data for the new classification scheme of multiparty disputes are published in the appendices.
Cdc2 Kinase-dependent Disassembly of Endoplasmic Reticulum (ER) Exit Sites Inhibits ER-to-Golgi Vesicular Transport during Mitosis
Authors: Kano Fumi , Tanaka Arowu R. , Yamauchi Shinobu , Kondo Hisao , Murata Masayuki
Published: July 2004

We observed the disassembly of endoplasmic reticulum (ER) exit sites (ERES) by confocal microscopy during mitosis in Chinese hamster ovary (CHO) cells by using Yip1A fused to green fluorescence protein (GFP) as a transmembrane marker of ERES. Photobleaching experiments revealed that Yip1A-GFP, which was restricted to the ERES during interphase, diffused throughout the ER network during mitosis. Next, we reconstituted mitotic disassembly of Yip1A-GFP–labeled ERES in streptolysin O-permeabilized CHO cells by using mitotic L5178Y cytosol. Using the ERES disassembly assay and the anterograde transport assay of GFP-tagged VSVGts045, we demonstrated that the phosphorylation of p47 by Cdc2 kinase regulates the disassembly of ERES and results in the specific inhibition of ER-to-Golgi transport during mitosis.
NrCAM Coupling to the Cytoskeleton Depends on Multiple Protein Domains and Partitioning into Lipid Rafts
Authors: Falk Julien , Thoumine Olivier , Dequidt Caroline , Choquet Daniel , Faivre-Sarrailh Catherine
Published: July 2004

NrCAM is a cell adhesion molecule of the L1 family that is implicated in the control of axonal growth. Adhesive contacts may promote advance of the growth cone by triggering the coupling of membrane receptors with the F-actin retrograde flow. We sought to understand the mechanisms leading to clutching the F-actin at the site of ligand-mediated clustering of NrCAM. Using optical tweezers and single particle tracking of beads coated with the ligand TAG-1, we analyzed the mobility of NrCAM-deletion mutants transfected in a neuroblastoma cell line. Deletion of the cytoplasmic tail did not prevent the coupling of NrCAM to the actin flow. An additional deletion of the FNIII domains to remove cis-interactions, was necessary to abolish the rearward movement of TAG-1 beads, which instead switched to a stationary behavior. Next, we showed that the actin-dependent retrograde movement of NrCAM required partitioning into lipid rafts as indicated by cholesterol depletion experiments using methyl-β-cyclodextrin. Recruitment of the raft component caveolin-1 was induced at the adhesive contact between the cell surface and TAG-1 beads, indicating that enlarged rafts were generated. Photobleaching experiments showed that the lateral mobility of NrCAM increased with raft dispersion in these contact areas, further suggesting that TAG-1–coated beads induced the coalescence of lipid rafts. In conclusion, we propose that anchoring of NrCAM with the retrograde actin flow can be triggered by adhesive contacts via cooperative processes including interactions with the cytoplasmic tail, formation of cis-complex via the FNIII repeats, and lipid raft aggregation.
Cell Context-specific Effects of the β-Tubulin Glycylation Domain on Assembly and Size of Microtubular Organelles
Authors: Thazhath Rupal , Jerka-Dziadosz Maria , Duan Jianming , Wloga Dorota , Gorovsky Martin A. , Frankel Joseph , Gaertig Jacek
Published: July 2004

Tubulin glycylation is a posttranslational modification found in cells with cilia or flagella. The ciliate Tetrahymena has glycylation on ciliary and cortical microtubules. We showed previously that mutating three glycylation sites on β-tubulin produces immotile 9 + 0 axonemes and inhibits cytokinesis. Here, we use an inducible glycylation domain mutation and epitope tagging to evaluate the potential of glycylation-deficient tubulin for assembly and maintenance of microtubular systems. In axonemes, the major defects, including lack of the central pair, occurred during assembly, and newly made cilia were abnormally short. The glycylation domain also was required for maintenance of the length of already assembled cilia. In contrast to the aberrant assembly of cilia, several types of cortical organelles showed an abnormally high number of microtubules in the same mutant cells. Thus, the consequences of deficiency in tubulin glycylation are organelle type specific and lead to either insufficient assembly (cilia) or excessive assembly (basal bodies and cortical microtubules). We suggest that the diverse functions of the β-tubulin glycylation domain are executed by spatially restricted microtubule-associated proteins.
Insulin Stimulation of GLUT4 Exocytosis, but Not Its Inhibition of Endocytosis, Is Dependent on RabGAP AS160
Authors: Zeigerer Anja , McBrayer Mary Kate , McGraw Timothy E.
Published: July 2004

Insulin maintains whole body blood glucose homeostasis, in part, by regulating the amount of the GLUT4 glucose transporter on the cell surface of fat and muscle cells. Insulin induces the redistribution of GLUT4 from intracellular compartments to the plasma membrane, by stimulating a large increase in exocytosis and a smaller inhibition of endocytosis. A considerable amount is known about the molecular events of insulin signaling and the complex itinerary of GLUT4 trafficking, but less is known about how insulin signaling is transmitted to GLUT4 trafficking. Here, we show that the AS160 RabGAP, a substrate of Akt, is required for insulin stimulation of GLUT4 exocytosis. A dominant-inhibitory mutant of AS160 blocks insulin stimulation of exocytosis at a step before the fusion of GLUT4-containing vesicles with the plasma membrane. This mutant, however, does not block insulin-induced inhibition of GLUT4 endocytosis. These data support a model in which insulin signaling to the exocytosis machinery (AS160 dependent) is distinct from its signaling to the internalization machinery (AS160 independent).
Water? What's so special about it?
Authors: Finney John L.
Published: July 2004

What
is
so special about water? Why does it have the properties it has, and how might these reasons be relevant to its apparent biological importance? By exploring the structure and dynamics of water, from the isolated molecule and its interactions, through its many crystalline phases and to its so–called anomalous liquid phase, some of its apparently unusual behaviour is rationalized. The way in which it interacts with some relatively simple interfaces is also discussed. As a result of this exploration, a checklist of possible molecular–level reasons for its biological importance is devised.
Characteristics of nearly dry enzymes in organic solvents: implications for biocatalysis in the absence of water
Authors: Clark Douglas S.
Published: July 2004

We have examined enzymes in nearly anhydrous organic solvents spanning a wide range of dielectric constants using a combination of electron paramagnetic resonance (EPR) spectroscopy, molecular dynamics simulations, high–pressure kinetic studies and the electrostatic model of Kirkwood. This approach enabled us to investigate the relationship between catalytic activity, protein flexibility and solvent polarity for an enzymatic reaction proceeding through a highly polar transition state in the near absence of water. Further insights into water–protein interactions and the involvement of water in enzyme structure and function have been obtained by EPR and multinuclear nuclear magnetic resonance studies of enzymes suspended and immobilized in organic solvents with and without added water. In these systems, correlations were observed between the water content and enzyme activity, flexibility, and active–site polarity, although the structural properties of suspended and immobilized enzymes differed markedly. These results have helped to elucidate the role of water in molecular events at the enzymic active site leading to improved biocatalysis in low–water environments.