Toxicology and genetic toxicology in the new era of "toxicogenomics": impact of "-omics" technologies.

The unprecedented advances in molecular biology during the last two decades have resulted in a dramatic increase in knowledge about gene structure and function, an immense database of genetic sequence information, and an impressive set of efficient new technologies for monitoring genetic sequences, genetic variation, and global functional gene expression. These advances have led to a new sub-discipline of toxicology: "toxicogenomics". We define toxicogenomics as "the study of the relationship between the structure and activity of the genome (the cellular complement of genes) and the adverse biological effects of exogenous agents". This broad definition encompasses most of the variations in the current usage of this term, and in its broadest sense includes studies of the cellular products controlled by the genome (messenger RNAs, proteins, metabolites, etc.). The new "global" methods of measuring families of cellular molecules, such as RNA, proteins, and intermediary metabolites have been termed "-omic" technologies, based on their ability to characterize all, or most, members of a family of molecules in a single analysis. With these new tools, we can now obtain complete assessments of the functional activity of biochemical pathways, and of the structural genetic (sequence) differences among individuals and species, that were previously unattainable. These powerful new methods of high-throughput and multi-endpoint analysis include gene expression arrays that will soon permit the simultaneous measurement of the expression of all human genes on a single "chip". Likewise, there are powerful new methods for protein analysis (proteomics: the study of the complement of proteins in the cell) and for analysis of cellular small molecules (metabonomics: the study of the cellular metabolites formed and degraded under genetic control). This will likely be extended in the near future to other important classes of biomolecules such as lipids, carbohydrates, etc. These assays provide a general capability for global assessment of many classes of cellular molecules, providing new approaches to assessing functional cellular alterations. These new methods have already facilitated significant advances in our understanding of the molecular responses to cell and tissue damage, and of perturbations in functional cellular systems.As a result of this rapidly changing scientific environment, regulatory and industrial toxicology practice is poised to undergo dramatic change during the next decade. These advances present exciting opportunities for improved methods of identifying and evaluating potential human and environmental toxicants, and of monitoring the effects of exposures to these toxicants. These advances also present distinct challenges. For example, the significance of specific changes and the performance characteristics of new methods must be fully understood to avoid misinterpretation of data that could lead to inappropriate conclusions about the toxicity of a chemical or a mechanism of action. We discuss the likely impact of these advances on the fields of general and genetic toxicology, and risk assessment. We anticipate that these new technologies will (1) lead to new families of biomarkers that permit characterization and efficient monitoring of cellular perturbations, (2) provide an increased understanding of the influence of genetic variation on toxicological outcomes, and (3) allow definition of environmental causes of genetic alterations and their relationship to human disease. The broad application of these new approaches will likely erase the current distinctions among the fields of toxicology, pathology, genetic toxicology, and molecular genetics. Instead, a new integrated approach will likely emerge that involves a comprehensive understanding of genetic control of cellular functions, and of cellular responses to alterations in normal molecular structure and function.     

"Mixing" as an ethnoetiology of HIV/AIDS in Malaysia's multinational factories

Minah Karan, the stigmatizing label appended to Malay factory women in the 1980s, signaled a dangerous female sexuality that risked spreading beyond the factory gates and infecting Malaysia's idea(l)s of its traditional kampung culture. This article narrates how Minah Karan, as the former antihero of development, was reconstituted in the 1990s, with the government's labeling of factories as "high-risk settings" for HIV/AIDS. This is an ethnoetiology based not on any evidential epidemiological data but on the racial and gendered "mixing" that transpires behind factory walls: a fear that the "mixing of the sexes" means ipso facto "sexual mixing" among the races. The article demonstrates how importation of the high-risk label articulates at the local level the new and contested linkages, economic, religious, and scientific, constitutive of globalization. The pragmatic nature and imperatives of this high-risk process are discerned in factory women's accounts of how they negotiate the interactional imperatives of factory work, because transnational structures of productivity violate the social boundaries that have long connoted political stability, moral integrity, ethnic community, and individual safety. The article concludes by questioning whether ethnoetiologies, especially when they concern sexual networks, become social etiologies, because this would locate ethnoetiologies as central to conventional public health praxis rather than as ethnographic exotica in the margins.     

"Florigen ": an intriguing concept of plant biology.

"Florigen" is the name that Mikhail Chailakhyan coined in 1937 for the putative hormone regulating flowering. At this concept, plant physiologists arrived following early research concerning the effects of temperature and day length on the transition from vegetative to reproductive stages of plants. The existence of florigen was postulated on the experimental backgrounds involving i) the response of plants to inductive conditions; ii) transmission of a flowering stimulus by grafting; iii) extraction of this stimulus from induced plants. This experimental results showed the existence of florigen at least as concept because they always failed to offer the experimental evidence of its chemical existence. The myth of florigen persisted as long as the end of the Seventies, when physiologists began to consider flowering as a complex process in which various classes of hormones might variously interplay.     

There is a difference between scientific hypothesis and the "phylogenetic presumption" by Rasnitsyn (concerning the paper by I.Ia. Pavlinov, 2005. J. Gen. Biology. V. 66. No 5)

The arguments by Pavlinov against my critical analysis of the concept of the "phylogenetic presumptions" proposed by Rasnitsyn are briefly discussed. It is proved that these arguments are invalid because they are based on the substitution of terms. Instead of the term "phylogenetic presumption" introduced by Rasnitsyn just as an analogue of the presumption of innocence in jurisprudence, Pavlinov considers the presumption in the wider understanding, i.e. as a "preliminary statement".     

Situational Designations in "Glossoethnographic" Perspective

Soviet and foreign linguists and educators continually stress the importance of studying a foreign language within its cultural context. Accordingly, a new field of applied linguistics has emerged, at the borderline between linguistics and foreign language instruction, that we have termed "glossoethnography" [see 1, 2, 4, 61. This new area of linguistics has not yet sufficiently delimited i t s subject matter: it abuts on other areas that are also relatively new and as yet ill defined, such as sociolinguistics, ethnolinguistics, linguistic anthropology, linguistic typology (for the various definitions of these disciplines, see reference 7). The many interesting examples adduced in studies in this new area all deal with specific national features of linguistic means of expression (sometimes in combination with paralinguistic means). However, these specific features exist on different levels: there are the specific features of the real objects expressed in language, and then there are those of the linguistic forms themselves, which are independent of the properties of the real objects to which they refer.     

Telomeres and double-strand breaks - all's well that "ends" well. ..

Bailey, S. Telomeres and Double-Strand Breaks - All's Well that "Ends" Well. ... Radiat. Res. 169, 1-7 (2008). Sometimes one's life (including one's science) makes a lot more sense when viewed from the perspective of time, reflected back on over a number of years. That has indeed been the case for me. Strangely enough, the story begins with chromosomes and "ends" with telomeres, both at Colorado State University. And, just as with chromosomes, a lot happened in between. Telomeres were first identified based on their function-they protected the physical ends of chromosomes from interaction with broken DNA ends created by ionizing radiation. While I was at Los Alamos National Laboratory, the sequence of human telomeres was discovered, making probes available that allowed us to re-examine and provide direct support of these early observations; thus began my fascination with telomeres. Chromosome orientation in situ hybridization (CO-FISH) also came onto the scene while I was in Los Alamos. This strand-specific modification of standard FISH, especially when combined with telomeric sequence probes, has proven to be a powerful approach that provides information not available by any other means. Applications have included pericentric inversion detection, distinction between leading- and lagging-strand telomeres, and identification of telomere-double-strand break (DSB) fusions. We also provided the first direct evidence that DSB repair proteins (DNA-PK in particular) are required for mammalian telomeric end capping, and we have been characterizing telomere dysfunction in NHEJ and HR repair-deficient backgrounds ever since. Cells must correctly distinguish between DNA ends represented by telomeres and DNA ends produced by DSBs if all is to end well. Just as these studies have provided new insight into the complex, often surprising, interactions at DNA ends, they also provoke new questions. Whereas it is now well established that DSB repair proteins associate with telomeres, most recently we've been asking whether the reverse scenario holds: Do telomere proteins interact with DSBs? We find that DSBs induced by ionizing radiations are not sufficient to recruit the essential telomere protein TRF2 as an early damage response, so perhaps this interplay is a one-way street. The rest of the story waits to unfold.     

One hospital's experience with a "Do not resuscitate" policy.

A "No not resuscitate" policy was instituted at McMaster University Medical Centre, Hamilton, in January 1979. Its objectives were to ensure that physicians decide on the appropriateness of resuscitation attempts before they might be needed; to have each physician consult his or her patients, or the families of incompetent patients, to determine their wishes concerning further treatment; and to provide legal protection of or physicians and the hospital in regard to the policy. To determine the effectiveness of the "Do not resuscitate" policy a questionnaire was sent to a sample of the professional staff of the hospital; the overall response rate was 87%. The respondents felt that a better way of informing hospital staff of the policy and its objectives was needed. However, the results of the questionnaire suggested that, on the whole, the policy was perceived as beneficial to both patients and physicians at the hospital.     

Coding repeats and evolutionary "agility"

The rapid generation of new shapes observed in the living world is the result of genetic variation, especially in "morphological" developmental genes. Many of these genes contain coding tandem repeats. Fondon and Garner have shown that expansions and contractions of these repeats are associated with the great diversity of morphologies observed in the domestic dog, Canis familiaris. In particular, they found that the repeat variations in two genes were significantly associated with changes in limb and skull morphology. These results open the possibility that such a mechanism contributes to the diversity of life.     

Effect of aldehydes on polyamine metabolism. I. Method used to determine CO2 produced "in vitro" in enzymatic reactions: its application in evaluation of S-adenosylmethionine decarboxylase (SAMD) activity

In this paper the Authors describe a new method they have adopted (in studies reported in accompanying papers II and III) for measuring S-adenosylmethionine decarboxylase activity in entire cells and cell fractions. The new method is a general one for recovering and measuring labelled carbon dioxide formed "in vitro" during enzymatic reactions. It presents several advantages when compared to traditional methods.     

Human cold agglutinins against "cryptic" erythrocyte antigens.

Two examples of human IgM cold agglutinins agglutinated human RBC only after enzyme treatment in vitro. Proteases were optimally effective, neuraminidase was also effective. The cold agglutinins did not coat native RBC but were directed against "cryptic" RBC determinants. The cold agglutinins belonged to the anti -I/-i complex indicating a "new" type of I/i determinants. They were strongly accessible to cold agglutinin interaction on native RBC of a patient with congenital dyserythropoietic anaemia. Enzyme treatment of RBC was shown to be not only suited for defining cold agglutinin specificities but also essential for detecting the "new" type of cold agglutinins, obviously causing autoimmune haemolytic anaemia in vivo.     

Reconciling the "old" and "new" views of protein allostery: a molecular simulation study of chemotaxis Y protein (CheY)

A combination of thirty-two 10-ns-scale molecular dynamics simulations were used to explore the coupling between conformational transition and phosphorylation in the bacteria chemotaxis Y protein (CheY), as a simple but representative example of protein allostery. Results from these simulations support an activation mechanism in which the beta4-alpha4 loop, at least partially, gates the isomerization of Tyr106. The roles of phosphorylation and the conserved Thr87 are deemed indirect in that they stabilize the active configuration of the beta4-alpha4 loop. The indirect role of the activation event (phosphorylation) and/or conserved residues in stabilizing, rather than causing, specific conformational transition is likely a feature in many signaling systems. The current analysis of CheY also helps to make clear that neither the "old" (induced fit) nor the "new" (population shift) views for protein allostery are complete, because they emphasize the kinetic (mechanistic) and thermodynamic aspects of allosteric transitions, respectively. In this regard, an issue that warrants further analysis concerns the interplay of concerted collective motion and sequential local structural changes in modulating cooperativity between distant sites in biomolecules.     

In the shadow of "death with dignity": medicine and cultural quandaries of the vegetative state

In this paper I address one site of technological development and cultural production, the permanent or persistent comatose condition and the institutions and practices that enable this life form to exist. As with other medical sites of ambiguity and change under recent scrutiny by anthropologists, the locations in which comatose bodies thrive are those in which the routinization of technology use in the clinic and a legitimating social and economic context come together to permit and create a further remapping of the notions of "life" and "person." I explore the new forms of knowledge, practice, and the body that are created at this site and how they are negotiated, and I discuss how the shifting understanding of "'culture" and "nature" both have an impact on and are informed by American quandaries about approaching death. I argue that beings who are neither fully alive, biologically dead, nor "naturally" self-regulating, yet who are sustained by modern medical practices, destabilize the existing social order in ways that are different from other hybrid forms, [medical anthropology, anthropology of the body, bioethics, personhood, culture/nature dichotomy]     

Prolines are not essential residues in the "barrel-stave" model for ion channels induced by alamethicin analogues.

In the "barrel-stave" model for voltage-gated alamethicin channels in planar lipid bilayers, proline residues, especially Pro14, are assumed to play a significant role. Taking advantage of a previous synthetic alamethicin analogue in which all eight alpha-aminoisobutyric acids were replaced by leucines, two new analogues were prepared in order to test the effects of Pro14 and Pro2 substitutions by alanines. The alpha-helical content of the three analogues in methanol solution remains predominant (between 63 and 80%). Macroscopic conductance experiments show that a high voltage dependence is conserved, although the apparent mean number of monomers forming the channels is significantly reduced when the substitution occurs at position 14. This is confirmed in single-channel experiments which further reveal faster fluctuations for the modified analogues. These results demonstrate that, although prolines, especially Pro14, are favorable residues for alamethicin-like events, they are not absolute prerequisites for the development of highly voltage-dependent multistate conductances.     

CULTURE OF HUMAN GENITAL "T-STRAIN" PLEUROPNEUMONIA-LIKE ORGANISMS.

Ford, Denys K. (University of British Columbia, Vancouver, Canada). Culture of human genital "T-strain" pleuropneumonia-like organisms. J. Bacteriol. 84:1028-1034. 1962.-The conditions under which "T-strain" pleuropneumonia-like organisms, as described by Shepard, are best cultured were investigated. The organisms were found to grow on several types of nutrient agar and broth, of which PPLO medium supplemented with yeast extract and horse serum was the simplest. Subculture was possible through broth cultures, provided the broths were not incubated longer than 16 hr. The organisms on agar required either Fortner's anaerobic atmosphere or 10% CO(2), but broth cultures grew aerobically. "T-strains" grew over a pH range of 6.8 to 7.8, and a temperature range of 30 to 36 C. They were viable after storage for 16 days at 4 C and for 90 days at -20 C, and they resisted lyophilization. They were sensitive to 1.5 mug per ml of tetracycline and streptomycin, but were resistant to ampicillin and penicillin. Quantitative studies showed maximal concentration in broth of 10(6) to 10(7) organisms per ml, and logarithmic multiplication for the first 12 hr of broth culture, with a subsequent rapid decline in number. Colonial morphology was maintained after numerous subcultures.     

Chemesthesis and the chemical senses as components of a "chemofensor complex"

An important function of the chemical senses is to warn against dangerous biological and chemical agents in the environment. The discovery in recent years of "taste" receptor cells outside the oral cavity that appear to have protective functions has raised new questions about the nature and scope of the chemical senses in general and of chemesthesis in particular. The present paper briefly reviews these findings within the context of what is currently known about the body's chemically sensitive protective mechanisms, including nonsensory processes that help to expel or neutralize threatening agents once they have been encountered. It is proposed that this array of defense mechanisms constitutes a "chemofensor complex" in which chemesthesis is the most ubiquitous, functionally diverse, and interactive chemosensory component.     

"New chronic" patients.

A five-year follow-up of 1467 mental hospital patients showed that 501 had died, 449 had been discharged, and 517 were still resident. During this period 81 "new chronic" patients aged under 65 were admitted: 49 were readmissions and 15 of 32 first admissions had had previous periods in other psychiatric hospitals. Many new chronic patients were old chronic with intervals of community care, and one-third of them were likely to require permanent care. These findings provide no comfort for those who believe that present DHSS plans for mental health services can ever be realised.     

Evidence against the presence of "inhibitors" in coumarin treated patients.

Coumarin drugs or vitamin K absence cause a decrease of factor II, VII, IX and X activities and the appearance of pre-factors into the circulation. Such pre-factors have been postulated to inhibit thrombin conversion. The current of research on the alleged activity of such "inhibitors" is taken into consideration. Thrombotest discrepancy, mixing experiments etc.) speak against the inhibitor theory. So far the only sure demonstration of the presence of coumarin induced pre-factors has been obtained by immunological means. However, this does not say anything about their biological activity. These pre-factors could well be "inert" as far as clotting is concerned. Until new, unequivocal data on the subject will be available, any method or technique claiming to be able to detect or monitor the "inhibitory" effect should be accepted with extreme caution. Too many unjustified views have been put forward in recent years.     

Novel chloroplasts and unusual cellular ultrastructure in the "resurrection" plant Myrothamnus flabellifolia Welw. (Myrothamnaceae)

The vacuoles of three "resurrection" plants, Myrothamnus flabellifolia, Anastatica hierochuntica and Selaginella dregei were found to contain large quantities of osmiophilic material which may be part of the "resurrection" mechanism. Myrothamnus differed from the others by having mitochondria, and possibly plastids, which are separated from the remainder of the cytoplasm by sheaths or membranes during desiccation. Upon "resurrection" these barriers appear to be perforated and explain in part the faster rate of "resurrection" in Myrothamnus than in other "resurrection" plants. The chloroplasts of Myrothamnus are remarkable in that they possess "staircase" granum stacks of a type not previously described in any other plant tissue.     

The central image makes "big" dreams big: The central image as the emotional heart of the dream.

"Big dreams" are hard to define. This paper considers "big" dreams under several more easily definable subcategories: memorable dreams; important dreams (labeled by dreamer); significant dreams; and impactful dreams. Past studies are reviewed, and five new preliminary studies are presented showing that a powerful Central Image (CI) distinguishes "big" dreams in all subcategories. 1) Dreams labeled "important" by the dreamer have higher CI intensity than dreams labeled "unimportant." 2) Dreams labeled "especially significant" have especially high CI intensity. 3) Impactful dreams (leading to a new discovery) have a very high CI intensity. 4) The dreams of people who score very "thin" on the Boundary Questionnaire (BQ)--sometimes called "dream-people"--have higher CI intensity than the dreams of people who score "thick." 5) In a separate, larger group, there is a significant positive correlation between CI intensity and "thinness." It appears that CI intensity is an important measure of the "bigness" of dreams. The present results are consistent with the Contemporary Theory of Dreaming which states that dreams involve making connections guided by emotion, that the Ci of the dream pictures the emotion, and that CI intensity measures the power of the underlying emotion. "Big" dreams are dreams with great emotional power and have powerful Central Images. (PsycINFO Database Record (c) 2010 APA, all rights reserved)