Novel approaches to the treatment of small-cell lung cancer

Small-cell lung cancer (SCLC) is characterized by its initial responsiveness to chemotherapy and the appearance of early metastases. Although combination chemotherapy, in some instances together with radiation, has improved the prognosis of this disease, in most patients SCLC ultimately recurs in a drug-resistant form. Several new strategies for the eradication of SCLC are being explored at the preclinical level. The identification of selective target molecules on the surface of SCLC cells, together with the progress made in antibody engineering, have provided new generations of antibodies and immunoconjugates as well as growth factor antagonists and inhibitors. In addition, recent advances in understanding the biology of SCLC have stimulated new investigations searching to counter the molecular basis underlying the increased proliferation and the apoptosis deficiency of SCLC cells. This can be achieved using antisense oligodeoxynucleotides that repress the expression of growth factor receptors and anti-apoptosis genes, or by gene replacement to compensate for the loss or inactivation of tumor suppressor genes.     

Technoscientific approaches to deep time

In this paper, I argue that in order to understand the process behind the knowledge production in the historical sciences, we should change our theoretical focus slightly to consider the historical sciences as technoscientific disciplines. If we investigate the intertwinement of technology and theory, we can provide new insights into historical scientific knowledge production, preconditions, and aims. I will provide evidence for my claim by showing the central features of paleontological and paleobiological data practices of the nineteenth and twentieth centuries. In order to work with something that is imperfect and incomplete (the fossil record), paleontologists used different technological devices. These devices process, extract, correct, simulate, and eventually present paleontological explananda. Therefore, the appearance of anatomical features of non-manipulable fossilized organisms, phenomena such as mass-extinctions, or the life-like display of extinct specimens in a museum's hall, depend both on the correct use of technological devices and on the interplay between these devices and theories. Consequently, in order to capture its underlying epistemology, historical sciences should be analyzed and investigated against other technoscientific disciplines such as chemistry, synthetic biology, and nanotechnology, and not necessarily only against classical experimental sciences. This approach will help us understand how historical scientists can obtain their epistemic access to deep time.     

Newer data on the role of complement system in toxicity of endotoxin

Résumé L'effet d'une dose létale d'endotoxine, qui abaisse in vivo le taux du C3 du rat ne se manifeste pas chez les rats rendus tolérants à cette substance.     

Chemical approaches to intermediates of enzyme catalysis

Zusammenfassung Die Untersuchung von Enzymsubstratkomplexen auf katalyse-induzierte Änderungen der chemischen Reaktivität hat sich als ein aufschlussreicher experimenteller Zugang zum Mechanismus enzymatischer Reaktionen erwiesen. Ternäre Systeme bestehend aus Enzym, Substrat und einem geeigneten Reagens (Tetranitromethan=TNM) sind auf katalyse-abhängige Reaktionen geprüft worden, die nur im vollständigen System, jedoch nicht mit Reagens und Enzym allein oder Reagens und Substrat allein beobachtet werden. Untersuchungen mit Aldolasen und Aspartat-Aminotransferase haben ergeben, dass katalyseinduzierte Reaktivität sowohl auf dem Substrat-als auch auf dem Enzymteil eines Enzym-Substratkomplexes nachgewiesen werden kann.Im Reaktionsmechanismus von Muskelaldolase (eine Lysinaldolase) und von Hefealdolase (eine Metallaldolase) lässt sich mit TNM ein intermediäres Carbanion des Substrats nachweisen. Die TNM-carbanion-Reaktion lässt sich spektralphotometrisch verfolgen und ist benutzt worden, um carboxypeptidase-behandelte Muskelaldolase und den Effekt von Cofaktoren auf die Hefealdolase zu untersuchen.Katalyse-induzierte Reaktivitätsveränderungen einer Enzymseitenkette sind bei der Aspartat-Aminotransferase beobachtet worden. Ein essentieller Tyrosylrest, der in der Abwesenheit von Substrat nicht mit TNM reagiert, wird ungewöhnlich reaktiv im Laufe der Katalyse und ermöglicht dabei seine selektive Nitrierung.Die katalyse-synchrone oder synkatalytische Aktivierung dieses Aminosäurerests scheint ein integraler Bestandteil des katalytischen Mechanismus von Aspartat-Aminotransferase zu sein und wird vermutlich durch katalyse-induzierte Konformationsänderungen des Enzym-Coenzym-Substratkomplexes hervorgebracht. Mögliche funktioneile Zusammenhänge synkatalytischer Reaktivitätsänderungen funktioneller Gruppen mit der Konformationsflexibilität des Enzymproteins und dem Vorkommen metastabiler Zwischenprodukte in der Enzymkatalyse werden diskutiert.     

Conceptual approaches to avian navigation systems

Summary The general basis of migratory orientation in birds is most probably an endogenous time-and-direction program. Directions are selected with respect to celestial and geomagnetic clues. Using these clues, a bird may reach a large population-specific area; however, it will hardly be able to find a particular location, for instance its previous breeding site. Homing to a familiar site over several hundred kilometres of unfamiliar terrain appears to be based on the smelling of atmospheric trace compounds. Conceptual approaches to the mechanism of olfactory navigation have as yet only reached an early state of speculation.     

A cautionary note on pentacyanoammonioferrate use for determining L-canavanine occurrence in biological materials

Summary Caution must be taken in the prevelant use of the pentacyanoammonioferrate reagent for the detection of L-canavanine in biological materias. This reagent reacts with L-histidine at neutral pH to form a pentacyanoammonioferate-histidine complex that is mistaken readily for its canavanine-containing counterpart.This work was supported by a grant from the National Science Foundation (PCM-78-20167). This is publication number 81-7-199 of the Kentucky Agriculatural Experiment Station, Lexington     

Biochemical approaches to the study of plant-fungal interactions in arbuscular mycorrhiza

This communication compares some biochemical methods for quantifying colonization by arbuscular mycorrhizal (AM) fungi. The degree of mycorrhizal colonization can conveniently be measured by determining fungal specific sterols. AM-colonized plants show a specific synthesis of 24-methylene cholesterol and an enhanced level of campesterol (=24-methyl cholesterol). A gene probe for nitrate reductase, the key enzyme for nitrogen assimilation, has been developed, which allows the monitoring of the distribution of this enzyme in fungi. Among the phytohormones tested, only abscisic acid (ABA) is found at a considerably higher level in AM-colonized plants than in controls. The concentration of ABA is about twenty times higher in spores and hyphae of the AM fungusGlomus than in maize roots. Other phytohormones (auxins, cytokinins) do not show such alterations after mycorrhizal colonization. The roots of gramineous plants become yellow as a result of mycorrhizal colonization. The yellow pigment(s) formed is (are) deposited in larger quantities in the vacuole(s) of the root parenchyma and endodermis cells during the development of the gramineous plants. A substance isolated from such roots has now been identified as a C-14 carotenoid with two carboxylic groups, and named mycorradicin.     

Multi-model approaches to phylogenetics: Implications for idealization

Phylogenetic models traditionally represent the history of life as having a strictly-branching tree structure. However, it is becoming increasingly clear that the history of life is often not strictly-branching; lateral gene transfer, endosymbiosis, and hybridization, for example, can all produce lateral branching events. There is thus motivation to allow phylogenetic models to have a reticulate structure. One proposal involves the reconciliation of genealogical discordance. Briefly, this method uses patterns of disagreement – discordance – between trees of different genes to add lateral branching events to phylogenetic trees of taxa, and to estimate the most likely cause of these events. I use this practice to argue for: (1) a need for expanded accounts of multiple-models idealization, (2) a distinction between automatic and manual de-idealization, and (3) recognition that idealization may serve the meso-level aims of science in a different way than hitherto acknowledged.     

Genetic and molecular approaches to synthesis and action of the yeast killer toxin

Summary The K1 killer toxin ofSaccharomyces cerevisiae is a secreted, virally-coded protein lethal to sensitive yeasts. Killer yeasts are immune to the toxin they produce. This killer system has been extensively examined from genetic and molecular perspectives. Here we review the biology of killer yeasts, and examine the synthesis and action of the protein toxin and the immunity component. We summarise the structure of the toxin precursor gene and its protein products, outline the proteolytic processing of the toxin subunits from the precursor, and their passage through the yeast secretory pathway. We then discuss the mode of action of the toxin, its lectin-like interaction with a cell wall glucan, and its probable role in forming channels in the yeast plasma membrane. In addition we describe models of how a toxin precursor species functions as the immunity component, probably by interfering with channel formation. We conclude with a review of the functional domains of the toxin structural gene as determined by site-directed mutagenesis. This work has identified regions associated with glucan binding, toxin activity, and immunity.     

Experimental approaches to study functional recovery following cerebral ischemia

Valid experimental models and behavioral tests are indispensable for the development of therapies for stroke. The translational failure with neuroprotective drugs has forced us to look for alternative approaches. Restorative therapies aiming to facilitate the recovery process by pharmacotherapy or cell-based therapy have emerged as promising options. Here we describe the most common stroke models used in cell-based therapy studies with particular emphasis on their inherent complications, which may affect behavioral outcome. Loss of body weight, stress, hyperthermia, immunodepression, and infections particularly after severe transient middle cerebral artery occlusion (filament model) are recognized as possible confounders to impair performance in certain behavioral tasks and bias the treatment effects. Inherent limitations of stroke models should be carefully considered when planning experiments to ensure translation of behavioral data to the clinic.     

Failure of ontological excess baggage as a criterion of the ontic approaches to quantum theory

This article presents a discussion of the notion of quantum ontological excess baggage, first proposed by Hardy. It is argued here that this idea does not have the significance suggested in his paper. It is shown that if this concept is properly analyzed, it fails to pose any threat to the ontic approach to quantum theory in general.     

Technical approaches to induce selective cell death of pluripotent stem cells

Despite the recent promising results of clinical trials using human pluripotent stem cell (hPSC)-based cell therapies for age-related macular degeneration (AMD), the risk of teratoma formation resulting from residual undifferentiated hPSCs remains a serious and critical hurdle for broader clinical implementation. To mitigate the tumorigenic risk of hPSC-based cell therapy, a variety of approaches have been examined to ablate the undifferentiated hPSCs based on the unique molecular properties of hPSCs. In the present review, we offer a brief overview of recent attempts at selective elimination of undifferentiated hPSCs to decrease the risk of teratoma formation in hPSC-based cell therapy.