bluuebunny/crossref_metadata_2025 huggingface dataset:
2,3,7,8-Tetrachlorodibenzo-
p
-Dioxin Kills Immature Thymocytes by Ca
2+
-Mediated Endonuclease Activation
Authors: McConkey David J. , Hartzell Pia , Duddy Steven K. , Håkansson Helen , Orrenius Sten
Published: October 2006

Suspensions of thymocytes from young rats were incubated with 2,3,7,8- tetrachlorodibenzo-
p
-dioxin (TCDD), which resulted in a sustained increase in cytosolic free Ca
2+
concentration followed by DNA fragmentation and loss of cell viability. Both the Ca
2+
increase and DNA fragmentation were prevented in cells treated with the inhibitor of protein synthesis, cycloheximide, and DNA fragmentation and cell killing were not detected when cells were incubated in a "Ca
2+
-free" medium or pretreated with high concentrations of the calcium probe, quin-2 tetraacetoxymethyl ester. These results indicate that TCDD can kill immature thymocytes by initiating a suicide process similar to that previously described for glucocorticoid hormones.
Blocking of EGF-Dependent Cell Proliferation by EGF Receptor Kinase Inhibitors
Authors: Yaish Pnina , Gazit Aviv , Gilon Chaim , Levitzki Alexander
Published: October 2006

A systematic series of low molecular weight protein tyrosine kinase inhibitors were synthesized; they had progressively increasing affinity over a 2500-fold range toward the substrate site of epidermal growth factor (EGF) receptor kinase domain. These compounds inhibited EGF receptor kinase activity up to three orders of magnitude more than they inhibited insulin receptor kinase, and they also effectively inhibited the EGF-dependent autophosphorylation of the receptor. The most potent compounds effectively inhibited the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on the EGF-independent proliferation of these cells. The potential use of tyrosine protein kinase inhibitors as antiproliferative agents is demonstrated.
Brain Imaging: Applications in Psychiatry
Authors: Andreasen Nancy C.
Published: October 2006

Various brain imaging techniques have become available in the past decade. These include techniques to evaluate brain structure, such as computed tomography and magnetic resonance imaging, and techniques to assess functional activity, such as measurement of regional cerebral blood flow, single photon emission computed tomography, and positron emission tomography. These techniques can be used to map brain structure and function in normal human beings, and they have enlarged our knowledge of the pathophysiology of mental illnesses by demonstrating structural, metabolic, and neurochemical abnormalities in a wide range of mental disorders.
Phosphatidylinositol-Glycan Anchors of Membrane Proteins: Potential Precursors of Insulin Mediators
Authors: Romero Guillermo , Luttrell Louis , Rogol Alan , Zeller Konrad , Hewlett Erik , Larner Joseph
Published: October 2006

BC
3
H1 myocytes release membrane-bound alkaline phosphatase to the incubation medium upon stimulation with insulin, following a time course that is consistent with the generation of dimyristoylglycerol and the appearance of a putative insulin mediator in the extracellular medium. The use of specific blocking agents shows, however, that alkaline phosphatase release and dimyristoylglycerol production are independent processes and that the blockade of either event inhibits the production of insulin mediator. These experiments suggest a new model of insulin action.
The Steroid and Thyroid Hormone Receptor Superfamily
Authors: Evans Ronald M.
Published: October 2006

Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.
Yeast: an Experimental Organism for Modern Biology
Authors: Botstein David , Fink Gerald R.
Published: October 2006

The yeasts
Saccharomyces cerevisiae
and
Schizosaccharomyces pombe
have become popular and successful model systems for understanding eukaryotic biology at the cellular and molecular levels. The reasons for this success are experimental tractability, especially in applying classical and molecular genetic methods to associate genes with proteins and functions within the cell.
Site-Specific Oligonucleotide Binding Represses Transcription of the Human c-
myc
Gene in Vitro
Authors: Cooney Michael , Czernuszewicz Graznya , Postel Edith H. , Flint S. Jane , Hogan Michael E.
Published: October 2006

A 27-base-long DNA oligonucleotide was designed that binds to duplex DNA at a single site within the 5′ end of the human c-
myc
gene, 115 base pairs upstream from the transcription origin P1. On the basis of the physical properties of its bound complex, it was concluded that the oligonucleotide forms a colinear triplex with the duplex binding site. By means of an in vitro assay system, it was possible to show a correlation between triplex formation at -115 base pairs and repression of c-
myc
transcription. The possibility is discussed that triplex formation (site-specific RNA binding to a DNA duplex) could serve as the basis for an alternative program of gene control in vivo.
Genetic Analysis of the Human Malaria Parasite
Plasmodium falciparum
Authors: Walliker David , Quakyi Isabella A. , Wellems Thomas E. , McCutchan Thomas F. , Szarfman Ana , London William T. , Corcoran Lynn M. , Burkot Thomas R. , Carter Richard
Published: October 2006

Malaria parasites are haploid for most of their life cycle, with zygote formation and meiosis occurring during the mosquito phase of development. The parasites can be analyzed genetically by transmitting mixtures of cloned parasites through mosquitoes to permit cross-fertilization of gametes to occur. A cross was made between two clones of
Plasmodium falciparum
differing in enzymes, drug sensitivity, antigens, and chromosome patterns. Parasites showing recombination between the parent clone markers were detected at a high frequency. Novel forms of certain chromosomes, detected by pulsed-field gradient gel electrophoresis, were produced readily, showing that extensive rearrangements occur in the parasite genome after cross-fertilization. Since patients are frequently infected with mixtures of genetically distinct parasites, mosquito transmission is likely to provide the principal mechanisms for generating parasites with novel genotypes.
Neurosteroids: Cytochrome P-450
scc
in Rat Brain
Authors: Le Goascogne Claude , Robel Paul , Gouézou Monique , Sananes Nicole , Baulieu Etienne-Emile , Waterman Michael
Published: October 2006

The steroid hormones corticosterone and testosterone are supplied to the central nervous system by endocrine glands, the adrenals and gonads. In contrast, the 3β-hydroxy-Δ5-derivatives of cholesterol, pregnenolone and dehydroepiandrosterone, accumulate in the rat brain through mechanisms independent of peripheral sources. Immunohistochemical studies have been performed with specific antibodies to bovine adrenal cytochrome P-450
scc
, which is involved in cholesterol side-chain cleavage and pregnenolone formation. The enzyme was localized in the white matter throughout the brain. Scarce clusters of cell bodies were also stained in the entorhinal and cingulate cortex and in the olfactory bulb. These observations strongly support the existence of "neurosteroids," which have been posited on the basis of biochemical, physiological, and behavioral studies.
Direct Demonstration of Macula Densa-Mediated Renin Secretion
Authors: Skøtt Ole , Briggs Josephine P.
Published: October 2006

An in vitro method has been used to examine whether secretion of renin from the juxtaglomerular apparatus is affected by changes in the sodium chloride concentration of the tubular fluid at the macula densa. Single juxtaglomerular apparatuses were microdissected from rabbits and the tubule segment containing the macula densa was perfused, while simultaneously the entire juxtaglomerular apparatus was superfused, and the fluid was collected for renin measurement. In this preparation, in which influences from renal nerves and local hemodynamic effects are eliminated, a decrease in the tubular sodium chloride concentration at the macula densa results in a prompt stimulation of the renin release rate.
Naturally Occurring Plasmid Carrying Genes for Enterotoxin Production and Drug Resistance
Authors: Gyles Carlton L. , Palchaudhuri Sunil , Maas Werner K.
Published: October 2006

Escherichia coli
strain 86, isolated from a piglet with diarrhea, carries plasmid-linked genes for resistance to tetracycline, streptomycin, and sulfonamides and for production of heat-labile and heat-stable enterotoxin. Results of (i) genetic experiments involving conjugal transfer and phage P1-mediated transduction and (ii) physical experiments involving electron microscopic examination of plasmid DNA and heteroduplex analysis show that a single conjugative plasmid carries the genes for drug resistance and production of enterotoxin.
Implantation of
Bacteroides gingivalis
in Nonhuman Primates Initiates Progression of Periodontitis
Authors: Holt Stanley C. , Ebersole Jeffrey , Felton Jeffrey , Brunsvold Michael , Kornman Kenneth S.
Published: October 2006

Although periodontitis is a bacterial disease, its multidimensional nature and its bacterial complexity have made it difficult to definitively prove that specific microorganisms initiate the disease process. The successful implantation of a rifampin-resistant strain of the putative periodontal pathogen
Bacteroides gingivalis
into the periodontal microbiota of monkeys (
Macaca fascicularis
) resulted in an increase in the systemic levels of antibody to the microorganism and rapid and significant bone loss.
Human Ribosomal RNA Genes: Orientation of the Tandem Array and Conservation of the 5′ End
Authors: Worton Ronald G. , Sutherland Joanne , Sylvester James E. , Willard Huntington F. , Bodrug Sharon , Dubé Ian , Duff Catherine , Kean Vanora , Ray Peter N. , Schmickel Roy D.
Published: October 2006

The multiple copies of the human ribosomal RNA genes (rDNA) are arranged as tandem repeat clusters that map to the middle of the short arms of chromosomes 13, 14, 15, 21, and 22. Concerted evolution of the gene family is thought to be mediated by interchromosomal recombination between rDNA repeat units, but such events would also result in conservation of the sequences distal to the rDNA on these five pairs of chromosomes. To test this possibility, a DNA fragment spanning the junction between rDNA and distal flanking sequence has been cloned and characterized. Restriction maps, sequence data, and gene mapping studies demonstrate that (i) the rRNA genes are transcribed in a telomere-to-centromere direction, (ii) the 5′ end of the cluster and the adjacent non-rDNA sequences are conserved on the five pairs of chromosomes, and (iii) the 5′ end of the cluster is positioned about 3.7 kb upstream from the transcription initiation site of the first repeat unit. The data support a model of concerted evolution by interchromosomal recombination.
Risk of Human Immunodeficiency Virus (HIV-1) Infection Among Laboratory Workers
Authors: Weiss Stanley H. , Goedert James J. , Gartner Suzanne , Popovic Mikulas , Waters David , Markham Phillip , di Marzo Veronese Fulvia , Gail Mitchell H. , Barkley W. Emmett , Gibbons Joseph , Gill Fred A. , Leuther Michael , Shaw George M. , Gallo Robert C. , Blattner William A.
Published: October 2006

In a prospective cohort study of 265 laboratory and affiliated workers, one individual with no recognized risk factors for human immunodeficiency virus type 1 (HIV-1) infection was HIV-1 seropositive at the time of entry into the study. Molecular analyses of two HIV-1 isolates derived in two independent laboratories from a blood sample from this worker showed that the isolates were indistinguishable from a genotypic form of HIV-1 present in the H9/HTLV-III
B
cell line. Exposure to this strain of virus most probably occurred during work with concentrated virus or culture fluids from virus-producing cell lines under standard Biosafety Level 3 containment. Although no specific incident leading to this infection has been identified, undetected skin contact with virus culture supernatant might have occurred. This worker was the only one found to be positive among the subgroup of 99 workers who shared a work environment involving exposure to concentrated virus. The incidence rate of 0.48 per 100 person-years exposure indicates that prolonged laboratory exposure to concentrated virus is associated with some risk of HIV-1 infection, which is comparable to the risk for health care workers experiencing a needle stick exposure. While none of the ten workers with parenteral exposure to HIV-1 in this cohort became infected, a worker in another laboratory did seroconvert following an injury with a potentially contaminated needle. Strict Biosafety Level 3 containment and practices should be followed when working with concentrated HIV-1 preparations, and further refinement of the procedures may be necessary.
Salivary Gland Lysates from the Sand Fly
Lutzomyia longipalpis
Enhance
Leishmania
Infectivity
Authors: Titus Richard G. , Ribeiro José M. C.
Published: October 2006

Leishmaniasis is a parasitic disease transmitted by phlebotomine sand flies. The role of sand fly saliva in transmission of the disease was investigated by injecting mice with
Leishmania major
parasites in the presence of homogenized salivary glands from
Lutzomyia longipalpis
. This procedure resulted in cutaneous lesions of
Leishmania major
that were routinely five to ten times as large and contained as much as 5000 times as many parasites as controls. With inocula consisting of low numbers of
Leishmania major
, parasites were detected at the site of injection only when the inoculum also contained salivary gland material. This enhancing effect of sand fly salivary glands on cutaneous leishmaniasis occurred with as little as 10 percent of the contents of one salivary gland of one fly. Material obtained from other bloodsucking arthropods could not mediate the phenomenon.
Molecular Cloning of Human and Rat Complementary DNA Encoding Androgen Receptors
Authors: Chang Chawnshang S. , Kokontis John , Liao Shutsung
Published: October 2006

Complementary DNAs (cDNAs) encoding androgen receptors were obtained from human testis and rat ventral prostate cDNA libraries. The amino acid sequence deduced from the nucleotide sequences of the cDNAs indicated the presence of a cysteine-rich DNA-binding domain that is highly conserved in all steroid receptors. The human cDNA was transcribed and the RNA product was translated in cell-free systems to yield a 76-kilodalton protein. The protein was immunoprecipitable by human autoimmune antibodies to the androgen receptor. The protein bound androgens specifically and with high affinity.
Cloning of Human Androgen Receptor Complementary DNA and Localization to the X Chromosome
Authors: Lubahn Dennis B. , Joseph David R. , Sullivan Patrick M. , Willard Huntington F. , French Frank S. , Wilson Elizabeth M.
Published: October 2006

The androgen receptor (AR) mediates the actions of male sex steroids. Human AR genomic DNA was cloned from a flow-sorted human X chromosome library by using a consensus nucleotide sequence from the DNA-binding domain of the family of nuclear receptors. The AR gene was localized on the human X chromosome between the centromere and q13. Cloned complementary DNA, selected with an AR-specific oligonucleotide probe, was expressed in monkey kidney (COS) cells and yielded a high-affinity androgen-binding protein with steroid-binding specificity corresponding to that of native AR. A predominant messenger RNA species of 9.6 kilobases was identified in human, rat, and mouse tissues known to contain AR and was undetectable in tissues lacking AR androgen-binding activity, including kidney and liver from androgen-insensitive mice. The deduced amino acid sequence of AR within the DNA-binding domain has highest sequence identity with the progesterone receptor.
Increased Attention Enhances Both Behavioral and Neuronal Performance
Authors: Spitzer Hedva , Desimone Robert , Moran Jeffrey
Published: October 2006

Single cells were recorded from cortical area V4 of two rhesus monkeys (
Macaca mulatta
) trained on a visual discrimination task with two levels of difficulty. Behavioral evidence indicated that the monkeys' discriminative abilities improved when the task was made more difficult. Correspondingly, neuronal responses to stimuli became larger and more selective in the difficult task. A control experiment demonstrated that changes in general arousal could not account for the effects of task difficulty on neuronal responses. It is concluded that increasing the amount of attention directed toward a stimulus can enhance the responsiveness and selectivity of the neurons that process it.
Saccharin and Other Sweeteners: Mutagenic Properties
Authors: Batzinger Robert P. , Ou Suh-Yun L. , Bueding Ernest
Published: October 2006

Saccharin preparations commonly distributed as artificial sweeteners exhibited mutagenic activity in bacterial tests. When administered orally to mice, mutagenic activity was demonstrable in the urines of these animals as well as in a host-mediated assay. Highly purified saccharin was not mutagenic in the direct assay, but the urines of mice to which this material had been administered exhibited mutagenic effects on one tester strain (
Salmonella typhimurium
TA100). Two other sweeteners, neohesperidin dihydrochalcone and xylitol, had no detectable mutagenic activity in any of these assays using his
-
Salmonella typhimurium
strains TA100 or TA98.
Amino Acid Preferences for Specific Locations at the Ends of α Helices
Authors: Richardson Jane S. , Richardson David C.
Published: October 2006

A definition based on α-carbon positions and a sample of 215 α helices from 45 different globular protein structures were used to tabulate amino acid preferences for 16 individual positions relative to the helix ends. The interface residue, which is half in and half out of the helix, is called the N-cap or C-cap, whichever is appropriate. The results confirm earlier observations, such as asymmetrical charge distributions in the first and last helical turn, but several new, sharp preferences are found as well. The most striking of these are a 3.5:1 preference for Asn at the N-cap position, and a preference of 2.6:1 for Pro at N-cap + 1. The C-cap position is overwhelmingly dominated by Gly, which ends 34 percent of the helices. Hydrophobic residues peak at positions N-cap + 4 and C-cap - 4.
Evidence of Estrogen Receptors in Normal Human Osteoblast-Like Cells
Authors: Eriksen Erik F. , Colvard Douglas S. , Berg Nicholas J. , Graham Mark L. , Mann Kenneth G. , Spelsberg Thomas C. , Riggs B. Lawrence
Published: October 2006

In seven strains of cultured normal human osteoblast-like cells, a mean of 1615 molecules of tritium-labeled 17β-estradiol per cell nucleus could be bound to specific nuclear sites. The nuclear binding of the labeled steroid was temperature-dependent, steroid-specific, saturable, and cell type-specific. These are characteristics of biologically active estrogen receptors. Pretreatment with 10 nanomolar estradiol in vitro increased the specific nuclear binding of progesterone in four of six cell strains, indicating an induction of functional progesterone receptors. RNA blot analysis demonstrated the presence of messenger RNA for the human estrogen receptor. The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism.
In Vivo Uncoating and Efficient Expression of Foreign mRNAs Packaged in TMV-Like Particles
Authors: Gallie Daniel R. , Sleat David E. , Watts John W. , Turner Philip C. , Wilson T. Michael A.
Published: October 2006

The ribonucleocapsids of many plant viruses are extremely stable. The protein coat protects the RNA genome against degradation during the accumulation and spread of progeny virions. Chimeric single-stranded RNA molecules were transcribed in vitro from recombinant plasmids and later encapsidated, in vitro, into ribonucleoprotein particles (pseudoviruses) 60 nanometers long that resembled tobacco mosaic virus. Transcripts encoding an assayable enzyme, chloramphenicol acetyltransferase (CAT), were packaged into pseudovirus particles to assess the utility of this single-stranded RNA delivery system in a wide range of cell types. In all cases, packaged CAT messenger RNA was uncoated and transiently expressed. Significantly higher levels of CAT activity were detected with packaged than with naked CAT messenger RNA after inoculation of plant protoplasts in the presence of polyethylene glycol or abrasive inoculation of intact leaf surfaces. Structural events that lead to the uncoating and expression of CAT messenger RNA showed no cell specificity. This observation may support the view that the comparatively restricted host range of a true plant virus results from events that occur later during the infection cycle.
Molecular Genetics of Inherited Variation in Human Color Vision
Authors: Nathans Jeremy , Piantanida Thomas P. , Eddy Roger L. , Shows Thomas B. , Hogness David S.
Published: October 2006

The hypothesis that red-green "color blindness" is caused by alterations in the genes encoding red and green visual pigments has been tested and shown to be correct. Genomic DNA's from 25 males with various red-green color vision deficiencies were analyzed by Southern blot hybridization with the cloned red and green pigment genes as probes. The observed genotypes appear to result from unequal recombination or gene conversion (or both). Together with chromosome mapping experiments, these data identify each of the cloned human visual pigment genes.
Microtubules in Prokaryotes
Authors: Margulis Lynn , To Leleng , Chase David
Published: October 2006

Longitudinally aligned microtubules, about 220 Å in diameter, have been seen in the protoplasmic cylinders of the following spirochetes (symbiotic in the hindguts of dry-wood and subterranean termites):
Pillotina
sp.,
Diplocalyx
sp.,
Hollandina
sp. They are also present in a gliding bacterium from
Pterotermes occidentis
. These microtubules are probably composed of tubulin, as determined by staining with fluorescent antibodies to tubulin and comigration with authentic tubulin on acrylamide gels.
Treponema reiteri
lack tubulin by these same criteria. These observations support the hypothesis of the symbiotic origin of cilia and flagella from certain spirochetes.
An Ancient Developmental Induction: Heat-Shock Proteins Induced in Sporulation and Oogenesis
Authors: Kurtz Stephen , Rossi Janice , Petko Lawrence , Lindquist Susan
Published: October 2006

Every eukaryotic and prokaryotic organism tested to date synthesizes a small number of heat-shock proteins in response to heat and other forms of stress. A particular pattern of heat-shock gene expression was observed during ascospore development in
Saccharomyces
: heat-shock proteins hsp26 and hsp84 were strongly induced, whereas hsp70, the most highly conserved of these proteins, was neither induced nor inducible by heat shock. Instead, two proteins related to hsp70 were induced. A strikingly similar pattern of expression occurs during oogenesis in
Drosophila
, suggesting that it may be one of the earliest developmental pathways to evolve in eukaryotic cells.
Brain Glutamate Decarboxylase Cloned in λgt-11: Fusion Protein Produces γ-Aminobutyric Acid
Authors: Kaufman Daniel L. , McGinnis James F. , Krieger Neil R. , Tobin Allan J.
Published: October 2006

Glutamate decarboxylase (GAD; E.C. 4.1.1.15) converts glutamate to λ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the vertebrate central nervous system. This report describes the isolation of a GAD complementary DNA clone by immunological screening of a λgt-11 brain complementary DNA expression library. The fusion protein produced by this clone catalyzes the conversion of glutamate to GABA and carbon dioxide, confirming its identity as GAD. Antibodies to β-galactosidase remove GAD enzymatic activity from solution, showing that this activity is associated with the fusion protein. In immunoblotting experiments all three available antisera to GAD reacted with the fusion polypeptide and with two major polypeptides (molecular size, 60,000 and 66,000 daltons) in brain extracts.
Social Relationships and Social Cognition in Nonhuman Primates
Authors: Cheney Dorothy , Seyfarth Robert , Smuts Barbara
Published: October 2006

Complex social relationships among nonhuman primates appear to contribute to individual reproductive success. Experiments with and behavioral observations of natural populations suggest that sophisticated cognitive mechanisms may underlie primate social relationships. Similar capacities are usually less apparent in the nonsocial realm, supporting the view that at least some aspects of primate intelligence evolved to solve the challenges of interacting with conspecifics.
Cells in Temporal Cortex of Conscious Sheep Can Respond Preferentially to the Sight of Faces
Authors: Kendrick K. M. , Baldwin B. A.
Published: October 2006

To investigate whether the temporal cortex of a nonprimate species contains cells responsive to the sight of faces, a study was made in conscious sheep of the responses of neurons in this brain region to the sight of faces. Of 561 cells from which responses were recorded, 40 responded preferentially to faces. Different categories of these cells were influenced by dominance (presumably indicated by the presence and size of horns), breed and familiarity, and threatening faces such as those of humans and dogs. These results demonstrate that cells that respond preferentially to faces are present in the temporal cortex of a nonprimate species, and that the responses of these cells are influenced by factors relevant to social interaction.
Linear Plasmids of the Bacterium
Borrelia burgdorferi
Have Covalently Closed Ends
Authors: Barbour Alan G. , Garon Claude F.
Published: October 2006

The genetics of spirochetes, a division of eubacteria, has been little studied. Double-stranded linear plasmids were found in
Borrelia burgdorferi
, the agent of Lyme disease. A 49-kilobase linear plasmid contained the
ospA
and
ospB
genes, which encode the major outer membrane proteins of strain B31. Molecules of the 49-kilobase plasmid rapidly reannealed after alkaline denaturation; rapid renaturation was prevented if the 49-kilobase plasmids were first treated with S1 nuclease. When denatured plasmid molecules were examined directly, single-stranded circles of approximately 100-kilobase circumference were seen. These studies provide direct visual evidence that the linear plasmids have covalently closed ends. This form of DNA occurs in some animal viruses, but it has not heretofore been described in prokaryotic organisms.
Smooth Muscle-Mediated Connective Tissue Remodeling in Pulmonary Hypertension
Authors: Mecham Robert P. , Whitehouse Loren A. , Wrenn David S. , Parks William C. , Griffin Gail L. , Senior Robert M. , Crouch Edmond C. , Stenmark Kurt R. , Voelkel Norbert F.
Published: October 2006

Abnormal accumulation of connective tissue in blood vessels contributes to alterations in vascular physiology associated with disease states such as hypertension and atherosclerosis. Elastin synthesis was studied in blood vessels from newborn calves with severe pulmonary hypertension induced by alveolar hypoxia in order to investigate the cellular stimuli that elicit changes in pulmonary arterial connective tissue production. A two- to fourfold increase in elastin production was observed in pulmonary artery tissue and medial smooth muscle cells from hypertensive calves. This stimulation of elastin production was accompanied by a corresponding increase in elastin messenger RNA consistent with regulation at the transcriptional level. Conditioned serum harvested from cultures of pulmonary artery smooth muscle cells isolated from hypertensive animals contained one or more low molecular weight elastogenic factors that stimulated the production of elastin in both fibroblasts and smooth muscle cells and altered the chemotactic responsiveness of fibroblasts to elastin peptides. These results suggest that connective tissue changes in the pulmonary vasculature in response to pulmonary hypertension are orchestrated by the medial smooth muscle cell through the generation of specific differentiation factors that alter both the secretory phenotype and responsive properties of surrounding cells.
Guam Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Linked to a Plant Excitant Neurotoxin
Authors: Spencer Peter S. , Nunn Peter B. , Hugon Jacques , Ludolph Albert C. , Ross Stephen M. , Roy Dwijendra N. , Robertson Richard C.
Published: October 2006

The decline in the high incidence of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer-type dementia among the Chamorro population of the western Pacific islands of Guam and Rota, coupled with the absence of demonstrable viral and hereditable factors in this disease, suggests the gradual disappearance of an environmental factor selectively associated with this culture. One candidate is seed of the neurotoxic plantCycas circinalisL., a traditional source of food and medicine which has been used less with the Americanization of the Chamorro people after World War II. Macaques were fed theCycasamino acid β-N-methylamino-L-alanine, a low-potency convulsant that has excitotoxic activity in mouse brain, which is attenuated byN-methyl-D-aspartate receptor antagonists. These animals developed corticomotoneuronal dysfunction, parkinsonian features, and behavioral anomalies, with chromatolytic and degenerative changes of motor neurons in cerebral cortex and spinal cord. In concert with existing epidemiological and animal data, these findings support the hypothesis that cycad exposure plays an important role in the etiology of the Guam disease.
Toward a Universal Law of Generalization for Psychological Science
Authors: Shepard Roger N.
Published: October 2006

A psychological space is established for any set of stimuli by determining metric distances between the stimuli such that the probability that a response learned to any stimulus will generalize to any other is an invariant monotonic function of the distance between them. To a good approximation, this probability of generalization (i) decays exponentially with this distance, and (ii) does so in accordance with one of two metrics, depending on the relation between the dimensions along which the stimuli vary. These empirical regularities are mathematically derivable from universal principles of natural kinds and probabilistic geometry that may, through evolutionary internalization, tend to govern the behaviors of all sentient organisms.
Design of Liposomes for Enhanced Local Release of Drugs by Hyperthermia
Authors: Yatvin Milton B. , Weinstein John N. , Dennis Warren H. , Blumenthal Robert
Published: October 2006

Liposomes can be designed to release an entrapped drug preferentially at temperatures attainable by mild local hyperthermia. In a test system in vitro, protein synthesis by Escherichia coli is inhibited and killing of the cells is enhanced by heating neomycin-containing liposomes to their phase transition temperature to maximize drug release. In the presence of serum the ratio of release at 44 degrees C to that at 37 degrees C can be made greater than 100:1, suggesting possible applications in the treatment of tumors or local infection.
X-Ray Holograms at Improved Resolution: A Study of Zymogen Granules
Authors: Howells M. , Jacobsen C. , Kirz J. , Feder R. , McQuaid K. , Rothman S.
Published: October 2006

X-ray holography offers the possibility of three-dimensional microscopy with resolution higher than that of the light microscope and with contrast based on x-ray edges. In principle, the method is especially advantageous for biological samples if x-rays in the wavelength region between the carbon and oxygen K edges are used. However, until now the achieved resolution has not exceeded that of the light microscope because of the poor coherence properties of the x-ray sources and the low resolution of the detectors that were available. With a recently developed x-ray source based on an undulator on an electron storage ring, and high resolution x-ray resist, a hologram has been recorded at about 400-angstrom resolution. The experiment utilized x-rays with wavelengths of 24.7 angstroms and required a 1-hour exposure of the pancreatic zymogen granules under study.
Females' Choice of "Good Genotypes" as Mates Is Promoted by an Insect Mating System
Authors: Watt Ward B. , Carter Patrick A. , Donohue Kathleen
Published: October 2006

Can animal mating systems result in the choice of mates carrying genotypes that are otherwise favored by natural selection? This question is addressed by studying, in natural populations of
Colias
butterflies, how the phosphoglucose isomerase (PGI) enzyme genotype of males mating
Colias
females varies with degree of female mate discrimination. Certain PGI genotypes (as predicted from their biochemical properties) have been found previously to have an advantage in diverse fitness-related properties: flight capacity, survivorship, and overall mating success. It is shown here that males of these same genotypes have even greater advantage in remating older, more discriminating females than they do in mating previously unmated, less discriminating females. Assortative mating is not found and thus cannot explain this effect. The mating system of these insects does, at least in this case, result in active female choice of generally favorable male genotypes as mates.
Effects of Alcohol on the Generation and Migration of Cerebral Cortical Neurons
Authors: Miller Michael W.
Published: October 2006

Prenatal exposure to alcohol produces many developmental defects of the central nervous system, such as microcephaly, mental retardation, motor dysfunction, and cognitive deficiencies. Therefore, the generation of neurons in the cerebral cortex was examined in the offspring of female rats fed a diet containing ethanol. Prenatal exposure to ethanol delayed and extended the period during which cortical neurons were generated, reduced the number of neurons in the mature cortex with the same time of origin, and altered the distribution of neurons generated on a particular day. Thus, the proliferation and migration of cortical neurons are profoundly affected by in utero exposure to ethanol.
Computing with Neural Circuits: A Model
Authors: Hopfield John J. , Tank David W.
Published: October 2006

A new conceptual framework and a minimization principle together provide an understanding of computation in model neural circuits. The circuits consist of nonlinear graded-response model neurons organized into networks with effectively symmetric synaptic connections. The neurons represent an approximation to biological neurons in which a simplified set of important computational properties is retained. Complex circuits solving problems similar to those essential in biology can be analyzed and understood without the need to follow the circuit dynamics in detail. Implementation of the model with electronic devices will provide a class of electronic circuits of novel form and function.
Inhibition of Secretion of Hepatitis B Surface Antigen by a Related Presurface Polypeptide
Authors: Persing David H. , Varmus Harold E. , Ganem Don
Published: October 2006

The presurface (preS) proteins of hepatitis B virus are structural components of the viral envelope that may play important roles in virion assembly and infectivity. They are specified by a large open reading frame that includes the coding region for the major surface (S) protein in its 3′ half. Translation of the preS proteins initiates upstream from the S region, giving rise to proteins that are composed of the S domain and an additional 163 (preS1) or 55 (preS2) amino acids. Little is known about the biosynthesis and assembly of these proteins. The expression of the S and preS1 proteins was examined by transfecting cultured mammalian cells with viral DNA and injecting synthetic messenger RNA's into
Xenopus
oocytes. In contrast to the proteins encoded by the S region, the preS1 proteins are not detectably secreted into the culture medium. Furthermore, when the S and preS1 proteins are synthesized together, secretion of the S proteins is specifically and strongly inhibited. The results suggest a unique molecular interaction during secretion of the S and preS proteins that may be important for virus assembly.
Antidepressant and Circadian Phase-Shifting Effects of Light
Authors: Lewy Alfred J. , Sack Robert L. , Miller L. Stephen , Hoban Tana M.
Published: October 2006

Bright light can suppress nighttime melatonin production in humans, but ordinary indoor light does not have this effect. This finding suggested that bright light may have other chronobiologic effects in humans as well. Eight patients who regularly became depressed in the winter (as day length shortens) significantly improved after 1 week of exposure to bright light in the morning (but not after 1 week of bright light in the evening). The antidepressant response to morning light was accompanied by an advance (shift to an earlier time) in the onset of nighttime melatonin production. These results suggest that timing may be critical for the antidepressant effects of bright light.
Calculation of the Relative Change in Binding Free Energy of a Protein-Inhibitor Complex
Authors: Bash Paul A. , Singh U. Chandra , Brown Frank K. , Langridge Robert , Kollman Peter A.
Published: October 2006

By means of a thermodynamic perturbation method implemented with molecular dynamics, the relative free energy of binding was calculated for the enzyme thermolysin complexed with a pair of phosphonamidate and phosphonate ester inhibitors. The calculated difference in free energy of binding was 4.21 ± 0.54 kilocalories per mole. This compares well with the experimental value of 4.1 kilocalories per mole. The method is general and can be used to determine a change or "mutation" in any system that can be suitably represented. It is likely to prove useful for protein and drug design.
Fertility Policy in China: Future Options
Authors: Greenhalgh Susan , Bongaarts John
Published: October 2006

A wide range of social, economic, and demographic criteria are used to evaluate China's present one-child policy and five alternative fertility policies that might guide China's population control efforts until the end of the century when the one-child policy is scheduled to be abandoned. These criteria include the policies' macrodemographic impact on total population size and population aging; their microdemographic effects on the family's ability to support the elderly, its economic capabilities, and the position of women; and their cultural acceptability to the majority Han Chinese population. The results suggest that the least desirable strategy is to retain the present policy; all the two-child alternatives perform better than the current one-child policy in achieving the policy goals considered.
Acetaminophen: Potentially Toxic Metabolite Formed by Human Fetal and Adult Liver Microsomes and Isolated Fetal Liver Cells
Authors: Rollins D. E. , von Bahr C. , Glaumann H. , Moldéus P. , Rane A.
Published: October 2006

A reactive metabolite of acetaminophen is hepatotoxic in humans when the drug is ingested in large overdoses. The ability of the human fetal and adult liver to oxidize acetaminophen by trapping the potentially toxic metabolite as a glutathione conjugate has been measured. Oxidation by fetal liver was approximately ten times slower than by adult liver. However, there was a definite increase in acetaminophen oxidation with fetal age. Isolated human fetal liver cells conjugated acetaminophen with sulfate but not with glucuronic acid. The results indicate that the human fetal liver is able to detoxify acetaminophen by conjugation. However, it also catalyzes the formation of an active metabolite of acetaminophen through oxidation. Hence the fetus remains at risk should a large dose of the drug cross into the fetal circulation.
Dopamine Receptor Binding Predicts Clinical and Pharmacological Potencies of Antischizophrenic Drugs
Authors: Creese Ian , Burt David R. , Snyder Solomon H.
Published: October 2006

Tritiated haloperidol and tritiated dopamine label postsynaptic dopamine receptors in mammalian brain. Clinical potencies of butyrophenones, phenothiazines, and related drugs correlate closely with their ability to inhibit tritiated haloperidol binding. These binding methods provide a simple in vitro means for evaluating new drugs as potential antischizophrenic agents.
Gene Synthesis Machines: DNA Chemistry and Its Uses
Authors: Caruthers Marvin H.
Published: October 2006

Deoxyoligonucleotides can now be synthesized rapidly and in high yield because of recent advances in nucleic acid chemistry. Key innovations include solid-phase synthesis on silica-based supports and the development of stable deoxynucleoside phosphoramidites as synthons. When incorporated into manual, semiautomatic, or automatic instruments, these new procedures can be used to prepare probes, mixed probes, deoxyoligonucleotides for priming DNA synthesis, analogues of deoxyoligonucleotides, and DNA segments containing more than 100 deoxynucleotides.
Identification of a Transcriptional Enhancer Element Upstream from the Proto-Oncogene
fos
Authors: Deschamps Jacqueline , Meijlink Frits , Verma Inder M.
Published: October 2006

Sequences upstream from the proto-oncogene
fos
were shown to be essential for its transcription. Transient expression of the chloramphenicol acetyltransferase (CAT) gene linked to upstream sequences of the
fos
gene including its promoter reveals that sequences located 64 to 404 base pairs 5′ to the
fos
cap site contain a typical transcriptional enhancer. Moreover, these enhancer sequences, which are strikingly conserved between mouse and human
fos
genes, coincide with a deoxyribonuclease I-hypersensitive site in the chromatin. The expression of the
fos
-CAT fusion genes was stimulated only two to three times by the
fos
inducer 12-
O
-tetradecanoyl phorbol-13-acetate. The
fos
enhancer does not appear to be tissue-specific.
Dynamic Modification of the Vestibulo-Ocular Reflex by the Nodulus and Uvula
Authors: Waespe Walter , Cohen Bernard , Raphan Theodore
Published: October 2006

The time constant of the decay of slow-phase eye velocity of postrotatory nystagmus or optokinetic after-nystagmus is reduced during exposure to a stationary visual surround (visual suppression). It is also reduced after tilting the head (tilt suppression). A "dump" mechanism in the vestibulo-ocular reflex has been proposed to rapidly discharge activity from the central vestibular system during both types of suppression. Monkeys lost this mechanism after lesions of the nodulus and uvula. They also lost the ability to habituate the time constant of nystagmus on repeated exposure to optokinetic and vestibular stimuli. Periodic alternating nystagmus, which is believed to represent an instability in the vestibulo-ocular reflex, was observed in two of three monkeys. These data indicate that the nodulus and uvula play an important role in suppressing, habituating, and stabilizing the vestibulo-ocular reflex.
Endocrine Pancreas: Three-Dimensional Reconstruction Shows Two Types of Islets of Langerhans
Authors: Baetens D. , Malaisse-Lagae F. , Perrelet A. , Orci L.
Published: October 2006

Three-dimensional reconstructions of islets of Langerhans, based on immunofluorescent staining of successive serial sections with antiserums to insulin, glucagon, somatostatin, and pancreatic polypeptide reveal a marked difference in the number of cells containing glucagon and pancreatic polypeptide depending on the anatomical location of the islet in the pancreas. The two types of islets are situated in regions of exocrine tissue that are drained by different excretory ducts. This demonstration contradicts the assumption that all islets in the pancreas are similar in their endocrine cell content.
Preparation of Bispecific Antibodies by Chemical Recombination of Monoclonal Immunoglobulin G
1
Fragments
Authors: Brennan Maureen , Davison Peter F. , Paulus Henry
Published: October 2006

Preparation of bispecific antibodies by the chemical reassociation of monovalent fragments derived from monoclonal mouse immunoglobulin G1 is inefficient because of side reactions during reoxidation of the multiple disulfide bonds linking the heavy chains. These side reactions can be avoided by using specific dithiol complexing agents such as arsenite and effecting disulfide formation with a thiol activating agent such as 5,5′-dithiobis(2-nitrobenzoic acid). In this way bispecific antibodies were obtained in high yield and free of monospecific contaminants from monoclonal mouse immunoglobulin G1 fragments. The bispecific antibodies were used as agents for the selective immobilization of enzymes.
Heat Shock Elicits Production of Sexual Inducer in
Volvox
Authors: Kirk David L. , Kirk Marilyn M.
Published: October 2006

In the green alga
Volvox carteri
, heat shock had an unusual and adaptive effect mediated by induced production of a well-defined effector molecule. Females of this species normally reproduce asexually in the absence of a potent sexual inducer produced by mature sexual males, but they generated egg-bearing sexual daughters after a brief exposure to elevated temperatures. This response involved an "autoinduction" of sexuality, in which heat-shocked somatic cells made and released the sexual inducer, which then redirected development of the reproductive cells. Males, including a sterile mutant incapable of producing inducer in the usual manner, also produced the inducer in response to heat shock. The phenomenon probably is of significance in the wild, where
Volvox
reproduces asexually in temporary ponds in spring but becomes sexual and produces dormant, overwintering zygotes before the ponds dry up in the summer heat.
Maturational Changes in Cerebral Function in Infants Determined by
18
FDG Positron Emission Tomography
Authors: Chugani Harry T. , Phelps Michael E.
Published: October 2006

2-Deoxy-2[
18
F]fluoro-D-glucose positron emission tomography performed in human infants during development revealed progressive changes in local cerebral glucose utilization. In infants 5 weeks of age and younger, glucose utilization was highest in the sensorimotor cortex, thalamus, midbrain-brainstem, and cerebellar vermis. By 3 months, glucose metabolic activity had increased in the parietal, temporal, and occipital cortices and the basal ganglia, with subsequent increases in frontal and various association regions occurring by 8 months. These functional changes measured with positron emission tomography are in agreement with behavioral, neurophysiological, and anatomical alterations known to occur during infant development.
Mechanisms of Human Motion Perception Revealed by a New Cyclopean Illusion
Authors: Shadlen Michael , Carney Thom
Published: October 2006

A new cyclopean illusion of motion may bear on neural mechanisms of direction selectivity. Stationary flickering patterns were presented to each eye, and the resulting fused pattern was perceived to be moving. To determine direction of motion, the visual system seems to integrate image components differing by 90 degrees in spatial and temporal phase. On the other hand, image speed seems to be derived from displacement of features over time. A model of neural direction selectivity is discussed in light of these results.
Nigerian Geophagical Clay: A Traditional Antidiarrheal Pharmaceutical
Authors: Vermeer Donald E. , Ferrell Ray E.
Published: October 2006

The chief geophagical clay entering the West African market system comes from the village of Uzalla, Nigeria. Village inhabitants ascribe antidiarrheal properties to the clay, and they use it in traditional medicinal preparations to counteract intestinal problems. Mineralogical analyses demonstrate a striking similarity between the Uzalla village clay and the clay in the commercial pharmaceutical Kaopectate.