bluuebunny/crossref_metadata_2025 huggingface dataset:
Left-Handed DNA in Vivo
Authors: Jaworski Adam , Hsieh Wang-Ting , Blaho John A. , Larson Jacquelynn E. , Wells Robert D.
Published: October 2006

Left-handed DNA is shown to exist and elicit a biological response in
Escherichia coli
. A plasmid encoding the gene for a temperature-sensitive Eco RI methylase (MEco RI) was cotransformed with different plasmids containing inserts that had varying capacities to form left-handed helices or cruciforms with a target Eco RI site in the center or at the ends of the inserts. Inhibition of methylation in vivo was found for the stable inserts with the longest left-handed (presumably Z) helices. In vitro methylation with the purified MEco RI agreed with the results in vivo. Supercoil-induced changes in the structure of the primary helix in vitro provided confirmation that left-handed helices were responsible for this behavior. The presence in vivo of left-handed inserts elicits specific deletions and plasmid incompatibilities in certain instances.
Mandelonitrile β-Glucuronide: Synthesis and Characterization
Authors: Fenselau Catherine , Pallante Sharon , Batzinger Robert P , Benson Walter R. , Barron Robert P. , Sheinin Eric B. , Maienthal Millard
Published: October 2006

Mandelonitrile β-glucuronide, the compound patented as Laetrile®, has been synthesized from rabbit liver uridine diphosphate-glucuronosyl transferase immobilized on beaded sepharose, has been analyzed by thin-layer chromatography, nuclear magnetic resonance, and gas chromatography-mass spectrometry, and has been tested for cytotoxicity and mutagenic activity with
Salmonella typhimurium
strains TA 98 and TA 100. Several commercial laetrile preparations contained no glucuronide; they contained amygdalin and neoamygdalin instead. Mandelonitrile, mandelonitrile glucuronide, and a mixture of amygdalin and neoamygdalin were each found to be mutagenic.
Stereoselective Organic Reactions: Catalysts for Carbonyl Addition Processes
Authors: Evans David A.
Published: October 2006

Important advances are being made in the development of stereoselective organic reactions. Some of the emerging research directions that hold forth great promise in this area deal with the development of chiral catalysts for these processes. This review attempts to unify one aspect of this field, the development of catalysts and catalyst models for the enantioselective addition of hydride and carbon nucleophiles to carbonyl substrates. Mechanistic constructs for the stereodifferentiating transition states are provided.
Directional Selection and the Evolution of Breeding Date in Birds
Authors: Price Trevor , Kirkpatrick Mark , Arnold Steven J.
Published: October 2006

In many bird species, those pairs that breed earlier in the season have higher reproductive success than those that breed later. Since breeding date is known to be heritable, it is unclear why it does not evolve to an earlier time. Under assumptions outlined by Fisher, a model is developed that shows how breeding date may have considerable additive genetic variance, appear to be under directional selection, and yet not evolve. These results provide a general explanation for a persistent correlation of fitness with a variety of traits in natural populations.
A Specific Amino Acid Binding Site Composed of RNA
Authors: Yarus Michael
Published: October 2006

A specific, reversible binding site for a free amino acid is detectable on the intron of the
Tetrahymena
self-splicing ribosomal precursor RNA. The site selects arginine among the natural amino acids, and prefers the L- to the D-amino acid. The dissociation constant is in the millimolar range, and amino acid binding is at or in the catalytic rG splicing substrate site. Occupation of the G site by L-arginine therefore inhibits splicing by inhibiting the binding of rG, without inhibition of later reactions in the splicing reaction sequence. Arginine binding specificity seems to be directed at the side chain and the guanidino radical, and the alpha-amino and carboxyl groups are dispensable for binding. The arginine site can be placed within the G site by structural homology, with consequent implications for RNA-amino acid interaction, for the origin of the genetic code, for control of RNA activities, and for further catalytic capabilities for RNA.
Restricted Lateral Diffusion of PH-20, a PI-Anchored Sperm Membrane Protein
Authors: Phelps Bonnie M. , Primakoff Paul , Koppel Dennis E. , Low Martin G. , Myles Diana G.
Published: October 2006

The rate of lateral diffusion of integral membrane proteins is constrained in cells, but the constraining factors for most membrane proteins have not been defined. PH-20, a sperm surface protein involved in sperm-egg adhesion, was shown to be anchored in the plasma membrane by attachment to the lipid phosphatidylinositol and to have a diffusion rate that is highly restricted on testicular sperm, being more than a thousand times slower than lipid diffusion. These results support the hypothesis that lateral mobility of a membrane protein can be regulated exclusively by interactions of its ectodomain.
Inactivation of the Retinoblastoma Susceptibility Gene in Human Breast Cancers
Authors: Lee Eva Y.-H. P. , To Hoang , Shew Jin-Yuh , Bookstein Robert , Scully Peter , Lee Wen-Hwa
Published: October 2006

Mutational inactivation of the retinoblastoma susceptibility (RB) gene, a recessive cancer gene, has been implicated in the genesis of retinoblastoma and certain other human neoplasms. This gene is now shown to be inactivated in two of nine human breast cancer cell lines examined. The RB gene of one cell line had a homozygous internal duplication of a 5-kilobase region containing exons 5 and 6. The RB messenger RNA transcript was correspondingly lengthened, and its translation was probably terminated prematurely due to a shifted reading frame. The other cell line had a homozygous deletion of the RB gene that removed the entire gene beyond exon 2. The RB gene product, pp110
RB
, was not detectable in either cell line by immunoprecipitation with specific antibodies. These findings are significant in relation to proposed genetic mechanisms of breast cancer formation.
A Ligase-Mediated Gene Detection Technique
Authors: Landegren Ulf , Kaiser Robert , Sanders Jane , Hood Leroy
Published: October 2006

An assay for the presence of given DNA sequences has been developed, based on the ability of two oligonucleotides to anneal immediately adjacent to each other on a complementary target DNA molecule. The two oligonucleotides are then joined covalently by the action of a DNA ligase, provided that the nucleotides at the junction are correctly base-paired. Thus single nucleotide substitutions can be distinguished. This strategy permits the rapid and standardized identification of single-copy gene sequences in genomic DNA.
Autologous Red Cell Agglutination Assay for HIV-1 Antibodies: Simplified Test with Whole Blood
Authors: Kemp Bruce E. , Rylatt Dennis B. , Bundesen Peter G. , Doherty Richard R. , McPhee Dale A. , Stapleton David , Cottis Louise E. , Wilson Kim , John Michele A. , Khan Julie M. , Dinh Denise P. , Miles Stephen , Hillyard Carmel J.
Published: October 2006

An antibody detection procedure based on agglutination of autologous red cells has been developed for samples of whole blood. A nonagglutinating monoclonal antibody to human red blood cells conjugated to a synthetic peptide antigen (in this case residues 579 to 601 of the HIV-1 envelope precursor, Arg-Ile-Leu-Ala-Val-Glu-Arg-Tyr-Leu-Lys-Asp-Gln-Gln-Leu-Leu-Gly-Ile-Trp-Gly-Cys-Ser-Gly-Lys) permitted the detection of antibodies to the human immunodeficiency virus type 1 (HIV-1) in 10 microliters of whole blood within 2 minutes. Agglutination was specifically inhibited by addition of synthetic peptide antigen but not by unrelated peptides. The frequency of false positive results was 0.1% with HIV-1 seronegative blood donors (
n
= 874). The false negative results were approximately 1% (
n
= 81). The autologous red cell agglutination test is potentially suitable for simple, rapid, qualitative screening for antibodies to a variety of antigens of medical and veterinary diagnostic significance.
Expression of a Distinctive
BCR-ABL
Oncogene in Ph
1
-Positive Acute Lymphocytic Leukemia (ALL)
Authors: Clark Steven S. , McLaughlin Jami , Timmons Michael , Pendergast Ann Marie , Ben-Neriah Yinon , Dow Lois W. , Crist William , Rovera Giovanni , Smith Stephen D. , Witte Owen N.
Published: October 2006

The Philadelphia chromosome (Ph
1
) is a translocation between chromosomes 9 and 22 that is found in chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia patients (ALL). In CML, this results in the expression of a chimeric 8.5-kilobase
BCR-ABL
transcript that encodes the P210
BCR-ABL
tyrosine kinase. The Ph
1
chromosome in ALL expresses a distinct ABL-derived 7-kilobase messenger RNA that encodes the P185
ALL-ABL
protein. Since the expression of different oncogene products may play a role in the distinctive presentation of Ph
1
-positive ALL versus CML, it is necessary to understand the molecular basis for the expression of P185
ALL-ABL
. Both P210
BCR-ABL
and P185
ALL-ABL
are recognized by an antiserum directed to
BCR
determinants in the amino-terminal region of both proteins. Antisera to
BCR
determinants proximal to the
BCR-ABL
junction in CML immunoprecipitated P210
BCR-ABL
but not P185
ALL-ABL
. Nucleotide sequence analysis of complementary DNA clones made from RNA from the Ph
1
-positive ALL SUP-B15 cell line, and S1 nuclease protection analysis confirmed the presence of
BCR-ABL
chimeric transcripts in Ph
1
-positive ALL cells. In Ph
1
-positive ALL,
ABL
sequences were joined to
BCR
sequences approximately 1.5 kilobases 5′ of the CML junction. P185
ALL-ABL
represents the product of a
BCR-ABL
fusion gene in Ph
1
-positive ALL that is distinct from the
BCR-ABL
fusion gene of CML.
Identification of Human Uromodulin as the Tamm-Horsfall Urinary Glycoprotein
Authors: Pennica Diane , Kohr William J. , Kuang Wun-Jing , Glaister Debbie , Aggarwal Bharat B. , Chen Ellson Y. , Goeddel David V.
Published: October 2006

The primary structure of human uromodulin, a 616-amino acid, 85-kilodalton glycoprotein with in vitro immunosuppressive properties, was determined through isolation and characterization of complementary DNA and genomic clones. The amino acid sequence encoded by one of the exons of the uromodulin gene has homology to the low-density-lipoprotein receptor and the epidermal growth factor precursor. Northern hybridization analyses demonstrate that uromodulin is synthesized by the kidney. Evidence is provided that uromodulin is identical to the previously characterized Tamm-Horsfall glycoprotein, the most abundant protein in normal human urine.
Another Flame Retardant, Tris-(1,3-Dichloro-2-Propyl)-Phosphate, and Its Expected Metabolites Are Mutagens
Authors: Gold Marian Deborah , Blum Arlene , Ames Bruce N.
Published: October 2006

A flame retardant used in children's sleepwear, tris-(1,3-dichloro-2-propyl)phosphate (Fyrol FR2) is a mutagen in the
Salmonella
-mammalian tissue homogenate test after it has been activated by mouse or rat liver homogenate. The expected enzymatic hydrolysis product, 1,3-dichloro-2-propanol, is similarly a mutagen after activation by liver homogenate. A proposed metabolite of the flame retardant, 1,3-dichloro-2-propanone, is a potent mutagen in the absence of such activation. A flame retardant with similar structure, tris-(2,3-dibromopropyl)phosphate (tris-BP), was shown previously to be a mutagen, to cause sterility in animals, to be a carcinogen, and to be absorbed through human skin. These and other flame retardants have characteristic nuclear magnetic resonance spectra that can be used to determine which flame retardant is present in commercially purchased sleepwear. Sleepwear treated with tris-BP, Fyrol FR2, and other chemical additives was being sold in late 1977.
Vasoconstriction: A New Activity for Platelet-Derived Growth Factor
Authors: Berk Bradford C. , Alexander R. Wayne , Brock Tommy A. , Gimbrone Michael A. , Webb R. Clinton
Published: October 2006

Platelet-derived growth factor (PDGF) is a potent mitogen for vascular smooth muscle cells that has been implicated in the pathogenesis of atherosclerosis. The potential role of PDGF in the altered vasoreactivity of atherosclerotic vessels has been studied through an examination of its effects on contractility in the rat aorta. PDGF caused a concentration-dependent contraction of aortic strips and was significantly more potent on a molar basis than the classic vasoconstrictor peptide angiotensin II. Furthermore, PDGF increased the cytosolic free calcium concentration in cultured rat aortic smooth muscle cells. These observations suggest a new biological activity for PDGF that may contribute to the enhanced vasoreactivity of certain atherosclerotic vessels.
Human CSF-1: Molecular Cloning and Expression of 4-kb cDNA Encoding the Human Urinary Protein
Authors: Wong Gordon G. , Temple Patricia A. , Leary Anne C. , Witek-Giannotti JoAnn S. , Yang Yu-Chung , Ciarletta Agnes B. , Chung Margaret , Murtha Patricia , Kriz Ronald , Kaufman Randal J. , Ferenz Catherine R. , Sibley Barbara S. , Turner Katherine J. , Hewick Rodney M. , Clark Steven C. , Yanai Nobuya , Yokota Hajime , Yamada Muneo , Saito Minoru , Motoyoshi Kazuo , Takaku Fumimaro
Published: October 2006

A 4-kilobase complementary DNA (cDNA) encoding human macrophage-specific colony-stimulating factor (CSF-1) was isolated. When introduced into mammalian cells, this cDNA directs the expression of CSF-1 that is structurally and functionally indistinguishable from the natural human urinary CSF-1. Direct structural analysis of both the recombinant CSF-1 and the purified human urinary protein revealed that these species contain a sequence of at least 40 amino acids at their carboxyl termini which are not found in the coding region of a 1.6-kilobase CSF-1 cDNA that was previously described. These results demonstrate that the human CSF-1 gene can be expressed to yield at least two different messenger RNA species that encode distinct but related forms of CSF-1.
The
sor
Gene of HIV-1 Is Required for Efficient Virus Transmission in Vitro
Authors: Fisher Amanda G. , Ensoli Barbara , Ivanoff Lucinda , Chamberlain Mark , Petteway Stephen , Ratner Lee , Gallo Robert C. , Wong-Staal Flossie
Published: October 2006

The genome of the human immunodeficiency virus HIV-1 contains at least eight genes, of which three (
sor
, R, and 3′
orf
) have no known function. In this study, the role of the
sor
gene was examined by constructing a series of proviral genomes of HIV-1 that either lacked the coding sequences for
sor
or contained point mutations in
sor
. Analysis of four such mutants revealed that although each clone could generate morphologically normal virus particles upon transfection, the mutant viruses were limited in their capacity to establish stable infection. Virus derived from transfection of Cos-1 cells (OKT4
-
) with
sor
mutant proviral DNA's was resistant to transmission to OKT4
+
"susceptible" cells under cell-free conditions, and was transmitted poorly by coculture. In contrast, virus derived from clones with an intact
sor
frame was readily propagated by either approach. Normal amounts of
gag-
,
env-
, and pol-derived proteins were produced by all four mutants and assays in both lymphoid and nonlymphoid cells indicated that their trans-activating capacity was intact and comparable with wild type. Thus the
sor
gene, although not absolutely required in HIV virion formation, influences virus transmission in vitro and is crucial in the efficient generation of infectious virus. The data also suggest that
sor
influences virus replication at a novel, post-translational stage and that its action is independent of the regulatory genes
tat
and
trs
.
Interaction of a Liver-Specific Nuclear Factor with the Fibrinogen and α
1
-Antitrypsin Promoters
Authors: Courtois Gilles , Morgan John G. , Campbell Linda A. , Fourel Genevieve , Crabtree Gerald R.
Published: October 2006

The orderly and sequential activation of genes during development is hypothesized to be related to the selective expression of groups of regulatory proteins acting primarily at the level of transcription. A nuclear protein was found in hepatocytes, but not other cell types, that binds to a sequence required for hepatocyte-specific transcription of the gene for the β chain of fibrinogen. This protein, hepatocyte nuclear factor 1 (HNF1), also interacts with homologous sequences required for optimal promoter function of the genes for the α chain of fibrinogen and α
1
-antitrypsin. The promoter or enhancer regions for several viral and cellular genes not expressed in the liver did not compete for this binding. The restricted expression of HNF1 and its selective interaction with the control regions of several liver-specific genes indicate that it is involved in developmentally regulated gene expression in the liver.
The 35-Nucleotide Spliced Leader Sequence Is Common to All Trypanosome Messenger RNA's
Authors: Walder Joseph A. , Eder Paul S. , Engman David M. , Brentano Steven T. , Walder Roxanne Y. , Knutzon Deborah S. , Dorfman David M. , Donelson John E.
Published: October 2006

In Trypanosomatidae the messenger RNA's (mRNA's) that code for the variant surface glycoproteins (VSG's), tubulins, calmodulin, and at least a subset of other proteins contain a common 35-nucleotide leader sequence at their 5′ ends. Hybrid-arrested in vitro translation has been used to show that all mRNA's in both African and South American trypanosomes contain this 35-nucleotide sequence. Oligonucleotides complementary to this sequence blocked translation of all trypanosome mRNA's in a rabbit reticulocyte lysate system, but did not inhibit translation of mRNA's from other organisms lacking this sequence. An oligonucleotide complementary to the VSG mRNA downstream from the spliced leader sequence arrested only VSG synthesis. Thus, the 35-nucleotide leader sequence is a general feature of all trypanosome mRNA's. The high specificity of oligonucleotides complementary to the spliced leader for their target sequence suggests that analogues permeable to the cell membrane may be useful in the treatment of trypanosomal infections.
Conservation of Brain Amyloid Proteins in Aged Mammals and Humans with Alzheimer's Disease
Authors: Selkoe Dennis J. , Bell Douglas S. , Podlisny Marcia B. , Price Donald L. , Cork Linda C.
Published: October 2006

The formation of clusters of altered axons and dendrites surrounding extracellular deposits of amyloid filaments (neuritic plaques) is a major feature of the human brain in both aging and Alzheimer's disease. A panel of antibodies against amyloid filaments and their constituent proteins from humans with Alzheimer's disease cross-reacted with neuritic plaque and cerebrovascular amyloid deposits in five other species of aged mammals, including monkey, orangutan, polar bear, and dog. Antibodies to a 28-amino acid peptide representing the partial protein sequence of the human amyloid filaments recognized the cortical and microvascular amyloid of all of the aged mammals examined. Plaque amyloid, plaque neurites, and neuronal cell bodies in the aged animals showed no reaction with antibodies to human paired helical filaments. Thus, with age, the amyloid proteins associated with progressive cortical degeneration in Alzheimer's disease are also deposited in the brains of other mammals. Aged primates can provide biochemically relevant models for principal features of Alzheimer's disease: cerebrovascular amyloidosis and neuritic plaque formation.
Ranking Possible Carcinogenic Hazards
Authors: Ames Bruce N. , Magaw Renae , Gold Lois Swirsky
Published: October 2006

This review discusses reasons why animal cancer tests cannot be used to predict absolute human risks. Such tests, however, may be used to indicate that some chemicals might be of greater concern than others. Possible hazards to humans from a variety of rodent carcinogens are ranked by an index that relates the potency of each carcinogen in rodents to the exposure in humans. This ranking suggests that carcinogenic hazards from current levels of pesticide residues or water pollution are likely to be of minimal concern relative to the background levels of natural substances, though one cannot say whether these natural exposures are likely to be of major or minor importance.
Human Amnion Membrane Serves as a Substratum for Growing Axons in Vitro and in Vivo
Authors: Davis George E. , Blaker Scott N. , Engvall Eva , Varon Silvio , Manthorpe Marston , Gage Fred H.
Published: October 2006

The epithelial cell layer of human amnion membrane can be removed while the basement membrane and stromal surfaces remain morphologically intact. Such a preparation has been used as a substratum for the in vitro culture of dissociated neurons. Embryonic motor neurons from chick ciliary ganglion attached to both surfaces but grew extensive neurites only on the basement membrane. On cross sections of rolled amnion membranes, regenerating axons of cultured neurons were guided along pathways of basement membrane that were immunoreactive with an antibody to laminin. In addition, when rolled amnion membranes were implanted into a lesion cavity between the rat septum and hippocampus, cholinergic neurons extended axons through the longitudinally oriented implant into the hippocampus. Thus, this amnion preparation can serve as a bridge to promote axonal regeneration in vivo in damaged adult brain.
Expression and Properties of Two Types of Protein Kinase C: Alternative Splicing from a Single Gene
Authors: Ono Yoshitaka , Kikkawa Ushio , Ogita Kouji , Fujii Tomoko , Kurokawa Tsutomu , Asaoka Yoshinori , Sekiguchi Kazuo , Ase Katsuhiko , Igarashi Koichi , Nishizuka Yasutomi
Published: October 2006

Two complementary DNA's, encoding the complete sequences of 671 and 673 amino acids for subspecies of rat brain protein kinase C, were expressed in COS 7 cells. The complementary DNA sequence analysis predicted that the two enzymes are derived from different ways of splicing and differ from each other only in the short ranges of their carboxyl-terminal regions. Both enzymes showed typical characteristics of protein kinase C that responded to Ca2
+
, phospholipid, and diacylglycerol. The enzymes showed practically identical physical and kinetic properties and were indistinguishable from one of the several subspecies of protein kinase C that occurs in rat brain but not in untransfected COS 7 cells. Partial analysis of the genomic structure confirmed that these two subspecies of protein kinase C resulted indeed from alternative splicing of a single gene.
Computer Simulations of the Diffusion of a Substrate to an Active Site of an Enzyme
Authors: Sharp K. , Fine R. , Honig B.
Published: October 2006

Computer simulations of the diffusion of a substrate to an enzyme active site were performed. They included the detailed shape of the protein and an accurate description of its electrostatic potential. Application of the method to the diffusion of the superoxide anion to the protein superoxide dismutase revealed that the electric field of the enzyme enhances the association rate of the anion by a factor of 30 or more. Calculated changes in the association rate as a function of ionic strength and amino acid modification paralleled the observed behavior. Design principles of superoxide dismutase are considered with respect to insights provided by the simulations. A possible means of enhancing the enzyme turnover rate through site-directed mutagenesis is proposed.
Does the Release of Potassium from Astrocyte Endfeet Regulate Cerebral Blood Flow?
Authors: Paulson Olaf B. , Newman Eric A.
Published: October 2006

Local increases in neuronal activity within the brain lead to dilation of blood vessels and to increased regional cerebral blood flow. Increases in extracellular potassium concentration are known to dilate cerebral arterioles. Recent studies have suggested that the potassium released by active neurons is transported through astrocytic glial cells and released from their endfeet onto blood vessels. The results of computer simulations of potassium dynamics in the brain indicate that the release of potassium from astrocyte endfeet raises perivascular potassium concentration much more rapidly and to higher levels than does diffusion of potassium through extracellular space, particularly when the site of a potassium increase is some distance from the vessel wall. On the basis of this finding, it is proposed that the release of potassium from astrocyte endfeet plays an important role in regulating regional cerebral blood flow in response to changes in neuronal activity.
Structure of the Nucleotide Activation Switch in Glycogen Phosphorylase a
Authors: Sprang Stephen , Goldsmith Elizabeth , Fletterick Robert
Published: October 2006

Adenosine monophosphate is required for the activation of glycogen phosphorylase b and for release of the inhibition of phosphorylase a by glucose. Two molecules of adenosine monophosphate (AMP) bind to symmetry related sites at the subunit interface of the phosphorylase dimer. Adenosine triphosphate (ATP) binds to the same site, but does not promote catalytic activity. The structure of glucose-inhibited phosphorylase a bound to AMP and also of the complex formed with glucose and ATP is described. Crystallographic refinement of these complexes reveals that structural changes are associated with AMP but not ATP binding. The origin of these effects can be traced to different effector binding modes exhibited by AMP and ATP, respectively. The conformational changes associated with AMP binding traverse multiple paths in the enzyme and link the effector and catalytic sites.
Dual Infection of the Central Nervous System by AIDS Viruses with Distinct Cellular Tropisms
Authors: Koyanagi Yoshio , Miles Steven , Mitsuyasu Ronald T. , Merrill Jean E. , Vinters Harry V. , Chen Irvin S. Y.
Published: October 2006

Human immunodeficiency virus (HIV) is the causative agent of the acquired immune deficiency syndrome (AIDS). A large number of AIDS patients show evidence of neurologic involvement, known as AIDS-related subacute encephalopathy, which has been correlated with the presence of HIV in the brain. In this study, two genetically distinct but related viruses were isolated from one patient from two different sources in the central nervous system: brain tissue and cerebrospinal fluid. Both viruses were found to replicate in peripheral blood lymphocytes, but only virus from brain tissue will efficiently infect macrophage/monocytes. The viruses also differ in their ability to infect a brain glioma explant culture. This infection of the brain-derived cells in vitro is generally nonproductive, and appears to be some form of persistent or latent infection. These results indicate that genetic variation of HIV in vivo may result in altered cell tropisms and possibly implicate strains of HIV with glial cell tropism in the pathogenesis of some neurologic disorders of AIDS.
Injury Litigation and Liability Insurance Dynamics
Authors: Huber Peter
Published: October 2006

Prices for some lines of liability insurance have increased sharply in recent years, even while the real amount of coverage provided has declined. What accounts for these changes? The large financial inertia inherent in the insurance business, forecasting errors repeated across the industry, and herd-like reactions among many insurers have made the market adjustments exceptionally abrupt. But the most likely underlying cause for the current crisis in liability insurance is the inexorable expansion in liability law.
Apolipoprotein B-48 Is the Product of a Messenger RNA with an Organ-Specific In-Frame Stop Codon
Authors: Chen San-Hwan , Habib Geetha , Yang Chao-Yuh , Gu Zi-Wei , Lee Bo Rong , Weng Shi-Ai , Silberman Steven R. , Cai Sheng-Jian , Deslypere J. P. , Rosseneu Maryvonne , Gotto Antonio M. , Li Wen-Hsiung , Chan Lawrence
Published: October 2006

The primary structure of human apolipoprotein (apo) B-48 has been deduced and shown by a combination of DNA excess hybridization, sequencing of tryptic peptides, cloned complementary DNAs, and intestinal messenger RNAs (mRNAs) to be the product of an intestinal mRNA with an in-frame UAA stop codon resulting from a C to U change in the codon CAA encoding Gln
2153
in apoB-100 mRNA. The carboxyl-terminal Ile
2152
of apoB-48 purified from chylous ascites fluid has apparently been cleaved from the initial translation product, leaving Met
2151
as the new carboxyl-terminus. These data indicate that ∼85% of the intestinal mRNAs terminate within ∼0.1 to 1.0 kilobase downstream from the stop codon. The other ∼15% have lengths similar to hepatic apoB-100 mRNA even though they have the same in-frame stop codon. The organ-specific introduction of a stop codon to a mRNA appears unprecedented and might have implications for cryptic polyadenylation signal recognition and RNA processing.
Food Deprivation Increases Oral and Intravenous Drug Intake in Rats
Authors: Carroll Marilyn E. , France Charles P. , Meisch Richard A.
Published: October 2006

Rats given continuous access to etonitazene hydrochloride in their drinking water (5 micrograms per milliliter) more than doubled their drug intake while deprived of food. Another group of rats with implanted jugular catheters self-administered etonitazene (10 micrograms per kilogram) intravenously on a continuous reinforcement schedule, and the number of infusions increased significantly on days when they were deprived of food. These results suggest that feeding condition may be a powerful determinant of drug-reinforced behavior.
Actin Polymerization and ATP Hydrolysis
Authors: Korn Edward D. , Carlier Marie-France , Pantaloni Dominique
Published: October 2006

F-actin is the major component of muscle thin filaments and, more generally, of the microfilaments of the dynamic, multifunctional cytoskeletal systems of nonmuscle eukaryotic cells. Polymeric F-actin is formed by reversible noncovalent self-association of monomeric G-actin. To understand the dynamics of microfilament systems in cells, the dynamics of polymerization of pure actin must be understood. The following model has emerged from recent work. During the polymerization process, adenosine 5′-triphosphate (ATP) that is bound to G-actin is hydrolyzed to adenosine 5′-diphosphate (ADP) that is bound to F-actin. The hydrolysis reaction occurs on the F-actin subsequent to the polymerization reaction in two steps: cleavage of ATP followed by the slower release of inorganic phosphate (P
i
). As a result, at high rates of filament growth a transient cap of ATP-actin subunits exists at the ends of elongating filaments, and at steady state a stabilizing cap of ADP ⋅ P
i
-actin subunits exists at the barbed ends of filaments. Cleavage of ATP results in a highly stable filament with bound ADP ⋅ P
i
, and release of P
i
destabilizes the filament. Thus these two steps of the hydrolytic reaction provide potential mechanisms for regulating the monomer-polymer transition.
Genetic Ablation: Targeted Expression of a Toxin Gene Causes Microphthalmia in Transgenic Mice
Authors: Breitman Martin L. , Clapoff Susan , Rossant Janet , Tsui Lap-Chee , Glode L. Michael , Maxwell Ian H. , Bernstein Alan
Published: October 2006

Lineage-specific regulatory elements can be used to direct expression of a variety of genes to specific tissues in transgenic mice. If the hybrid constructs contain a gene encoding a cytotoxic gene product, then genetic ablation of a specific cell lineage can be achieved. We have generated six transgenic mice by introducing into fertilized eggs the mouse γ2-crystallin promoter fused to the coding region of the diphtheria toxin A-chain gene. Three of these mice and all the transgenic offspring analyzed were microphthalmic. The lenses of these mice displayed considerable heterogeneity: some were almost normal morphologically but reduced in size, whereas others were grossly aberrant and deficient in nuclear fiber cells. These studies indicate that programmed ablation of specific cell types can be stably transmitted through the germ line.
Similarity of Synthetic Peptide from Human Tumor to Parathyroid Hormone in Vivo and in Vitro
Authors: Horiuchi Noboru , Caulfield Michael P. , Fisher John E. , Goldman Mark E. , McKee Roberta L. , Reagan Jane E. , Levy Jay J. , Nutt Ruth F. , Rodan Sevgi B. , Schofield Timothy L. , Clemens Thomas L. , Rosenblatt Michael
Published: October 2006

One mechanism considered responsible for the hypercalcemia that frequently accompanies malignancy is secretion by the tumor of a circulating factor that alters calcium metabolism. The structure of a tumor-secreted peptide was recently determined and found to be partially homologous to parathyroid hormone (PTH). The amino-terminal 1-34 region of the factor was synthesized and evaluated biologically. In vivo it produced hypercalcemia, acted on bone and kidney, and stimulated 1,25-dihydroxy-vitamin D
3
formation. In vitro it interacted with PTH receptors and, in some systems, was more potent than PTH. These studies support a long-standing hypothesis regarding pathogenesis of malignancy-associated hypercalcemia.
Three-Dimensional Structure of the Adenovirus Major Coat Protein Hexon
Authors: Roberts Michael M. , White Janice L. , Grütter Markus G. , Burnett Roger M.
Published: October 2006

The three-dimensional crystal structure of the adenovirus major coat protein is presented. Adenovirus type 2 hexon, at 967 residues, is now the longest polypeptide whose structure has been determined crystallographically. Taken with our model for hexon packing, which positions the 240 trimeric hexons in the capsid, the structure defines 60% of the protein within the 150 × 10
6
dalton virion. The assembly provides the first details of a DNA-containing animal virus that is 20 times larger than the spherical RNA viruses previously described. Unexpectedly, the hexon subunit contains two similar β-barrels whose topology is identical to those of the spherical RNA viruses, but whose architectural role in adenovirus is very different. The hexon structure reveals several distinctive features related to its function as a stable protective coat, and shows that the type-specific immunological determinants are restricted to the virion surface.
University-Industry Research Relationships in Biotechnology: Implications for the University
Authors: Blumenthal David , Gluck Michael , Louis Karen Seashore , Stoto Michael A. , Wise David
Published: October 2006

The growth of university-industry research relationships in biotechnology has raised questions concerning their effects, both positive and negative, on universities. A survey of over 1200 faculty members at 40 major universities in the United States reveals that biotechnology researchers with industrial support publish at higher rates, patent more frequently, participate in more administrative and professional activities and earn more than colleagues without such support. At the same time, faculty with industry funds are much more likely than other biotechnology faculty to report that their research has resulted in trade secrets and that commercial considerations have influenced their choice of research projects. Although the data do not establish a causal connection between industrial support and these faculty behaviors, our findings strongly suggest that university-industry research relationships have both benefits and risks for academic institutions. The challenge for universities is to find ways to manage these relationships that will preserve the benefits while minimizing the risks.
Morphological Identification of Serotonin-Accumulating Neurons in the Living Retina
Authors: Vaney David I.
Published: October 2006

Neurons that accumulate the transmitter serotonin have been identified in the living retina by being labeled with 5,7-dihydroxytryptamine (5,7-HT), an autofluorescent serotonin analog. Iontophoretic injection of Lucifer yellow into the labeled cells under microscopic control revealed that the serotonin-accumulating neurons in rabbit retina constitute two morphological types of amacrine cells, termed S1 and S2, whose distal dendrites are stratified at the inner margin of the inner plexiform layer. The dendritic overlap of the S1 type is extraordinarily large: each point on the retina is covered by the fields of 550 to 900 S1 amacrines, and 6 to 8 meters of their dendrites are packed into each square millimeter of retina. Such a pervasive neuropil may provide an effective substrate for diffuse transmitter release, as proposed for serotonergic fibers elsewhere in the central nervous system.
A Plant Flavone, Luteolin, Induces Expression of
Rhizobium meliloti
Nodulation Genes
Authors: Peters N. Kent , Frost John W. , Long Sharon R.
Published: October 2006

The symbiotic interaction of
Rhizobium meliloti
and alfalfa results in the formation of nitrogen-fixing root nodules.
Rhizobium meliloti
nodABC
genes are required for the early host responses of cortical cell divisions and root hair curling. The induction of
nodABC
expression by alfalfa exudates demonstrates host-symbiont signaling at an early stage in nodule development. The inducer molecule for
nodABC
expression was isolated from plant exudate by constructing a
nodABC
-
lacZ
fusion to monitor the inducing activity. From ultraviolet-visible absorption spectra, proton nuclear magnetic resonance, and mass spectrometry, the inducer was determined to be 3′,4′,5,7-tetrahydroxyflavone (luteolin). Luteolin is a normal secondary plant metabolite found throughout the plant kingdom that may serve to control
nodABC
expression during nodule development. This regulatory role for a flavone contrasts with the function of some flavonoids as defense compounds.
Lung Cancer and Indoor Air Pollution in Xuan Wei, China
Authors: Mumford J. L. , He X. Z. , Chapman R. S. , Cao S. R. , Harris D. B. , Li X. M. , Xian Y. L. , Jiang W. Z. , Xu C. W. , Chuang J. C. , Wilson W. E. , Cooke M.
Published: October 2006

In Xuan Wei County, Yunnan Province, lung cancer mortality is among China's highest and, especially in females, is more closely associated with indoor burning of "smoky" coal, as opposed to wood or "smokeless" coal, than with tobacco smoking. Indoor air samples were collected during the burning of all three fuels. In contrast to wood and smokeless coal emissions, smoky coal emission has high concentrations of submicron particles containing mutagenic organics, especially in aromatic and polar fractions. These studies suggested an etiologic link between domestic smoky coal burning and lung cancer in Xuan Wei.
Circadian Timing of Cancer Chemotherapy
Authors: Hrushesky W. J. M.
Published: October 2006

Animal studies have indicated that the time of administration of adriamycin and cisplatin, two widely used anticancer drugs, has a profound effect on their toxicity. This effect in cancer chemotherapy was studied in 31 patients with advanced ovarian cancer. Patients received at least eight monthly courses of adriamycin that were followed 12 hours later by cisplatin, with adriamycin randomly administered at either 6 a.m. or 6 p.m. The results show that in the group receiving adriamycin in the evening and cisplatin in the morning (i) twice as many patients required reductions in dosage and delays in treatment, (ii) four times as many treatments had to be delayed, (iii) drug dosages had to be modified downward three times as often, and (iv) even with more dose attenuation and treatment delays, treatment complications were still about two times more common as in the group receiving adriamycin in the morning and cisplatin in the evening. These findings show that the circadian stage at which anticancer drugs are given to patients should be carefully considered.
Qinghaosu
(Artemisinin): an Antimalarial Drug from China
Authors: Klayman Daniel L.
Published: October 2006

The herb
Artemisia annua
has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called
qinghaosu
(QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of
Plasmodium falciparum
. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.
Biotechnology in Pharmaceuticals: The Japanese Challenge
Authors: Dibner Mark D.
Published: October 2006

The products of biotechnology are being developed for new diagnostics and therapeutics, and it is predicted that they will have great impact on the pharmaceutical industry. In the United States, pharmaceutical companies are incorporating biotechnology into their research and development programs, often with the contractual assistance of small biotechnology firms. Their strongest competition is arising in Japan, where there are now concerted government and industry efforts to expand biotechnology capabilities and to optimize commercialization. Strategies used by the United States and Japan to incorporate biotechnology into their pharmaceutical industries are examined and compared.
A Model for the Tertiary Structure of p21, the Product of the
ras
Oncogene
Authors: McCormick Frank , Clark Brian F. C. , la Cour Troels F. M. , Kjeldgaard Morten , Norskov-Lauritsen Leif , Nyborg Jens
Published: October 2006

A model was developed for the structure of p21, the protein with a molecular weight of 21,000 that is produced by the
ras
genes. This model predicts that p21 consists of a central core of β-sheet structure, connected by loops and α helices. Four of these loops comprise the guanine nucleotide binding site. The phosphoryl binding region is made up of amino acid sequences from 10 to 16 and from 57 to 63 of p21. The latter sequence may contain a site for magnesium binding. Amino acids defining guanine specificity are Asn-116 and Asp-119, and sequences around amino acid 145 may contribute to guanine binding. The model makes it possible to visualize how oncogenic mutations of p21 affect interaction with guanine nucleotides.
Neurovisceral and Skeletal G
M1
-Gangliosidosis in Dogs with β-Galactosidase Deficiency
Authors: Alroy Joseph , Orgad Uri , Ucci Angelo A. , Schelling Scott H. , Schunk Kenneth L. , Warren Christopher D. , Raghavan Srinivasa S. , Kolodny Edwin H.
Published: October 2006

β-galactosidase-deficient siblings in two litters of English springer spaniel puppies showed a progressive neurological impairment, dwarfism, orbital hypertelorism, and dysostosis multiplex. An excess of G
M1
-ganglioside was found in the brain. Three abnormal oligosaccharides were present in samples of urine, brain, liver, and cartilage. Light microscopy of selected tissue specimens revealed cytoplasmic vacuoles in neurons, circulating blood cells, macrophages, and chondrocytes. Ultrastructural studies demonstrated that these membrane-bound vacuoles were of two types—one containing lamellated membranes and the other, finely granular material. These clinical and pathological findings are similar to those observed in human patients affected by the infantile form of G
M1
-gangliosidosis.
Tissue Plasminogen Activator Reduces Neurological Damage After Cerebral Embolism
Authors: Zivin Justin A. , Fisher Marc , DeGirolami Umberto , Hemenway Carl C. , Stashak Joan A.
Published: October 2006

Intravenous administration of tissue plasminogen activator immediately after the injection of numerous small blood clots into the carotid circulation in rabbit embolic stroke model animals caused a significant reduction in neurological damage. In vitro studies indicate that tissue plasminogen activator produced substantial lysis of clots at concentrations comparable to those expected in vivo, suggesting that this may be the mechanism of action of this drug. Drug-induced hemorrhages were not demonstrable. Tissue plasminogen activator may be of value for the immediate treatment of embolic stroke.
Osmotic Adaptation by Gram-Negative Bacteria: Possible Role for Periplasmic Oligosaccharides
Authors: Miller Karen J. , Kennedy Eugene P. , Reinhold Vernon N.
Published: October 2006

The cyclic (1 → 2)-β-D-glucans produced by species of
Agrobacterium
and
Rhizobium
resemble the membrane-derived oligosaccharides of
Escherichia coli
in their periplasmic localization, intermediate size, and (1 → 2)-β-D-glucan backbones. The regulation of the biosynthesis of cyclic (1 → 2)-β-D-glucan by
Agrobacterium tumefaciens
is now shown to parallel the osmotic regulation of membrane-derived oligosaccharide biosynthesis in
Escherichia coli
. This result suggests a general role for periplasmic oligosaccharides in the osmotic adaptation of Gram-negative bacteria as ecologically diverse as enteric and soil bacteria.
Cell Line Segregation During Peripheral Nervous System Ontogeny
Authors: Le Douarin Nicole M.
Published: October 2006

The peripheral nervous system of vertebrates arises from the neural crest and the ectodermal placodes. Construction of quail-chick chimaeras has provided significant information on the migration and fate of the neural crest and placodal cells. Transplantation of neural crest tissue to various sites in these chimaeras has demonstrated that the differentiation of neural crest cells is controlled by environmental influences during their migration and, particularly, during gangliogenesis. Experiments with in vitro and monoclonal antibody techniques have shown that these environmental cues act on a heterogeneous population of neural crest cells whose developmental potencies are partly restricted to definite differentiation pathways.
Multiple Sensitive Periods in the Development of the Primate Visual System
Authors: Harwerth Ronald S. , Smith Earl L. , Duncan Gary C. , Crawford M. L. J. , von Noorden Gunter K.
Published: October 2006

Early in life, abnormal visual experience may disrupt the developmental processes required for the maturation and maintenance of normal visual function. The effects of retinal image deprivation (monocular form deprivation) on four psychophysical functions were investigated in rhesus monkeys to determine if the sensitive period is of the same duration for all types of visual information processing. The basic spectral sensitivity functions of rods and cones have relatively short sensitive periods of development (3 and 6 months) when compared to more complex functions such as monocular spatial vision or resolution (25 months) and binocular vision (>25 months). Therefore, there are multiple, partially overlapping sensitive periods of development and the sensitive period for each specific visual function is probably different.
Behavioral Facilitation of Reproduction in Sexual and Parthenogenetic
Drosophila
Authors: Crews David , Teramoto Linden T. , Carson Hampton L.
Published: October 2006

In a normal bisexual laboratory strain of
Drosophila mercatorum
, females housed with either fertile or sterile males lay more eggs than do females housed in pairs or as isolates. Females of a derived parthenogenetic strain have suffered genetic loss of this behavioral facilitation of egg production, a loss comparable to the loss of sexual receptivity. Despite these losses there has been a large increase in fecundity in the parthenogenetic strain. These findings are compared with those in a parthenogenetic lizard.
Government Policies and the Cost of Doing Research
Authors: Kennedy Donald
Published: October 2006

The changes in the political economy of science are the natural outcome of two trends: science itself has become a more capital-intensive activity at the same time that federal support for research programs has slowed its growth. The results of the accumulating shortfall in the capital base for university research—increased seeking of support from private industry, efforts to circumvent peer review and competitive allocation, and a falling-out between institutions and investigators over how to divide up available resources—threaten to unravel what has been an extraordinary way of doing science.