bluuebunny/crossref_metadata_2025 huggingface dataset:
Site-Specific, Sustained Release of Drugs to the Brain
Authors: Bodor Nicholas , Farag Hassan H. , Brewster Marcus E.
Published: October 2006

A dihydropyridine-pyridinium salt type of redox system is used in a general and flexible method for site-specific or sustained delivery (or both) of drugs to the brain. A biologically active compound linked to a lipoidal dihydropyridine carrier easily penetrates the blood-brain barrier. Oxidation of the carrier part in vivo to the ionic pyridinium salt prevents its elimination from the brain, while elimination from the general circulation is accelerated. Subsequent cleavage of the quaternary carrier-drug species results in sustained delivery of the drug in the brain and facile elimination of the carrier part.
Blue Light and Bilirubin Excretion
Authors: McDonagh Antony F. , Palma Lucita A. , Lightner David A.
Published: October 2006

Blue light converts bilirubin in the skin of jaundiced rats to metastable geometric isomers that are transported in blood and excreted in bile. The same reaction probably occurs in jaundiced babies exposed to light, particularly during treatment with phototherapy. Excretion of unisomerized bilirubin is prevented by intramolecular hydrogen bonding, and the pigment has to be metabolized to more polar derivatives to be excreted efficiently.
Hearing in the Elephant (
Elephas maximus
)
Authors: Heffner Rickye , Heffner Henry
Published: October 2006

Auditory thresholds were determined for a 7-year-old Indian elephant. The hearing range extended from 17 hertz to 10.5 kilohertz. The results indicate that the inverse relationship between functional interaural distance (that is, the distance between the two ears divided by the speed of sound) and high-frequency hearing limit is valid even for very large mammals.
Evidence for a Vesicular Transport Mechanism in Hepatocytes for Biliary Secretion of Immunoglobulin A
Authors: Renston Richard H. , Jones Albert L. , Christiansen William D. , Hradek Gary T. , Underdown Brian J.
Published: October 2006

Quantitative electron microscopic autoradiography and diaminobenzidine cytochemistry provide evidence for an uptake and vesicular transport mechanism for iodine-125-labeled immunoglobulin A from plasma to bile by hepatocytes in vivo. The data confirm the existence of a hepatobiliary pathway for secretion of immunoglobulin A into the intestine and are consistent with a vesicular transport mechanism for biliary proteins within liver parenchymal cells.
Acetylcholine Receptor: Complex of Homologous Subunits
Authors: Raftery Michael A. , Hunkapiller Michael W. , Strader Catherine D. , Hood Leroy E.
Published: October 2006

The acetylcholine receptor from the electric ray
Torpedo californica
is composed of five subunits; two are identical and the other three are structurally related to them. Microsequence analysis of the four polypeptides demonstrates amino acid homology among the subunits. Further sequence analysis of both membrane-bound and Triton-solubilized, chromatographically purified receptor gave the stoichiometry of the four subunits (40,000:50,000:60,000:65,000 daltons) as 2:1:1:1, indicating that this protein is a pentameric complex with a molecular weight of 255,000 daltons. Genealogical analysis suggests that divergence from a common ancestral gene occurred early in the evolution of the receptor. This shared ancestry argues that each of the four subunits plays a functional role in the receptor's physiological action.
Evolution of the Hemoglobin S and C Genes in World Populations
Authors: Kan Yuet Wai , Dozy Andrée M.
Published: October 2006

A polymorphic
Hpa
I endonuclease recognition site on the 3′ side of the β-globin gene was used to analyze the evolution of the β-globin gene mutants S and C. Study of the worldwide distribution of the normal and variant
Hpa
I sites showed that the mutation which resulted in the variant 13.0-kilobase fragment arose in a localized region in West Africa. It predated the hemoglobin S and C mutations, both of which arose separately from a chromosome with the variant 13.0-kilobase
Hpa
I site. In contrast, the sickle genes in other parts of Africa and in Asia are associated with the normal 7.6-kilobase
Hpa
I fragment, indicating that the sickle mutations in these other areas arose separately from that in West Africa.
Alterations in Brain Norepinephrine Metabolism Induced by Environmental Stimuli Previously Paired with Inescapable Shock
Authors: Cassens Geraldine , Roffman Mark , Kuruc Alvin , Orsulak Paul J. , Schildkraut Joseph J.
Published: October 2006

Footshock stress produced an immediate increase in brain concentrations of 3-methoxy-4-hydroxyphenylglycol sulfate (MHPG-SO
4
), a major metabolite of the neurotransmitter norepinephrine, in the rat brain. Twenty-four hours after footshock stress, when concentrations had returned to baseline, increases in MHPG-SO
4
and emotional behavior could be elicited by previously neutral environmental stimuli that had been paired with the stress.
Human Aging and Spatial Vision
Authors: Sekuler Robert , Hutman Lucinda P. , Owsley Cynthia J.
Published: October 2006

The ability to see spatial structures of a wide range of sizes was measured for two groups of observers (mean ages, 18 and 73 years). All observers had good visual acuity. Although older and younger observers did not differ in ability to see targets with fine structure (high spatial frequencies), older observers were only one-third as sensitive to targets with coarse structure (low spatial frequencies) as were younger observers. This difference cannot be attributed to ocular pathology in the older observers or to changes in criterion. Older observers were also less able than younger observers to see moving targets. The reduced sensitivity of the older observers may adversely affect routine perceptual activities, such as face recognition and visually guided postural behavior, that depend upon low spatial frequencies.
Suppression of Prolactin Secretion in Normal Young Women by 2-Hydroxyestrone
Authors: Fishman J. , Tulchinsky D.
Published: October 2006

The nonuterotropic natural estrogen 2-hydroxyestrone administered to normal young women results in a prompt and profound suppression of serum prolactin in most of the subjects. With the exception of dopamine, this is the only endogenous material known to strongly inhibit prolactin secretion, and its action suggests that the physiological regulation of prolactin by estrogens in the human is dual in nature, consisting of stimulation by estradiol and inhibition by its catechol estrogen metabolite.
Preserved Learning and Retention of Pattern-Analyzing Skill in Amnesia: Dissociation of Knowing How and Knowing That
Authors: Cohen Neal J. , Squire Larry R.
Published: October 2006

Amnesic patients acquired a mirror-reading skill at a rate equivalent to that of matched control subjects and retained it for at least 3 months. The results indicate that the class of preserved learning skills in amnesia is broader than previously reported. Amnesia seems to spare information that is based on rules or procedures, as contrasted with information that is data-based or declarative—"knowing how" rather than "knowing that." The results support the hypothesis that such a distinction is honored by the nervous system.
Stereospecific Nicotine Receptors on Rat Brain Membranes
Authors: Romano Carmelo , Goldstein Avram
Published: October 2006

A stereospecific binding site for nicotine has been detected on rat brain membranes. Competition studies with cholinergic agonists suggest that this site is a nicotinic cholinergic receptor.
Therapy of Mouse Lymphoma with Monoclonal Antibodies to Glycolipid: Selection of Low Antigenic Variants in Vivo
Authors: Young William W. , Hakomori Sen-Itiroh
Published: October 2006

Growth of mouse lymphoma L5178Y, which contains large quantities of the gangliotriosylceramide (GgOs
3
Cer), in DBA/2 mice was suppressed by passive immunization with monoclonal immunoglobulin G3 antibodies to GgOs
3
Cer, but not by immunoglobulin M antibodies with or without added complement. Most groups of mice treated with monoclonal immunoglobulin G3 antibodies did not develop tumors, but the tumor that appeared in a treated animal had a much lower amount of the GgOs
3
Cer than the cells used for inoculation. Thus, passive immunization either prevented growth of the lymphoma or caused selection of a variant with a lower quantity of the antigen GgOs
3
Cer.
Water Intake in Hypovolemic Sheep: Effects of Crushing the Left Atrial Appendage
Authors: Zimmerman Mark B. , Blaine Edward H. , Stricker Edward M.
Published: October 2006

Sheep increased their water intake in proportion to the amount of protein-free, isosmotic fluid that was removed from their blood by ultrafiltration. This behavioral response to hypovolemia was eliminated by crushing the left atrial appendage of the heart. The surgical maneuver had no effect on basal water intake or on the drinking response to a salt load. These findings suggest that left atrial stretch receptors, which influence secretion of antidiuretic hormone when stimulated, may also play an important role in mediating thirst during hypovolemia.
Difference in Brain Densities Between Chronic Alcoholic and Normal Control Patients
Authors: Golden Charles J. , Graber Benjamin , Blose Irwin , Berg Richard , Coffman Jeffrey , Bloch Solomon
Published: October 2006

The densities of the brains of 11 chronic alcoholics were compared with those of 11 age-matched normal control subjects. Densities were determined from the density numbers generated by computerized tomography at three levels of the brain-the highest level of the lateral ventricles and the next two higher levels-with adjustments made to control for possible artifacts in the data. The advantage of the dominant hemisphere over the nondominant hemisphere was lessened in alcoholics.
Prenatal Exposure to Synthetic Progestins Increases Potential for Aggression in Humans
Authors: Reinisch June Machover
Published: October 2006

Seventeen females and eight males exposed during gestation to synthetic progestins showed a significantly higher potential for physical aggression than their sex-matched unexposed siblings. Exposure to androgen-based compounds appeared to be most closely associated with aggressive responses. There were no differences in verbal aggression or IQ between exposed and unexposed siblings.
Abnormal Chromosome Behavior in
Neurospora
Mutants Defective in DNA Methylation
Authors: Foss Henriette M. , Roberts Christopher J. , Claeys Karen M. , Selker Eric U.
Published: October 2006

The function and regulation of DNA methylation in eukaryotes remain unclear. Genes affecting methylation were identified in the fungus
Neurospora crassa
. A mutation in one gene,
dim-2
, resulted in the loss of all detectable DNA methylation. Abnormal segregation of the methylation defects in crosses led to the discovery that the methylation mutants frequently generate strains with extra chromosomes or chromosomal parts. Starvation for
S
-adenosylmethionine, the presumed methyl group donor for DNA methylation, also produced aneuploidy. These results suggest that DNA methylation plays a role in the normal control of chromosome behavior.
Raphe Inhibition of Sympathetic Preganglionic Neurons
Authors: Cabot John B. , Wild J. Martin , Cohen David H.
Published: October 2006

Anatomical and electrophysiological studies suggest that the medullary raphe gives rise to a monosynaptic, inhibitory projection on sympathetic preganglionic neurons. Physiological and behavioral data indicate that this sympathoinhibitory pathway participates in the central control of cardiovascular function.
To Know with the Nose: Keys to Odor Identification
Authors: Cain William S.
Published: October 2006

Successful odor identification depends on (i) commonly encountered substances, (ii) a long-standing connection between an odor and its name, and (iii) aid in recalling the name. The absence of any one ingredient impairs performance dramatically, but the presence of all three permits ready identification of scores of substances, with performance seemingly limited only by the inherent confusability of the stimuli.
Mutagenicity of Malonaldehyde, a Decomposition Product of Peroxidized Polyunsaturated Fatty Acids
Authors: Mukai Frank H. , Goldstein Bernard D.
Published: October 2006

Incubation of histidine requiring auxotrophs of the bacterium
Salmonella typhimurium
with malonaldehyde, a three-carbon dialdehyde, produced an increased number of revertants in specific strains. Mutagenesis was only observed in frameshift mutants with normal excision repair and did not occur in those base-pair substitution mutants tested. The results are consistent with the cross-linking of bacterial DNA by malonaldehyde leading to mutagenesis expressed through the error-prone repair system.
Carbon Monoxide: a Putative Neural Messenger
Authors: Verma Ajay , Hirsch David J. , Glatt Charles E. , Ronnett Gabriele V. , Snyder Solomon H.
Published: October 2006

Carbon monoxide, an activator of guanylyl cyclase, is formed by the action of the enzyme heme oxygenase. By in situ hybridization in brain slices, discrete neuronal localization of messenger RNA for the constitutive form of heme oxygenase throughout the brain has been demonstrated. This localization is essentially the same as that for soluble guanylyl cyclase messenger RNA. In primary cultures of olfactory neurons, zinc protoporphyrin-9, a potent selective inhibitor of heme oxygenase, depletes endogenous guanosine 3′,5′-monophosphate (cGMP). Thus, carbon monoxide, like nitric oxide, may be a physiologic regulator of cGMP. These findings, together with the neuronal localizations of heme oxygenase, suggest that carbon monoxide may function as a neurotransmitter.
PAC-1: a Mitogen-Induced Nuclear Protein Tyrosine Phosphatase
Authors: Rohan Patricia J. , Davis Paula , Moskaluk Christopher A. , Kearns Mary , Krutzsch Henry , Siebenlist Ulrich , Kelly Kathleen
Published: October 2006

Tyrosine phosphorylation of proteins is required for signal transduction in cells and for growth regulation. A mitogen-induced gene (
PAC-1
) has been cloned from human T cells and encodes a 32-kilodalton protein that contains a sequence that defines the enzymatic site of known protein phosphotyrosine phosphatases (PTPases). Other than this sequence, PAC-1 is different from several other known related PTPases exemplified by PTP-1b. PAC-1 is similar to a phosphatase induced by mitogens or heat shock in fibroblasts, a yeast gene, and a vaccinia virus-encoded serine-tyrosine phosphatase (VH1). PAC-1 was predominantly expressed in hematopoietic tissues and localized to the nucleus in transfected COS-7 cells and in mitogen-stimulated T cells.
Conserved Structures and Diversity of Functions of RNA-Binding Proteins
Authors: Burd Christopher G. , Dreyfuss Gideon
Published: October 2006

In eukaryotic cells, a multitude of RNA-binding proteins play key roles in the posttranscriptional regulation of gene expression. Characterization of these proteins has led to the identification of several RNA-binding motifs, and recent experiments have begun to illustrate how several of them bind RNA. The significance of these interactions is reflected in the recent discoveries that several human and other vertebrate genetic disorders are caused by aberrant expression of RNA-binding proteins. The major RNA-binding motifs are described and examples of how they may function are given.
SH2-Containing Phosphotyrosine Phosphatase as a Target of Protein-Tyrosine Kinases
Authors: Feng Gen-Sheng , Hui Chi-Chung , Pawson Tony
Published: October 2006

A mouse phosphotyrosine phosphatase containing two Src homology 2 (SH2) domains, Syp, was identified. Syp bound to autophosphorylated epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors through its SH2 domains and was rapidly phosphorylated on tyrosine in PDGF- and EGF-stimulated cells. Furthermore, Syp was constitutively phosphorylated on tyrosine in cells transformed by v-
src
. This mammalian phosphatase is most closely related, especially in its SH2 domains, to the
corkscrew
(
csw
) gene product of
Drosophila
, which is required for signal transduction downstream of the Torso receptor tyrosine kinase. The
Syp
gene is widely expressed throughout embryonic mouse development and in adult tissues. Thus, Syp may function in mammalian embryonic development and as a common target of both receptor and nonreceptor tyrosine kinases.
Chloramine Mutagenesis in
Bacillus subtilis
Authors: Shih Katherine Lu , Lederberg Joshua
Published: October 2006

Chloramine (which occurs widely as a by-product of sanitary chlorination of water supplies) is shown to be a weak mutagen, when reversion of
trp
C to
trp
+
in
Bacillus subtilis
is used as an assay. Some DNA-repair mutants appear to be more sensitive to chloramine, suggesting the involvement of DNA targets in bactericide. The influence of plating media on survival of cells treated with chloramine suggests a bacterial repair system acting upon potentially lethal lesions induced by chloramine.
A Genetic Linkage Map of the Mouse: Current Applications and Future Prospects
Authors: Copeland Neal G. , Jenkins Nancy A. , Gilbert Debra J. , Eppig Janan T. , Maltais Lois J. , Miller Joyce C. , Dietrich William F. , Weaver Alix , Lincoln Stephen E. , Steen Robert G. , Stein Lincoln D. , Nadeau Joseph H. , Lander Eric S.
Published: October 2006

Technological advances have made possible the development of high-resolution genetic linkage maps for the mouse. These maps in turn offer exciting prospects for understanding mammalian genome evolution through comparative mapping, for developing mouse models of human disease, and for identifying the function of all genes in the organism.
Neural Induction by the Secreted Polypeptide Noggin
Authors: Lamb Teresa M. , Knecht Anne K. , Smith William C. , Stachel Scott E. , Economides Aris N. , Stahl Neil , Yancopolous George D. , Harland Richard M.
Published: October 2006

The Spemann organizer induces neural tissue from dorsal ectoderm and dorsalizes lateral and ventral mesoderm in
Xenopus
. The secreted factor noggin, which is expressed in the organizer, can mimic the dorsalizing signal of the organizer. Data are presented showing that noggin directly induces neural tissue, that it induces neural tissue in the absence of dorsal mesoderm, and that it acts at the appropriate stage to be an endogenous neural inducing signal. Noggin induces cement glands and anterior brain markers, but not hindbrain or spinal cord markers. Thus, noggin has the expression pattern and activity expected of an endogenous neural inducer.
Multiple RNA Polymerase Conformations and GreA: Control of the Fidelity of Transcription
Authors: Erie Dorothy A. , Hajiseyedjavadi Omid , Young Mark C. , von Hippel Peter H.
Published: October 2006

Pre-steady state kinetics of misincorporation were used to investigate the addition of single nucleotides to nascent RNA by
Escherichia coli
RNA polymerase during transcription elongation. The results were fit with a branched kinetic mechanism that permits conformational switching, at each template position, between an activated and an unactivated enzyme complex, both of which can bind nucleotide triphosphates (NTPs) from solution. The complex exists most often in the long-lived activated state, and only becomes unactivated when transcription is slowed. This model permits multiple levels of nucleotide discrimination in transcription, since the complex can be "kinetically trapped" in the unactivated state in the absence of the correct NTP or if the 3′ terminal residue is incorrectly matched. The transcription cleavage factor GreA (or an activity enhanced by GreA) increased the fidelity of transcription by preferential cleavage of transcripts containing misincorporated residues in the unactivated state of the elongation complex. This cleavage mechanism by GreA may prevent the formation of "dead-end" transcription complexes in vivo.
Guanidinium Chloride Induction of Partial Unfolding in Amide Proton Exchange in RNase A
Authors: Mayo Stephen L. , Baldwin Robert L.
Published: October 2006

Amide (NH) proton exchange rates were measured in 0.0 to 0.7 M guanidinium chloride (GdmCl) for 23 slowly exchanging peptide NH protons of ribonuclease A (RNase A) at pH
*
5.5 (uncorrected pH measured in D
2
O), 34°C. The purpose was to find out whether GdmCl induces exchange through binding to exchange intermediates that are partly or wholly unfolded. It was predicted that, when the logarithm of the exchange rate is plotted as a function of the molarity of GdmCl, the slope should be a measure of the amount of buried surface area exposed to GdmCl in the exchange intermediate. The results indicate that these concentrations of GdmCl do induce exchange by means of a partial unfolding mechanism for all 23 protons; this implies that exchange reactions can be used to study the unfolding and stability of local regions. Of the 23 protons, nine also show a second mechanism of exchange at lower concentrations of GdmCl, a mechanism that is nearly independent of GdmCl concentration and is termed "limited structural fluctuation."
Association of the APC Tumor Suppressor Protein with Catenins
Authors: Su Li-Kuo , Vogelstein Bert , Kinzler Kenneth W.
Published: October 2006

Mutations of
APC
appear to initiate sporadic and inherited forms of human colorectal cancer. Although these mutations have been well characterized, little is known about the function of the
APC
gene product. Two cellular proteins that associate with APC were identified by nucleotide sequence analysis and peptide mapping as the E-cadherin-associated proteins α- and β-catenin. A 27-residue fragment of APC containing a 15-amino acid repeat was sufficient for the interaction with the catenins. These results suggest an important link between tumor initiation and cell adhesion.
Chromosome Condensation in
Xenopus
Mitotic Extracts Without Histone H1
Authors: Ohsumi Keita , Katagiri Chiaki , Kishimoto Takeo
Published: October 2006

The contribution of histone H1 to mitotic chromosome condensation was examined with the use of a cell-free extract from
Xenopus
eggs, which transforms condensed sperm nuclei into metaphase chromosomes. When H1 was removed from the extract, the resultant metaphase chromosomes were indistinguishable from those formed in complete extract. Nucleosomal spacing was the same for both. Thus, H1 is not required for the structural reorganization that leads to condensed metaphase chromosomes in this egg extract.
Distinct Roles for Cyclin-Dependent Kinases in Cell Cycle Control
Authors: van den Heuvel Sander , Harlow Ed
Published: October 2006

The key cell-cycle regulator Cdc2 belongs to a family of cyclin-dependent kinases in higher eukaryotes. Dominant-negative mutations were used to address the requirement for kinases of this family in progression through the human cell cycle. A dominant-negative Cdc2 mutant arrested cells at the G
2
to M phase transition, whereas mutants of the cyclin-dependent kinases Cdk2 and Cdk3 caused a G
1
block. The mutant phenotypes were specifically rescued by the corresponding wild-type kinases. These data reveal that Cdk3, in addition to Cdc2 and Cdk2, executes a distinct and essential function in the mammalian cell cycle.
Dissociation of Object and Spatial Processing Domains in Primate Prefrontal Cortex
Authors: Wilson Fraser A. W. , Scalaidhe Séamas P. Ó. , Goldman-Rakic Patricia S.
Published: October 2006

Areas and pathways subserving object and spatial vision are segregated in the visual system. Experiments show that the primate prefrontal cortex is similarly segregated into object and spatial domains. Neurons that code information related to stimulus identity are dissociable, both by function and region, from those that code information related to stimulus location. These findings indicate that the prefrontal cortex contains separate processing mechanisms for remembering "what" and "where" an object is.
Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates
Authors: Trail P. A. , Willner D. , Lasch S. J. , Henderson A. J. , Hofstead S. , Casazza A. M. , Firestone R. A. , Hellström I. , Hellström K. E.
Published: October 2006

Immunoconjugates (BR96-DOX) were prepared between chimeric monoclonal antibody BR96 and the anticancer drug doxorubicin. The monoclonal antibody binds an antigen related to Lewis Y that is abundantly expressed at the surface of cells from many human carcinomas; it has a high degree of tumor selectivity and is internalized after binding. BR96-DOX induced complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and cured 70 percent of mice bearing extensive metastases of a human lung carcinoma. Also, BR96-DOX cured 94 percent of athymic rats with subcutaneous human lung carcinoma, even though the rats, like humans and in contrast to mice, expressed the BR96 target antigen in normal tissues.
Induction of Apoptosis by the Low-Affinity NGF Receptor
Authors: Rabizadeh Shahrooz , Oh Justin , Zhong Li-tao , Yang Jie , Bitler Catherine M. , Butcher Larry L. , Bredesen Dale E.
Published: October 2006

Nerve growth factor (NGF) binding to cellular receptors is required for the survival of some neural cells. In contrast to TrkA, the high-affinity NGF receptor that transduces NGF signals for survival and differentiation, the function of the low-affinity NGF receptor, p75
NGFR
, remains uncertain. Expression of p75
NGFR
induced neural cell death constitutively when p75
NGFR
was unbound; binding by NGF or monoclonal antibody, however, inhibited cell death induced by p75
NGFR
. Thus, expression of p75
NGFR
may explain the dependence of some neural cells on NGF for survival. These findings also suggest that p75
NGFR
has some functional similarities to other members of a superfamily of receptors that include tumor necrosis factor receptors, Fas (Apo-1), and CD40.
Greater Susceptibility to Mutations in Lagging Strand of DNA Replication in
Escherichia coli
than in Leading Strand
Authors: Veaute Xavier , Fuchs Robert P. P.
Published: October 2006

Models of DNA replication in
Escherichia coli
involve an asymmetric DNA polymerase complex that replicates concurrently the leading and the lagging strands of double-stranded DNA. The effect of asymmetry on mutagenesis was tested with pairs of plasmids containing the unidirectional ColE1 origin of replication and a single lesion located in the leading or lagging strand. The lesion used was the covalent adduct that the chemical carcinogen
N
-2-acetylaminofluorene (AAF) forms with the C-8 position of guanine. Whether SOS was induced or not, mutations arose at about a 20-fold higher frequency when the AAF adduct was located in the lagging strand than when in the leading strand.
Antisense Oligonucleotides as Therapeutic Agents—Is the Bullet Really Magical?
Authors: Stein C. A. , Cheng Y.-C.
Published: October 2006

Because of the specificity of Watson-Crick base pairing, attempts are now being made to use oligodeoxynucleotides (oligos) in the therapy of human disease. However, for a successful outcome, the oligo must meet at least six criteria: (i) the oligos can be synthesized easily and in bulk; (ii) the oligos must be stable in vivo; (iii) the oligos must be able to enter the target cell; (iv) the oligos must be retained by the target cell; (v) the oligos must be able to interact with their cellular targets; and (vi) the oligos should not interact in a non-sequence-specific manner with other macromolecules. Phosphorothioate oligos are examples of oligos that are being considered for clinical therapeutic trials and meet some, but not all, of these criteria. The potential use of phosphorothioate oligos as inhibitors of viral replication is highlighted.
Retinal Degeneration in Choroideremia: Deficiency of Rab Geranylgeranyl Transferase
Authors: Seabra Miguel C. , Brown Michael S. , Goldstein Joseph L.
Published: October 2006

Rab geranylgeranyl transferase (GG transferase) is a two-component enzyme that attaches 20-carbon isoprenoid groups to cysteine residues in Rab proteins, a family of guanosine triphosphate-binding proteins that regulate vesicular traffic. The mutant gene in human choroideremia, an X-linked form of retinal degeneration, encodes a protein that resembles component A of rat Rab GG transferase. Lymphoblasts from choroideremia subjects showed a marked deficiency in the activity of component A, but not component B, of Rab GG transferase. The deficiency was more pronounced when the substrate was Rab3A, a synaptic vesicle protein, than it was when the substrate was Rab1A, a protein of the endoplasmic reticulum. The data imply the existence of multiple component A proteins, one of which is missing in choroideremia.
Modulation of Anxiety and Neuropeptide Y-Y1 Receptors by Antisense Oligodeoxynucleotides
Authors: Wahlestedt Claes , Pich Emilio Merlo , Koob George F. , Yee Frances , Heilig Markus
Published: October 2006

The function of neuropeptide Y, one of the most abundant peptide transmitters of the mammalian brain, remains unclear because of a lack of specific receptor antagonists. An antisense oligodeoxynucleotide corresponding to the NH
2
-terminus of the rat Y1 receptor was constructed and added to cultures of rat cortical neurons. This treatment resulted in a reduced density of Y1 (but not Y2) receptors and diminished the decrease in adenosine 3′,5′-monophosphate (cAMP) usually seen after Y1 receptor activation. Repeated injection of the same oligodeoxynucleotide into the lateral cerebral ventricle of rats was followed by a similar reduction of cortical Y1 (but not Y2) receptors. Such antisense-treated animals displayed behavioral signs of anxiety. Thus, specific inhibition of neurotransmitter receptor expression can be accomplished in the living brain and demonstrates that altered central neuropeptide Y transmission produces an anxiety-like state.
Distinct Functions of SR Proteins in Alternative pre-mRNA Splicing
Authors: Zahler Alan M. , Neugebauer Karla M. , Lane William S. , Roth Mark B.
Published: October 2006

Alternative splicing of precursor messenger RNAs (pre-mRNAs) is a common mechanism of regulating gene expression. SR proteins are a family of pre-mRNA splicing factors that are structurally related and evolutionarily conserved. Any member of the SR family can complement a splicing-deficient extract that lacks the entire family of SR proteins. Here it is demonstrated that particular SR proteins have distinct functions in alternative pre-mRNA splicing in vitro. In addition, SR proteins are differentially expressed in a variety of tissues. These results suggest a fundamental role for SR proteins in the regulation of alternative splicing.
Selectivity for Polar, Hyperbolic, and Cartesian Gratings in Macaque Visual Cortex
Authors: Gallant Jack L. , Braun Jochen , Van Essen David C.
Published: October 2006

The neural basis of pattern recognition is a central problem in visual neuroscience. Responses of single cells were recorded in area V4 of macaque monkey to three classes of periodic stimuli that are based on spatial derivative operators: polar (concentric and radial), hyperbolic, and conventional sinusoidal (Cartesian) gratings. Of 118 cells tested, 16 percent responded significantly more to polar or hyperbolic (non-Cartesian) gratings than to Cartesian gratings and only 8 percent showed a significant preference for Cartesian gratings. Among cells selective for non-Cartesian gratings, those that preferred concentric gratings were most common. Cells selective for non-Cartesian gratings may constitute an important intermediate stage in pattern recognition and the representation of surface shape.
Regulation of the Human hsp70 Promoter by p53
Authors: Agoff S. Nicholas , Hou Jeannie , Linzer Daniel I. , Wu Barbara
Published: October 2006

The tumor suppressor p53 is a nuclear phosphoprotein with characteristics of a transcription factor. It displays sequence-specific DNA binding, contains a potent transactivation domain, and has been implicated as both a transcriptional activator and a repressor. Transcription of the human
hsp70
gene is stimulated by adenovirus E1a protein. This E1a transactivation of the hsp70 promoter is mediated by CCAAT binding factor (CBF). It is demonstrated here that p53 both represses transcription from the human hsp70 promoter and also interacts with CBF. Thus, the repression of the hsp70 promoter by p53 may be mediated by direct protein-protein interaction with CBF. These results suggest that protein-protein interaction between p53 and specific transcription factors may be an additional mechanism by which p53 regulates gene expression.
In Situ Stimulation of Aerobic PCB Biodegradation in Hudson River Sediments
Authors: Harkness M. R. , McDermott J. B. , Abramowicz D. A. , Salvo J. J. , Flanagan W. P. , Stephens M. L. , Mondello F. J. , May R. J. , Lobos J. H. , Carroll K. M. , Brennan M. J. , Bracco A. A. , Fish K. M. , Warner G. L. , Wilson P. R. , Dietrich D. K. , Lin D. T. , Morgan C. B. , Gately W. L.
Published: October 2006

A 73-day field study of in situ aerobic biodegradation of polychlorinated biphenyls (PCBs) in the Hudson River shows that indigenous aerobic microorganisms can degrade the lightly chlorinated PCBs present in these sediments. Addition of inorganic nutrients, biphenyl, and oxygen enhanced PCB biodegradation, as indicated both by a 37 to 55 percent loss of PCBs and by the production of chlorobenzoates, intermediates in the PCB biodegradation pathway. Repeated inoculation with a purified PCB-degrading bacterium failed to improve biodegradative activity. Biodegradation was also observed under mixed but unamended conditions, which suggests that this process may occur commonly in river sediments, with implications for PCB fate models and risk assessments.
Demic Expansions and Human Evolution
Authors: Cavalli-Sforza Luigi L. , Menozzi Paolo , Piazza Alberto
Published: October 2006

Geographic expansions are caused by successful innovations, biological or cultural, that favor local growth and movement. They have had a powerful effect in determining the present patterns of human genetic geography. Modern human populations expanded rapidly across the Earth in the last 100,000 years. At the end of the Paleolithic (10,000 years ago) only a few islands and other areas were unoccupied. The number of inhabitants was then about one thousand times smaller than it is now. Population densities were low throughout the Paleolithic, and random genetic drift was therefore especially effective. Major genetic differences between living human groups must have evolved at that time. Population growths that began afterward, especially with the spread of agriculture, progressively reduced the drift in population and the resulting genetic differentiation. Genetic traces of the expansions that these growths determined are still recognizable.
Selection of Bacterial Virulence Genes That Are Specifically Induced in Host Tissues
Authors: Mahan Michael J. , Slauch James M. , Mekalanos John J.
Published: October 2006

A genetic system was devised that positively selects for bacterial genes that are specifically induced when bacteria infect their host. With the pathogen
Salmonella typhimurium
, the genes identified by this selection show a marked induction in bacteria recovered from mouse spleen. Mutations in all
ivi
(in vivo-induced) genes that were tested conferred a defect in virulence. This genetic system was designed to be of general use in a wide variety of bacterial-host systems and has several applications in both vaccine and antimicrobial drug development.
Carboxyl Methylation of Ras-Related Proteins During Signal Transduction in Neutrophils
Authors: Philips Mark R. , Pillinger Michael H. , Staud Roland , Volker Craig , Rosenfeld Melvin G. , Weissmann Gerald , Stock Jeffry B.
Published: October 2006

In human neutrophils, as in other cell types, Ras-related guanosine triphosphate-binding proteins are directed toward their regulatory targets in membranes by a series of posttranslational modifications that include methyl esterification of a carboxyl-terminal prenylcysteine residue. In intact cells and in a reconstituted in vitro system, the amount of carboxyl methylation of Ras-related proteins increased in response to the chemoattractant
N
-formyl-methionyl-leucyl-phenylalanine (FMLP). Activation of Ras-related proteins by guanosine-5′-
O
-(3-thiotriphosphate) had a similar effect and induced translocation of p22

rac2

from cytosol to plasma membrane. Inhibitors of prenylcysteine carboxyl methylation effectively blocked neutrophil responses to FMLP. These findings suggest a direct link between receptor-mediated signal transduction and the carboxyl methylation of Ras-related proteins.
Antibody-Catalyzed Degradation of Cocaine
Authors: Landry Donald W. , Zhao Kang , Yang Ginger X.-Q. , Glickman Michael , Georgiadis Taxiarchis M.
Published: October 2006

Immunization with a phosphonate monoester transition-state analog of cocaine provided monoclonal antibodies capable of catalyzing the hydrolysis of the cocaine benzoyl ester group. An assay for the degradation of radiolabeled cocaine identified active enzymes. Benzoyl esterolysis yields ecgonine methyl ester and benzoic acid, fragments devoid of cocaine's stimulant activity. Passive immunization with such an artificial enzyme could provide a treatment for dependence by blunting reinforcement.
Transient Transfection and Expression in the Obligate Intracellular Parasite
Toxoplasma gondii
Authors: Soldati Dominique , Boothroyd John C.
Published: October 2006

Toxoplasma gondii
is a protozoan pathogen that produces severe disease in humans and animals. This obligate intracellular parasite provides an excellent model for the study of how such pathogens are able to invade, survive, and replicate intracellularly. DNA encoding chloramphenicol acetyltransferase was introduced into
T. gondii
and transiently expressed with the use of three vectors based on different
Toxoplasma
genes. The ability to introduce genes and have them efficiently and faithfully expressed is an essential tool for understanding the structure-function relation of genes and their products.
Permeation of Manganese, Cadmium, Zinc, and Beryllium Through Calcium Channels of an Insect Muscle Membrane
Authors: Fukuda Jun , Kawa Kazuyoshi
Published: October 2006

Larval muscle fibers of a beetle,
Xylotrupes dichotomus
, produce calcium spikes that are maintained when the fibers are bathed in saline solutions containing manganese, cadmium, zinc, or beryllium instead of calcium. This indicates that these cations permeate the calcium channels of the muscle fiber. By contrast, cobalt, nickel, and magnesium are nonpermeating and behave as competitive inhibitors of the permeation of the other divalent cations. Some of the permeating cations suppress delayed rectification.
Negative Regulation of G1 in Mammalian Cells: Inhibition of Cyclin E-Dependent Kinase by TGF-β
Authors: Koff Andrew , Ohtsuki Masahiko , Polyak Kornelia , Roberts James M. , Massagué Joan
Published: October 2006

Transforming growth factor-β (TGF-β) is a naturally occurring growth inhibitory polypeptide that arrests the cell cycle in middle to late G1 phase. Cells treated with TGF-β contained normal amounts of cyclin E and cyclin-dependent protein kinase 2 (Cdk2) but failed to stably assemble cyclin E-Cdk2 complexes or accumulate cyclin E-associated kinase activity. Moreover, G1 phase extracts from TGF-β-treated cells did not support activation of endogenous cyclin-dependent protein kinases by exogenous cyclins. These effects of TGF-β, which correlated with the inhibition of retinoblastoma protein phosphorylation, suggest that mammalian G1 cyclin-dependent kinases, like their counterparts in yeast, are targets for negative regulators of the cell cycle.
The Nitrogenase FeMo-Cofactor and P-Cluster pair: 2.2 Å Resolution Structures
Authors: Chan Michael K. , Kim Jongsun , Rees D. C.
Published: October 2006

Structures recently proposed for the FeMo-cofactor and P-cluster pair of the nitrogenase molybdenum-iron (MoFe)-protein from
Azotobacter vinelandii
have been crystallographically verified at 2.2 angstrom resolution. Significantly, no hexacoordinate sulfur atoms are observed in either type of metal center. Consequently, the six bridged iron atoms in the FeMo-cofactor are trigonally coordinated by nonprotein ligands, although there may be some iron-iron bonding interactions that could provide a fourth coordination interaction for these sites. Two of the cluster sulfurs in the P-cluster pair are very close together (∼2.1 angstroms), indicating that they form a disulfide bond. These findings indicate that a cavity exists in the interior of the FeMo-cofactor that could be involved in substrate binding and suggest that redox reactions at the P-cluster pair may be linked to transitions of two cluster-bound sulfurs between disulfide and sulfide oxidation states.
How Does HIV Cause AIDS?
Authors: Weiss Robin A.
Published: October 2006

Many questions have been posed about acquired immunodeficiency syndrome (AIDS) pathogenesis. Is human immunodeficiency virus (HIV) both necessary and sufficient to cause AIDS? Is AIDS essentially an autoimmune disease, triggering apoptosis, or is virus infection the cause of T helper lymphocyte depletion? What is the significance of HIV tropism and the role of macrophages and dendritic cells in AIDS? Is there viral latency and why is there usually a long period between infection and AIDS? Is HIV variation a crucial aspect of its pathogenesis and, if so, do virulent strains emerge? Although this article provides few definitive answers, it aims to focus commentary on salient points. Overall, it is increasingly evident that both the tropism and burden of HIV infection correlate closely with the manifestations of disease.
Footprinting the Sites of Interaction of Antibiotics with Catalytic Group I Intron RNA
Authors: von Ahsen Uwe , Noller HHarry F.F
Published: October 2006

Aminoglycoside inhibitors of translation have been shown previously to inhibit in vitro self-splicing by group I introns. Chemical probing of the phage T4-derived sunY intron shows that neomycin, streptomycin, and related antibiotics protected the N-7 position of G96, a universally conserved guanine in the binding site for the guanosine cofactor in the splicing reaction. The antibiotics also disrupted structural contacts that have been proposed to bring the 5′ cleavage site of the intron into proximity to the catalytic core. In contrast, the strictly competitive inhibitors deoxyguanosine and arginine protected only the N-7 position of G96. Parallels between these results and previously observed protection of 16
S
ribosomal RNA by aminoglycosides raise the possibility that group I intron splicing and transfer RNA selection by ribosomes involve similar RNA structural motifs.
New Domain Motif: the Structure of Pectate Lyase C, a Secreted Plant Virulence Factor
Authors: Yoder Marilyn D. , Keen Noel T. , Jurnak Frances
Published: October 2006

Pectate lyases are secreted by pathogens and initiate soft-rot diseases in plants by cleaving polygalacturonate, a major component of the plant cell wall. The three-dimensional structure of pectate lyase C from
Erwinia chrysanthemi
has been solved and refined to a resolution of 2.2 angstroms. The enzyme folds into a unique motif of parallel β strands coiled into a large helix. Within the core, the amino acids form linear stacks and include a novel asparagine ladder. The sequence similarities that pectate lyases share with pectin lyases, pollen and style proteins, and tubulins suggest that the parallel β helix motif may occur in a broad spectrum of proteins.
Common Forms of Synaptic Plasticity in the Hippocampus and Neocortex in Vitro
Authors: Kirkwood Alfredo , Dudek Serena M. , Gold Joel T. , Aizenman Carlos D. , Bear Mark F.
Published: October 2006

Activity-dependent synaptic plasticity in the superficial layers of juvenile cat and adult rat visual neocortex was compared with that in adult rat hippocampal field CA1. Stimulation of neocortical layer IV reliably induced synaptic long-term potentiation (LTP) and long-term depression (LTD) in layer III with precisely the same types of stimulation protocols that were effective in CA1. Neocortical LTP and LTD were specific to the conditioned pathway and, as in the hippocampus, were dependent on activation of
N
-methyl-D-aspartate receptors. These results provide strong support for the view that common principles may govern experience-dependent synaptic plasticity in CA1 and throughout the superficial layers of the mammalian neocortex.
Heteromorphic Sex Chromosomes in Male Rainbow Trout
Authors: Thorgaard Gary H.
Published: October 2006

A pair of subtelocentric chromosomes differs in the size of the short arm in male, but not female, rainbow trout (
Salmo gairdneri
). The morphological similarity of the X and Y chromosomes, and the observation of Y chromosomes intermediate between the X and normal Y, suggest that the sex chromosomes are at an early stage of differentiation in this species.
Androgen Concentration in Motor Neurons of Cranial Nerves and Spinal Cord
Authors: Sar Madhabananda , Stumpf Walter E.
Published: October 2006

After injection of [
3
H]dihydrotestosterone, a major testosterone metabolite, radioactivity is concentrated in nuclei of certain cells in the midbrain, pons, medulla oblongata, cerebellum, and spinal cord. While there is some overlap between androgen and estrogen target neuron distribution, certain motor neurons appear to be selectively labeled by androgen; in contrast, estrogen localization prevails in sensory neurons. These results may help to explain why male sexual behavior in some rodents is not fully activated with dihydrotestosterone alone but in addition requires estradiol, a testosterone metabolite.
Clomid or Nafoxidine Administered to Neonatal Rats Causes Reproductive Tract Abnormalities
Authors: Clark James H. , McCormack Shirley
Published: October 2006

A single injection of either Clomid or Nafoxidine in neonatal rats causes multiple abnormalities of the reproductive tract of the adult female animal. These anomalies include cystic ovaries, ovarian hypoplasia, hilus cell tumors, oviductal hyperplasia, pyometra, epithelial metaplasia, uterine cystic hyperplasia, and tumors of the uterus.
Fragile Sites on Human Chromosomes: Demonstration of Their Dependence on the Type of Tissue Culture Medium
Authors: Sutherland Grant R.
Published: October 2006

The observation of heritable fragile sites on human chromosomes prepared from lymphocyte cultures has been shown to depend on the type of tissue culture medium in which the lymphocytes are grown. The sites are observed at a much greater frequency when medium 199 is used than when RPMI 1640, Ham's F10, Eagle's (basal), and CMRL 1969 are used. One site on the X chromosome is of clinical significance in that it is a marker for X-linked mental retardation.
Polarity Reversal in Nerve-Free Hydra
Authors: Marcum Beverly A. , Campbell Richard D. , Romero José
Published: October 2006

Hydra experimentally depleted of all nerve cells and nerve stem cells (interstitial cells) demonstrate normal polarity reversal. Thus hydra epithelial cells are capable of controlling complex developmental patterning phenomena.
Alcohol Tolerance in a Cholinergic Nerve Terminal: Relation to the Membrane Expansion-Fluidization Theory of Ethanol Action
Authors: Curran M. , Seeman P.
Published: October 2006

Phrenic nerve terminals from rats subjected to long-term ethanol treatment were more resistant to ethanol (in vitro) than terminals from sucrose-fed rats, as measured by the effect of ethanol on the frequency of miniature end plate potentials. Long-term ethanol exposure may thus induce the synthesis of more rigid membrane lipids, reducing membrane "fluidizability." This may provide a neurocellular basis for ethanol tolerance and cross-tolerance with anesthetics and barbiturates.