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Showing papers by "University of California, San Francisco published in 1982"


Journal ArticleDOI
09 Apr 1982-Science
TL;DR: A new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids.
Abstract: After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.

4,753 citations


Journal ArticleDOI
TL;DR: A method to explore geometrically feasible alignments of ligands and receptors of known structure and finds distinctly different geometries that provide good steric fits seems well-suited for generating starting conformations for energy refinement programs and interactive computer graphics routines.

2,197 citations


Journal ArticleDOI
01 Nov 1982-Cell
TL;DR: It is proposed that tumorigenesis by MMTV is strongly favored by proviral insertion within the int1 locus, perhaps as a consequence of enhanced expression of a novel cellular oncogene.

1,781 citations


Journal ArticleDOI
01 Oct 1982-Cell
TL;DR: The Xenopus embryo undergoes 12 rapid synchronous cleavages followed by a period of slower asynchronous divisions more typical of somatic cells, termed the midblastula transition (MBT), which shows that at the MBT the blastomeres become motile and transcriptionally active for the first time.

1,587 citations


Journal ArticleDOI
TL;DR: An 18-item version of the Client Satisfaction Questionnaire (CSQ-18) was included in an experimental study of the effects of pretherapy orientation on psychotherapy outcome and demonstrated that a subset of items from the scale performed as well as the CSQ-8 and often better.

1,392 citations


Journal ArticleDOI
24 Dec 1982-Science
TL;DR: Initial results suggest that the amount of this protein correlates with the titer of the agent, and the resistance of thisprotein to digestion by proteinase K distinguished it from proteins of similar molecular weight found in normal hamster brain.
Abstract: Purification of prions from scrapie-infected hamster brain yielded a protein that was not found in a similar fraction from uninfected brain. The protein migrated with an apparent molecular size of 27,000 to 30,000 daltons in sodium dodecyl sulfate polyacrylamide gels. The resistance of this protein to digestion by proteinase K distinguished it from proteins of similar molecular weight found in normal hamster brain. Initial results suggest that the amount of this protein correlates with the titer of the agent.

1,263 citations


Journal ArticleDOI
TL;DR: Evidence indicates that a profound reorganization of human brain function takes place during adolescence: the amount of deep sleep and the rate of brain metabolism fall sharply; the latency of certain event-related potentials declines; the capacity to recover function after brain injury diminishes; and adult problem-solving "power" appears.

1,231 citations


Journal ArticleDOI
01 Oct 1982-Cell
TL;DR: It is shown here that a plasmid containing a cloned gene coding for a yeast leucine tRNA comes under developmental control when injected into cleaving eggs, suggesting that the MBT is triggered by the DNA through titration of suppressor components present in the egg.

1,105 citations


Journal ArticleDOI
TL;DR: Theoretically based distinctions linked to measurable differences in appearance are described for three smiles: felt smiles (spontaneous expressions of positive emotion), false smiles (deliberate attempts to appear as if positive emotion is felt when it isn't); and, miserable smiles (acknowledgements of feeling miserable but not intending to do much about it).
Abstract: Theoretically based distinctions linked to measurable differences in appearance are described for three smiles: felt smiles (spontaneous expressions of positive emotion); false smiles (deliberate attempts to appear as if positive emotion is felt when it isn't); and, miserable smiles (acknowledgements of feeling miserable but not intending to do much about it). Preliminary evidence supports some of the hypotheses about how these three kinds of smile differ.

887 citations


Journal ArticleDOI
22 Jul 1982-Nature
TL;DR: The surface antigen of hepatitis B virus has been synthesized in the yeast Saccharomyces cerevisiae by using an expression vector that employs the 5′-flanking region of yeast alcohol dehydrogenase I as a promoter to transcribe surface antigen coding sequences.
Abstract: The surface antigen of hepatitis B virus (HBsAg) has been synthesized in the yeast Saccharomyces cerevisiae by using an expression vector that employs the 5′-flanking region of yeast alcohol dehydrogenase I as a promoter to transcribe surface antigen coding sequences. The protein synthesized in yeast is assembled into particles having properties similar to the 22-nm particles secreted by human cells.

843 citations


Journal ArticleDOI
24 Sep 1982-Science
TL;DR: Longer photographic exposure of immunofluorescently labeled cells in the fluorescence microscope yields images with increased sensitivity, making feasible multiple data collection, as with serial optical sectioning.
Abstract: n-Prop]yl gallate (0.1 to 0.25 molar, in glycerol) reduces by a factor of 10 the rate of fading of fluorescence of cell structures labeled with tetramethylrhodamine or fluorescein-conjugated antibodies. Hence, prolonged photographic exposure of immunofluorescently labeled cells in the fluorescence microscope yields images with increased sensitivity, making feasible multiple data collection, as with serial optical sectioning.

Journal ArticleDOI
20 Aug 1982-JAMA
TL;DR: If this new technique involving delivery of DC shocks to an electrode catheter positioned adjacent to the His bundle proves safe and effective, it should supplant the need for open heart surgical procedures for His-bundle ablation.
Abstract: Five patients with recurrent bouts of supraventricular tachycardia proved resistant or became intolerant of both conventional and experimental drugs. These patients were subjected to a new procedure involving delivery of DC shocks to an electrode catheter positioned adjacent to the His bundle. Complete atrioventricular (AV) block was produced in all, one patient died suddenly six weeks after shock therapy, and the remainder had complete AV block with follow-up intervals ranging from four to 12 months. Shock therapy was associated with mild elevations of creatine phosphokinase MB (31 +/- 18 units), but there was no hemodynamic evidence of tricuspid insufficiency. If this new technique proves safe and effective, it should supplant the need for open heart surgical procedures for His-bundle ablation.

Book ChapterDOI
TL;DR: This chapter discusses the serum transport of steroid hormones, where the steroid-receptor complex apparently moves into the nucleus where it modifies the chromatin transcriptional activity which results in altered levels of protein synthesis.
Abstract: Publisher Summary This chapter discusses the serum transport of steroid hormones Steroid hormones are extensively bound to plasma proteins including albumin, corticosteroid binding globulin (CBG), and sex hormone binding globulin (SHBG) Because of its high concentration, albumin binding is important in determining the magnitude of the nonprotein bound or free fraction of a steroid in plasma The generally accepted model of steroid hormone action suggests that free steroid (in equilibrium with circulating binding proteins) diffuses passively through target cell membranes and binds to a soluble intracellular receptor The steroid-receptor complex apparently moves into the nucleus where it modifies the chromatin transcriptional activity which results in, among other things, altered levels of protein synthesis CBG has been differentiated from the intracellular glucocorticoid and progesterone receptors by its inability to bind synthetic glucocorticoids and progestins

Journal ArticleDOI
08 Apr 1982-Nature
TL;DR: In an attempt to identify the nature of the putative morphogen, a method whereby extracts of polarizing region cells and chemicals can be locally applied to the wing bud by being bound to implanted beads and other inert carriers is developed.
Abstract: The polarizing region, a small group of cells at the posterior margin of the limb bud, acts as a signalling region to specify the pattern of structures which develop across the anteroposterior axis of the limb1. When a polarizing region is grafted to the anterior margin of a second limb, a mirror-image symmetrical limb develops1,2. There is indirect evidence that the signal from the polarizing region is a diffusible morphogen3. In an attempt to identify the nature of the putative morphogen, we have developed a method whereby extracts of polarizing region cells and chemicals can be locally applied to the wing bud by being bound to implanted beads and other inert carriers. The chemicals tested included hyaluronidase, dibutyryl cyclic AMP and thalidomide. All experiments have been negative until, at the suggestion of Dr J. Pitts, we tested retinoic acid because of its effects on cell to cell communication and cell differentiation, and we have now for the first tune been able to mimic the action of the polarizing region with a defined chemical.

Journal ArticleDOI
01 Oct 1982-Cell
TL;DR: A gene (MF alpha) coding for alpha-factor, a tridecapeptide mating factor secreted by yeast alpha cells, was cloned and sequenced in this paper.

Journal ArticleDOI
14 Oct 1982-Nature
TL;DR: It is found that NA and cyclic AMP block the Ca2-activated K+ conductance in hippocampal pyramidal cells and that this blockade occurs at a step subsequent to the entry of Ca2+ into the neurone, which greatly increases the number of spikes elicited by a depolarizing stimulus.
Abstract: The hippocampus, as well as a variety of other brain regions, is known to receive a diffuse projection of noradrenaline (NA) containing fibres which originates in the brain stem1–4. Although there is considerable evidence for the involvement of this system in a variety of behaviours5–7, the precise cellular actions of NA are poorly understood. Early studies emphasized the direct inhibitory effects of NA8–12; more recent experiments have shown that at several sites, NA, or stimulation of NA-containing afferents, can also facilitate excitatory synaptic responses13–18. This has led to the concept that NA increases the ‘signal-to-noise’ ratio of neurones13, acting as an ‘enabling’ device4 which allows cells to respond more briskly to conventional synaptic excitation. In the olfactory bulb, NA reduces inhibitory postsyn-aptic potentials by a presynaptic action19, which could contribute to enhanced excitatory synaptic responses. However, in other systems, NA has been reported to enhance excitatory responses to iontophoretically applied transmitters, and it was proposed that NA increases the sensitivity of the neurone to these excitatory transmitters13–15. We report here experiments that could explain such direct effects. We have found that NA and cyclic AMP block the Ca2+-activated K+ conductance in hippocampal pyramidal cells and that this blockade occurs at a step subsequent to the entry of Ca2+ into the neurone. As a consequence, the spike frequency adaptation or accommodation which normally occurs with depolarizing stimuli is severely reduced. Thus, NA greatly increases the number of spikes elicited by a depolarizing stimulus.

Journal ArticleDOI
21 May 1982-Science
TL;DR: Retroviruses have proved to be useful reagents for studying genetic and epigenetic changes in eukaryotic cells, and their capacity to establish a DNA (proviral) form of their RNA genomes as a stable component of host chromosomes, in either somatic or germinal cells.
Abstract: Retroviruses have proved to be useful reagents for studying genetic and epigenetic (such as regulatory) changes in eukaryotic cells, for assessing functional and structural relationships between transposable genetic elements, for inducing insertional mutations, including some important in oncogenesis, and for transporting genes into eukaryotic cells, either after natural transduction of putative cellular oncogenes or after experimental construction of recombinant viruses. Many of these properties of retroviruses depend on their capacity to establish a DNA (proviral) form of their RNA genomes as a stable component of host chromosomes, in either somatic or germinal cells.

Journal ArticleDOI
TL;DR: In this paper, the authors used divergent fan beam convolutional reconstruction with a minimal complete (180 degrees plus the fan angle) data set and showed that by proper weighting of the initial data set, image quality essentially equivalent to the quality of reconstructions from 360 degrees data sets is obtained.
Abstract: The problem of using a divergent fan beam convolution reconstruction algorithm in conjunction with a minimal complete (180 degrees plus the fan angle) data set is reviewed. It is shown that by proper weighting of the initial data set, image quality essentially equivalent to the quality of reconstructions from 360 degrees data sets is obtained. The constraints on the weights are that the sum of the two weights corresponding to the same line-integral must equal one, in regions of no data the weights must equal zero, and the weights themselves as well as the gradient of the weights must be continuous over the full 360 degrees. After weighting the initial data with weights that satisfy these constraints, image reconstruction can be conveniently achieved by using the standard (hardwired if available) convolver and backprojector of the specific scanner.

Journal ArticleDOI
21 Jan 1982-Nature
TL;DR: Activation of adjacent cellular genes by retroviral DNA can involve mechanisms other than provision of a transcriptional promoter in the vicinity of a putative cellular oncogene.
Abstract: Proviruses of avian leukosis virus (ALV) are located in the vicinity of a putative cellular oncogene (c-myc) in ALV-induced bursal lymphomas. Enhanced expression of c-myc occurs in association with proviruses found in any of three configurations: (I) on the 5′ side (‘upstream’) of c-myc in the same transcriptional orientation; (II) on the 3′ side (‘downstream’) of c-myc in the same orientation; (III) upstream, in the transcriptional orientation opposite to that of c-myc. Thus, activation of adjacent cellular genes by retroviral DNA can involve mechanisms other than provision of a transcriptional promoter.

Journal ArticleDOI
TL;DR: Intracellular recordings from CA1 pyramidal cells in the rat hippocampal slice preparation have been used to study the neuronal pathways involved in hippocampal synaptic inhibition.
Abstract: 1. Intracellular recordings from CA1 pyramidal cells in the rat hippocampal slice preparation have been used to study the neuronal pathways involved in hippocampal synaptic inhibition. 2. When direct comparisons are made in a single pyramidal cell, orthodromic stimulation delivered to stratum (s.) radiatum in normal recording conditions is found to be more effective than antidromic stimulation in producing inhibitory post-synaptic potentials (i.p.s.p.s). 3. Orthodromic i.p.s.p.s in normal conditions appear to be complex, multiphasic events, whereas antidromic i.p.s.p.s are relatively simple. The orthodromic i.p.s.p. involves both a GABA-mediated dendritic component and a non-GABA-mediated component neither of which is activated by antidromic stimulation. 4. Barbiturates induce a late depolarizing phase of the orthodromic response, a `depolarizing i.p.s.p.', which is mediated by GABA. The depolarizing i.p.s.p. is not produced by antidromic stimulation. 5. Injections of tetrodotoxin and bicuculline methiodide localized to either somatic or apical dendritic regions reveal that the depolarizing i.p.s.p. is produced by GABA released from neuronal elements in the dendritic field which acts on pyramidal cell dendrites. 6. The depolarizing i.p.s.p. is strongly temperature-dependent and increases in amplitude and duration progressively as slices are cooled from 37 to 22 °C. 7. Depolarizing i.p.s.p.s can be produced by orthodromic stimulation in s. oriens as well as in s. radiatum. In each case the depolarizing i.p.s.p.s appear localized to the dendrites in the field stimulated. 8. We conclude that the depolarizing i.p.s.p. evident in the presence of barbiturates is caused by the same synaptic release of GABA which in normal conditions produces hyperpolarizing dendritic i.p.s.p.s. 9. Numerous comparisons between orthodromic and antidromic stimulation indicate that dendritic i.p.s.p.s are activated by feed-forward pathways.

Journal ArticleDOI
TL;DR: The rat hippocampal slice preparation has been used in conjunction with intracellular recording and ionophoresis to study the action of γ‐aminobutyric acid (GABA) on CA1 pyramidal cells.
Abstract: 1. The rat hippocampal slice preparation has been used in conjunction with intracellular recording and ionophoresis to study the action of gamma-aminobutyric acid (GABA) on CA1 pyramidal cells.2. GABA elicits a hyperpolarizing (h.) response at the soma. The reversal potential of this h. response is the same as for inhibitory post-synaptic potentials (i.p.s.p.s) evoked by stimulating pyramidal cell axons.3. GABA elicits primarily depolarizing (d.) responses when applied to the apical dendrites, but h. responses can also be found.4. The GABA antagonists bicuculline methiodide, picrotoxin, penicillin, and pentylenetetrazole are all ten to one hundred times more potent on the d. response than on the h. response. Hyperpolarizing responses are uncovered in the dendrites when intermediate doses of these drugs block the d. response.5. The GABA analogue, 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP), which has been proposed to activate synaptic receptors preferentially in other systems, elicits h. responses in the dendrites. It is one seventh as potent as GABA in eliciting d. responses.6. Pentobarbitone enhances d. responses to a much greater extent than h. responses, while diazepam enhances h. responses to a greater extent.7. Nipecotic acid, low temperature, and low sodium media all increase the size of d. responses to ionophoretically applied GABA indicating that an active uptake process limits their size.8. We conclude that h. responses reflect the activation of synaptic receptors which are highly concentrated on the pyramidal cell soma-initial segment, but are also present on the dendrites. Depolarizing responses, which are evoked in the dendrites, reflect the activation of extrasynaptic receptors.9. We propose that an ordinarily undetectable amount of synaptically released GABA can ;spill' over onto extrasynaptic (d.) receptors. Depolarizing receptor activation can be detected in the presence of pentobarbitone. Spillover is markedly enhanced at subphysiological temperatures presumably due to enhanced release of GABA and impairment of the GABA uptake system.


Journal ArticleDOI
07 Jan 1982-Nature
TL;DR: The sequence of the highly polymorphic region near the human insulin gene, which begins 363 base pairs before the start of transcription and extends upstream, indicated that it is generated by variation in the number and arrangement of members of a family of tandemly repeating nucleotides whose structure is related to ACAGGGGTGTGTGGGG.
Abstract: The sequence of the highly polymorphic region near the human insulin gene, which begins 363 base pairs before the start of transcription and extends upstream, indicated that it is generated by variation in the number and arrangement of members of a family of tandemly repeating nucleotides whose structure is related to ACAGGGGTGTGGGG. Another 15-base pair sequence, repeated twice near the human gene, is located ∼325 base pairs on either side of the polymorphic region. One member is in the transcriptional control region.

Journal ArticleDOI
01 Dec 1982-Cell
TL;DR: Comparisons between the sequences of v- myb and c-myb indicate that transduction of c-Myb to form v-myB probably resulted from an initial DNA rearrangement and the subsequent use of a spliced RNA as an intermediate.

Journal ArticleDOI
26 Nov 1982-Science
TL;DR: The 14C-labeled 2-deoxy-D-glucose method has several advantages over conventional electrophysiological mapping techniques and should prove useful in analyzing retinotopic organization in various visual areas of the brain and in different species.
Abstract: We have anatomically analyzed retinotopic organization using the 14C-labeled 2-deoxy-D-glucose method. The method has several advantages over conventional electrophysiological mapping techniques. In the striate cortex, the anatomical substrate for retinotopic organization is surprisingly well ordered, and there seems to be a systematic relationship between ocular dominance strips and cortical magnification. The 2-deoxyglucose maps in this area appear to be largely uninfluenced by known differences in long-term metabolic activity. This method should prove useful in analyzing retinotopic organization in various visual areas of the brain and in different species.

Journal ArticleDOI
28 Oct 1982-Nature
TL;DR: A size polymorphism associated with the processed gene in the population examined is detected, and a region of apparent secondary structure homology between a 5′ flanking region of the functional metallothionein-II gene and that of a mouse metallothsionin-I gene is observed.
Abstract: The complete nucleotide sequence of two of the human metallothionein gene family has been compared. One is a functional metallothionein-II gene, the other a pseudogene, lacking introns, terminating in a poly(A) tail and flanked by two direct repeats. In addition, we have detected a size polymorphism associated with the processed gene in the population, examined, and we have observed a region of apparent secondary structure homology between of 5' flanking region of the functional metallothionein-II gene and that of a mouse metallothionein-I gene.

Journal ArticleDOI
TL;DR: There appeared to be a correlation between levels of c-myb expression and hemopoietic activity of the tissues and cells examined, which suggests that c- myb may be expressed primarily in immature hemopOietic cells.
Abstract: The oncogenes (v-onc genes) of rapidly transforming retroviruses have homologs (c-onc genes) in the genomes of normal cells. In this study, we characterized and quantitated transcription from four c-onc genes, c-myb, c-myc, c-erb, and c-src, in a variety of chicken cells and tissues. Electrophoretic analysis of polyadenylated RNA, followed by transfer to nitrocellulose and hybridization to cloned onc probes showed that c-myb, c-myc, and c-src each give rise to a single mature transcript, whereas c-erb gives rise to multiple transcripts (B. Vennstrom and J. M. Bishop, Cell, in press) which vary in abundance among different cells and tissues. Transcription from c-myb, c-myc, c-erb, and c-src was quantitated by a "dot-blot" hybridization assay. We found that c-myc, c-erb, and c-src transcription could be detected in nearly all cells and tissues examined, whereas c-myb transcription was detected only in some hemopoietic cells; these cells, however, belong to several different lineages. Thus, in no case was expression of a c-onc gene restricted to a single cell lineage. There appeared to be a correlation between levels of c-myb expression and hemopoietic activity of the tissues and cells examined, which suggests that c-myb may be expressed primarily in immature hemopoietic cells. An examination of c-onc RNA levels in target cells and tissues for viruses carrying the corresponding v-onc genes revealed no obvious correlation, direct or inverse, between susceptibility to transformation by a given v-onc gene and expression of the homologous c-onc gene.

Journal ArticleDOI
TL;DR: All RPs, whether in self-initiated or pre-planned acts, appear related specifically to preparation for a motor action, and distributions suggest that cortical areas other than area 4 and 6 contribute importantly, especially to type II.

Journal ArticleDOI
TL;DR: No differences between the molecular properties of the agents from hamster and murine sources were observed using primarily the incubation time interval method with the former and end‐point titration with the latter.
Abstract: The titer of the scrapie agent was determined by measurements of time intervals from inoculation to onset of illness and from inoculation to death. Both intervals were found to be inversely proportional to the size of the dose injected intracerebrally into random-bred weanling Syrian hamsters. The logarithms of the time intervals minus a time factor were linear functions of the logarithm of the inoculum size. The time factors were determined by regression analysis in order to maximize these linear relationships. An equation relating the titer of the inoculum to the dilution of the sample and the length of the time intervals was developed. This equation facilitates the use of a computerized data base. Validation of these relationships was provided by comparing samples for which the agent was measured both by end-point titration and by time interval assay. Agreement between the two methods was generally within +/-0.5 log10 median infective dose units. No differences between the molecular properties of the agents from hamster and murine sources were observed using primarily the incubation time interval method with the former and end-point titration with the latter. The advantages of this new approach based on time interval measurements are considerable with respect to time and resources.

Journal ArticleDOI
01 Jan 1982-Cell
TL;DR: It is proposed that the viral glycoproteins and some of the ACTH precursor are transported by a constitutive pathway, while mature ACTH is stored in secretory granules where its release is enhanced by stimulation.