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The neural signal for skin indentation depth. I. Changing indentations.

Psychophysical tests on human subjects showed that judgments of skin indentation depth made when the fingertip was indented at rates from 0.2 to 16 mm/sec were quite insensitive to changes in indentation velocity. Similar results were obtained on the forearm at indentation velocities of 0.4 to 16 mm/sec. Recordings were made from mechanoreceptors in the monkey's hand that were able to respond over the same range of velocities and at comparable depths to determine how skin indentation depth might be signaled (coded) at the receptor level and to examine the rate sensitivity of the possible depth codes. It was found that most of the receptors with foci under the stimulator were recruited relatively early during an indentation, especially at velocities of 1.6 mm/sec and higher, making it improbable that the full range of indentation depths is signaled by the "subsurface" recruitment of different receptors at different indentation depths. A subsurface recruitment code involving subcutaneous receptors is not likely since subjects could feel virtually none of the stimuli after skin anesthesia. Progressive recruitment with depth of receptors whose foci lie further and further away from the stimulator ("lateral" recruitment) was considered an unlikely depth code because changing the area of the stimulator had little effect on its perceived depth. Also, it was shown that subjects could sense the curvature of the indentation (the profile of the depth at right angles to the skin surface), which requires information about the depth of individual patches of skin beneath the stimulator. There is no obvious way that a lateral recruitment code can provide this information. Thus it is probable that the discharge rate of some or all of the receptors excited by the indentation is involved in indicating its depth. Both impulse frequency and receptor recruitment at any given depth increased as the velocity of the indentation increased. The demonstrated reliability of information about skin indentation depth in humans indicates that the central neural circuitry responsible for judgments of skin indentation depth is able to compensate for the rate-sensitive receptor signals.

Adult

Cloning of cDNA coding for carbamyl phosphate synthetase I and changes in levels of CPS1 mRNA during hepatocarcinogenesis.

cDNA coding for carbamyl phosphate synthetase I was cloned from recombinant plasmid with insert complementary to the mRNA for CPS1 followed by hybrid-selected translation screening. The length of the insert CPS1 cDNA was approximately 800 base pairs. Using this cDNA as a probe, it was found by dot-blot analysis of the total RNAs and poly(A)+-RNAs isolated from rat livers with different pathological lesions induced by diethylnitrosamine that the levels of CPS1 mRNA were decreased, the decrease being correlated with the malignancy of hepatocytes during carcinogenesis.

Animals

Worldwide trends in asthma mortality.

Statistics for deaths from asthma yield widely variable mortality rates between countries. Validation studies show significant inaccuracies in certification of cause of death in older subjects, and probable underreporting of asthma deaths in some countries, explaining some of the international differences noted. The introduction of the ninth revision of the World Health Organisation International Classification of Diseases brought a step increase in reported asthma mortality rates in 1979, but the last decade has seen a gradual increase in mortality rates in many countries, especially in young people, not explained by this change in code. Diagnostic transfer does not adequately explain these increases. Individuals at risk of death from asthma are more likely to be non-caucasian, non-compliant, and young, with a history of previous life-threatening episodes, hospital admissions, and precipitous attacks. Studies of circumstances of death have emphasized overreliance on beta-agonists and underuse of corticosteroids as two primary deficiencies in management, but there remains debate about the causality of the association between increased asthma mortality and increased usage of beta-agonists. The gradual increase in asthma mortality seen in New Zealand over the last 40 years, with episodic increases in the rising baseline, together with similar but more gradual changes in other countries, raises concerns about whether current treatment practices may adversely affect asthma severity and mortality. Further studies are required to validate asthma mortality statistics, and to establish causation of deaths.

Adolescent

Analysis of several bovine lutropin beta subunit cDNAs reveals heterogeneity in nucleotide sequence.

Several, independent lutropin beta subunit cDNA clones have been isolated from a lambda gt-11 pituitary cDNA library. The complete nucleotide sequence of four clones was determined. A number of single nucleotide differences were detected including three changes within the coding sequence. One of these nucleotide changes resulted in a change in the predicted amino acid sequence, while two did not. These changes may reflect heterogeneity in the animals from which pituitaries were obtained, or they may reflect errors which occurred during the construction or cloning of the cDNA. Two other differences in nucleotide sequence suggest differences in the processing of precursor mRNAs. One difference involves the deletion of three nucleotides from the coding sequence of one of the clones. This probably reflects the use of alternate splicing sites at intron-exon boundaries. The other likely processing difference is reflected by the fact that one of the clones contains a much longer 3' untranslated region than the other clones. This difference probably arose due to a single nucleotide difference leading to selection of an alternate polyadenylation site.

Amino Acid Sequence

International trends in the incidence of bone cancer are not related to drinking water fluoridation.

BACKGROUND: Because osteosarcomas may develop in rats exposed to fluoridated water, water fluoridation might pose a cancer risk to humans. METHODS: A time trend analysis of the cumulative risk (CR) of bone cancer for the period 1958-1987 for 40 cancer registry areas showed an increased risk for young males in Canada, Europe, and the United States, and a decreased lifetime risk for either sex in Europe. RESULTS: This was unrelated to water fluoridation and may have resulted from changes in coding practices. Bone cancer risk was inversely related to the incidence of cancers of unknown origin, suggesting that bone metastases were erroneously coded as primary bone cancer. In 1968-1972, most areas recorded more bone cancer deaths than new cases of the disease. CONCLUSIONS: The mortality/incidence ratio, but not the incidence rate (IR), has dropped sharply since then, which erodes the basis of past inferences relating cancer mortality to fluoridation.

Animals

Evolution of chromosome bands: molecular ecology of noncoding DNA.

Giemsa dark bands, G-bands, are a derived chromatin character that evolved along the chromosomes of early chordates. They are facultative heterochromatin reflecting acquisition of a late replication mechanism to repress tissue-specific genes. Subsequently, R-bands, the primitive chromatin state, became directionally GC rich as evidenced by Q-banding of mammalian and avian chromosomes. Contrary to predictions from the neutral mutation theory, noncoding DNA is positionally constrained along the banding pattern with short interspersed repeats in R-bands and long interspersed repeats in G-bands. Chromosomes seem dynamically stable: the banding pattern and gene arrangement along several human and murine autosomes has remained constant for 100 million years, whereas much of the noncoding DNA, especially retroposons, has changed. Several coding sequence attributes and probably mutation rates are determined more by where a gene lives than by what it does. R-band exons in homeotherms but not G-band exons have directionally acquired GC-rich wobble bases and the corresponding codon usage: CpG islands in mammals are specific to R-band exons, exons not facultatively heterochromatinized, and are independent of the tissue expression pattern of the gene. The dynamic organization of noncoding DNA suggests a feedback loop that could influence codon usage and stabilize the chromosome's chromatin pattern: DNA sequences determine affinities of----proteins that together form----a chromatin that modulates----rate constants for DNA modification that determine----DNA sequences. Theories of hierarchical selection and molecular ecology show how selection can act on Darwinian units of noncoding DNA at the genome level thus creating positionally constrained DNA and contributing minimal genetic load at the individual level.

Base Sequence

Legalized abortion: effect on national trends of maternal and abortion-related mortality (1940 through 1976).

Both non-abortion-related maternal and abortion-related mortality declined prior to the Supreme Court decisions of 1973. In order to determine the effect of legalized abortion on maternal mortality, we have analyzed the secular trends in national abortion mortality ratios for 1940 through 1976, compared the trends to those maternal mortality ratios, and hypothesized reasons for differences between these trends. Between 1940 and 1950 and after 1965, deaths from abortion declined more rapidly than deaths from other causes associated with childbirth. However, between 1951 and 1965, maternal mortality related to pregnancy of childbirth declined more rapidly than abortion-related mortality. Five possible explanations exist for the more rapid decline in abortion deaths since 1965--selected underreporting, changes in coding practices, improved safety of illegal abortion, introduction of more effective contraception, and increased availability of legal abortion. We consider the last two explanations as the most likely reasons for the accelerated decline in abortion-related deaths.

Abortion, Legal

Joint angle signaling by muscle spindle receptors.

Nerve impulses were recorded from sensory fibers supplying the tibialis anterior and soleus muscles of anesthetized cats as the ankle joint was moved from one end of the flexion-extension axis to the other and back again in steps of 6-7 degrees. The rate of movement from one position to the next was 40 deg/s and each position was held for 16-18 s. Plots were made of receptor discharge frequency as a function of ankle joint angle during joint movement (dynamic input-output (I-O) functions) as well as 2 and 15 s after movement terminated (2 and 15 s static I-O functions). Only receptors with a sustained (5s) static response within the physiological range were studied. A total of 229 tibialis anterior receptors met this criterion, of which 11 were identified as tendon organs. One hundred and five soleus receptors were studied, of which 6 were tendon organs. Thus tendon organ activity accounted for only a small part of the muscle afferent signal under passive conditions. The spindle receptors in soleus and tibialis anterior divided the ankle flexion-extension range about equally between them, those in soleus signaling over the flexion half of the range and those in tibialis anterior over the extension half. At angles where the receptors in a particular muscle did not signal joint angle, the tendon of the muscle was observed to be slack. Thus the total muscle afferent discharge in a relaxed animal is high at one end of the range, declines progressively as the ankle is displaced to an intermediate position, and then increases again as the joint moves toward the opposite end of the range. The spindle receptors within an individual muscle were recruited rather early as the muscle came under tension so that over most of a muscle's signaling range joint angle could have been coded by changes in receptor discharge frequency but not by which spindle receptors were active. To evaluate the information signaled by individual muscle spindle receptors, the following measurements were made from plots of impulse frequency vs joint angle: dynamic response, defined as the frequency difference between the dynamic and 2 s static I-O functions during muscle lengthening; adaptation, defined as the frequency difference between the 2 and 15 s static I-O functions during muscle lengthening.(ABSTRACT TRUNCATED AT 400 WORDS)

Adaptation, Physiological

The nucleoside deaminases for cytidine and adenosine: structure, transition state stabilization, mechanism, and evolution.

Enzymatic deamination of cytidine and adenosine bases in RNA have recently been shown to be mechanisms for changing the coding specificity of messenger and transfer RNAs. The structures of the enzymes that carry out deamination of the corresponding nucleosides have been analyzed by X-ray crystallography. They are quite different from one another in most respects, including quaternary and tertiary structure, but they have similar chemical groups in their active sites. Both enzymes envelope their nucleoside substrates completely, perhaps accounting for the fact that they are inactive on RNA substrates. Much has been learned about catalytic mechanisms from the structures of the enzymes and their complexes with transition state analog inhibitors. Catalysis proceeds with the activation by zinc of a bound water molecule, presumably to hydroxide ion, which attacks the appropriate carbon to generate a tetrahedral intermediate. The detailed stereochemistry of the two resulting chiral centers is diastereoisomeric. Details of the ensuing proton transfer steps necessary to generate and release the products are also apparently different in the two enzymes. Thus, the active site similarities are probably the result of convergent evolution.

Adenosine Deaminase

Characterization of a loss-of-function mutation in the isopenicillin N synthetase gene of Acremonium chrysogenum.

The N-2 strain of Acremonium chrysogenum accumulates the beta-lactam precursor tripeptide delta-(L-alpha-amino-adipoyl)-L-cysteinyl-D-valine and has no discernible activity for three of the cephalosporin C (Ce) biosynthetic enzymes. This phenotype is consistent with a mutation either within pcbC [the isopenicillin N synthetase (IPNS)-encoding gene] or in a pathway-regulator gene. To distinguish these possibilities we have cloned and sequenced pcbC from strain N-2. There is a single C----T mutation at nt 854 within the coding sequence, changing aa 285 from proline to leucine. An IPNS-specific monoclonal antibody recognises a catalytically inactive IPNS protein in extracts of N-2 cells. These findings suggest that strain N-2 carries a simple IPNS mutation and that IPNS or its biosynthetic product isopenicillin N is involved in regulation of the later stages of the Ce biosynthetic pathway.

Acremonium

Integration of woodchuck hepatitis virus (WHV) DNA at two chromosomal sites (Vk and gag-like) in a hepatocellular carcinoma.

Integration of woodchuck hepatitis virus (WHV) DNA into the liver DNA of a woodchuck infected by the virus was investigated. Clonal viral integration was not detected three months before the appearance of four hepatocellular carcinomas (HCC). Integration of the viral DNA was detected in all four HCCs, of which one was chosen to determine the structure of the viral integration completely in a single tumor. The integration occurred in two sites. One part contains the viral DNA from the middle of the gene encoding surface antigen to two-thirds of the way through the gene encoding X protein (X) with no structural changes. The coding frame of the truncated X gene continues into the chromosomal sequence to make a possible fusion protein. The integration seems to have occurred by recombination within two direct repeats of the viral genome in one junction and by homologous recombination between viral DNA and chromosomal DNA in the other junction. The viral DNA is integrated into a spacer of the immunoglobulin L-chain Vk (IgVk) region without any chromosomal rearrangement accompanying the integration. The viral DNA at the second site has a complex structural rearrangement: part of the preS gene is duplicated and attached to the terminus of the gene encoding core antigen in a head-to-tail fashion, followed by three small fragments derived from other parts of the viral DNA. The integrated preS gene has its own 5' regulatory element and a coding frame consisting of the truncated preS gene, the other parts of viral DNA and the chromosomal sequence.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence

Maturational aspects of periodicity coding in cat primary auditory cortex.

The click-following responses for single units in the primary auditory cortex of the cat were explored as a function of age. Recordings were obtained in kittens from 9-53 days of age and assembled in four age groups; 10-15 days, 16-21 days, 22-27 days and 30-60 days. Age group means were compared to results obtained in adult cats. The stimulus consisted of one second long click trains presented every three seconds with click rates ranging from 1-32 clicks per second. The response was characterized by entrainment, rate Modulation Transfer Function (rMTF), vector strength (VS) and temporal Modulation Transfer Function (tMTF). Maturational effects on periodicity coding comprised changes in overall responsiveness as well as click-rate dependent changes. The number of spikes elicited by single stimuli increased on average 3-fold between the second post-natal week and adulthood, probably as a result of more efficient synapses in the central auditory pathway and some improvement in thresholds. Adaptation became less pronounced with age; neurons started to respond to the later clicks in the 8/s and 16/s click trains from the third post natal week on. By the end of the first post-natal month the click following responses resembled the adult ones qualitatively, however, increased firing rates and spontaneous rates together with rebound responses continued to produce quantitative differences between the 30-60 days olds and the adults. Limiting rates for the tMTF (50% of the response at 1/s) increased from 6 Hz in the 10-15 day old to 12 Hz in adults. The decrease in the duration of the post-activation suppression coupled with the increased response with age to trains with higher click rates suggested that the maturation of inhibitory processes in the cortex play a major role in this rate dependence.

Acoustic Stimulation

Intraoperative myocardial protection: a comparison of blood and asanguineous cardioplegia.

Cardiac arrest was achieved in 84 patients using asanguineous cardioplegia and in 97 patients using cold blood potassium cardioplegia. The patient groups were similar in age, sex ratio, and preoperative risk factors. Other than the cardioplegic solution used, the conduct of each operation was identical. There were no differences in mean total pump time (118 minutes for the asanguineous cardioplegia group versus 117 minutes for the cold blood cardioplegia group) or cross-clamp time (73.5 versus 70 minutes, respectively). However, the blood cardioplegia group had a greater number of distal anastomoses per patient (3.9 versus 3.7; p less than 0.05). Myocardial protection was assessed clinically and by serial electrocardiograms. Cellular integrity was determined by release of the myocardial isoenzyme of serum creatine kinase (CK-MB). Cellular morphology was studied in 6 randomly selected patients in each group by electron microscopic examination of left ventricular myocardial samples obtained before and after bypass. Three patients given blood cardioplegia and 5 given asanguineous cardioplegia required intraaortic balloon counterpulsation at termination of bypass. There were no ultrastructural changes in either group. Electrocardiographic changes (Minnesota code) occurred in 12 of 84 patients receiving asanguineous cardioplegia versus 12 of 97 patients receiving cold blood potassium cardioplegia. To maintain a satisfactory cardiac index (greater than 2.0 L/min/m2), 38 of 84 patients given asanguineous cardioplegia versus 25 of 97 patients given blood cardioplegia required inotropic support up to 24 hours postoperatively (p less than 0.05). Infarct size determined from CK-MB release was significantly greater (p less than 0.05) in patients given asanguineous cardioplegia (36.27 gm-equivalents) than in those given blood cardioplegia (26.7 gm-equivalents).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Transfusion

An appraisal of the epidemic rise of coronary heart disease and its decline.

Epidemiologists have used mortality statistics to demonstrate a sharp rise in the incidence of coronary heart disease in several countries since the turn of the century and a decline in some countries since the late 1960s. However, increased longevity, changes in coding and diagnostic practices, and familiarity with the clinical and pathological features of the disease make the increase largely spurious. Diagnostic errors in certified causes of death in general, and coronary heart disease in particular, indicate that vital statistics are too unreliable for determining whether there has been an increase and a subsequent decline in the incidence of coronary heart disease.

Aged

Evolution of the mouse t haplotype: recent and worldwide introgression to Mus musculus.

Mouse t haplotypes are variants of chromosome 17, consisting of four inversions. Despite the homozygous lethality and pleiotropic effect on embryonic development, sperm production, and recombination, they have widely spread in natural populations of the house mouse (10-40% in frequency) because of the meiotic drive advantage. We sequenced 14 Tcp-1 (t-complex polypeptide 1) genes from four t haplotypes, nine wild mice, and a rat as a reference. From a comparison of intron sequences of 610 base pairs, we dated the origin of t haplotypes to 2.9 +/- 0.7 million years ago, which predates the splitting of Mus musculus subspecies (approximately 1 million years ago). However, the Tcp-1 intron sequences of t haplotypes from different M. musculus subspecies from various parts of the world show no divergence, indicating the recent introgression (no earlier than 0.8 million years ago) of a single ancestral type. Nucleotide changes in coding regions are also consistent with this conclusion. Hence, polymorphisms among t haplotypes including lethality factors have accumulated during this short time period independently in each M. musculus subspecies.

Animals

The changing pattern of coronary heart disease in Australia.

In this paper we describe a method for constructing long series of comparable mortality statistics from published figures that are subject to periodic changes in coding practice. The case discussed in some detail is that of Australian coronary heart disease mortality 1931-1985, the coding of which has been liable to alteration on four occasions due to revisions to the procedures of the International Classification of Diseases. Reference is made to comparable work on US figures and it is shown that the Australian data require relatively smaller adjustments.

Adult

Postnatal shift of tonotopic organization in the chick auditory cortex analogue.

The existence of an ontogenetic shift of tonotopic organization throughout the auditory pathway concomitant with cochlea maturation is a matter of controversy. Using the 2-deoxyglucose method we demonstrate here for the first time the shift phenomenon in an auditory forebrain structure, field L, the auditory cortex analogue of the chick. During the first postnatal month isofrequency contours move to positions where, in younger chicks, lower frequencies (up to half an octave) are represented. This developmentally changing place code of sound frequencies at the forebrain level is similar to the one previously reported for brain stem auditory nuclei. It raises the question of constancy of frequency-related pitch perception during development and may be a complication of early auditory learning and memory.

Acoustic Stimulation