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Biomedical subjects

S Weaver

Publications and source records attributed to S Weaver.

At least 19 recordsLinked to original sources

Influence of a menhaden oil diet on cercarial penetration of Schistosoma mansoni.

The ability of a menhaden oil (MO) diet to influence cercarial penetration into mouse tail skin was evaluated. Male CD-1 mice 4-6 wk old (15.2 g average weight) were fed a 0, 10%, or 20% MO-supplemented diet for 2 wk. After this time mice were infected with either 65 +/- 3 or 145 +/- 3 [35S]methionine/cysteine-labeled cercariae for 1 hr by tail immersion. Twenty-four hours and 7 days later groups of mice were killed and their tail skin removed and autoradiographed. At 24 hr postinfection, mice fed a 20% MO diet had significantly higher cercarial penetration than controls and 10% MO diets (56% +/- 5.2 vs. 44% +/- 2.9, P = 0.02, 1-tailed t-test). After 7 days mice fed a 20% MO diet retained more radioactive foci than controls or 10% MO diets (21% +/- 2.0 vs. 15% +/- 1.3, P = 0.01, 1-tailed t-test).

Animals

Isolation and characterization of a cytosolic aldehyde dehydrogenase-encoding cDNA from mouse liver.

A series of overlapping cDNA clones encoding AHD-2, the constitutive liver cytosolic aldehyde dehydrogenase of the mouse, were isolated from lambda gt11 libraries by screening with antibody and hybridization probes. Together, these clones span 2036 bp, virtually the entire Ahd-2 transcript. The protein corresponding to the cDNA contains 501 amino acids (aa) with a predicted Mr of 54467. The aa sequence is 87% and 84% identical to liver cytosolic AHDs of human and horse, respectively. Major and minor transcription start points (tsp), located 43 and 44 bp upstream from the ATG codon, respectively, were identified by primer extension analysis. The sequence of a 700-bp genomic fragment containing the first exon and 546 bp of 5'-flanking DNA was determined. TATA and CCAAT motifs are located 31 and 73 bp, respectively, from the major tsp.

Aldehyde Dehydrogenase

Radiographic abnormalities in Vermont granite workers exposed to low levels of granite dust.

The issue of whether low levels of granite dust exposure lead to radiographic abnormalities after a lifetime of exposure has not been settled. In 1983, we carried out a radiographic survey of the Vermont granite industry, consisting of quarry and stone shed workers who had been exposed to the low dust levels prevailing in the industry since 1938 to 1940. Films were read by three "B" readers, using the ILO classification system, which requires the identification of both rounded and irregular opacities, as well as combinations of both. X-ray films were taken of 972 workers, out of a total work force of approximately 1,400. Of these films, 28 (3 percent) were interpreted by either two or three of the three readers as showing abnormalities consistent with pneumoconiosis. Only seven films (or 0.7 percent of the entire cohort) showed nodular or rounded opacities of the type typically seen in uncomplicated silicosis. The remainder of the abnormal x-ray films showed irregular opacities, largely in the lower lung zones, which are of uncertain significance, but may be related to heavy cigarette smoking and aging, and possibly dust inhalation. In addition, total gravimetric dust concentrations in the workplace were measured; 417 respirable-size mass samples showed concentrations of 601 micrograms/cu m +/- 368 micrograms/cu m. Using previously published estimates of 10 percent quartz in granite dust, the average quartz concentration was 60 micrograms/cu m. Twelve percent of the samples exceeded 100 micrograms/cu m, the current OSHA standard for quartz. We conclude that control of quartz exposure in the Vermont granite industry to levels which are on average less than the current OSHA standard has essentially eliminated definite radiographic changes of silicosis. The significance of the irregular opacities in the lower lung zones seen on a majority of the 28 x-ray films judged to be abnormal is not clear.

Adult

The child as proband. High prevalence of unrecognized and untreated hyperlipidemia in parents of hyperlipidemic children.

The authors evaluated the lipids of parents of hypercholesterolemic children to assess the prevalence of unrecognized and/or untreated hyperlipidemia. Biologic parents of 34 children had measurements of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (n = 47) or total cholesterol only (n = 14). Lipid abnormalities were defined according to guidelines established by the National Cholesterol Education Program. Abnormal values were defined as total cholesterol greater than 240 mg/dl, low-density lipoprotein (LDL) cholesterol greater than 160 mg/dl, HDL cholesterol less than 35 mg/dl, and triglycerides greater than 250 mg/dl. Borderline values were defined as total cholesterol between 200 and 240 mg/dl and LDL cholesterol between 130 and 160 mg/dl. Abnormal values were found in 32/61 (52%) and borderline values were found in 12/61 (20%) parents. Of the abnormal parents, 13/32 (41%) had unrecognized or known but untreated hyperlipidemia, and 9/12 (75%) of the borderline parents had unrecognized abnormalities. In all families where both parents were tested, at least 1 had a lipid abnormality. The authors conclude that when children with hypercholesterolemia are identified, parents should also have lipids assessed. Treatment programs for children should also be directed at the parents.

Adult

Polymorphism and gene conversion in mouse alpha-globin haplotypes.

We have cloned and characterized three distinct alpha-globin haplotypes obtained from inbred strains of the mouse, Mus domesticus. We report here the complete nucleotide sequence of the six alpha-globin genes that the haplotypes contain. Our analysis of these genes and those from one other previously described haplotype indicates that recurrent gene conversion events have played a major role in their history. The pattern of nucleotide substitutions suggests that conversions have occurred both within and between haplotypes. Limited segments of coding and noncoding DNA have been involved in these gene conversion events. In two of the haplotypes, the nonallelic genes of each maintain DNA sequence identity over discrete intervals and encode the same alpha-globin polypeptide. On the other hand, the coding regions of some genes have accumulated replacement changes that result in distinct alpha-globins. In one instance, these changes appear to reflect positive selection of advantageous mutations.

Amino Acid Sequence

A naturally occurring deletion in the mouse Hbbs beta-globin gene cluster.

A restriction fragment size difference of 1.9 kilobases exists between the C57BL/10 (Hbbs) and BALB/c (Hbbd) beta-globin gene clusters in the vicinity of the Hbb-y and Hbb-bh0 genes. This length difference is the result of a deletion that removes the majority of the C57BL/10 Hbb-bh0 gene. The Hbb-bh0 deletion appears to be widespread among Hbbs-carrying mice. In addition to the deletion, 119 base pairs of DNA of unknown origin are found in C57BL/10 DNA at the point of discontinuity. The existence of this deletion is inconsistent with reports of transcripts homologous to the third exon of the Hbb-bh0 gene in both C57BL/10 embryos and in a cell line carrying the Hbbs haplotype. We propose that the Hbb-bh0 gene is a recently disabled pseudogene.

Animals

Chromosomal rearrangements associated with LINE elements in the mouse genome.

Two segments of DNA that have apparently inserted in the interval between the two adult beta-globin genes in BALB/c (Hbbd haplotype) but not in C57B1/10 (Hbbs haplotype) mouse strains have been described (1). These putative insertions, each about 1000 bp in length, mapped near a repetitive element. To determine the precise position of these alleged insertions, their target sites, and the nature of their boundaries, we cloned and sequenced the appropriate regions of both chromosomes. One of the two segments is not an insertion but rather a region between two independently integrated L1 repetitive elements (LINEs) (2), one in Hbbd and the other in the Hbbs chromosome. The other segment is an insertion of 940 bp which is located within the L1 element in the Hbbd chromosome. This insert is unusual in that it exists in only one copy in the BALB/c genome.

Animals

Evolution of the mouse beta-globin genes: a recent gene conversion in the Hbbs haplotype.

We have determined the complete nucleotide sequence of the two nonallelic adult beta-globin genes of the C57BL/10 mouse. These genes, designated beta s and beta t, show a sequence similarity of 99.6% over the region bordered by the translational start and stop codons. Both beta s and beta t encode functional polypeptide chains that are identical. A comparison of the C57BL/10 beta-globin haplotype, Hbbs, with that of the BALB/c mouse, Hbbd, suggests that the two haplotypes have distinct evolutionary histories. The two adult beta-globin genes of the Hbbd haplotype, beta dmaj and beta dmin, are 16% divergent at the nucleotide level and encode distinct polypeptides that are synthesized in differing amounts. Our analysis indicates that a gene correction mechanism has been operating on the Hbbs chromosome to keep beta s and beta t evolving in concert, whereas on the Hbbd chromosome, beta dmin has diverged considerably from beta dmaj. We suggest that gene conversion is responsible for the maintained similarity of the Hbbs genes. Furthermore, we attribute the divergence of the Hbbd genes in part to the absence of a region of simple-sequence DNA within the large intervening sequence of beta dmin. We propose that this region of DNA plays a role in facilitating gene conversion. The deletion of this area in beta dmin introduced a block of nonhomology between the beta dmaj-beta dmin gene pair and thus may have inhibited further gene correction within the Hbbd haplotype.

Amino Acid Sequence

The mouse globin pseudogene beta h3 is descended from a premammalian delta-globin gene.

The beta h3 pseudogene of the BALB/c mouse contains sequence defects which prevent transcription and translation to produce a beta-globin. Comparison with other globin gene sequences indicates that beta h3 arose by recombination between an adult beta-globin gene and some significantly diverged globin sequence. Analysis of noncoding sequences shows that the 3' end of mouse beta h3 and the human delta-globin gene are both descended from an ancestral gene, which we call proto-delta. The origin of proto-delta must predate the mammalian radiation. A member of the L1 family of interspersed repetitive elements is inserted into the 3' untranslated delta-homologous sequence in beta h3 from BALB/c. beta h3 is a widespread feature of the rodent beta-globin complex, which has been fixed in the genome for 35 million years. Independent inactivation events produced pseudogenes located between the adult and nonadult beta-globin genes in the rodent, primate, rabbit, and goat lineages. One model to explain the abundance and evolutionary persistence of pseudogenes postulates that the mammalian genome simply has no efficient mechanism for deleting nonessential sequences. Consequently, the genomes of higher eukaryotes have been growing, by the accumulation of duplications, with doubling times of 200 +/- 100 million years.

Animals

A comparative in vitro study of thienamycin.

The in vitro activity of thienamycin was compared to that of other antibiotics against a large panel of bacteria obtained in blood cultures from cancer patients. This compound was the most active against gram-positive cocci and also proved to be extremely active against the gram-negative bacteria. It was also very active against multi-resistant gram-negative bacilli. Because of its broad spectrum of activity including Pseudomonas spp., thienamycin deserves clinical testing in the future.

Anti-Bacterial Agents

Comparative in vitro study of SQ26,776.

A new monocyclic beta-lactam antibiotic, SQ26,776, was evaluated in vitro against clinical isolates, and its activity was compared with that of other cephalosporins, penicillins, and aminoglycosides. This compound was very active against the majority of the aerobic gram-negative bacilli tested, including 47 multiresistant strains. It had no activity against the gram-positive cocci. It also showed activity comparable to that of moxalactam, ceftazidime, ceftriaxone, thienamycin, and tobramycin. It was superior to mezlocillin. The in vitro activity suggests that SQ26,776 should prove useful in settings in which the most likely pathogens are gram-negative bacilli.

Aminoglycosides

In vitro susceptibilities of Aeromonas hydrophila against new antibiotics.

The antibiotic susceptibilities of 16 clinical isolates of Aeromonas hydrophila obtained from cancer patients with septicemia were studied. Of the new beta-lactam antibiotics tested, azthreonam and moxalactam were the most active, followed by cefoperazone, cefotaxime, and ceftizoxime. Excellent activity was demonstrated by chloroamphenicol, tetracycline, aminoglycosides, and trimethoprim-sulfamethoxazole. Semisynthetic penicillins had no appreciable activity against this organism.

Aeromonas

The adult beta-globin genes of the "single" type mouse C57BL.

A set of four clones containing the two adult beta-globin genes of the "single" type mouse C57BL/10 (genotype Hbbs/Hbbs) were isolated from a library of cloned restriction fragments. The two genes, designated beta s and beta t, were physically mapped onto a 32 kb segment of the chromosome carried by the four clones. Beta s and beta t form a stable heteroduplex 1850 bp long, indicating that they are intact and conserved at this level of resolution throughout their length, including their intervening sequences. The beta s gene allelic with the beta dmaj gene of the BALB/c mouse (genotype Hbbd/Hbbd). These two alleles, as well as their surrounding sequences, are highly conserved. In contrast, heteroduplexes of beta t with its BALB/c allele, beta dmin, revealed three extensive but localized rearrangements. One region of non-homology falls within the large intervening sequence, IVS2. To the 5' side of the beta/beta dmin gene position two unequal substitutions were observed; each results in the net insertion of about 1000 bp into the Hbbd chromosome. The beta/b dmin gene position is bracketed by a 1450 bp inverted repeat. One of the 1000 bp substitutions maps within this inverted repeat.

Animals

DNA sequence organization of the beta-globin complex in the BALB/c mouse.

Clones containing five non-adult beta-globin genes were isolated from a library of BALB/c DNA. Together, the newly cloned regions comprise a contiguous block of 32 kb of the mouse genome. Restriction mapping of genomic DNA established the physical linkage of these non-adult genes to the two adult beta-globin genes as well as the two adult genes to each other. Thus this entire BALB/c beta-globin complex consists of seven linked genes, all with the same transcriptional orientation, arrayed over 70 kb of DNA. The order of these genes is: 5'-epsilon y3-beta h0-beta h1-beta h2-beta h3-beta major-beta minor-3' Portions of each of the five newly identified genes have been sequenced. Only one, epsilon y3, encodes a previously described globin. beta h0 and beta h1, which are closely related, differ significantly from both adult and embryonic globins. The beta h2 sequence is more closely related to the adult genes than to the other non-adult genes. However, it is the sequence least homologous to both of these classes. The 5' half of the beta h3 gene (preceding codon 75) has an aberrant structure. The rest of this sequence is intact, resembling an adult beta-globin gene except for an inserted base at cocon 90, resulting in a frameshift. Consequently, the beta h3 sequence cannot be translated to produce a normal beta-globin.

Animals

DNA fragments of the Mus musculus beta globin haplotypes Hbbs and Hbbd.

Two alternative haplotypes at the complex locus controlling hemoglobin beta chain synthesis in Mus musculus were compared at the DNA level. As expected, Hbbd homozygotes--which as adults synthesize two species of beta chain--have two genes for beta globin. Adult mice homozygous for the Hbbs haplotype make only a single type of beta polypeptide, yet they also have two beta globin genes. Apparently the two Hbbs genes encode identical proteins, or one of the two genes is not detectably expressed. The Hbbs and Hbbd haplotypes are thus more similar at the DNA level than studies of their polypeptide products have indicated.

Animals