Biomedical subjects
Publications and source records attributed to E G Moss.
Short RNAs regulate gene expression in many species. Some are generated from any double-stranded RNA and degrade complementary RNAs; others are encoded by genes and repress specific mRNAs. Both, it turns out, are processed and handled by similar proteins. These pathways offer a glimpse into a world of small RNAs.
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A second case has been found of a nematode gene involved in developmental timing that encodes a short, non-coding RNA. Both RNAs are expressed at specific times and appear to repress target genes by interacting with their 3' untranslated regions. A coincidence? Or does this pathway attract small RNA regulators?
Mutations in the heterochronic gene lin-28 of C. elegans cause precocious development where diverse events specific to the second larval stage are skipped. lin-28 encodes a cytoplasmic protein with a cold shock domain and retroviral-type (CCHC) zinc finger motifs, consistent with a role for LIN-28 in posttranscriptional regulation. The 3'UTR of lin-28 contains a conserved element that is complementary to the 22 nt regulatory RNA product of lin-4 and that resembles seven such elements in the 3'UTR of the heterochronic gene lin-14. Both lin-4 activity and the lin-4-complementary element (LCE) are necessary for stage-specific regulation of lin-28. Deleting the LCE produces a dominant gain-of-function allele that causes a retarded phenotype, indicating that lin-28 activity is a switch that controls choices of stage-specific fates.
The heterochronic genes of Caenorhabditis elegans encode part of a regulatory system that controls the temporal component of cell fates in development. The genes have been characterized genetically and molecularly, and their study has so far revealed a genetic hierarchy that specifies sequences of developmental events, a novel RNA-mediated mechanism of gene regulation and a reprogramming phenomenon associated with arrested development.
The inability of certain poliovirus strains to infect mice can be overcome by the expression of human poliovirus receptors in mice or by the presence of a particular amino acid sequence of the B-C loop of the viral capsid protein VP1. We have identified changes in an additional capsid structure that permit host-restricted poliovirus strains to infect mice. Variants of the mouse-virulent P2/Lansing strain were constructed containing amino acid changes, deletions and insertions in the B-C loop of VP1. These variants were attenuated in mice, demonstrating the importance of the B-C loop sequence in host range. Passage of two of the B-C loop variants in mice led to the selection of viruses that were substantially more virulent. The increased neurovirulence of these strains was mapped to two different suppressor mutations in the N-terminus of VP1. Whereas the B-C loop of VP1 is highly exposed on the surface of the capsid, near the five-fold axis of symmetry, the suppressor mutations are in the interior of the virion, near the three-fold axis. Introduction of the suppressor mutations into the genome of the mouse-avirulent P1/Mahoney strain resulted in neurovirulent viruses, demonstrating that the P2/Lansing B-C loop sequence is not required to infect mice. Because the internal host range determinants are in a structure known to be important in conformational transitions of the virion, the host range of poliovirus may be determined by the ability of virions to undergo transitions catalyzed by cell receptors.
The poliovirus P2/P712 strain is an attenuated virus that is closely related to the type 2 Sabin vaccine strain. By using a mouse model for poliomyelitis, sequences responsible for attenuation of the P2/P712 strain were previously mapped to the 5' noncoding region of the genome and a central region encoding VP1, 2Apro, 2B, and part of 2C. To identify specific determinants that attenuate the P2/P712 strain, recombinants between this virus and the mouse-adapted P2/Lansing were constructed and their neurovirulence in mice was determined. By using this approach, the attenuation determinant in the central region was mapped to capsid protein VP1. Candidate attenuating sequences in VP1 and the 5' noncoding region were identified by comparing the P2/P712 sequence with that of vaccine-associated isolate P2/P117, and the P2/117 sequences were introduced into the P2/Lansing-P2/P712 recombinants by site-directed mutagenesis. Results of neurovirulence assays in mice indicate that an A at nucleotide 481 in the 5' noncoding region and isoleucine (Ile) at position 143 of capsid protein VP1 are the major determinants of attenuation of P2/P712. These determinants also attenuated neurovirulence in transgenic mice expressing human poliovirus receptors, a new model for poliomyelitis in which virulent viruses are not host restricted. These results demonstrate that A-481 and Ile-143 are general determinants of attenuation.
Deep vein thrombosis is a serious medical problem that may lead to pulmonary embolus. The authors discuss the noninvasive diagnosis of deep vein thrombosis using venous occlusion plethysmography and ultrasonic duplex scanning.
A mouse model for poliomyelitis was used to identify genomic sequences that attenuate neurovirulence of poliovirus strain P2/P712. This type 2 strain is avirulent in primates and mice yet grows as well as virulent strains in cell culture. The approach used was to exchange portions of the genome of the mouse-virulent P2/Lansing strain with the corresponding region from P2/P712 to identify sequences that could attenuate Lansing neurovirulence in mice. A full-length infectious cDNA of P2/P712 was assembled and used to construct recombinants between P2/P712 and P2/Lansing. The results of neurovirulence testing of 11 recombinants indicated that strong attenuating determinants are located in the 5' noncoding region of P2/P712 and a region encoding capsid protein VP1 and 2Apro, 2B, and part of 2C. An attenuating determinant was further localized to between nucleotides 456 and 628 of P2/P712. A third sequence from P2/P712, nucleotides 752 to 2268, encoding VP4, VP2, and part of VP3, was weakly attenuating. The sequence from nucleotide 4454, approximately halfway through the 2C-coding region, to the end of the P2/P712 genome did not contain attenuating determinants. Nucleotide sequence analysis revealed that P2/P712 differs from the type 2 Sabin vaccine strain by only 22 nucleotides. Six differences lead to amino acid changes in the coding region, and four differences are in the 5' noncoding region. These studies show that, like the type 1 and type 3 Sabin vaccine strains, the attenuated type 2 strain P712 contains multiple attenuating sequences, including strongly attenuating sequences in the 5' noncoding region of the genome.
The mouse-adapted strain of poliovirus type 2 (Lansing) induces fatal poliomyelitis in mice after intracerebral inoculation, whereas mice inoculated with poliovirus type 1 (Mahoney) show no signs of disease. Previous work indicated that the adaptation to mouse virulence is associated with the viral capsid proteins and that mutations in neutralization antigenic site I of poliovirus reduce neurovirulence of the Lansing strain in mice. The role of antigenic site I in mouse neurovirulence was further explored by constructing an antigenic hybrid virus. Six amino acids in antigenic site I of the Mahoney strain were replaced with a sequence specific for the Lansing strain by using a mutagenesis cartridge. The hybrid virus was neutralized by polyclonal antisera elicited by the type 1 and type 2 strains of poliovirus and by neutralizing monoclonal antibodies directed against antigenic site I of type 2 virus. The hybrid virus induced paralytic disease in mice, an observation demonstrating that a short sequence of amino acids in antigenic site I is an important determinant of poliovirus host range. Antigenic site I may be involved in attachment of poliovirus to cells of the mouse central nervous system.
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A case of varices of the entire esophagus in a patient who had undergone resection of a substernal thyroid gland 29 years previously is reported. Dilated esophageal veins, varices, may serve as collateral channels between the portal and systemic systems. When the superior vena cava is obstructed, blood from the upper extremities and head is returned to the heart via downhill varices. Obstruction of the superior vena cava proximal to the azygos vein results in varices of the upper esophagus. Obstruction distal to the asygos vein, as in this patient, results in varices of the entire esophagus. Portacaval shunt has no place in the management of these patients. Downhill varices should be considered in any patient with superior vena caval obstruction from any cause.
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