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There is increasing support for the concept that in all of their varied immunologic functions, T lymphocytes act through a dual specificity. In the case of intracellular viral infections, the recognition required for cytolysis involves both a "self" component, coded for by the genes that specify the major transplantation antigens, and an "X" component, provided by viral antigens expressed on the target-cell surface.
The development of congenic mouse strains identical at the H-2K and H-2D loci but differing by I-region associated (Ia) determinants has permitted an association to be established between Ia determinants and stimulation in mixed lymphocyte culture reactions (MLR). The present experiments were undertaken to establish whether the Ir-coded control of MLR operated at the level of recognition or of stimulation. Reciprocal MLR were established between A.TH and A.TL mouse spleen cells in the presence or absence of anti-Ia sera directed either at determinants of the stimulating or responding cells. The number of T cells responding was assessed by the virus plaque assay. Anti-Ia sera directed against the responding cells were no more inhibitory of the MLR than normal mouse serum. In contrast, anti-Ia sera directed against determinants of the mitomycin-treated stimulating cells markedly inhibited activation of T cells in the MLR.
Gene fusion has been used to produce the cytoplasmic domain of an endocytic receptor. DNA sequences coding for the 52 COOH-terminal amino acids of the mannose receptor from human macrophages, including the 41-amino acid cytoplasmic tail, were fused to the codons specifying the carbohydrate-recognition domain (CRD) of rat mannose-binding protein. The fusion protein was expressed in Escherichia coli and purified in one step on mannose-Sepharose, making use of the carbohydrate-binding activity of the CRD. The tail peptide was released from the fusion protein using endoproteinase Arg-C. This method provides an alternative to chemical synthesis for the production of midlength peptides.
Viral interference programmable repeat (VIPR) systems use a noncontiguous code for RNA-guided transcriptional silencing. How the Vipr protein and a VIPR RNA (vrRNA) comprising alternating GGY and NN segments achieve precise DNA targeting is unknown. Here, we present 21 cryo-electron microscopy structures that help explain the mechanism of target engagement. Vipr protomers oligomerize along the vrRNA to form a right-handed helical filament, sequestering each GGY motif and positioning the adjacent NN bases for target base pairing. DNA binding, in which every third nucleotide is skipped, results in a gapped vrRNA-DNA hybrid helix that encircles the nontarget DNA strand to form a geometric triplex. These findings suggest that triplex-mediated target-strand handoff could enable noncontiguous and programmable RNA-guided DNA recognition in VIPR systems.
The sequential fulfillment of the principle of succession necessarily guides the main steps of the genetic code evolution to be reflected in its structure. The general scheme of the code series formation is proposed basing on the idea of "group coding" (Woese, 1970). The genetic code supposedly evolved by means of successive divergence of pra-ARS's loci, accompanied by increasing specification of recognition capacity of amino acids and triplets. The sense of codons had not been changed on any step of stochastic code evolution. The formulated rules for code series formation produce a code version, similar to the contemporary one. Based on these rules the scheme of pra-ARS's divergence is proposed resulting in the grouping of amino acids by their polarity and size. Later steps in the evolution of the genetic code were probably based on more detailed features of the amino acids (for example, on their functional similarities like their interchangeabilities in isofunctional proteins).
Specific inhibition of mammalian lysyl-tRNA synthetase by polyU is shown. Inhibition of the enzyme is dependent on the length of the oligonucleotide, since oligoU molecules with a length of less than 8 residues do not inhibit the aminoacylation, whilst the effect of oligoU molecules with a length of about 30 residues is the same as that of polyU. Inhibition is a result of recognition by the enzyme of the tRNALys anticodon sequence (UUU) coded by polyU. Aminoacylation of the oligoU molecule with attached CCA sequence (G(U)20-CCA) by yeast and mammalian lysyl-tRNA synthetases is demonstrated.
Small (100-260 kb), nested deletions were characterized in DNA from two unrelated patients with familial adenomatous polyposis coli (APC). Three candidate genes located within the deleted region were ascertained and a previous candidate gene, MCC, was shown to be located outside the deleted region. One of the new genes contained sequence identical to SRP19, the gene coding for the 19 kd component of the ribosomal signal recognition particle. The second, provisionally designated DP1 (deleted in polyposis 1), was found to be transcribed in the same orientation as MCC. Two other cDNAs, DP2 and DP3, were found to overlap, forming a single gene, DP2.5, that is transcribed in the same orientation as SRP19.
To study the recognition processes and interaction of peptides and proteins, a model has been suggested according to which the first steps of complex formation of molecules are defined by G/C and A/U complementarity of codon roots of amino acid forming the molecules contact sites or surfaces. In contrast to amino acid--antiamino acid interaction code (L. B. Mekler, 1969), the code of codon roots involves the interaction of amino acids independently of the base structures in nucleotide triplets in positions 1 and 3. The analysis of the spectra of point mutations homologous proteins confirms the possible role of the root code.
A programme for pattern recognition and automatic diagnosis on digitally converted electrocardiograms is described. Pattern recognition is carried out on the 12 classical leads and diagnosis is given in the Minnesota Code, 1968 variant. The programme was written in FORTRAN and tested in a FELIX C 256 computer.
The MET14 gene of Saccharomyces cerevisiae, encoding APS kinase (ATP:adenylylsulfate-3'-phosphotransferase, EC 2.7.1.25), has been cloned. The nucleotide sequence predicts a protein of 202 amino acids with a molecular mass of 23,060 dalton. Translational fusions of MET14 with the beta-galactosidase gene (lacZ) of Escherichia coli confirmed the results of primer extension and Northern blot analyses indicating that the ca. 0.7 kb mRNA is transcriptionally repressed by the presence of methionine in the growth medium. By primer extension the MET14 transcripts were found to start between positions -25 and -45 upstream of the initiator codon. Located upstream of the MET14 gene is a perfect match (positions -222 to -229) with the previously proposed methionine-specific upstream activating sequence (UASMet). This is the same as the consensus sequence of the Centromere DNA Element I (CDEI) that binds the Centromere Promoter Factor I (CPFI) and of two regulatory elements of the PHO5 gene to which the yeast protein PHO4 binds. The human oncogenic protein c-Myc also has the same recognition sequence. Furthermore, in the 270 bp upstream of the MET14 coding region there are several matches with a methionine-specific upstream negative (URSMet) control element. The significance of these sequences was investigated using different upstream deletion mutations of the MET14 gene which were fused to the lacZ gene of E. coli and chromosomally integrated. We find that the methionine-specific UASMet and one of the URSMet lie in regions necessary for strong activation and weak repression of MET14 transcription, respectively. We propose that both types of control are exerted on MET14.
Classical phenylketonuria is an autosomal recessive disease caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). The abolition of an invariant BamHI site located in the coding sequence of the PAH gene (exon 7) led to the recognition of two new point mutations at codon 272 and 273 (272gly----stop and 273ser----phe, respectively). Both mutations were detected in north eastern France or Belgium and occurred on the background of RFLP haplotype 7 alleles. The present study supports the view that the clinical heterogeneity in PKU is accounted for by the large variety of mutant genotypes associated with PAH deficiencies.
We have cloned a human MDR3 complementary DNA, coding for a P-glycoprotein, into a mammalian expression vector and cotransfected it with a selectable marker into drug-sensitive human BRO melanoma cells. With low frequency we obtained stable, MDR3-expressing clones. Immunocytochemical and immunoblotting analysis of these clones using the monoclonal antibody C219 indicated that human MDR3 P-glycoprotein, like human MDR1 P-glycoprotein, was mainly localized in the plasma membrane and probably glycosylated. Although a significant fraction of the cells (5-10%) in one of the MDR3-expressing clones expressed as much P-glycoprotein as a clearly drug-resistant MDR1-transfected clone, we found no resistance against a range of drugs affected by multidrug resistance. The drugs tested included vincristine, colchicine, VP16-213, daunorubicin, doxorubicin, actinomycin D, and gramicidin D. We did not detect enhanced daunorubicin efflux either in any of the MDR3-expressing cells by fluorescence microscopy. Direct selection with vincristine, actinomycin D, gramicidin D, or daunorubicin of BRO cells transfected with expression constructs containing the regular MDR3 complementary DNA, or a complementary DNA representing a major MDR3 splice variant (C(-141)), likewise failed to yield resistant clones. Thus, although human MDR3 P-glycoprotein is highly similar to human MDR1 P-glycoprotein, we found no indications that it can transport drugs. We investigated the cross-reactivity of the monoclonal antibodies C219, C494, JSB-1, HYB-241, and MRK16, recognizing human MDR1 P-glycoprotein, with human MDR3 P-glycoprotein using immunocytochemistry and immunoblotting. Apart from monoclonal antibody C219, none of the monoclonal antibodies showed detectable cross-reactivity with human MDR3 P-glycoprotein. In our hands, monoclonal antibodies MRK16 and HYB-241 were most suitable for sensitive and specific cytochemical detection of human MDR1 P-glycoprotein.
The study of face-selective neurons in the monkey temporal lobe, and face recognition deficits in humans after brain damage have both become very active fields of investigation. Face-selective neurons appear to be members of ensembles for coding faces rather than individual face detectors or grandmother cells. They reflect the more general role of temporal cortex in pattern recognition. In humans there are a variety of face-processing impairments that result from damage to different areas, and which reflect interference at different levels of processing of the facial image.
The structure of a gene encoding a 70-kDa heat-shock protein (HSP70) from the unicellular alga, Chlamydomonas reinhardtii, is described. This gene shows a remarkable expression pattern, because it is inducible by light as well as by elevated temperature [von Gromoff et al., Mol. Cell. Biol. 9 (1989) 3911-3918]. As a first step in the investigation of trans-acting factors involved in environmentally controlled expression of this hsp70 gene, the nucleotide sequence of the entire gene, including its 5'- and 3'-flanking regions was determined. Although the deduced amino acid sequence exhibits a high degree of conservation to the HSP70 from higher plants, the C. reinhardtii gene has a unique structure among the members of the hsp70 gene family. While most hsp70 genes have only one or no intron, the coding region of the C. reinhardtii gene is interrupted by six introns. Besides putative TATA and CCAAT boxes, two heat-shock elements (HSE) were found in the promoter region, and a third HSE motif was located within the fourth intron. A computer search for regulatory cis-acting elements revealed a noted similarity of a 5'-upstream sequence motif to the G-box motif conserved in higher plants. A polyadenylation recognition sequence canonical for nuclear genes of C. reinhardtii is located downstream from the coding sequence.
The central theme of this communication is the recognition of an immunodiagnostic potential in a herpes virus antigen, the molecular interrelationship of which with cervical tumor cells is described. In addition to the productive infection caused by herpes simplex virus type 2 (HSV-2) we are confronted by latency and, as suggested by recent studies, by cancer. These different types of virus-host cell interactions are discussed at the host, as well as at the cellular level. A defined level of molecular interaction between host and viral gene products must exist if the virus is to co-exist with the host, as is the case in latency and carcinogenesis. The molecular interpretations posit the presence, in the squamous cervical tumor cells, of a product of the expression of the viral genome that has immunodiagnostic potential. The antigen designated AG-4 fulfills these predictions and appears to have immunodiagnostic potential. AG-4 is present in cervical tumor biopsies, but not in normal cervical tissue. It is a structural component of the HSV-2 virion that, in tissue cultures infected with HSV-2, is synthesized preferentially under conditions that prevent the normal replication of the virus. In view of its structural nature it is most probably virus-coded. AG-4 antibody identified in complement fixation assays with antigen prepared in tissue culture, disappears following successful tumor removal and reappears during cancer recurrence. This antibody also potentially identifies those patients with cervical atypia that are at high risk of neoplastic progression. The clinical benefits of the assay are evident.
The evolution of the human brain is characterized by profound changes in structure and function, despite relatively limited divergence in protein-coding genes compared to other primates. This paradox has led to increasing recognition of gene regulatory elements (GREs) as primary drivers of evolutionary innovation. In this review, we synthesize current knowledge on the role of conserved noncoding elements (CNEs), human accelerated regions (HARs), and transposable element (TE)-derived sequences in shaping gene regulatory networks (GRNs) underlying brain development. Comparative analyses across humans and closely related primates, including the chimpanzee, gorilla, and orangutan, reveal that while core regulatory architectures are highly conserved, subtle changes in regulatory elements drive species-specific gene expression patterns. We highlight how CNEs provide a stable regulatory framework, whereas HARs and TE-derived elements introduce lineage-specific modifications that fine-tune neurodevelopmental processes. Advances in functional genomics, including CRISPR-based perturbations, massively parallel reporter assays, and single-cell multi-omics, have enabled direct interrogation of regulatory function, linking sequence variation to cellular phenotypes. Furthermore, we discuss how regulatory evolution contributes to both cognitive innovation and susceptibility to neurological disorders. Despite significant progress, challenges remain in establishing causal relationships between regulatory variation and phenotypic outcomes. Future integration of multi-omics data and comparative models will be essential for resolving these complexities. Together, this review provides a comprehensive framework for understanding the molecular basis of primate brain evolution through the lens of gene regulation.
The immunologic theory of aging proposes that the normal process of aging in man and all animals is pathogenetically related to faulty immunological processes and may be analogous to a type of autoimmune phenomena ultimately involving all body tissues. It may be said that the sharply increased incidence in elderly humans of the autoimmune and immunodeficiency "diseases of age" are thought to be greatly potentiated by the age-related decline in immune surveillance mechanisms particularly involving self/non-self discriminatory abilities. The major histocompatibility complex has emerged as a complex of "supergenes" coding for antigens whose ultimate biological function may be to serve as recognition units allowing lymphocytes to recognize self from non-self on an immunological basis. Also, recent data are consistent with our supposition that differences in age-specific peaks of various immune functional parameters in genetically homozygous mice may be influenced by genes linked to the major histocompatibility complex. These differences may account, at least in part, for the highly strain-dependent, age-specific incidence of certain diseases, including autoimmune and malignant diseases in the mouse. Heightened susceptibility to develop a particular disease in a susceptible animal occurs when a certain balance is reached between the interplay of immune functional parameters which mature, differentiate, or decline at different rates in the same animal. The age-specificity of this balance may be under partial control of H-2 or HLA-linked genes.
The primary purpose of this research was to determine how imaginal and verbal encoding strategies intereact with various stimulus characteristics to either enhance or retard recognition; the secondary purpose of these studies was to test the conceptual coding hypothesis of Ellis, 1972. A between-groups multivariate factorial analysis of covariance experiment and a within-subjects multivariate factorial analysis of variance experiment were conducted. In Experiment 1 it was found that low-codability shapes were better recognized under the verbal encoding set rather than the imaginal encoding verbal encoding sets; and high-codability shapes were not better recognized than low-codability shapes. However, in Experiment 2, where instructional set was a within-subjects factor, it was found that low-codability shapes were not better recognized under the verbal encoding set than the imaginal encoding set.