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PubMed2026

Personalized functional topography-based multisite brain age prediction modeling reveals divergent neurodevelopment in major depression.

Major depressive disorder (MDD) is associated with widespread alterations in functional brain networks across the lifespan. However, heterogeneity in atypical brain development among patients with MDD remains largely uncharacterized. Using a multisite resting-state functional MRI dataset consisting of 1,105 MDD patients and 1,065 healthy controls, we constructed a harmonized multicenter brain age prediction model based on individualized functional topography and identified two patient subgroups with positive or negative brain age gaps (BAGs). In patients with a positive BAG (BAG+), expansion of the salience network (SAL) into the dorsolateral prefrontal and ventrolateral prefrontal cortices, in addition to contraction of the sensorimotor and dorsal attention networks (DAN), contributes to accelerated brain aging. Conversely, in the negative BAG (BAG-) group, SAL expansion into the orbitofrontal cortex (OFC) and contraction of the visual and sensorimotor networks (SMN) were linked to delayed brain development. These subgroups also exhibited distinct neurodevelopmental trajectories. Clinically, BAG+ patients showed stronger associations between higher-order network topography and mood symptoms, whereas BAG- patients exhibited links between visual/default mode network topography and insomnia. At the molecular level, both groups showed enrichment of genes related to synaptic signaling but displayed distinct expression patterns and divergent expression trajectories in key neurodevelopmental gene sets. Notably, antidepressant treatment modulated the brain in ways that were specific to each subgroup. These findings reveal heterogeneous neurodevelopmental profiles in MDD with distinct biological and clinical signatures, offering insights into personalized precision medicine for this disorder.

Humans↗
PubMed1995

A comparative study of higher primate foamy viruses, including a new virus from a gorilla.

Few foamy (spuma) retroviruses have been investigated in molecular detail, despite their previous isolation from several mamalian species, including ten neutralization serotypes from various primates. Here, we have studied a new gorilla foamy virus (SFV-Gg) and investigated its functional and phylogenetic relationship to the human (HFV) and other primate foamy viruses, including that recently described in orangutans (SFV-11). Nucleotide sequencing of PCR products obtained from the R/U5 region of the LTR, gag, and pol genes revealed a close relationship between HFV and three chimpanzee isolates (SFV-6, SFV-7, and SFV-cpz). The SFV-Gg, SFV-11, rhesus macaque (SFV-1), and African green monkey (SFV-3) isolates were more divergent. To explore functional relationships, primate foamy virus transactivation of HFV LTR driven beta-galactosidase expression in a newly constructed cell line, BHLL, was investigated. HFV, SFV-6, and SFV-7 potently transactivated HFV LTR driven lacZ gene expression, SFV-Gg induced expression approximately 10-fold less efficiently, and SFV types 1, 2, 3, and 11 did not significantly transactivate the HFV LTR. It was, thus, possible to assay serum neutralizing activity in SFV-infected primates against HFV, SFV-6, and SFV-7 by reduction of beta-galactosidase activity following infection of the indicator cell line. Sera from infected chimpanzees and gorillas neutralized, to varying degrees, each of these three viruses, whereas orangutan sera did not. Our results, based on DNA sequences and functional assays, support the conclusion that HFV is closely related to foamy viruses of chimpanzee origin.

Animals↗
PubMed2004

Expression of phosphacan and neurocan during early development of mouse retinofugal pathway.

We have investigated whether the two major brain chondroitin sulfate (CS) proteoglycans (PGs), phosphacan and neurocan, are expressed in patterns that correlate to the axon order changes in the mouse retinofugal pathway. Expression of these proteoglycans was examined by polyclonal antibodies against phosphacan and N- and C-terminal fragments of neurocan. In E13-E15 mouse embryos, when most optic axons grow in the chiasm and the optic tract, phosphacan and neurocan were observed in the inner regions of the retina. In the chiasm and the tract, phosphacan but not neurocan was expressed prominently at the midline and in the deep parts of the tract. Both proteoglycans were observed on the chiasmatic neurons, which have been shown to regulate axon divergence at the chiasmatic midline and the chronotopic fiber ordering in the tract, but phosphacan appeared to be the predominant form that persists to later developmental stages. Intense staining of both proteoglycans was also observed in a strip of glial-like elements in lateral regions of the chiasm, partitioning axons in the stalk from those in the tract. We conclude that phosphacan but not neurocan is likely the major carrier of the CS glycosaminoglycans that play crucial functions in axon divergence and age-related axon ordering in the mouse optic pathway. Furthermore, localization of these carrier proteins in the optic pathway raises a possibility that these two proteoglycans regulate axon growth and patterning not only through the sulfated sugars but also by interactions of the protein parts with guidance molecules on the optic axons.

Animals↗
PubMed2001

Expression of presenilin-1 and Notch-1 receptor in human embryonic CNS.

In vitro studies have shown that the Alzheimer's disease-related presenilin-1 protein can mediate Notch-1 receptor cleavage during signalling. In the present study, we compared the distribution of presenilin-1 and Notch-1 receptor immunoreactivities in human embryonic CNS tissue during the first trimester of development. Our aim was to gain insight into whether these proteins are likely to interact functionally during human fetal brain development. CNS material was obtained from routine abortions, cryosectioned and studied by means of immunohistochemistry with antibodies to presenilin-1 and Notch-1. At very early stages of embryonic development (four to five gestational weeks) intensive presenilin-1 immunoreactivity could be seen predominantly in neurites in the ventral horn of the spinal cord, where it overlapped with 200-kDa neurofilament immunoreactivity. Presenilin-1 immunoreactivity was also seen in neuroblasts of the ventricular zone of the tel- and mesencephalon, as well as of the brainstem. Notch-1 receptor appeared in neuronal and ependymal cells throughout the CNS. Seven- to eight-week CNS tissue showed similar patterns of presenilin-1 and Notch-1 receptor expression in the spinal cord and cerebral cortex as was seen at five weeks. Both proteins were localised in the neuroepithelial cell layer lining the ventricles, as well as in the cortical plate layer, where immunoreactivity was seen in the cell bodies. In addition, presenilin-1 immunoreactivity was seen in thin neurites in the subplate of the developing cortex. At 10 weeks, presenilin-1 immunoreactivity was reduced in the spinal cord. These results show that, although presenilin-1 and Notch-1 receptor are localised to the same differentiating cell populations in the human cerebral cortex, making a direct interaction possible, these proteins are otherwise confined to different neurons or neuronal compartments, suggesting a role for presenilin-1 during early CNS differentiation that does not involve Notch-1 receptor processing. Double staining for presenilin-1 in the endoplasmic reticulum and presenilin-1 in the Golgi showed overlap to some extent in investigated CNS regions, but not in neurites. This suggests that presenilin-1 function during neurogenesis is not exclusively correlated to protein processing within the endoplasmic reticulum and Golgi, but that presenilin-1 may also be involved in other processes, such as axonal and dendritic outgrowth or synaptic formation. In summary, our findings provide supportive evidence that the presenilin-1 protein is involved in the development and maturation of the human fetal CNS. The presence of presenilin-1 immunoreactivity in both the cell bodies and neurites of developing neurons strongly suggests divergent mechanisms of function for presenilin-1 during human brain development. These may include interactions with any of the Notch receptor proteins, as well as Notch-independent mechanisms.

Biomarkers↗
PubMed1997

Different consequences of incorporating chloroplast ribosomal proteins L12 and S18 into the bacterial ribosomes of Escherichia coli.

We have incorporated chloroplast ribosomal proteins (R-proteins) L12 and S18 into Escherichia coli ribosomes and examined the hybrid ribosomes for their ability to form polysomes in vivo and perform poly(U)-dependent poly(Phe) synthesis in vitro. The rye chloroplast S18 used for the experiment is a highly divergent protein (170 amino acid residues; E. coil S18, 74 residues), containing a repeating, chloroplast-specific, heptapeptide motif, and has amino acid sequence identity of only 35% to E. coli S18. When expressed in E. coli, chloroplast S18 was assembled in E. coli ribosomes. The latter formed polysomes in vivo at about the same rate as the host ribosomes, indicating that the replacement of E. coli S18 with its chloroplast homologue has only a minor, if any, effect on function. The L12 protein is much more conserved in sequence and chain length, and is known to have a very important function. The Arabidopsis chloroplast L12 used in the experiment was incorporated into E. coli 50S subunits that associated with the 30S subunits to form ribosomes, but the latter were unable to form polysomes. This result indicates functional inactivation of E. coil ribosomes by a chloroplast R-protein. To further confirm this result, we overproduced chloroplast L12 through the use of a secretion vector and purified the protein to homogeneity. Chloroplast L12 could be efficiently incorporated in vitro into L7/12-lacking E. coli ribosomes, but the hybrid ribosomes were totally inactive in poly(U)-dependent poly(Phe) synthesis. Computer modeling of the spatial structure of all known chloroplast L12 proteins (using E. coli L12 coordinates) indicated a 'chloroplast loop' present only in chloroplast L12. The presence of this loop might have a role in the observed inactivation. Taken together with previously reported results (summarized in this paper), it would appear that the features of chloroplast R-proteins concerned with specific functions are more divergent than their assembly properties. We have previously described methods suitable for overproduction and purification of chloroplast R-proteins that are encoded in organellar DNA (approximately 20), but that gave poor yield for those encoded in the nuclear DNA (approximately 45). Here we describe a method that overcomes this problem and allows the purification of nucleus-encoded chloroplast R-proteins in milligram quantities.

Amino Acid Sequence↗
PubMed1995

Evaluation of digitally reconstructed radiographs (DRRs) used for clinical radiotherapy: a phantom study.

Digitally reconstructed radiographs produced from a commercial CT simulator have been evaluated using an in-house test phantom. The phantom consists of a polystyrene cubic block of dimension 15 cm. It contains four test patterns to measure contrast detail, modulation transfer function, ray line divergence accuracy, and spatial distortion. A total of six CT data sets, which vary by CT slice thickness and separation between slices, as well as CT slice reconstruction area have been used to analyze digitally reconstructed radiographs produced by the system. Results show that contrast detail is independent of slice thickness and separation but dependent upon slice reconstruction area for small object diameters (< or = 1.5 mm). Half field (24-cm diameter) reconstruction images provide lower threshold contrasts than full field (48-cm diameter) scans. The modulation transfer function for each data set was calculated and the spatial frequency at which the modulation transfer function is 50% (f50) of the maximum indicates that high contrast resolution depends on slice thickness for both the full and half field reconstructions. For full field scans, f50 values were 0.19, 0.10, and 0.10 line pairs/mm for the 2 mm/2 mm (slice thickness/separation), 5 mm/3 mm, and 5 mm/5 mm data sets, respectively. Similarly, half field f50 values were 0.19, 0.10, and 0.10 line pairs/mm for these same three thickness/separation data sets, respectively. The error in the ray tracing component of the digitally reconstructed radiograph algorithm for source to skin distances between 60 and 200 cm was 1.0 mm while the spatial linearity error was < or = 2.5 mm. Errors in CT simulator collimator and table rotations were calculated by measuring the angle between a grid pattern inlayed onto two orthogonal faces of the phantom and a graphical grid superimposed onto the digitally reconstructed radiograph by the CT simulator software. Measured angular differences were < or = 1.0 degree. The largest error in shifting the CT simulator field isocenter was 2.2 mm and occurred on the 5-mm slice thickness and separation CT data sets.

Biophysical Phenomena↗
PubMed1998

Mutation analysis of PobR and PcaU, closely related transcriptional activators in acinetobacter.

Acinetobacter PobR and PcaU are transcriptional activators that closely resemble each other in primary structure, DNA-binding sites, metabolic modulators, and physiological function. PobR responds to the inducer-metabolite p-hydroxybenzoate and activates transcription of pobA, the structural gene for the enzyme that converts p-hydroxybenzoate to protocatechuate. This compound, differing from p-hydroxybenzoate only in that it contains an additional oxygen atom, binds to PcaU and thereby specifically activates transcription of the full set of genes for protocatechuate catabolism. Particular experimental attention has been paid to PobR and PcaU from Acinetobacter strain ADP1, which exhibits exceptional competence for natural transformation. This trait allowed selection of mutant strains in which pobR function had been impaired by nucleotide substitutions introduced by PCR replication errors. Contrary to expectation, the spectrum of amino acids whose substitution led to loss of function in PobR shows no marked similarity to the spectrum of amino acids conserved by the demand for continued function during evolutionary divergence of PobR, PcaU, and related proteins. Surface plasmon resonance was used to determine the ability of mutant PobR proteins to bind to DNA in the pobA-pobR intergenic region. Deleterious mutations that strongly affect DNA binding all cluster in and around the PobR region that contains a helix-turn-helix motif, whereas mutations causing defects in the central portion of the PobR primary sequence do not seem to have a significant effect on operator binding. PCR-generated mutations allowing PobR to mimic PcaU function invariably caused a T57A amino acid substitution, making the helix-turn-helix sequence of PobR more like that of PcaU. The mutant PobR depended on p-hydroxybenzoate for its activity, but this dependence could be relieved by any of six amino acid substitutions in the center of the PobR primary sequence. Independent mutations allowing PcaU to mimic PobR activity were shown to be G222V amino acid substitutions in the C terminus of the 274-residue protein. Together, the analyses suggest that PobR and PcaU possess a linear domain structure similar to that of LysR transcriptional activators which largely differ in primary structure.

Acinetobacter↗
PubMed2004

Unprecedented genomic diversity of AhR1 and AhR2 genes in Atlantic salmon (Salmo salar L.).

Aryl hydrocarbon receptor (AhR) genes encode proteins involved in mediating the toxic responses induced by several environmental pollutants. Here, we describe the identification of the first two AhR1 (alpha and beta) genes and two additional AhR2 (alpha and beta) genes in the tetraploid species Atlantic salmon (Salmo salar L.) from a cosmid library screening. Cosmid clones containing genomic salmon AhR sequences were isolated using a cDNA clone containing the coding region of the Atlantic salmon AhR2gamma as a probe. Screening revealed 14 positive clones, from which four were chosen for further analyses. One of the cosmids contained genomic AhR sequences that were highly similar to the rainbow trout (Oncorhynchus mykiss) AhR2alpha and beta genes. SMART RACE amplified two complete, highly similar but not identical AhR type 2 sequences from salmon cDNA, which from phylogenetic analyses were determined as the rainbow trout AhR2alpha and beta orthologs. The salmon AhR2alpha and beta encode proteins of 1071 and 1058 residues, respectively, and encompass characteristic AhR sequence elements like a basic-helix-loop-helix (bHLH) and two PER-ARNT-SIM (PAS) domains. Both genes are transcribed in liver, spleen and muscle tissues of adult salmon. A second cosmid contained partial sequences, which were identical to the previously characterized AhR2gamma gene. The last two cosmids contained partial genomic AhR sequences, which were more similar to other AhR type 1 fish genes than the four characterized salmon AhR2 genes. However, attempts to amplify the corresponding complete cDNA sequences of the inserts proved very difficult, suggesting that these genes are non-functional or very weakly transcribed in the examined tissues. Phylogenetic analyses of the conserved regions did, however, clearly indicate that these two AhRs belong to the AhR type 1 clade and have been assigned as the Atlantic salmon AhR1alpha and AhR1beta genes. Taken together, these findings demonstrate that multiple AhR genes are present in Atlantic salmon genome, which likely is a consequence of previous genome duplications in the evolutionary past of salmonids. Plausible explanations for the high incidence of AhR genes in fish and more specifically in salmonids, like rapid divergences in specialized functions, are discussed.

Amino Acid Sequence↗
PubMed2004

Age-related changes in nigrostriatal dopaminergic function are accentuated in +/- brain-derived neurotrophic factor mice.

The effects of a deletion for the brain derived neurotrophic factor (BDNF) allele (+/- BDNF) upon age-related changes in nigrostriatal dopaminergic (NSDA) function were assessed. Behavioral (beam crossing and spontaneous activity) and neurochemical (potassium-stimulated dopamine release from superfused striatum) measures were compared among Young (4-5 month), Middle (11-13 month) and Aged (19-21 month) +/- BDNF and their wild type littermate control (+/+ BDNF) mice. No statistically significant differences were obtained between +/+ and +/- BDNF mice at the Young age sampling period for any of the behavioral or neurochemical measures. Behavioral and neurochemical responses indices of NSDA function begin to diverge between +/+ and +/- Middle age BDNF mice and maximal differences were observed at the Aged period. For both movement and stereotypy times, scores obtained from +/+ mice were significantly decreased compared with +/- BDNF mice at the Aged period and center time scores of +/+ mice were decreased at both the Middle and Aged periods compared with +/- BDNF mice. Neurochemically, potassium-stimulated DA release of +/+ mice was significantly greater than +/- BDNF mice with maximal differences obtained at the Aged period. These results demonstrate marked differences in age-related changes of NSDA function between +/+ and +/- BDNF mice and suggest that the deletion of one allele for BDNF may make these mice more susceptible to age-related declines in NSDA function.

Aging↗
PubMed1992

The lamellar organization of the rat substantia nigra pars reticulata: distribution of projection neurons.

As a major output station of the basal ganglia, the pars reticulata of the substantia nigra has stimulated much interest. In the past two decades there has been a growing body of evidence for a partition of this structure into separate channels to express the striatal processing. To further our knowledge on the functional partitioning of the rodent substantia nigra pars reticulata, the regional distribution of the nigral efferent cell groups that provide innervation of thalamus, colliculus and tegmentum has been detailed in rat using the wheatgerm agglutinin conjugated with horseradish peroxidase as an axonal tracer. To ensure a total visualization of the nigral efferent neurons we have, in a preliminary study, determined the total extent of the nigral terminal field in each of the nigral target structures using the anterograde transport of wheatgerm agglutinin-horseradish peroxidase and Phaseolus vulgaris leucoagglutinin. At variance with the classical view that nigral cells innervating distinct target structures form functionally distinct subnuclei, the results suggest a nigral compartmentation that rather relies upon specific associations of efferent cell groups. As disclosed, these associations are specified by topographic rules and spatially ordered in a series of curved laminae enveloping an excentrated dorsolateral core. In this onion-like model of the substantia nigra pars reticulata, each lamella defines an associative unit composed of a set of neurons innervating particular loci of thalamus, colliculus and/or tegmentum. This lamellar partitioning bestows the ability upon the substantia nigra to dispatch the striatal outflow via parallel and divergent channels to functionally associated target areas in thalamus and brainstem.

Animals↗
PubMed2005

Rates of divergence in gene expression profiles of primates, mice, and flies: stabilizing selection and variability among functional categories.

The extent to which natural selection shapes phenotypic variation has long been a matter of debate among those studying organic evolution. We studied the patterns of gene expression polymorphism and divergence in several datasets that ranged from comparisons between two very closely related laboratory strains of mice to comparisons across a considerably longer time scale, such as between humans and chimpanzees, two species of mice, and two species of Drosophila. The results were analyzed and interpreted in view of neutral models of phenotypic evolution. Our analyses used a number of metrics to show that most mRNA levels are evolutionary stable, changing little across the range of taxonomic distances compared. This implies that, overall, widespread stabilizing selection on transcription levels has prevented greater evolutionary changes in mRNA levels. Nevertheless, the range of rates of divergence is large with highly significant differences in the rate and patterns of transcription divergence across functional classes defined on the basis of the gene ontology annotation (primates and mice datasets) or on the basis of the pattern of sex-biased gene expression (Drosophila). Moreover, rates of divergence of sex-biased genes in the contrast between Drosophila species show a distinct pattern from that observed in the contrast between populations of D. melanogaster. Hence, we discuss the time scale of the changes observed and its consequences for the relationship between variation in gene expression within and between species. Finally, we argue that differences in mRNA levels of the magnitudes observed herein could be explained by a remarkably small number of generations of directional selection.

Animals↗
PubMed2002

Training products of experts by minimizing contrastive divergence.

It is possible to combine multiple latent-variable models of the same data by multiplying their probability distributions together and then renormalizing. This way of combining individual "expert" models makes it hard to generate samples from the combined model but easy to infer the values of the latent variables of each expert, because the combination rule ensures that the latent variables of different experts are conditionally independent when given the data. A product of experts (PoE) is therefore an interesting candidate for a perceptual system in which rapid inference is vital and generation is unnecessary. Training a PoE by maximizing the likelihood of the data is difficult because it is hard even to approximate the derivatives of the renormalization term in the combination rule. Fortunately, a PoE can be trained using a different objective function called "contrastive divergence" whose derivatives with regard to the parameters can be approximated accurately and efficiently. Examples are presented of contrastive divergence learning using several types of expert on several types of data.

Journal Article↗
PubMed2006

Buffering of crucial functions by paleologous duplicated genes may contribute cyclicality to angiosperm genome duplication.

Genome duplication followed by massive gene loss has permanently shaped the genomes of many higher eukaryotes, particularly angiosperms. It has long been believed that a primary advantage of genome duplication is the opportunity for the evolution of genes with new functions by modification of duplicated genes. If so, then patterns of genetic diversity among strains within taxa might reveal footprints of selection that are consistent with this advantage. Contrary to classical predictions that duplicated genes may be relatively free to acquire unique functionality, we find among both Arabidopsis ecotypes and Oryza subspecies that SNPs encode less radical amino acid changes in genes for which there exists a duplicated copy at a "paleologous" locus than in "singleton" genes. Preferential retention of duplicated genes encoding long complex proteins and their unexpectedly slow divergence (perhaps because of homogenization) suggest that a primary advantage of retaining duplicated paleologs may be the buffering of crucial functions. Functional buffering and functional divergence may represent extremes in the spectrum of duplicated gene fates. Functional buffering may be especially important during "genomic turmoil" immediately after genome duplication but continues to act approximately 60 million years later, and its gradual deterioration may contribute cyclicality to genome duplication in some lineages.

Arabidopsis↗
PubMed2004

Glycosomes: parasites and the divergence of peroxisomal purpose.

Peroxisomes are membrane-bounded organelles that compartmentalize a variety of metabolic functions. Perhaps the most divergent peroxisomes known are the glycosomes of trypanosomes and their relatives. The glycolytic pathway of these organisms resides within the glycosome. The development of robust molecular genetic and proteomic approaches coupled with the completion of the genome sequence of the pathogens Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major provides an opportunity to determine the complement of proteins within the glycosome and the function of compartmentation. Studies now suggest that regulation of glycolysis is a strong driving force for maintenance of the glycosome.

Animals↗
PubMed1997

Stem cells in prostatic epithelia.

The normal prostate is, structurally and functionally, a highly complex glandular tissue in which populations of epithelial and stromal cells interact, one with the other, and are under a constant state of proliferation, differentiation, elimination and selective secondary replenishment so that functional integrity of the tissue is maintained. The ability of normal prostatic tissue to maintain its structure and function is dependent upon retention of cells, generally regarded as 'stem cells', which are able to respond by proliferation and selective differentiation within a wide range of phenotypic alternatives. With respect to cells in the epithelial compartment, replenishment is possible at several levels from within distinct pathways of normal cellular differentiation. It is now appreciated that fully differentiated prostatic epithelial cells retain a far greater degree of phenotypic 'plasticity' than was earlier apparent from morphological examination of the intact tissue. This inherent plasticity, coupled with the ability of the intact tissue to respond to diverse environmental (particularly humoral) stimuli by regenerating a wide and divergent spectrum of functional prostatic epithelial phenotypes is its strength--but also its weakness. Disturbance and distortion of the homeostatic regulatory mechanisms, whether physical or humoral, which control the normal sequence of epithelial proliferation, differentiation and elimination exposes these cells, particularly multipotent 'stem cells', to an increased probability of genetic change, thus resulting in either transient, or permanent, neoplastic transformation.

Basement Membrane↗
PubMed2000

An optimization approach to multi-dimensional time domain acoustic inverse problems.

An optimization approach to a multi-dimensional acoustic inverse problem in the time domain is considered. The density and/or the sound speed are reconstructed by minimizing an objective functional. By introducing dual functions and using the Gauss divergence theorem, the gradient of the objective functional is found as an explicit expression. The parameters are then reconstructed by an iterative algorithm (the conjugate gradient method). The reconstruction algorithm is tested with noisy data, and these tests indicate that the algorithm is stable and robust. The computation time for the reconstruction is greatly improved when the analytic gradient is used.

Acoustics↗
PubMed2005

Metabolism and functional roles of endogenous D-serine in mammalian brains.

It has now been well established that D-serine, a coagonist for the N-methyl-D-aspartate (NMDA) glutamate receptors (NR1/NR2 type), is maintained at a high concentration in mammalian brains for life and shows a brain-selective and NMDA receptor R2B subunit-related distribution, overturning the hitherto generally accepted theory that D-amino acid is not always present in mammalian tissues. D-Serine in the brain has been shown to be contained in both the glia and neurons and to have specific processes of biosynthesis, extracellular release, uptake, and degradation. Moreover, the selective elimination of D-serine reduces the NMDA receptor-mediated intracellular signaling and long-term potentiation of synaptic connections. Together with the anti-psychotic and anti-ataxic property of D-serine and the pivotal roles of the NMDA receptor in divergent higher brain functions, these observations support the view that the D-amino acid may be involved as an endogenous modulator for the NMDA receptor in various neuropsychiatric functions and their pathological conditions.

Animals↗
PubMed1987

Structure and expression of class I MHC genes in the miniature swine.

The genome of the miniature swine, unlike other species, contains a relatively small class I MHC gene family, consisting of only seven members. This provides an excellent system in which to identify and characterize the regulatory mechanisms which operate to both coordinately and differentially regulate the expression of a multi-gene family. The structure of class I SLA genes, like other class I genes, consists of eight exons encoding a leader sequence, three extracytoplasmic domains, a transmembrane domain and intracytoplasmic domains. Despite the common structure, two sub-families of class I genes can be distinguished within the SLA family. One, containing the closely related PD1 and PD14 genes, encodes the classical transplantation antigens. Another contains the highly divergent PD6; the functions of the products of this subfamily, if any, are not known. The class I SLA genes share some common regulatory mechanisms, as evidenced by the fact that all three genes analyzed are transcribed in mouse L cells. Furthermore, interferon treatment of transfected mouse L cells enhances expression of all three genes. Both PD1 and PD6 are transcribed in vivo, where the highest levels of expression are observed in lymphoid tissues. Superimposed on the common patterns of class I gene expression are distinct ones, as evidenced by the findings that PD1 is preferentially expressed in B cells, whereas PD6 is preferentially expressed in T cells. These differences may reflect the extensive divergence of the 5' flanking sequences of these genes. Future studies will be aimed at elucidating the precise molecular interactions and mechanisms which give rise to the observed differential expression.

Animals↗