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PubMed1998

Immunoglobulin transgenes as targets for somatic hypermutation.

This review describes studies on somatic hypermutation of immunoglobulin genes that were started in the mid-80s in collaboration with Ralph Brinster. Almost all of the experiments were carried out using Ig transgenes as targets for the somatic mutation mechanism. Ig transgenes can be very good targets of somatic mutation, despite many different transgene integration sites. Thus, the required cis-acting elements must be present within the approximately 10 kb of the transgene. Only the Ig variable region and its proximate flanks are mutated, not the constant region in unmanipulated sequences. Several Ig gene enhancers are permissive for somatic mutation and they do not have to be associated with the Ig promoter they normally interact with. However, the mutation process does seem to be specific for Ig genes. No mutations were found in several housekeeping genes isolated from cells that had very high levels of somatic hypermutation of their Ig genes. This suggests that the Ig enhancers provide the lg gene specificity. An exception is the Bcl-6 gene, encoding a transcription factor, which was found to be mutated in normal human memory B cells. When the transcriptional promoter that is located upstream of the variable region is duplicated upstream of the constant region, this region is mutated as well. This suggests a transcription coupled model in which a mutator factor associates with the RNA polymerase at the initiation of transcription, travels with the polymerase during elongation, and causes mutations during polymerase pausing. Our recent data with an artificial substrate for somatic mutation suggest that the mutations are increased by increased stability of the secondary structures in the nascent RNA, and the specific nucleotides that are mutated are due to preferences of a mutator factor.

Animals↗

PubMed2026

Loss of interruption in the HTT CAG repeat is associated with somatic expansion and loss of medium spiny neurons in Huntington's disease.

Synonymous loss-of-interruption variants in the expanded CAG repeat sequence of Huntingtin (HTT) accelerate the clinical onset and progression of Huntington's disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN pathology. Here, we show that MSNs with large (111-150 CAG) and very large (>150 CAG) somatic expansions are rare in early manifest HD but accumulate in proportion with duration of disease. In patients with the deleterious CAG-CCG loss-of-interruption (CAG-CCG LOI) modifier, the proportion of MSNs with large and very large expansions is increased ∼5-fold despite reduced small somatic expansions in blood, and caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and onset of HD but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.

Huntington’s disease↗

PubMed2004

Induction of somatic hypermutation by antigen-specific B cell receptors in the human BL2 cell line.

The role of the B cell antigen receptor in the induction of somatic hypermutation is presently unclear. We established stable transfectants of the human BL2 cell line expressing hen-egg lysozyme-specific IgM or IgA and compared their ability to induce somatic hypermutation of the endogenous rearranged heavy-chain gene. We found that IgM and IgA were both able to induce somatic hypermutation in an antigen dose-independent manner. The mutations displayed most of the characteristics of somatic hypermutation in vivo. Notably, some replacements introduced stop codons in the coding region. Our data suggest that class-switched memory B cells may undergo somatic hypermutation. They also suggest that the transmembrane/cytoplasmic domains of the class-switched isotypes modulate the signaling and down-modulation activities of the BCR in an antigen dose-dependent manner.

Amino Acid Sequence↗

PubMed2003

Somatic translocation and differential expression of Ig mu transgene copies implicate a role for the Igh locus in memory B cell development.

Memory B cells of mice with Ig mu transgenes often carry transgene copies that have moved into the Igh locus via somatic translocation. This phenomenon has been attributed to a selection pressure for somatic hypermutations, which generally are observed at much higher frequencies in translocated copies than in ectopic copies. We tested this idea by immunizing Ig-mu transgenic mice in a manner designed to select B cells that required only one V(H) mutation for a switch in antigenic specificity and recruitment into the memory pool. Despite the minimal mutation requirement, hybridomas carrying somatic translocations to the Igh locus were obtained. Importantly, this occurred despite the fact that translocated and untranslocated mu-transgenes were mutated comparably. Evidently, a strong selection advantage was conferred upon B cells by the somatic translocations. Among the hybridomas, translocated mu-transgenes were active, while ectopic mu-transgenes were uniformly silent. The translocated copy that had conferred an affinity-based selection advantage was expressed at the highest level. Moreover, translocated copies were differentially expressed among hybridoma members, which belonged to a common post-mutational lineage. This suggests that adjustments in transgene expression levels had occurred during memory cell development. These results indicate that, apart from their potential influences on somatic hypermutagenesis and class switch recombination, elements in the Igh locus promote the selection of memory B cells in another way, possibly by regulating the level of Ig expression at various stages of antigen-driven differentiation.

Animals↗

PubMed2004

T cell-independent somatic hypermutation in murine B cells with an immature phenotype.

Somatic hypermutation contributes to the generation of antibody diversity and is strongly associated with the maturation of antigen-specific immune responses. We asked whether somatic hypermutation also plays a role in the generation of the murine immunoglobulin repertoire during B cell development. To facilitate identification of somatic mutations, we examined mouse systems in which only antibodies expressing lambda1, lambda2, and lambdax light chains can be generated. Somatic mutations were found in cells, which, by surface markers, RAG expression, and rapid turnover, had the phenotype of immature B cells. In addition, expression of AID was detected in these cells. The mutations were limited to V regions and were localized in known hotspots. Mutation frequency was not diminished in the absence of T cells. Our results support the idea that somatic hypermutation can occur in murine immature B cells and may represent a mechanism for enlarging the V gene repertoire.

Animals↗

PubMed2002

The different process of class switching and somatic hypermutation; a novel analysis by CD27(-) naive B cells.

The relationship between class switch recombination (CSR) and somatic hypermutation has been unclear. By using human CD27(-) naive B cells, we investigated the somatic hypermutation and producibility of immunoglobulins (Igs) that occur after CSR. Although neither adult CD27(-) nor cord blood B cells, which showed the unmutated Ig V-region genes, produced IgG, IgM, or IgA in response to conventional stimuli, they produced IgG and IgM but not IgA in the presence of Staphylococcus aureus Cowan strain (SAC) + interleukin-2 (IL-2) + IL-10 + anti-CD40 mAb + CD32 transfectants (CD40/CD32T). The naive B cells also produced IgE when combined with IL-4 + CD40/CD32T. In parallel with IgG production, the expression of mature gamma1 and gamma 2 transcripts was induced from naive B cells by the stimuli. The CD27 expression on human naive B cells was induced remarkably by CD40 signaling or B-cell receptor engagement, but somatic hypermutation could not be induced. The proliferation and differentiation into plasma cells were induced from naive B cells, whereas most of the plasma cells displayed very low levels of mutations in Ig V-region genes. CD27(-) naive B cells expressed activation-induced cytidine deaminase messenger RNA by the stimuli later than CD27(+) memory B cells. Our results demonstrate that CSR, but not noticeable somatic hypermutation, can be induced from CD27(-) naive B cells upon B-cell receptor engagement and CD40 signaling in cooperation with cytokines, suggesting that CSR and somatic hypermutation processes can occur independently, and the antibodies produced in this in vitro system are low-affinity antibodies.

Adult↗

PubMed2006

Antigen receptors and somatic hypermutation in B-cell chronic lymphocytic leukemia with Richter's transformation.

BACKGROUND AND OBJECTIVES: Activation-induced cytidine deaminase is essential for somatic hypermutation and class switch recombination of the immunoglobulin genes in B cells. It has been proposed that aberrant targeting of the somatic hypermutation machinery is instrumental in initiation and progression of B-cell non Hodgkin's lymphomas. In this study, we investigated the B-cell receptor and the role of the somatic hypermutation machinery in B-cell chronic lymphocytic leukemias (B-CLL) prior to and after transformation to a lymphoma of a higher malignancy grade (Richter's transformation). DESIGN AND METHODS: We investigated the activity of the somatic hypermutation machinery in nine B-CLL and secondary diffuse large B-cell lymphomas by measuring the expression of activation-induced cytidine deaminase, in combination with mutation analysis of immunoglobulin (Ig) and non-Ig genes. Furthermore, the structure of the antigen receptors of B-CLL known to have developed a Richter's syndrome (RS B-CLL) was analyzed by comparing the most variable region of the Ig, the CDR3 region, to CDR3 sequences present in GenBank. RESULTS: Ig variable heavy chain (IgV(H)) gene studies revealed that Richter's transformation occurs almost exclusively in unmutated B-CLL. Furthermore, activated-induced cytidine deaminase expression and somatic hypermutation activity of most RS B-CLL were found to be higher than those of control (non-transforming) B-CLL. Finally, comparison of the IgVH-CDR3 regions showed a remarkable amino acid sequence homology between two RS B-CLL of our panel and two RS B-CLL described in the literature. INTERPRETATIONS AND CONCLUSIONS: The combined findings suggest a role for the Ig gene diversification apparatus during Richter's transformation and show that distinct RS-B-CLL may recognize recurrent antigenic epitopes.

Humans↗

PubMed2006

Cognitive-behavioral therapy for somatization disorder: a randomized controlled trial.

BACKGROUND: Patients diagnosed as having somatization disorder (SD) who present with a lifetime history of multiple, medically unexplained physical symptoms represent a significant challenge to health care providers. To date, no psychotherapeutic or pharmacologic intervention has been found to produce clinically meaningful improvement in symptoms or functioning of patients with SD. We examined the efficacy of cognitive-behavioral therapy (CBT) for SD. METHODS: Eighty-four participants meeting criteria for SD were randomly assigned to 1 of 2 conditions: (1) standard medical care augmented by a psychiatric consultation intervention or (2) a 10-session, manualized, individually administered CBT regimen added to the psychiatric consultation intervention. Assessments were conducted at baseline and 3, 9, and 15 months after baseline. The primary outcome measure was the severity scale of the Clinical Global Impression Scale for Somatization Disorder (CGI-SD). Secondary outcome measures were responder status as determined by clinical ratings, self-reported measures of physical functioning and somatic symptoms, and health care utilization assessed via medical records. RESULTS: Fifteen months after baseline, somatization symptoms were significantly less severe in the group treated with CBT (0.84 points on the CGI-SD 7-point scale) (P<.001). Patients treated with CBT also were significantly more likely to be rated as either very much improved or much improved than patients treated with only augmented standard medical care (40% [n = 17] vs 5% [n = 2]). Cognitive-behavioral therapy was associated with greater improvements in self-reported functioning and somatic symptoms and a greater decrease in health care costs. CONCLUSION: For patients diagnosed as having SD, CBT may produce clinical benefits beyond those that result from the current state-of-the-art treatment.

Adolescent↗

PubMed1984

An adoption study of somatoform disorders. I. The relationship of somatization to psychiatric disability.

The relationship between psychiatric impairment and disability due to somatic complaints was studied in 859 women adopted at an early age by nonrelatives in Sweden. The clinical data were derived from the comprehensive registrations for all medical treatment and sick-leave compensation that are kept about Swedish residents by the National Health Insurance Board. The adoptees were compared with nonadopted controls who were individually matched for social and demographic variables. We identified a somatization syndrome that is consistently associated with psychiatric impairment and repeated brief periods of disability with chief complaints of headache, backache, and abdominal distress on different occasions. A method for clinically distinguishing "somatizers" from other women was derived in one sample and was shown to have a classification accuracy of 97% in a replication sample. Somatizers accounted for 36% of all cases of psychiatric disability and 48% of all sick-leave occasions in adopted women. Compared with nonadoptees, there was an excess of somatizers in adoptees, a population known to have an excess of biological parents who are criminal and/or alcoholic.

Adoption↗

PubMed1995

A trial of the effect of a standardized psychiatric consultation on health outcomes and costs in somatizing patients.

BACKGROUND: Patients who somatize but who do not meet criteria for somatization disorder are common in the community. Virtually no research has been conducted to determine how to treat these patients. METHODS: We conducted a randomized controlled clinical trial of a psychiatric consultation intervention we had previously shown to improve the management of somatization disorder. The study population included 51 physicians treating 56 somatizing patients who had a history of seeking help for six to 12 lifetime unexplained physical symptoms. At the onset of the experiment, physicians randomized to the treatment condition received a consultation letter recommending a specific management approach; physicians randomized to the control/crossover condition received the consultation letter after 12 months. Data on health outcomes and charges were collected every 4 months for 2 years after randomization for 96% of subjects who entered the study. RESULTS: Patients of physicians who received the intervention reported significantly increased physical functioning, an improvement that remained stable during the year after the intervention. The intervention reduced annual medical care charges by $289 (95% confidence interval, $40 to $464) in 1990 constant dollars, which equates to a 32.9% reduction in the annual median cost of their medical care. CONCLUSIONS: Somatizing patients with a lifetime history of six to 12 unexplained physical symptoms reported better physical functioning after their primary care physician was provided appropriate treatment recommendations via a psychiatric consultation. Such a consultation is cost-effective because it reduces subsequent charges for medical care, while improving health outcomes in a chronically impaired population.

Adult↗

PubMed2005

Somatic acquisition and signaling of TGFBR1*6A in cancer.

CONTEXT: TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. OBJECTIVES: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. DESIGN, SETTING, AND PATIENTS: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. MAIN OUTCOME MEASURES: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation. RESULTS: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. CONCLUSIONS: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.

Activin Receptors, Type I↗

PubMed2025

Contributions of Common, Rare, and Somatic Genetic Variants to Incidence of Atrial Fibrillation.

IMPORTANCE: Atrial fibrillation (AF) has a complex genetic architecture involving common, rare, and somatic variants. The association between these components requires further investigation. OBJECTIVE: To examine the individual and combined contributions of polygenic, monogenic, and somatic genetic variants to AF incidence, and develop an integrated genomic model (IGM-AF) for improved risk prediction. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used whole-genome sequence data from participants of the UK Biobank, with follow-up for AF events through hospital records, death registries, and self-report. The UK Biobank recruited participants aged 40 to 69 years in the UK between 2006 and 2010. Study data were analyzed from August 2022 to November 2024. EXPOSURES: IGM-AF comprising an AF polygenic risk score (PRS), a composite rare variant gene set (AFgeneset), and somatic variants associated with clonal hematopoiesis of indeterminate potential (CHIP). Clinical AF risk was estimated using the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) score. MAIN OUTCOMES AND MEASURES: The primary outcome was hazard ratios (HRs) for 5-year incident AF attributable to PRS, AFgeneset, CHIP, and their interactions. The predictive performance of IGM-AF and its components was quantified using HRs, C statistics, and reclassification indices. RESULTS: A total of 416 085 individuals (mean [SD] age, 56.6 [8.0] years; 224 642 female [54.0%]) with 30 797 AF cases were included. The PRS (HR per 1 SD, 1.65; 95% CI, 1.63-1.67; P < 1 × 10-8), AFgeneset (HR, 1.63; 95% CI, 1.52-1.75; P = 1.46 × 10-42), and CHIP (HR, 1.26; 95% CI, 1.15-1.38; P = 1.41 × 10-6) were associated with incident AF. The 5-year cumulative incidence of AF was at least 2-fold among individuals having all 3 genetic drivers (common, rare, and somatic drivers) compared with those with only 1 driver. Integration of IGM-AF with a clinical risk model (CHARGE-AF) showed higher predictive performance (C statistic, 0.80; 95% CI, 0.80-0.80) compared with IGM-AF and CHARGE-AF alone. The classification of the at-risk population for AF was improved when IGM-AF was added to CHARGE-AF (net reclassification index, 0.08; 95% CI, 0.07-0.09). CONCLUSIONS AND RELEVANCE: Results of this cohort study demonstrated the complementary value of common, rare, and somatic variants in shaping genomic AF risk. Leveraging comprehensive genetic information may enhance screening and preventive interventions for AF.

Humans↗

PubMed1996

Common patterns of increased and decreased fos expression in midbrain and pons evoked by noxious deep somatic and noxious visceral manipulations in the rat.

Immunohistochemical detection of the protein product (Fos) of the c-fos immediate early gene was used to study neuronal activation in the rostral pons and midbrain of halothane-anesthetised rats following noxious deep somatic or noxious visceral stimulation. In animals exposed only to halothane anesthesia, Fos-like immunoreactive (IR) neurons were located in the midbrain periaqueductal gray matter, tectum, and parabrachial nucleus. Following noxious stimulation of hindlimb muscle, knee joint, vagal cardiopulmonary, or peritoneal nociceptors, there was, compared to halothane-only animals, a significant increase in the numbers of Fos-like (IR) cells in the caudal ventrolateral periaqueductal gray and the intermediate gray lamina of the superior colliculus. Given the general agreement that increased Fos expression is a consequence of increased neuronal activity, the finding that a range of noxious deep somatic and noxious visceral stimuli evoked increased neuronal activity in a discrete, caudal ventrolateral periaqueductal gray region is consistent with previous suggestions that this region is an integrator of deep noxious evoked reactions. The noxious deep somatic and noxious visceral manipulations also evoked, compared to halothane-only animals, reductions in the numbers of Fos-like IR cells in the stratum opticum of the superior colliculus and the unlaminated portion of the external subnucleus of the inferior colliculus. To our knowledge this is the first report of reductions in Fos-expression in the tectum evoked by noxious stimulation. In separate experiments, the effects of noxious deep somatic and noxious visceral manipulations on arterial pressure and heart rate were measured. The noxious visceral manipulations evoked substantial and sustained falls in arterial pressure (15-45 mmHg), and heart rate (75-100 bpm), whereas the depressor and bradycardiac effects of the noxious deep somatic manipulations were weaker, not as sustained, or entirely absent. As similar distributions and numbers of both increased and decreased Fos-like IR cells were observed after each of the deep noxious manipulations, it follows that the deep noxious evoked increases and decreases in Fos expression were not secondary to the evoked depressor or bradycardiac effects.

Animals↗

PubMed1998

Nucleolar targeting of 5S RNA in Xenopus laevis oocytes: somatic-type nucleotide substitutions enhance nucleolar localization.

In Xenopus laevis oocytes, 5S RNA is stored in the cytoplasm until vitellogenesis, at which time it is imported into the nucleus and targeted to nucleoli for ribosome assembly. This article shows that throughout oogenesis there is a pool of nuclear 5S RNA which is not nucleolar-associated. This distribution reflects that of oocyte-type 5S RNA, which is the major 5S RNA species in oocytes; only small amounts of somatic-type, which differs by six nucleotides, are synthesized. Indeed, 32P-labeled oocyte-type 5S RNA showed a degree of nucleolar localization similar to endogenous 5S RNA (33%) after microinjection. In contrast, 32P-labeled somatic-type 5S RNA showed significantly enhanced localization, whereby 70% of nuclear RNA was associated with nucleoli. A chimeric RNA molecule containing only one somatic-specific nucleotide substitution also showed enhanced localization, in addition to other somatic-specific phenotypes, including enhanced nuclear import and ribosome incorporation. The distribution of 35S-labeled ribosomal protein L5 was similar to that of oocyte-type 5S RNA, even when preassembled with somatic-type 5S RNA. The distribution of a series of 5S RNA mutants was also analyzed. These mutants showed various degrees of localization, suggesting that the efficiency of nucleolar targeting can be influenced by many discrete regions of the 5S RNA molecule.

Animals↗

PubMed1996

Somatic histone H1 microinjected into fertilized mouse eggs is transported into the pronuclei but does not disrupt subsequent preimplantation development.

We injected somatic subtypes of histone H1 into newly fertilized mouse eggs, which do not naturally contain this chromosomal protein, and examined the fate of the injected protein and its effect on preimplantation development of recipient eggs. Rhodamine-labelled H1 injected into the cytoplasm of 53 eggs was transported into the pronuclei in 51 cases, and this nuclear accumulation could be detected within 15 min of injection. Unlabelled histone H1, which was detected using immunofluorescence, was also transported following microinjection to the pronuclei, where it colocalized with the chromatin and remained associated with the nuclei following cleavage to the two-cell stage. Nuclear accumulation of injected H1 was inhibited when injected eggs were incubated in the presence of drugs that prevent mitochondrial electron transport or glycolysis, which indicates that nuclear transport occurs through an energy-dependent process, as previously observed in tissue culture cells. To determine whether the presence of somatic H1 in early embryonic nuclei would influence subsequent development, fertilized eggs were injected with an approximately physiological quantity (1-5 pg) of somatic H1 or, as controls, with another small basic protein, cytochrome c. Fifty-three eggs were injected with cytochrome c, of which 51 divided to the two-cell stage, and 32 (60%) reached the blastocyst stage, after 5 days in culture. One hundred and eleven eggs were injected with somatic H1, of which 95 divided to the two-cell stage, and 53 (48%) reached the blastocyst stage, after 5 days in culture. The two groups did not differ statistically (chi 2, P > 0.1) with respect to the fraction of injected embryos that developed to the blastocyst stage. These results show that, although mouse embryos lack the somatic subtypes of histone H1 until the four-cell stage of development, they are able to progress through preimplantation development when these subtypes are present beginning at the one-cell stage. This may imply that the distinctive chromatin composition that characterizes early embryos of a variety of species is not essential for early development in mammals.

Animals↗

PubMed1999

Review: Somatization in the elderly.

Somatization is a common medical problem encountered at all levels of medical care. It is strongly associated with use of services and may be difficult to treat. Somatization in the elderly has been traditionally seen as a masked presentation of depression. Population studies have shown no consistent increase in somatization among the elderly, and the elderly may down-play physical symptoms. Among the elderly depressed, somatization is common and may be commoner if physical illness is also present. Psychological distress is usually acknowledged, not masked, in the elderly depressed. Neuroticism, as well as psychiatric illness, may be an important aetiological factor for somatization in the elderly. Treatment strategies must attend to underlying psychiatric disorders, but there is a need for studies of treatment of the phenomenon in the elderly.

Adult↗

PubMedDate not supplied

Two-dimensional electrophoretic analysis of proteins associated with somatic embryogenesis development in Cupressus sempervirens L.

Two-dimensional gel electrophoretic analysis and histological studies were performed on somatic embryos in cypress. Embryogenic cultures were obtained from in vitro culture of immature seeds. On a modified Murashige and Skoog (MS) medium they showed an intense and repetitive cleavage polyembryogenesis phenomenon which maintained them in a continuous proliferating status instead of undergoing a complete embryogenic development. Only the addition of bovine serum albumin to the culture allowed somatic embryo development and maturation. Major histological differences were noticed between developing and nondeveloping embryogenic cultures. Attempts to find proteins that could be associated with developmental stages of somatic embryos have been achieved. Proteins were extracted and analyzed by two-dimensional electrophoresis from nondeveloping embryogenic cultures (S0) and from embryogenic cultures at three different stages of somatic embryo development: small size and rounded shape embryos (S1), increased size embryos with a well-developed suspensor (S2) and embryos with two well-separated cotyledons (S3). The results revealed some qualitative and quantitative protein variations between the two cultures. Some could be connected with the induction of pro-embryo differentiation whereas others should be more related to the mechanisms involved in somatic embryo development and maturation. Specific polypeptides associated with the presence of bovine serum albumin (BSA) in the medium have been detected.

Animals↗

PubMed2000

Spinal sources of noxious visceral and noxious deep somatic afferent drive onto the ventrolateral periaqueductal gray of the rat.

Studies utilizing the expression of Fos protein as a marker of neuronal activation have revealed that pain of deep somatic or visceral origin selectively activates the ventrolateral periaqueductal gray (vlPAG). Previous anatomical tracing studies revealed that spinal afferents to the vlPAG arose from the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus at all spinal segmental levels, with approximately 50% of vlPAG-projecting spinal neurons found within the upper cervical spinal cord. This study utilized detection of Fos protein to determine the specific populations of vlPAG-projecting spinal neurons activated by noxious deep somatic or noxious visceral stimulation. Pain of cardiac or peritoneal (i.e., visceral) origin activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the thoracic cord, whereas pain of hindlimb (i.e., deep somatic) origin activated neurons in the same laminar regions but in the lumbosacral cord. Each of these deep noxious manipulations also activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the upper cervical spinal cord. In a second set of experiments, the combination of retrograde tracing and Fos immunohistochemistry revealed that vlPAG-projecting spinal neurons activated by deep somatic pain were located in both the upper cervical and lumbosacral cord, whereas those activated by visceral pain were restricted to the thoracic spinal cord. Thus pain arising from visceral versus deep somatic body regions influences neural activity within the vlPAG via distinct spinal pathways. The findings also highlight the potential significance of the upper cervical cord in integrating pain arising from deep structures throughout the body.

Afferent Pathways↗