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PubMed2006

The study of Bfa1p(E438K) suggests that Bfa1 control the mitotic exit network in different mechanisms depending on different checkpoint-activating signals.

During mitosis, genomic integrity is maintained by the proper coordination of anaphase entry and mitotic exit via mitotic checkpoints. In budding yeast, mitotic exit is controlled by a regulatory cascade called the mitotic exit network (MEN). The MEN is regulated by a small GTPase, Tem1p, which in turn is controlled by a two-component GAP, Bfa1p-Bub2p. Recent results suggested that phosphorylation of Bfa1p by the polo-related kinase Cdc5p is also required for triggering mitotic exit, since it decreases the GAP activity of Bfa1p-Bub2p. However, the dispensability of GEF Lte1p for mitotic exit has raised questions about regulation of the MEN by the GTPase activity of Tem1p. We isolated a Bfa1p mutant, Bfa1p(E438K), whose overexpression only partially induced anaphase arrest. The molecular and biochemical functions of Bfa1p(E438K) are similar to those of wild type Bfa1p, except for decreased GAP activity. Interestingly, in BFA1(E438K) cells, the MEN could be regulated with nearly wild type kinetics at physiological temperature, as well as in response to various checkpoint-activating signals, but the cells were more sensitive to spindle damage than wild type. These results suggest that the GAP activity of Bfa1p-Bub2p is responsible for the mitotic arrest caused by spindle damage and Bfa1p overproduction. In addition, the viability of cdc5-2 delta bfa1 cells was not reduced by BFA1(E438K), suggesting that Cdc5p also regulates Bfa1p to activate mitotic exit by other mechanism(s), besides phosphorylation.

Cell Cycle Proteins↗
PubMed2006

Correlation of clinical and surgical findings to histological features (koilocytosis, papillary hyperplasia) suggesting papillomavirus involvement in the pathogenesis of cholesteatoma.

BACKGROUND: The clinical course of cholesteatoma is rather unpredictable, as some cases show aggressive development, while others have a mild, more 'benign' nature. The aim was to correlate the clinical course and surgical findings of cholesteatomas with histological features. MATERIAL/METHODS: The study included 45 patients with cholesteatoma, 29 of whom had surgically aggressive and 16 simple (not surgically aggressive) cholesteatoma. All patients underwent mastoid surgery and the cholesteatoma specimens were sent for histological examination. RESULTS: The clinical course of the cholesteatomas had a statistically significant association (p < 0.001) with the 'aggressiveness' found in surgery, suggesting that clinical history correlates well with surgical findings. All 29 specimens of patients with surgically aggressive cholesteatoma had characteristic papillary hyperplasia of the epithelium and marked koilocytosis, suggesting papillomavirus-incduced lesions. In contrast, none of the specimens of the 16 patients with simple (non-aggressive) cholesteatoma had papillary hyperplasia and there was no marked koilocytosis, as few koilocytes could occasionally be found. The difference was statistically significant (p < 0.001). In situ hybridization for human papillomnavirus (HPV) was performed in 14 specimens (7 each with aggressive and simple cholesteatomna). Positive staining was found in three aggressive cholesteatomas. All seven simple cholesteatomas were negative for HPV. CONCLUSIONS: The results of the present paper suggest that papillomaviruses may play an important role in the pathogenesis of cholesteatomas. Further studies with controls and the development of new methods to identify known and unknown types of papillomavirus are needed to explore their exact role.

Adult↗
PubMed2007

Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC.

DNA mismatch repair (MMR) mechanism contributes to the maintenance of genomic stability. Loss of MMR function predisposes to a mutator cell phenotype, microsatellite instability (MSI) and cancer, especially hereditary non-polyposis colorectal cancer (HNPCC). To date, five MMR genes, hMSH2, hMSH6, hMLH1, hPMS2, and hMLH3 are associated with HNPCC. Although, hMLH3 is suggested to be causative in HNPCC, its relevance to MMR needs to be confirmed to reliably assess significance of the inherited sequence variations in it. Recently, a human heterodimer hMLH1/hMLH3 (hMutLgamma) was shown to be able to assist hMLH1/hPMS2 (hMutLalpha) in the repair of mismatches in vitro. To repair mismatches in vivo, hMLH3 ought to localize in the nucleus. Our immunofluorescence analyses indicated that when all the three MutL homologues are natively expressed in human cells, endogenous hMLH1 and hPMS2 localize in the nucleus, whereas hMLH3 stays in the cytoplasm. Absence of hPMS2 and co-expression of hMLH3 with hMLH1 results in its partial nuclear localization. Our results are clinically relevant since they show that in the nuclear localization hMLH3 is dependent on hMLH1 and competitive with hPMS2. The continuous nuclear localization of hMLH1 and hPMS2 suggests that in vivo, hPMS2 (hMutLalpha) has a major activity in MMR. In absence of hPMS2, hMLH3 (hMutLgamma) is located in the nucleus, suggesting a conditional activity in MMR and supporting its role as a low-risk gene in HNPCC.

Adenosine Triphosphatases↗
PubMed1990

High affinity interaction between C4b-binding protein and vitamin K-dependent protein S in the presence of calcium. Suggestion of a third component in blood regulating the interaction.

The anticoagulant vitamin K-dependent protein S interacts with the complement regulatory protein C4b-binding protein (C4BP), both in purified systems and in plasma. The concentrations of these proteins in plasma are approximately equimolar (0.3 microM) and 30-40% of protein S in plasma is found in the noncomplexed state. Only the uncomplexed form of protein S displays anticoagulant activity and studies have shown that patients with a selective deficiency of free protein S have a high incidence of thrombosis. In this study, we report that the protein S-C4BP interaction is at least 100-fold tighter in the presence of Ca2+ than in EDTA. The KD in the presence of Ca2+ was estimated with a gel filtration technique to be less than 5 x 10(-10) M, whereas in the presence of EDTA, it was approximately 100-fold higher. Ca2+ titration experiments suggested that the Ca2+ sites which function in the protein S-C4BP interaction are of high affinity which, in turn, suggests that they may be independent of the gamma-carboxyglutamic acid region and may be present in the epidermal growth factor-like domains of protein S. The high affinity of the protein S-C4BP interaction in the presence of Ca2+ suggested that virtually all of the protein S in whole blood should be complexed with C4BP. However, even though the protein S-C4BP interaction in Ca2(+)-containing serum was shown to have the same high affinity as in purified systems, approximately 30-40% of the protein S in serum was free. These results appear best explained by the presence of a third component in whole blood which regulates the protein S-C4BP interaction, keeping approximately 30-40% of circulating protein S in its free, functionally anticoagulant form. It is speculated that persons with little free protein S may be deficient in this hypothetical third component.

Calcium↗
PubMed1990

Comparison of two different arterial tissues suggests possible 5-hydroxytryptamine2 receptor heterogeneity.

A comparison of activities and affinities of several known and novel compounds in the isolated rat thoracic aorta (RA) and the rabbit femoral artery (RFA) was undertaken to evaluate these two tissues for use in screening for functional 5-hydroxytryptamine2 (5-HT2) receptor activity. Affinities for 5-HT and for ketanserin against 5-HT-elicited contractions in both vascular tissues suggested the presence of homogeneous 5-HT2 receptors with values consistent with other reported 5-HT2 receptor preparations. However, further studies showed compounds which exhibited either partial agonism in the RFA and competitive antagonism of 5-HT in the RA, or antagonism of 5-HT in both arteries with different affinities. Affinity constants calculated from the isolated vascular tissue studies were compared with affinity constants calculated for inhibition of [3H]ketanserin binding in the frontal cortices of both the rat and the rabbit. There were no significant differences between the pKi values in the rat and the rabbit cortical membranes or between these pKi's in either species and the pA2 values in the RA. Several of the affinities for both the partial agonists and the antagonists in the RFA were significantly different from the binding pKi and the pA2 values in the RA. These findings suggest identity between the [3H]ketanserin binding site in the cortices of both species and the 5-HT2 receptor in the RA; however, the contractile 5-HT receptor in the RFA, although showing some characteristics of a 5-HT2 receptor, is significantly different. We suggest that there may be functional subtypes of the vascular 5-HT receptor.

Animals↗
PubMed1990

Evidence suggesting negative regulation of the erythropoietin gene by ribonucleoprotein.

The promoter regions of the mouse and human erythropoietin genes have regions of identity within 130 base pairs upstream of the cap site, suggesting a cis-acting regulatory role for the conserved sequences. We have used a double-stranded deoxyoligonucleotide corresponding to the -61 to -45 region relative to the start site of transcription of the mouse gene in DNA mobility shift assays. Nuclear extracts from kidneys of both control and cobalt-stimulated mice contain factors that bind to this oligonucleotide in a specific manner. One factor is a 47-kDa protein, whereas the others may be one or more ribonucleoproteins. Under denaturing conditions, four RNA species which show specific binding to the oligonucleotide were observed, suggesting that recognition of the oligonucleotide by ribonucleoprotein is mediated by the RNA component. In nuclear extracts of kidneys from stimulated animals, the amount of the two largest RNA species that bind to the oligonucleotide was reduced relative to that of control, whereas the other RNA species as well as the 47-kDa protein remained relatively unaffected. These results suggest that the ribonucleoprotein containing the down-regulated RNA species may be a negative transcriptional factor and that activation of the erythropoietin gene by cobalt salts may involve, in part, decreased binding of this factor, thus allowing transcription to proceed.

Animals↗
PubMed1978

Sequential expression of immunoglobulin on developing mouse B lymphocytes: a systematic survey that suggests a model for the generation of immunoglobulin isotype diversity.

Paired immunofluorescent staining with antibodies specific for the major isotypes of mouse immunoglobulin was used to study the ontogenetic expression of diversity of cell surface immunoglobulin. The first B lymphocytes to emerge, derived from cytoplasmic IgM+ precursors, express sIgM exclusively. Between birth and 3 days of age separate populations of sIgM+ B lymphocyte acquire a second isotype: sIgD, one of the subclasses of sIgG, or sIgA. At 3 days, all splenic B lymphocytes that bear sIg or sIgA also express sIgM, but virtually none stain for sIgD. By 7 days, a substantial porportion of sIgG+ or sIgA+ lymphocytes in spleen and most of those in lymph node express both sIgM ans sIgD. Anti-mu antibody treatment from birth prevented development of B lymphocytes expressing any isotype. These observations suggest that the immature sIgM+ B lymphocyte is the pivotal cell in the generation of the different sublines of B cells and that sIgD ig or IgA. The frequency of lymphocytes bearing only sIgG or sIgA is higher in old than in young mice, suggesting that sIgD and sIgM may be lost after stimulation by antigens. The occurrence of a nearly identical distribution of sIg isotypes on B lymphocytes from athymic, pathogen-free mice suggests that primary expression of isotype diversity does not require T cells.

Aging↗
PubMed1987

Efficacy of anomalous pancreatic drainage in choledochal cysts correlates with age of presentation and suggests etiology.

The etiology and pathogenesis of choledochal cysts, although frequently debated, are as yet unknown. Findings in three recent patients suggest a possible etiology that may also explain the variability in age at presentation. Each of these patients (ages 12 months, four years, and ten years) was found to have an Alonso-Lej Type I cyst and at operation had an absence of the distal intraduodenal common bile duct, suggesting the lack of a common channel with the main pancreatic duct. Partial decompression of the anatomically obstructed bile duct was afforded by an anomalously high insertion of the accessory pancreatic duct and communication with the duodenum by way of the main pancreatic duct. All patients were managed by excision and retrocolic choledochojejunostomy. The efficacy of decompression correlated with the age of presentation and size of the cyst. These findings suggest agenesis-atresia of the distal common bile duct as one possible etiology of choledochal cysts and may explain the variable age at presentation.

Biliary Tract↗
PubMed1984

Models for leprosy. An appraisal of graphic representations of the "spectrum" concept as models and a suggestion for a catastrophe theory model for leprosy.

Graphic representations of the spectrum concept of leprosy are examined in some detail as models for this disease. This reveals that this concept is somewhat inadequate and that the spectrum metaphor may itself be inappropriate because, by its very linearity of logic, it may not be able to depict the nonlinear behavior of leprosy properly. The assumptions underlying this concept and their logical consequences, brought out by the graphic representations, include an invariable relation between CMI and BI, identity of one type of leprosy with one specific level of CMI, a fixed sequence of types, and the consequent impossibility of skipping the sequence. However, our experience with leprosy does not bear out these assumptions. Further, development and progress of leprosy from a normal (nonleprous) state cannot be represented in these models. A search for alternative conceptual models therefore appears reasonable and even necessary. The catastrophe theory (a branch of topology in mathematics) describes a number of models for explaining how continuous causes could produce sudden or discontinuous changes. Of the various catastrophe theory models available, the relatively simple "cusp" model appears capable of application to leprosy. This model, as applied here, requires two control factors (identified tentatively as the amount of dead bacilli and the amount of living bacilli or their indicators) and one pattern of behavior, identified as progress towards limited or extensive disease. This model suggests under what conditions leprosy will change from one type to another and whether that will happen gradually or suddenly. It also suggests that for certain values of control factors the disease may manifest in one of two forms of borderline leprosy, and that lesions very similar to start with can progress to quite different states under similar conditions of change. The behavior of leprosy agrees more or less with that suggested by this model. The cusp model thus seems to: a) provide an insight into the behavior of leprosy, enabling us to understand the dynamics of the disease; b) explain some of its intriguing manifestations; c) ask meaningful questions; and d) plan new therapeutic approaches. Although this is a highly speculative and probably too simple a model, this attempt shows that it is possible to view leprosy outside the framework of the concepts of spectrum scale and polar types of leprosy, the conceptual models which dominate all of our current thinking about the disease.

Humans↗
PubMed1978

Different loci suggested to mediate tilt and spiral motion aftereffects.

Interocular transfer of two figural aftereffects was examined in orthotropes and strabismic subjects. Within both groups there were persons with an appreciable degree of stereoacuity and others who had little or none. Experimental evidence from a variety of sources has suggested that stereopsis depends upon binocularity of units in the geniculostriate system. For the tilt aftereffect, interocular transfer correlated with stereoacuity among both orthotropes and strabismics. For the spiral motion aftereffect, interocular transfer did not correlate with stereoacuity; it was present among orthotropes and absent among strabismic individuals. The correlation of stereoacuity with interocular transfer of the tilt aftereffect agrees with previous observations and is consistent with the interpreation that this effect is mediated at a cortical level. The lack of a correlation between stereoacuity and interocular transfer of the spiral motion aftereffect suggests that this effect is mediated by units other than those responsible for stereopsis. Richards and Smith, on the basis of certain phenomenal differences between the spiral motion aftereffect and other figural aftereffects, have suggested that the former is mediated at a midbrain level. If strabismic persons lack binocular units in midbrain, the present results are consistent with their hypothesis.

Afterimage↗
PubMed1981

[Suggestions made by adolescents to prevent suicide by adolescents (author's transl)].

738 examination papers were collected from adolescents aged 18 to 21 years on the subject of suggestions for preventing adolescents from committing suicide. The persons examined were female trainees for the nursing profession, consulting-room assistants, trainees in midwifery and male nurses undergoing training. The main reasons for suicide stated were a feeling of having been abandoned, or conflicts between the generations (19% each), whereas the main reasons for attempted suicide were stated to be problems connected with school and profession (24%), as well as unrequited or unhappy love (16%). It is actually true that first sexual disappointments or unhappy love accounted for 37% of 438 attempts at suicide in the city of Zürich within a period of 10 years. Continually recurring suggestions of prevention, both generally and specifically, were heart-to-heart talks with persons of the same age, inclusion of outsiders in the group, promotion of self-concept, and recognition as well as building up the personality of the adolescent concerned. The basic trend noticeable in 12 comprehensive suggestions regarding an overall prevention of adolescent suicide is that parents should not belittle their children's problems and worries, that groups of friends should be built up in early childhood, and that tactful sexual education is mandatory.

Adolescent↗
PubMed1995

Recessive mutations in the second largest subunit of TFIIIC suggest a new step in RNA polymerase III transcription.

An analysis of mutant S. cerevisiae strains selected for their ability to increase transcription by RNA polymerase (pol) III has identified 14 isolates in which this phenotype is recessive. Genetic linkage and complementation studies suggest that all 14 isolates contain recessive alleles of PCF1. PCF1 encodes the 131-kDa subunit of transcription factor IIIC (TFIIIC131) and was identified previously by dominant mutations that also increased transcription by pol III. The recessive mutation, pcf1-3, results in a conservative substitution (R728-->K) towards the carboxyl-terminus of the protein. This position is distinct from the site of the dominant mutation PCF1-1 (H190-->Y), which maps to a tetratricopeptide repeat (TPR). Site-directed mutagenesis at amino acid 728 generated one allele, pcf1-4, with a stronger phenotype than pcf1-3. Extracts from pcf1-3 and pcf1-4 strains increase pol III transcription two- to threefold and ninefold, respectively, over wild-type under conditions that permit either single or multiple rounds of initiation. The entire effect of these mutations in vitro can be accounted for by an increase in the amount of transcriptionally active TFIIIB. In contrast, PCF1-1 primarily affects the rate of preinitiation complex assembly. The genetic, molecular, and biochemical data suggest that amino acid 728 in TFIIIC131 constitutes part of a structural domain in this protein that affects TFIIIB activity by influencing a previously undefined step in transcription. This step is suggested to occur after the recruitment of TFIIIB to DNA.

Alleles↗
PubMed1995

[Formal uniform organization of quality parameters in public health--a methodological suggestion].

UNLABELLED: The relevance of many suggestions for quality management of medical practice and health care is still unsatisfactory. The mass of all the existing suggestions for quality assurance and quality control made a homogeneous method even more difficult all efforts should be directed at finding quality parameters for the most frequent performances in basic care (family doctors). A uniform method and setting up an institute will be important for coordination between specialists, medical societies and relevant institution for exchanging experiences, practice and findings. OBJECTIVE: Suggestions for a homogeneous method to develop quality parameters of medical care.

Adolescent↗
PubMed1994

Antigen receptors on Thy-1+ CD3- CS-initiating cell. In vitro desensitization with hapten-amino acid or hapten-Ficoll conjugates, versus hapten-protein conjugates, suggests different antigen receptors on the immune cells that mediate the early and late components of murine contact sensitivity.

In murine contact sensitivity (CS) models, cutaneous immune responses are caused by the activity of two different Ag-specific Thy-1+ CD5+ cells. These two different cell subsets act in an obligate sequence to mediate separate early and late components of CS that are accompanied respectively by skin swelling responses at 2 and 24 h after local challenge with the hapten. The early-acting CS-initiating cells are not conventional T cells inasmuch as they are surface negative for CD4, CD8, and CD3. In contrast to this non-MHC-restricted, CS-initiating cell, the classical late-acting CS effector T cell that is recruited locally is CD3+, CD4+, CD8-, and is MHC-restricted. In our study, we have conducted experiments in which a mixture of immune CS-initiating and CS-effector cells were desensitized by incubation in vitro at 37 degrees C with various hapten-amino acid and hapten-carrier conjugates, before i.v. transfer and subsequent ear challenge of normal recipient mice. Desensitization was achieved with multivalent complexes of the relevant hapten conjugated to a variety of unrelated nonmurine carrier proteins, and, in some instances, with monovalent hapten conjugated to amino acid. Because the CS-mediating cells were desensitized in a hapten-specific manner, but these same cells transferred CS reactivity that was hapten/MHC-class II specific, it was suggested previously that these results argued in favor of a two-receptor model for T cell recognition of Ag, one receptor for hapten and the other for MHC. Our study suggests that these findings need to be reinterpreted because CS reactions are mediated by two different, Thy-1+ Ag-specific cells that act in an obligate sequence. Our data suggest that the late-acting Ag/MHC-specific CS-effector T cells are not hapten-specific. In fact, desensitization with hapten alone has a locus of action solely on the Ag receptor of the first-acting Thy-1+ CS-initiating cells--which are therefore truly hapten-specific and which are required for local recruitment of the Ag/MHC-specific late CS-effector T cells.

Animals↗
PubMed1994

Roles of Pax-genes in developing and adult brain as suggested by expression patterns.

We have examined the transcript distribution of six members of the murine paired box-containing gene family (Pax-gene family) in midgestation embryo and adult brain using in situ hybridization analysis. The expression domains of several Pax-genes in the embryo brain were found to correspond with anatomical boundaries that coincide with neuromere landmarks and therefore respect former neuromere territories in the forebrain. The results are consistent with the concept of brain segmentation and suggest a role for Pax-genes in the brain regionalization. In the adult brain the expression of Pax-genes was observed in discreet areas, with a caudal to rostral restriction in the number of the expressed genes. In general the distribution of transcripts along the anterior-posterior axis was similar to that found in midgestation embryo brain, suggesting a role for Pax-genes in the commitment of the precursor cells to different neuronal cell fates and in the maintenance of specific brain cell subtypes. In the cerebellar cortex, the granular cell layer was found to express high levels of the Pax-6 gene, while putative Bergmann glia and cells surrounding the Purkinje cells contained Pax-3 transcripts. The main adult brain structures that expressed distinct Pax-mRNAs were the periglomerular and granular cell layer of olfactory bulb, nuclei of the septum, amygdala, and isthmus, which suggests a role for the Pax-gene family in the specification of the subcortical domains of the evolutionary old limbic system.

Aging↗
PubMed1993

Inhibition of norepinephrine release from rat cortex slices by opioids: differences among agonists in sensitivities to antagonists suggest receptor heterogeneity.

Receptors mediating opiate-induced inhibition of potassium-stimulated release of [3H]norepinephrine (NE) from slices of rat cortex incubated in vitro have been characterized by comparison of the pA2 values of the competitive antagonists, naloxone, D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nor-binaltorphimine, naltrindole and bremazocine against the agonists, Tyr-D-Ala-MePhe-Gly-ol (DAMGO), Tyr-D-Arg-Phe-Sar (TAPS), [D-Ser2, Leu5]enkephalyl-Thr (DSLET), beta-endorphin [beta-END(1-31)] and ethylketocyclazocine (EKC). There were significant differences among agonists in their sensitivities to each antagonist. The delta receptor selective agonist, DPDPE, and the kappa 1-agonist, U69593, did not inhibit NE release, indicating that delta and kappa 1 receptors are not involved. DAMGO, TAPS and DSLET generally behaved as mu agonists, although TAPS and DSLET were less sensitive to antagonism by CTOP than by DAMGO. TAPS and DSLET showed similar sensitivities to all antagonists, suggesting that they acted through similar receptors, possibly of the mu 1 type. beta-END(1-31) and EKC differed from DAMGO and from each other in their sensitivities to most antagonists. Shifts in agonist concentration-response curves induced by prior treatment of the rats with the noncompetitive antagonists, beta-funaltrexamine and naloxonazine, also suggested that EKC and beta-END(1-31) acted through mechanisms differing from those used by DAMGO, TAPS and DSLET. It is possible that EKC and beta-END(1-31) acted via kappa 2 and/or epsilon receptors. These results suggest that there is heterogeneity in the opioid receptors regulating NE release in rat cortex.

Amino Acid Sequence↗
PubMed1994

Intracerebral cytokine mRNA expression during fatal and nonfatal alphavirus encephalitis suggests a predominant type 2 T cell response.

Sindbis virus (SV) causes an acute encephalomyelitis in mice. A T cell-dependent inflammatory response is first detected 3 days after infection and includes T cells, B cells, and macrophages. The cytokines produced locally by intrinsic cells of the brain in response to infection and by infiltrating mononuclear cells and their contributions to outcome of infection have not been identified. Semiquantitative reverse transcriptase-PCR was used to evaluate the expression of mRNAs for IL-1 beta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, leukemia inhibitory factor (LIF), and TGF-beta in the brain during fatal and nonfatal SV encephalitis of immunocompetent BALB/cJ and immunodeficient scid/CB17 mice. IL-1 beta and IL-6 mRNAs were detected in uninfected mice before infection and were up-regulated within 24 h. TGF-beta mRNA was also constitutively expressed in uninfected mice. LIF mRNA was occasionally detected in uninfected mice but increased in amounts only in BALB/cJ not scid mice after infection. TNF-alpha, IL-4, and IL-10 mRNAs were not found in uninfected mice but were induced within 24 h and continued to rise through 7 days after infection with substantially higher levels in BALB/cJ than scid mice. These data suggest that intrinsic brain cells produce IL-1, IL-4, IL-6, IL-10, LIF, and TGF-beta mRNAs in response to viral infection. IFN-gamma and IL-2 mRNAs were detected only in BALB/cJ mice and not until 3 days after infection with the initiation of inflammation. IL-4 and IL-10 mRNAs were more persistent and more easily detectable than IL-2 and IFN-gamma mRNAs. These data suggest a predominant type 2 cytokine response in the brain during SV encephalitis. BALB/cJ mice infected with a neurovirulent strain of SV (NSV), had 100% mortality, whereas NSV-infected scid mice developed persistent nonfatal infection. Inflammation was more intense in NSV-infected mice, however, no substantial differences in cytokine mRNA levels were detected when compared with mice with nonfatal SV infection suggesting that the cytokines measured do not in and of themselves lead to fatal central nervous system disease.

Alphavirus Infections↗
PubMed1996

Analysis of a hot spot for DNA insertion suggests a mechanism for Ig switch recombination.

We recently reported that transfected DNA inserts into the VDJ-Cmu intron much more frequently than into average DNA, and that insertion within this intron occurs preferentially into the switch region. To gain information about the mechanisms involved in DNA insertion, we sequenced the 5' and 3' junctions of typical transformants. Although the junction sequences did not indicate a preferred insertion motif within the switch region, our results suggest that joining of the transfected and chromosomal DNAs is facilitated by short regions of identity. Our analysis of the insertions into the non-switch part of the intron suggests that breakage of the chromosomal DNA occurs preferentially at sites that are flanked by short complementary sequences. This correlation suggests that the self-complementary DNA might form short stem-loops, which, in turn, are prone to enzymatic cleavage and thus facilitate the insertion of transfected DNA. A model is proposed in which this effect can account for both the higher than average frequency of insertion into the VDJ-Cmu intron and the preference for the switch region within this intron. An extension of this model is proposed to explain why the repetitive switch regions are the preferred breakage/rejoining sites for isotype switch rearrangements.

Animals↗