Preferential Switching Research Articles

The history of SIVS and AIDS: epidemiology, phylogeny and biology of isolates from naturally SIV infected non-human primates (NHP) in Africa.

Simian immunodeficiency virus (SIV) naturally infects non-human primates in Africa. To date, 40 SIVs have been described both in natural hosts and in heterologous species. These viruses are highly diverse and the majority cluster in 6 relatively equidistant phylogenetic lineages. At least 8 SIVs are currently considered as recombinant viruses, based on different clustering patterns in different genomic regions. Only three types of genomes are known, based on the number of accessory genes: vpr-containing genomes, vpr-vpx containing genomes and vpr-vpu-containing genomes. vpx resulted by a duplication of the vpr gene following non-homologous recombination and is characteristic of SIVs infecting the Papionini tribe of monkeys and HIV-2 in humans. vpu is characteristic of SIVcpz and HIV-1 and may have originated from a recombination involving SIVs from cercopitecini monkeys. SIV seems to be non-pathogenic in the vast majority of natural hosts in spite of a high levels of viral replication. This is probably a consequence of virus-host adaptation, in which the incubation period of the disease generally exceeds the life span of the African primate host. SIVs also have a high propensity for cross-species transmission. In the new host, the outcome may vary from inapparent infection to highly pathogenic, the former being reported for African monkeys, whereas the latter being observed in macaques and humans. The high diversity of SIVs was generated by a high mutation rate due to a low fidelity of the reverse-transcriptase and active viral and host cell turnover, host-dependent evolution and recombination. Cross-species transmission is not rare, however preferential host switching may drive the majority of cross-species transmissions. Numerous SIVs tested so far are able to grow in vitro on human PBMC, therefore it has been postulated that SIV represents a threat for infection of humans in Central Africa and that AIDS is a zoonosis. However, although the simian origin of the two HIV types is broadly acknowledged, there are no data that AIDS is acquired like a zoonosis. SIV may undergo adaptation in the new human host in order to emerge in the general population. The study of SIV in their natural hosts should provide important clues to the real threat to human populations and also elucidate the mechanisms associated with a long-term persistent viral infection without clinical consequences for the host.

Hallmarks of homology recognition by RecA-like recombinases are exhibited by the unrelated Escherichia coli RecT protein.

Homologous recombination is a fundamental process for genome maintenance and evolution. Various proteins capable of performing homology recognition and pairing of DNA strands have been isolated from many organisms. The RecA family of proteins exhibits a number of biochemical properties that are considered hallmarks of homology recognition. Here, we investigated whether the unrelated Escherichia coli RecT protein, which mediates homologous pairing and strand exchange, also exhibits such properties. We found that, like RecA and known RecA homologs: (i) RecT promotes the co-aggregation of ssDNA with duplex DNA, which is known to facilitate homologous contacts; (ii) RecT binding to ssDNA mediates unstacking of the bases, a key step in homology recognition; (iii) RecT mediates the formation of a three-strand synaptic intermediate where pairing is facilitated by local helix destabilization, and the preferential switching of A:T base pairs mediates recognition of homology; and (iv) RecT-mediated pairing occurs from both 3'- and 5'-single-stranded ends. Taken together, our results show that RecT shares fundamental homology-recognition properties with the RecA homologs, and provide new insights on an underlying universal mechanism of homologous recognition.

Recent Results in Cophylogeny Mapping

Virtually every problem in biology benefits from consideration within an evolutionary frame work. Parasitism has been part of life ever since one organism was able to provide an environment for another: questions of parasitology naturally lend themselves to consideration of the shared ancient history of parasites and hosts. The derivation of that shared history is therefore an area of great interest to theoreticians and practitioners alike. The most intuitive approach to this is by cophylogeny mapping. Mathematically the problem is that of optimally mapping the dependent tree into the independent one, e.g., parasite into host or gene tree into organismal phylogeny. This article describes some of the recent advances in cophylogenetic simulation, significance testing, and theoretical properties of maps. In simulation the author shows that the number of ways of mapping the parasite phylogeny into that of the hosts does indeed grow exponentially quickly in most cases and shows no close correlation with the similarity between the phylogenies, and that under a simple coevolutionary model, the range of behaviours of simulated parasite phylogenies is extremely broad and would appear to confound efforts to infer model parameters from observed cases. In the area of significance testing the author demonstrates that the maximal number of inferred codivergence events is not necessarily the best statistic for measuring cophylogenetic agreement, and that significance testing by randomisation which does not alter the parasite tree substantially biases results, and provides a new test to determine whether phylogenetic similarity is consistent with preferential host switching.

Preferential Host Switching by Primate Lentiviruses Can Account for Phylogenetic Similarity with the Primate Phylogeny

Primate lentiviruses (PLV) from closely related primate species have been observed to be more closely related to each other than to PLV from more distantly related primate species. The current explanation for this observation is the codivergence hypothesis; that is, the divergence of a virus lineage results from the divergence of the host lineage. We show that, alternatively, frequent cross-species transmission of PLV, coupled with a tendency for more closely related primate species to exchange viruses "successfully," can result in apparent codivergence. This host-switching hypothesis reconciles several puzzling observations related to the evolution of PLV.

Effect of Charge Trapping on the Asymmetrical Shift of Memory Window in MFIS Devices

We investigated the effects of charge trapping on the asymmetrical increase of the memory window in metal-ferroelectric-insulator-semiconductor (MFIS) devices. We suggest that defect centers located at the SBN-Y 2 O 3 interface play important roles for generating the asymmetrical increase of the memory window: For example, electron trapping at the SBN-Y 2 O 3 interface via Fowler-Nordheim tunneling (FNT) injection from the Si substrate results in the preferential domain switching, causing the asymmetrical increase of the memory window. We also suggest that FNT injection in the Pt/SBN/Si MIS capacitors causes the symmetrical increase of the memory window because the SBN-Y 2 O 3 interface does not exist. However, charge trapping in the SBN layer reduces the memory window with time after FNT injection had stopped, while no significant degradation of the memory window was observed in the Pt/SBN-Y 2 O 3 /Si capacitors.

In situ class switching and differentiation to IgA-producing cells in the gut lamina propria.

One of the front lines of the immune defence is the gut mucosa, where immunoglobulin- (IgA) is continuously produced to react with commensal bacteria and dietary antigens. It is generally accepted that, after antigenic stimulation in the Peyer's patches, IgA+ lymphoblasts (B220+IgA+) migrate through the lymph and blood circulation, and eventually home to the lamina propria of the intestine. Mice that lack activation-induced cytidine deaminase (AID) are defective in class switch recombination (CSR) and somatic hypermutation. CSR changes the immunoglobulin heavy chain constant region (CH) gene being expressed from Cmu to other CH genes, resulting in a switch of the immunoglobulin isotype from IgM to IgG, IgE or IgA. AID-/- mice also secrete large amounts of immunoglobulin-mu (IgM) into faeces, and accumulate B220-IgM+ plasma cells as well as B220+IgM+ cells in the gut. Here we show that lamina propria B220+IgA+ cells have just completed CSR, as they still express both AID and transcripts from circular DNA that has been 'looped-out' during CSR. Lamina propria IgM+ B cells seem to be pre-committed to switching to IgA+ in vitro as well as in vivo. Culturing lamina propria IgM+ B cells together with lamina propria stromal cells enhances preferential switching and differentiation of B cells to IgA+ plasma cells. We conclude that IgA+ cells in the gut lamina propria are generated in situ from B220+IgM+ lymphocytes.

Allotype-associated variation in the human gamma3 switch region as a basis for differences in IgG3 production.

High and low serum concentrations of IgG3 are associated with the human G3 m(b) and G3 m(g) allotypes, respectively. We previously hypothesized that a low frequency of switching is the most likely defect in (g) allotype-positive individuals, and therefore analyzed the structure, recombination breakpoints, and binding of nuclear proteins to the switch (S)gamma3 regions of these two allotypes. There are no allotype-associated differences in the length and basic structure of the Sgamma3, since both contain eighteen 79-bp repeats. However, we found a number of allotype-associated nucleotide changes. As in the mouse system, there is a preferential switching to the B site, or switch nuclear protein/nuclear factor-kappaB motif, with a clustering of switch breakpoints at the most 5' residue of the B site. The B site sequence used most frequently in switching was found to be mutated at this nucleotide in the (g) allotype-associated Sgamma3. This change was shown by electrophoretic mobility shift assay to alter the binding of the switch nuclear protein/nuclear factor-kappaB protein to the B site. Taken together, these data suggest that polymorphism within Sgamma3 may contribute to allotype-associated differences in IgG3 switching, and that specific sequences within the Sgamma3 79-bp repeats could be mechanistically important for switch recombination.

Leukemia inhibitory factor induces differentiation of pituitary corticotroph function: an immuno-neuroendocrine phenotypic switch.

Leukemia inhibitory factor (LIF) promotes differentiated cell function in several systems. We recently reported LIF and LIF receptor expression in human fetal pituitary corticotrophs in vivo and demonstrated LIF stimulation of adrenocorticotrophin (ACTH) transcription in vitro, suggesting a role for LIF in corticotroph development. We therefore assessed the action of LIF on proliferating murine corticotroph cells (AtT20). LIF impairs proliferation of AtT20 cells (25% reduction versus control, P < 0.03), while simultaneously enhancing ACTH secretion (2-fold, P < 0.001) and augmenting ACTH responsiveness to corticotrophin-releasing hormone (CRH) action (4-fold, P < 0.001). This attenuation of cell growth is due to a block of cell cycle progression from G1 into S phase, as measured by flow cytometric analysis (24 +/- 0.8 versus 11.57 +/- 1.5, P < 0.001). Using bromodeoxyuridine incorporation assays, loss of cells in S phase was confirmed (25 +/- 0.08 to 9.4 +/- 1.4, P < 0.008). In contrast, CRH induced the G2/M phase (3.6 +/- 0.2 to 15.4 +/- 3, P < 0.001). This effect was blunted by LIF (P < 0.001 versus CRH alone). Cyclin A mRNA levels, which decline in S phase, were stimulated 3.5-fold by LIF and markedly suppressed by CRH. These results indicate a LIF-induced cell cycle block occurring at G1/S in corticotroph cells. Thus, LIF reduces proliferation, enhances ACTH secretion, and potentiates effects of CRH on ACTH secretion while blocking effects of CRH on the cell cycle. Responses of these three markers of differentiated corticotroph function indicate LIF to be a differentiation factor for pituitary corticotroph cells by preferential phenotypic switching from proliferative to synthetic.

Oral contraceptive switching patterns in the United Kingdom: an important potential confounding variable in studies of venous thromboembolism

To investigate whether patients changing from their current oral contraceptive (OC) are preferentially switched to third-generation preparations. The database comprised 12 months of medical records generated during 1990-91 from 693,705 patients and 153,687 OC users aged 14-45 years registered with 398 practices in the United Kingdom. Subjects who switched OC preparations were identified. A total of 16,197 women (10.5%) switched OC preparations at least once during the study period. There was a statistically significant net switching from second-generation OCs to third generation OCs with a ratio of 1.19 (95% CI, 1.12-1.26). This switching behavior took place in both younger (< 25 years) and older (> or = 25 years) OC users. In addition, a significant net switching was observed from progestogen-only pills to both second- and third-generation OCs. This was more pronounced in women > or = 25 years. Bias resulting from preferential switching of women from second-generation to third-generation OCs may have influenced the results of recently published studies on combined OCs and the risk of venous thromboembolism. Studies of venous thromboembolism in women using OCs should either restrict from the study women who have switched preparations or should include switching as a variable in any analysis.

Distinctive Kinetics of the Antibody-Forming Cell Response to Sendai Virus Infection of Mice in Different Anatomical Compartments

The single-cell ELISPOT assay was used to determine the frequency and isotype commitment of virus-specific antibody-forming cells (AFC) at different anatomical locations following intranasal Sendai virus infection of C57BL/6 and 129/Sv mice. AFC responses in the mediastinal and cervical lymph nodes showed sharp increases and declines, first of IgM AFC, peaking about 7 days after infection, and then of IgG and IgA AFC, peaking about 10 days after infection. A wave of IgM AFC preceding the other isotypes was less evident in the spleen, where peak frequencies of AFC occurred 14 days after infection. Virus-specific AFC appeared in the bone marrow with a unique kinetic pattern, increasing in frequency gradually over the first 3 weeks after infection to a plateau that remained constant. Circulating IgM and IgG achieved significant titers approximately a week after infection; IgM titers were transient, but IgG levels increased sharply and remained high, reflecting the longevity of the bone marrow AFC response. Strain differences in isotype bias were noted, particularly preferential switching to the γ2a gene in 129/Sv mice. The B-cell response to acute respiratory viral infection thus exhibits features that are distinct from the primary response to nonreplicating antigens.

Lipoprotein lipase and LDL receptors in human fetal membranes at term

<dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" view="all" class="author" id="aep-abstract-id14"><ce:section-title>Publisher Summary</ce:section-title><ce:abstract-sec view="all" id="aep-abstract-sec-id15"><ce:simple-para id="fsabs016" view="all">Most characteristics found for Peyer's patch (PP) M cells are attributable to those in nasal-associated lymphoid tissue (NALT)—with slight regional differences such as binding patterns of lectins. NALT is an important inducive site of immune responses after nasal immunization. Immunization via the nose is an effective way to induce mucosal immune responses at remote effector sites, and the NALT plays an important role in the induction of these responses. The preferential switching to IgA is an apparent characteristic of humoral immune responses elicited through the nose and is reflected by the presence of IL-6–producing T cells in the NALT after immunization. The NALT is equipped with a unique machinery to enrich for high-affinity IgA cells in the memory compartment. NALT is not only an important site for IgA induction, but is also capable of generating cytotoxic activity. Intrinsic capacities of cervical lymph nodes—particularly the superficial cervical and internal jugular—are instrumental for the mode of antigen presentation by specialized antigen-presenting cells to T cells, eventually leading to active immunologic tolerance.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>