Cellular competition independent of BAFF/B lymphocyte stimulator results in low frequency of an autoreactive clonotype in mature polyclonal B cell compartments

The peripheral B cell prosurvival cytokine BAFF/B lymphocyte stimulator (BLyS) has been proposed to participate in the regulation of immunological tolerance. Selective elimination or reconstitution of B cells expressing transgene-encoded, autoreactive BCRs upon systemic BLyS depletion or supplementation, respectively, was observed in two separate studies. Such findings led to a model positing a higher dependency of autoreactive B cells on BLyS. We tested this model by exploiting two targeted IgH transgenic mice (H chain knock-in [HKI]) that produce large numbers of follicular (FO) B cells that are either weakly or strongly autoreactive with nuclear autoantigens. Even though HKI B cells do not exhibit classical features of anergy, we found that mature, naive, autoreactive HKI B cells are outcompeted for representation in the periphery by a polyclonal B cell population. However, this is not due to a higher dependency of HKI B cells on BLyS for survival. Additionally, excess BLyS does not rescue HKI B cells from selective elimination. These findings suggest that some autoreactive FO B cells can fully develop while in competition with non-autoreactive cells for BLyS, but remain at a competitive disadvantage for other trophic factors that regulate peripheral stability. As such, our data indicate the existence of peripheral tolerance mechanisms that regulate the frequency of autoreactive FO B cells independent of the BLyS pathway.     

Level of B cell antigen receptor surface expression influences both positive and negative selection of B cells during primary development

To examine the effect of B cell Ag receptor (BCR) surface density on B cell development, we studied multiple lines of mice containing various copy numbers of an IgH micro delta transgene. The V(H) gene in this transgene encodes multireactive BCRs with low affinity for self Ags. These BCRs promote differentiation to a B cell subpopulation that shares some, but not all of the properties of marginal zone (MZ) B cells. Surface BCR level was found to be related to transgene gene copy number in these mice. In mice containing 1-15 copies of the transgene, elevated surface BCR levels were correlated with increased numbers of B cells in the MZ-like subset. However, in mice containing 20-30 copies of the transgene, massive clonal deletion of B cells was observed in the bone marrow, few B cells populated the spleen, and B cells were essentially absent from the lymph nodes. These data support the idea that autoantigens mediate not only negative, but positive selection of developing B cells as well. More importantly, they illustrate the profound influence of BCR surface density on the extent to which either of these selective processes take place.     

Granuloma pouch assay. II. Induction of 6-thioguanine resistance by MNNG and benzo[a]pyrene in vivo

Growth of granulation tissue was initiated with croton oil on the inside of a subcutaneous air pouch, on the back of adult male rats. Two days later, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and benzo[a]pyrene (BP) were applied directly into the pouch in doses ranging from 0.05 to 1.8 mg and from 0.03 to 0.5 mg, resp. The granulation tissue was excised after 48 h. Isolated single cells were checked for their 6-thioguanine resistance in vitro. The influence of cell density during expression time in vitro, of 6-thioguanine concentration and cell density in selective media on the recovery of mutant cells was investigated. The spontaneous mutation frequency was 0.53 x 10(-5). There was a dose-dependent increase in mutation frequencies with both compounds. The frequency was 5 times as high with MNNG as with BP.     

The information that receivers extract from alarm calls in suricates.

Field observations and acoustic analyses have shown that suricate (Suricata suricatta) alarm calls vary in their acoustic structure depending on predator type. In this study, we tested whether receivers respond appropriately when hearing a call in the absence of a predator. Although the only way for suricates to escape from predators is to retreat to boltholes, responses to playbacks could be divided into distinct categories. The subjects responded differently to alarm calls given in response to aerial or terrestrial predators and to recruitment calls emitted in response to snakes and deposits on the ground. Suricates also showed rather distinct responses to low, medium and high urgency aerial calls. Differences in the responses were less obvious for different levels of urgency in the terrestrial and recruitment calls. Suricate receivers thus gain information about both the predator type and level of urgency from the acoustic structures of their calls.     

Moving calls: a vocal mechanism underlying quorum decisions in cohesive groups

Members of social groups need to coordinate their behaviour when choosing between alternative activities. Consensus decisions enable group members to maintain group cohesion and one way to reach consensus is to rely on quorums. A quorum response is where the probability of an activity change sharply increases with the number of individuals supporting the new activity. Here, we investigated how meerkats (Suricata suricatta) use vocalizations in the context of movement decisions. Moving calls emitted by meerkats increased the speed of the group, with a sharp increase in the probability of changing foraging patch when the number of group members joining the chorus increased from two up to three. These calls had no apparent effect on the group's movement direction. When dominant individuals were involved in the chorus, the group's reaction was not stronger than when only subordinates called. Groups only increased speed in response to playbacks of moving calls from one individual when other group members emitted moving calls as well. The voting mechanism linked to a quorum probably allows meerkat groups to change foraging patches cohesively with increased speed. Such vocal coordination may reflect an aggregation rule linking individual assessment of foraging patch quality to group travel route.     

Social monitoring via close calls in meerkats

Social monitoring of the actions of group members is thought to be a key development associated with group living. Humans constantly monitor the behaviour of others and respond to them in a flexible way depending on past interactions and the current social context. While other primates have also been reported to change their behaviour towards other group members flexibly based on the current state of their relationship, empirical evidence is typically linked to contextually specific events such as aggressive or reproductive interactions. In the cooperatively breeding meerkat (Suricata suricatta), we investigated whether subordinate females use frequently emitted, non-agonistic close calls to monitor the location of the dominant female and whether they subsequently adjust their response based on recent social interactions during conflict and non-conflict periods. Subjects discriminated between the close calls of the dominant female and control playbacks, responding by approaching the loudspeaker and displaying submissive behaviour only if they were currently threatened by eviction. Our results suggest that meerkats assess the risk for aggressive interactions with close associates depending on social circumstances, and respond accordingly. We argue that social monitoring based on non-agonistic cues is probably a common mechanism in group-living species that allows the adjustment of behaviour depending on variation in relationships.     

Pre-induction priming of the uterine cervix with oral prostaglandin E2 and a placebo

A double blind study was undertaken to determine the effectiveness or oral prostaglandin E2 as a means of improving the pelvic score prior to induction of labour. 48 patients who were greater than 37 were gestation and who had Bishop scores of less than 6 entered the study. Ten tablets were given on an hourly regime. Of 25 patients in the prostaglandin group, 17 were considered successes (68.0%), whereas of 23 patients who received a placebo, 9 were successes (39.1%). No adverse effects were recorded. Prostaglandin E2 is therefore considered a safe and effective method for priming the unfavourable cervix prior to induction of labour.     

Effect of inhibiting nitric oxide production on mouse preimplantation embryo development and metabolism

Nitric oxide (NO) is a free radical that functions as a cell signaling molecule but at high concentrations can be toxic. It is formed from arginine, which is consumed by the mouse blastocyst, but its effect on early embryo development has been little studied. In this study, the role of NO in mouse preimplantation development has been examined in terms of developmental rate and oxidative metabolism. Zygotes were cultured in one of four media; potassium simplex optimization medium (KSOM), KSOM with amino acids (KSOMaa), KSOM without glutamine (KSOM-glut), or KSOM with 0.5 mM arginine (KSOMarg) +/- l-NAME (a specific inhibitor of NO production). End points were Day 4 blastocyst rates, cell counts determined using bisbenzimide and oxygen consumption. In KSOM and KSOM-glut, the blastocyst rate was decreased by 1 mM l-NAME from 50.2% +/- 3.1% and 37.4% +/- 4.5% to 6% +/- 3% and 0%, respectively. In KSOMaa, cavitation rates were unaltered but the blastocysts contained fewer cells (P < 0.001). Blastocysts cultured in KSOM and KSOM-glut consumed significantly more oxygen than those cultured in KSOMaa (P < 0.001 and P < 0.05, respectively). However, the addition of 0.1 mM or 1 mM l-NAME to KSOMaa significantly increased the amount of oxygen consumed (P < 0.05 and P < 0.001, respectively). The data suggest a physiological role for NO in mouse preimplantation metabolism and development. One possibility is that NO may limit oxygen consumption at the blastocyst stage at the level of mitochondrial cytochrome c oxidase.