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This is a tricky question, and it can be difficult to see how one might even begin to address it. Faced with an issue like this one, where exactly should we look for evidence?
Though philosophers have pursued numerous approaches here, one of the most important and influential is to begin with certain facts about people’s ordinary moral practices. The idea is that we can start out with facts about people’s usual ways of thinking or talking and use these facts to get some insight into questions about the true nature of morality.
Thinkers who take this approach usually start out with the assumption that ordinary thought and talk about morality has an objectivist character. For example, the philosopher Michael Smith claims that
we seem to think moral questions have correct answers; that the correct answers are made correct by objective moral facts; that moral facts are wholly determined by circumstances and that, by engaging in moral conversation and argument, we can discover what these objective moral facts determined by the circumstances are.
And Frank Jackson writes:
I take it that it is part of current folk morality that convergence will or would occur. We have some kind of commitment to the idea that moral disagreements can be resolved by sufficient critical reflection – which is why we bother to engage in moral debate. To that extent, some sort of objectivism is part of current folk morality.
Then, once one has in hand this claim about people’s ordinary understanding, the aim is to use it as part of a complex argument for a broader philosophical conclusion. It is here that philosophical work on these issues really shines, with rigorous attention to conceptual distinctions and some truly ingenious arguments, objections and replies. There is just one snag. The trouble is that no real evidence is ever offered for the original assumption that ordinary moral thought and talk has this objective character. Instead, philosophers tend simply to assert that people’s ordinary practice is objectivist and then begin arguing from there.
If we really want to go after these issues in a rigorous way, it seems that we should adopt a different approach. The first step is to engage in systematic empirical research to figure out how the ordinary practice actually works. Then, once we have the relevant data in hand, we can begin looking more deeply into the philosophical implications – secure in the knowledge that we are not just engaging in a philosophical fiction but rather looking into the philosophical implications of people’s actual practices.
Just in the past few years, experimental philosophers have been gathering a wealth of new data on these issues, and we now have at least the first glimmerings of a real empirical research program here. But a funny thing happened when people started taking these questions into the lab. Again and again, when researchers took up these questions experimentally, they did not end up confirming the traditional view. They did not find that people overwhelmingly favoured objectivism. Instead, the results consistently point to a more complex picture. There seems to be a striking degree of conflict even in the intuitions of ordinary folks, with some people under some circumstances offering objectivist answers, while other people under other circumstances offer more relativist views. And that is not all. The experimental results seem to be giving us an ever deeper understanding of why it is that people are drawn in these different directions, what it is that makes some people move toward objectivism and others toward more relativist views.
For a nice example from recent research, consider a study by Adam Feltz and Edward Cokely. They were interested in the relationship between belief in moral relativism and the personality trait openness to experience. Accordingly, they conducted a study in which they measured both openness to experience and belief in moral relativism. To get at people’s degree of openness to experience, they used a standard measure designed by researchers in personality psychology. To get at people’s agreement with moral relativism, they told participants about two characters – John and Fred – who held opposite opinions about whether some given act was morally bad. Participants were then asked whether one of these two characters had to be wrong (the objectivist answer) or whether it could be that neither of them was wrong (the relativist answer). What they found was a quite surprising result. It just wasn’t the case that participants overwhelmingly favoured the objectivist answer. Instead, people’s answers were correlated with their personality traits. The higher a participant was in openness to experience, the more likely that participant was to give a relativist answer.
Geoffrey Goodwin and John Darley pursued a similar approach, this time looking at the relationship between people’s belief in moral relativism and their tendency to approach questions by considering a whole variety of possibilities. They proceeded by giving participants mathematical puzzles that could only be solved by looking at multiple different possibilities. Thus, participants who considered all these possibilities would tend to get these problems right, whereas those who failed to consider all the possibilities would tend to get the problems wrong. Now comes the surprising result: those participants who got these problems right were significantly more inclined to offer relativist answers than were those participants who got the problems wrong.
Taking a slightly different approach, Shaun Nichols and Tricia Folds-Bennett looked at how people’s moral conceptions develop as they grow older. Research in developmental psychology has shown that as children grow up, they develop different understandings of the physical world, of numbers, of other people’s minds. So what about morality? Do people have a different understanding of morality when they are twenty years old than they do when they are only four years old? What the results revealed was a systematic developmental difference. Young children show a strong preference for objectivism, but as they grow older, they become more inclined to adopt relativist views. In other words, there appears to be a developmental shift toward increasing relativism as children mature. (In an exciting new twist on this approach, James Beebe and David Sackris have shown that this pattern eventually reverses, with middle-aged people showing less inclination toward relativism than college students do.)
So there we have it. People are more inclined to be relativists when they score highly in openness to experience, when they have an especially good ability to consider multiple possibilities, when they have matured past childhood (but not when they get to be middle-aged). Looking at these various effects, my collaborators and I thought that it might be possible to offer a single unifying account that explained them all. Specifically, our thought was that people might be drawn to relativism to the extent that they open their minds to alternative perspectives. There could be all sorts of different factors that lead people to open their minds in this way (personality traits, cognitive dispositions, age), but regardless of the instigating factor, researchers seemed always to be finding the same basic effect. The more people have a capacity to truly engage with other perspectives, the more they seem to turn toward moral relativism.
To really put this hypothesis to the test, Hagop Sarkissian, Jennifer Wright, John Park, David Tien and I teamed up to run a series of new studies. Our aim was to actually manipulate the degree to which people considered alternative perspectives. That is, we wanted to randomly assign people to different conditions in which they would end up thinking in different ways, so that we could then examine the impact of these different conditions on their intuitions about moral relativism.
Participants in one condition got more or less the same sort of question used in earlier studies. They were asked to imagine that someone in the United States commits an act of infanticide. Then they were told to suppose that one person from their own college thought that this act was morally bad, while another thought that it was morally permissible. The question then was whether they would agree or disagree with the following statement:
Since your classmate and Sam have different judgments about this case, at least one of them must be wrong.
Participants in the other conditions received questions aimed at moving their thinking in a different direction. Those who had been assigned to the “other culture” condition were told to imagine an Amazonian tribe, the Mamilons, which had a very different way of life from our own. They were given a brief description of this tribe’s rituals, values and modes of thought. Then they were told to imagine that one of their classmates thought that the act of infanticide was morally bad, while someone from this Amazonian tribe thought that the act was morally permissible. These participants were then asked whether they agreed or disagreed with the corresponding statement:
Since your classmate and the Mamilon have different judgments about this case, at least one of them must be wrong.
Finally, participants in the “extraterrestrial” condition were told about a culture that was just about as different from our own as can possibly be conceived. They were asked to imagine a race of extraterrestrial beings, the Pentars, who have no interest in friendship, love or happiness. Instead, the Pentars’ only goal is to maximise the total number of equilateral pentagons in the universe, and they move through space doing everything in their power to achieve this goal. (If a Pentar becomes too old to work, she is immediately killed and transformed into a pentagon herself.) As you might guess, these participants were then told to imagine a Pentar who thinks that the act of infanticide is morally permissible. Then came the usual statement:
Since your classmate and the Pentar have different judgments about this case, at least one of them must be wrong.
The results of the study showed a systematic difference between conditions. In particular, as we moved toward more distant cultures, we found a steady shift toward more relativist answers – with people in the first condition tending to agree with the statement that at least one of them had to be wrong, people in the second being pretty evenly split between the two answers, and people in the third tending to reject the statement quite decisively.
Note that all participants in the study are considering judgments about the very same act. There is just a single person, living in the United States, who is performing an act of infanticide, and participants are being asked to consider different judgments one might make about that very same act. Yet, when participants are asked to consider individuals who come at the issue from wildly different perspectives, they end up concluding that these individuals could have opposite opinions without either of them being in any way wrong. This result seems strongly to suggest that people can be drawn under certain circumstances to a form of moral relativism.
But now we face a new question. If we learn that people’s ordinary practice is not an objectivist one – that it actually varies depending on the degree to which people take other perspectives into account – how can we then use this information to address the deeper philosophical issues about the true nature of morality?
The answer here is in one way very complex and in another very simple. It is complex in that one can answer such questions only by making use of very sophisticated and subtle philosophical methods. Yet, at the same time, it is simple in that such methods have already been developed and are being continually refined and elaborated within the literature in analytic philosophy. The trick now is just to take these methods and apply them to working out the implications of an ordinary practice that actually exists.
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Joshua Knobe is an associate professor at Yale University, affiliated both with the Program in Cognitive Science and the Department of Philosophy.
Getting the DID number from a CallCentric SIP trunk for FreePBX
I’ve got a few DDI numbers from CallCentric all around the world (UK, US, Australia) and couldn’t figure our how to setup an ‘Inbound Route’ in FreePBX that used the number that had been dialled to route the call.
It turns out that you need to extract the number from the ‘SIP header’ information and there’s no setting in FreePBX to do this so it means hacking at the Asterisk config files just a little.
There are a few methods for doing this but these instructions should work for FreePBX/Asterisk –
When setting up your ‘SIP trunk’ in FreePBX under ‘PEER DETAILS’ you want to put the line –
“context=custom-get-did-from-sip”
then you need to edit the file /etc/asterisk/extensions_custom.conf and add the following lines –
Introduction
============
Blood-borne pathogens first encounter the adaptive immune system in the marginal zone region of the spleen where the convergence of innate and adaptive immune mechanisms insures an early and effective response to pathogen antigens ([@bib1], [@bib2]). Both thymic-independent and -dependent responses are elicited in response to infection ([@bib1], [@bib3]). The thymic-independent response involves the targeting and activation of marginal zone B cells (MZBs)[\*](#fn1){ref-type="fn"}through their interaction with the repetitive antigenic determinants of pathogens with complement and B cell antigen receptors ([@bib4], [@bib5]). In contrast, the thymic-dependent Ab response is driven by the interaction and reciprocal stimulation of APCs, T lymphocytes, and B cells. The organization of the splenic white pulp nodule into discrete zones enriched for either B cells, T cells, or APCs provide a spatial microenvironment that facilitates an efficient interaction of pathogens with the various cellular populations required for insuring an efficient immune response ([@bib6]--[@bib8]). Antigen presentation and stimulation of T and B cells ultimately results in the formation of germinal centers, high affinity neutralizing Abs, and memory cells. Recent reports have begun to define the cellular components and molecular signals that are necessary to establish the marginal zone. B cell intrinsic pathways have been described involving specific chemokines and their receptors, molecules involved in B cell activation, as well as adhesion molecules and their ligands ([@bib9], [@bib10]). Apart from the MZB, the other predominant cell of the marginal zone is the marginal zone macrophage (MZMO), which is distinct from the metallophilic macrophage, defined by the marker MOMA-1, located at the border of the marginal and follicular zone ([@bib11]). The MZMO is defined by its location, interspersed in several layers within the marginal zone, and by its expression of the markers MARCO and ER-TR9 ([@bib12], [@bib13]). The former molecule is a scavenger receptor belonging structurally to the class A receptor family whereas the latter is identical to the C-type lectin SIGN-RI ([@bib14]--[@bib17]). MARCO has been shown to bind a range of microbial Ags including *Staphylococcus aureus* and *Escherichia coli* whereas SIGN-RI is the predominant receptor for uptake of polysaccharide dextran by MZMOs. Even though both MZBs and MZMOs are implicated in both thymus-dependent and -independent immune responses, the exact roles of the two cell types in initiation of the response to blood-borne pathogens is not known. We now define a unique role for the MZMO in regulation of MZB retention and activation and show that movement of this subset of macrophages to the red pulp of the spleen involves signaling via SH2-containing inositol-5-phosphatase 1 (SHIP) and Bruton\'s tyrosine kinase (Btk). In addition, we show a direct interaction between MZMOs and MZBs via the MARCO receptor on MZMOs and a ligand on MZBs.
Materials and Methods
=====================
Mice.
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C57BL/6 mice obtained from The Jackson Laboratory were used as WT mice and controls unless otherwise stated. Founders of SHIP-deficient mice were provided by G. Krystal (Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada; reference [@bib18]) and Btk-deficient mice were purchased from The Jackson Laboratory. Op/op mice were provided by J. Pollard (Albert Einstein College of Medicine, New York, NY) and LysMCre transgenic mice ([@bib19]) were provided by I. Forster (Technical University of Munich, Germany). Abs and bacteria was injected i.v. in the tail vein and all experiments involving mice were performed in accordance with National Institutes of Health (NIH) guidelines. All mice were maintained under specific pathogen-free conditions at The Rockefeller University.
Antibodies and Reagents.
------------------------
For histological examination 6-μM frozen sections were stained, and for FACS^®^ analysis erythrocyte-depleted spleen cells were used. Macrophages were detected using MOMA-1, MARCO Abs from Serotec, and ER-TR9 from Accurate Chemical & Scientific Corp. Abs to CD1d, B220, CD19, CD21/CD35 (CRI/II), CD23, MAC-1, anti--rat alkaline phosphatase, and anti--rabbit horseradish peroxidase were from BD Biosciences. Secondary Abs for immunohistochemistry, anti-biotin, anti-FITC F(ab′) horseradish peroxidase, or alkaline phosphatase were from DakoCytomation and rabbit anti--SHIP used for Western blot was from Upstate Biotechnology. Vector Blue Alkaline Phosphatase Substrate from Vector Laboratories and DAB peroxidase substrate from Sigma-Aldrich were used for development of immunohistochemistry stains. Soluble MARCO receptor was provided by T. Pikkarainen (The Karolinska Institute, Stockholm, Sweden; reference [@bib20]) and was biotinylated using the EZ-Link™ kit from Pierce Chemical Co. The biotinylated soluble MARCO was detected using Streptavidin-CyChrome™ from BD Biosciences. *S. aureus* fluorescent bioparticles were purchased from Molecular Probes, Inc. and MACS anti-FITC and anti-biotin beads were from Miltenyi Biotec. Cl~2~MDP (or clodronate) and PBS liposomes were provided by Roche Diagnostics.
Conditional Targeting of SHIP.
------------------------------
Floxed SHIP mice were created by insertion of loxP sites flanking the 10th and 11th exons (see [Fig. 2](#fig2){ref-type="fig"} a) of the SHIP gene. The targeting vector was introduced into embryonic stem (ES) cells by electroporation and clones were selected with neomycin and ganciclovir and verified by Southern blot and PCR. Properly integrated ES clones were transiently transfected with a Cre-expressing plasmid. Clones were subsequently selected for a conditional floxed allele (SHIP^flox^) or null allele (SHIP^null^) using Southern blot and PCR. Appropriate ES clones were then injected into blastocysts to generate chimeric mice. The chimeric mice were then bred with C57BL/6 mice to achieve germline transmission. These mice were subsequently crossed with mice expressing Cre in the myeloid compartment (LysMcre; reference [@bib19]) to generate Cre^+^/null/flox mice. Mice were screened for respective genotype by PCR and SHIP protein expression using Western blot ([@bib21]) on equal numbers of spleen cells purified by MACS (Miltenyi Biotec) sorting according to protocol from the manufacturer. Relative expression of SHIP in macrophage and B cell populations (comparing wt/null with flox/null/cre) were estimated using Alpha imager software from Alpha Innotech Corp.
Results and Discussion
======================
Mice deficient in the inhibitory signaling molecule SHIP display pleiotropic defects in macrophages, NK cells, and lymphocytes ([@bib18], [@bib22]). A prominent feature of these mice is their splenomegaly resulting from dysregulation of myeloid proliferation. As seen in [Fig. 1](#fig1){ref-type="fig"} Figure 1.SHIP-deficient mice lack MZBs and MZMOs are displaced to the red pulp. (a) FACS^®^ profiles of single cell suspensions from the spleen of SHIP-heterozygous (SHIP^+/−^) and -deficient (SHIP^−/−^) mice. MZBs were measured as the CD19^+^, CRI^high^, and CD23^low^ population. The numbers shown represent percent of CD19^+^ cells for the depicted gates as an average of five mice. Numbers for the follicular B cells are shown for comparison. (b) Representative immunohistochemical analysis of above listed mice. At least four serial sections from each mouse were stained for MOMA-1^+^ (blue, top) metallophilic macrophages or MARCO^+^ MZMOs (blue, bottom). Sections were also stained for B220 (brown) to show the positioning of the follicle. ×10. , SHIP-deficient mice also display a specific defect in the organization of the splenic follicle with the loss of MZBs measured as the CD21^high^/CD23^low^ population in FACS^®^ and in sections as the B220^+^ cells localizing peripherally to the MOMA-1^+^ cells ([Fig. 1](#fig1){ref-type="fig"}, a and b). In the SHIP-deficient mice the MARCO^+^ MZMO cells are no longer organized within the marginal zone and adjacent to the MOMA-1 macrophages but are redistributed to the red pulp, whereas MOMA-1^+^ metallophils remain unaffected ([Fig. 1](#fig1){ref-type="fig"} b). Because SHIP is expressed in most hematopoietic cells, including lymphoid and myeloid subsets, we determined if this marginal zone phenotype in SHIP-deficient mice was the result of primary macrophage dysregulation. A conditional disruption of SHIP was generated in which macrophages displayed an approximate \>90% reduction in SHIP expression whereas B cell expression was reduced by \<10% ([Fig. 2](#fig2){ref-type="fig"} Figure 2.Conditional targeting of SHIP in macrophages results in MZMO displacement and reduced numbers of MZBs. (a) A targeting construct covering exons 10 to 13 of SHIP, from EcoRI (E) to HindIII (H), was made. Boxes represent exons and triangles represent loxP sites flanking exons 10 to 11 and a neomycin resistance gene (neo). Properly integrated ES cell clones were transiently transfected with Cre recombinase to create conditional floxed (SHIP^flox^) or null (SHIP^null^) clones. These cells were subsequently used to create floxed (flox) and null mice, which were crossed to mice expressing Cre from a macrophage-specific lysosomal promoter (cre). (b) Western blot analysis of MAC1^+^ and CD19^+^ spleen cells (SPC) from WT, WT/null, null/null, LysM floxed (flox/null/cre), and relative spleen size of 6-wk-old WT/null and flox/null/cre SHIP mice. (c) FACS^®^ and histological profiles of single cell suspensions from the spleen of the conditionally targeted SHIP KO mice. MZBs were measured as the CD19^+^, CRI^high^, and CD23^low^ population. The numbers shown represent percent of CD19^+^ cells for the depicted gates as an average of five mice and the numbers for the follicular B cells are shown for comparison. For representative immunohistochemical analysis, at least four serial sections were stained for MOMA-1^+^ (blue, top) metallophilic macrophages or MARCO^+^ MZMOs (blue, bottom). Sections were also stained for B220 (brown) to show the positioning of the follicle. Refer to [Fig. 1](#fig1){ref-type="fig"} for SHIP^+/−^ and SHIP^−/−^ profiles. ×10. , a and b). This is consistent with the expression patterns of Cre recombinase, driven by the lysosyme promoter used ([@bib19]). The mice developed a splenomegaly at ∼5 wk of age ([Fig. 2](#fig2){ref-type="fig"} b), similar to that of complete SHIP deletion, thus implicating a primary macrophage defect as the cause for splenomegaly in SHIP^−/−^ mice ([@bib18]). In addition, the mice displayed essentially the same marginal zone phenotype with significantly reduced MZBs as defined by flow cytometry and reorganization of the MZMOs as observed by histological staining ([Fig. 2](#fig2){ref-type="fig"} c). To confirm that the SHIP phenotype is B cell nonautonomous and that SHIP-deficient B cells can give rise to MZB populations when WT MZMOs are available, we produced BM chimeras using SHIP-deficient BM combined with WT BM and injected these cells into irradiated WT recipients. In the resulting chimeric mice the SHIP-deficient and WT BMs contributed equally to the MZB population (unpublished data).
In B cell lines it has been shown that SHIP functions as a negative regulator of cellular activation by regulating the association of the positive signaling kinase Btk with the membrane, thus raising the threshold required for stimulation ([@bib23]). It does so by hydrolyzing PIP~3~, the substrate for Btk association with the membrane, thereby reducing the ability of Btk to become membrane associated and activated ([@bib24]). Because both SHIP and Btk are expressed in macrophages and a link between these molecules had been suggested, we reasoned that the myeloid proliferation and MZMO phenotype leading to the loss of MZBs might be the result of inappropriate activation of Btk in macrophages of SHIP-deficient animals ([@bib25], [@bib26]). Disruption of Btk in macrophages may thus be sufficient to restore normal signaling thresholds in SHIP-deficient mice. Combining the SHIP deficiency with a Btk deficiency resulted in the restoration of both the normal marginal zone structure ([Fig. 3](#fig3){ref-type="fig"} Figure 3.SHIP and Btk interact in myeloid proliferation and activation. (a) FACS^®^ and histological profiles of single cell suspensions from the spleen of SHIP and Btk double KO mice (SHIP^−/−^/Btk^−^). MZBs were measured as the CD19^+^, CRI^high^, and CD23^low^ population. The numbers shown represent percent of CD19^+^ cells for the depicted gates as an average of four mice and the numbers for the follicular B cells are shown for comparison. For representative immunohistochemical analysis, at least four serial sections from were stained for MOMA-1^+^ (blue, top) metallophilic macrophages or MARCO^+^ MZMOs (blue, bottom). Sections were also stained for B220 (brown) to show the positioning of the follicle. ×10. (b) Relative spleen size of 5-wk-old heterozygous KO or double KO mice. a) and spleen size ([Fig. 3](#fig3){ref-type="fig"} b) indicating that Btk is an important target of SHIP in myeloid cells in vivo. Similarly, Btk deficiency counteracted the over responsiveness of myeloid progenitors to GM-CSF and M-CSF in SHIP-deficient mice (unpublished data). Both the dysregulation of myeloid proliferation and follicular architecture likely result from enhanced signaling through the Btk pathway in myeloid cells. Reversion of the MZB and myeloid phenotypes in SHIP^−/−^ mice by deletion of Btk suggests that Btk is the dominant Tec family member regulated by SHIP in these cells. The observation that other members of the family are expressed in macrophages and have been shown to be able to substitute for Btk both in vivo and in KO mice indicates a surprising degree of specificity to the SHIP inhibitory pathway ([@bib27]--[@bib29]).
These results suggested that MZMOs might be critical to the organization of the white pulp nodule and localization of MZBs in this structure. To test this directly we exploited the observation that MZMOs can be ablated by their preferential ingestion of macrophage-depleting liposomes ([@bib30]). At a low concentration of these liposomes we could see preferential depletion of MARCO^+^ MZMOs as opposed to the adjacent MOMA-1 macrophages ([Fig. 4](#fig4){ref-type="fig"}) Figure 4.MARCO^+^ MZMOs are required for retention of MZBs. Representative immunohistochemical analysis and FACS^®^ profiles of spleens from at least four WT mice treated with liposomes or untreated op/op mice. WT mice were injected i.v. with 100 μl PBS containing liposomes or with liposomes containing clodronate at a 1:24 dilution where MZMOs were preferentially depleted. 48 h later serial spleen sections were stained for MOMA-1^+^ (blue, top) metallophilic macrophages or MARCO^+^ (blue, middle) MZMOs. The sections were also stained for B220 (brown) to see the positioning of these populations in relation to the B cell follicle. ×10. Spleen cells were analyzed by FACS^®^ analysis for detection of MZBs as measured by the CD19^+^, CRI^high^, and CD23^low^ population. Numbers shown are the average percent-positive cells of four mice. Similar profiles are shown for untreated *op/op* mice (right). Data shown are representative of three independent experiments. . Other phagocytic cells in the spleen, such as red pulp macrophages and dendritic cells were largely unaffected by this treatment (not depicted). When MZMOs were depleted in this fashion, we observe a specific reduction in the MZBs by both flow cytometry and histological staining. In contrast, MOMA-1 macrophages are specifically absent in the CSF-1--deficient strain *op/op* but these mice retain MARCO^+^/ER-TR9^−^ MZMOs ([@bib31], [@bib32]). The absence of the MOMA-1^+^ cells and the ER-TR9 marker did not result in reduction in MZBs, but rather, an expansion of these cells is observed, indicating that the macrophage population that is required for MZB retention are the MARCO^+^ MZMOs.