Dynamics and Function of Langerhans Cells In Vivo: Dermal Dendritic Cells Colonize Lymph Node Areas Distinct from Slower Migrating Langerhans Cells

Langerhans cells (LCs) are prominent dendritic cells (DCs) in epithelia, but their role in immunity is poorly defined. To track and discriminate LCs from dermal DCs in vivo, we developed knockin mice expressing enhanced green fluorescent protein (EGFP) under the control of the langerin (CD207) gene. By using vital imaging, we showed that most EGFP(+) LCs were sessile under steady-state conditions, whereas skin inflammation induced LC motility and emigration to lymph nodes (LNs). After skin immunization, dermal DCs arrived in LNs first and colonized areas distinct from slower migrating LCs. LCs reaching LNs under steady-state or inflammatory conditions expressed similar levels of costimulatory molecules. Langerin and EGFP were also expressed on thymic DCs and on blood-derived, CD8alpha(+) DCs from all secondary lymphoid organs. By using a similar knockin strategy involving a diphtheria toxin receptor (DTR) fused to EGFP, we demonstrated that LCs were dispensable for triggering hapten-specific T cell effectors through skin immunization.

Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.

Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat(Y136F) mice) develop a fast-onset lymphoproliferative disorder involving polyclonal CD4 T cells that produce massive amounts of Th2 cytokines and trigger severe inflammation and autoantibodies. We analyzed whether the Lat(Y136F) pathology constitutes a bona fide autoimmune disorder dependent on TCR specificity. Using adoptive transfer experiments, we demonstrated that the expansion and uncontrolled Th2-effector function of Lat(Y136F) CD4 cells are not triggered by an MHC class II-driven, autoreactive process. Using Foxp3EGFP reporter mice, we further showed that nonfunctional Foxp3(+) regulatory T cells are present in Lat(Y136F) mice and that pathogenic Lat(Y136F) CD4 T cells were capable of escaping the control of infused wild-type Foxp3(+) regulatory T cells. These results argue against a scenario where the Lat(Y136F) pathology is primarily due to a lack of functional Foxp3(+) regulatory T cells and suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers Lat(Y136F) CD4 T cells with the ability to trigger the production of Abs and of autoantibodies in a TCR-independent, quasi-mitogenic fashion. Therefore, despite the presence of autoantibodies causative of severe systemic disease, the pathological conditions observed in Lat(Y136F) mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder.

Acoustic, volumetric, compressibility and refractivity properties and Flory’s reduction parameters of some homologous series of alkyl alkanoates from 298.15 to 333.15 K

The speeds of sound u in, densities ? and refractive indices nD of some homologous series, such as n-alkyl ethanoates, n-alkyl propionates, methyl alkanoates, ethyl alkanoates, dialkyl malonates, and alkyl haloalkanoates, were measured in the temperature range from 298.15 to 333.15 K. Molar volume V, isentropic and isothermal compressibilities ?S and ?T, molar refraction Rm, Eykman’s constant Cm, molecular radius r, Rao’s molar function R, thermal expansion coefficient a, thermal pressure coefficient ?, and Flory’s characteristic parameters image, P*, V*, and T* have been calculated from the measured experimental data. Applicability of Rao theory and Flory–Patterson–Pandey (FPP) theory have been examined and discussed for these alkanoates.

The postmodernist war on evidence-based practice

In this paper, we examine the war of words between those who contend that health care practice, including nursing, should primarily be informed by research (the evidence-based practice movement), and those who argue that there should be no restrictions on the sources of knowledge used by practitioners (the postmodernists). We review the postmodernist interventions of Dave Holmes and his colleagues, observing that the postmodernist style to which they adhere, which includes the use of continental philosophy, metaphors, and acerbic delivery, tends to obscure their substantive arguments. The heated nature of some responses to them has tended to have the same effect. However, the substantive arguments are important. Five main postmodernist charges are identified and discussed. The first argument, that the notion of ‘best evidence’ implies a hierarchical and exclusivist approach to knowledge, is persuasive. However, the contention that this hierarchy is maintained by the combined pressures of capitalism and vested interests within academia and the health services, is less well founded. Nevertheless, postmodernist contentions that the hierarchy embraced by the evidence-based practice movement damages health care because it excludes other forms of evidence that are needed to understand the complexity of care, it marginalizes important aspects of clinical knowledge, and it fails to take account of individuals or their experience, are all seen to be of some merit. However, we do not share the postmodernist conclusion that this adds up to a fascist order. Instead, we characterize evidence-based practice as a necessary but not sufficient component of health care knowledge.

“The new Cagliostro”: Onofroff, Rubén Darío and his story "La esfinge"

The article retraces the career of the famous hypnotist Onofroff and particularly his visit to Buenos Aires, where his activity, in 1895, provoked many discussions and some public embarrassment. In this context Darío, using a pseudonym, published his crónica “La esfinge”. We reproduce “La esfinge”, transcribing the original text of La Nación, with annotations identifying the literary and theosophical sources Darío used when he wrote it.

Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor.

Despite compromised T cell antigen receptor (TCR) signaling, mice in which tyrosine 136 of the adaptor linker for activation of T cells (LAT) was constitutively mutated (Lat(Y136F) mice) accumulate CD4(+) T cells that trigger autoimmunity and inflammation. Here we show that equipping postthymic CD4(+) T cells with LATY136F molecules or rendering them deficient in LAT molecules triggers a lymphoproliferative disorder dependent on prior TCR engagement. Therefore, such disorders required neither faulty thymic T cell maturation nor LATY136F molecules. Unexpectedly, in CD4(+) T cells recently deprived of LAT, the proximal triggering module of the TCR induced a spectrum of protein tyrosine phosphorylation that largely overlapped the one observed in the presence of LAT. The fact that such LAT-independent signals result in lymphoproliferative disorders with excessive cytokine production demonstrates that LAT constitutes a key negative regulator of the triggering module and of the LAT-independent branches of the TCR signaling cassette.

Climate Change Adaptation for Conservation in Madagascar

Madagascar's imperilled biota are now experiencing the effects of a new threat—climate change (Raxworthy et al. 2008). With more than 90% endemism among plants, mammals, reptiles and amphibians, the stakes are high. The pristine landscapes that allowed this exceptional biodiversity to survive past climate changes are largely gone. Deforestation has claimed approximately 90% of the island's natural forest (Ingram & Dawson 2005; Harper et al. 2007) and what remains is highly fragmented, providing a poor template for large-scale species range shifts. The impacts of current and future climate change may therefore be much different than past impacts, with profound implications for biodiversity.
We review evidence of past response to climate change, models of future change and projected biological response, developing insights to formulate adaptation actions for reducing extinction in Madagascar's biota. We then explore the cost of implementing actions and examine new income opportunities developing through efforts to mitigate climate change.

Beyond Poverty: Social Justice in a Global Marketplace

The social justice paradigm, developed in philosophy by John Rawls and others, reaches limits when confronted with diverse populations, unsound governments, and global markets.Its parameters are further limited by a traditional utilitarian approach to both industrial actors and consumer behaviors. Finally, by focusing too exclusively on poverty, as manifest in insufficient incomes or resources, the paradigm overlooks the oppressive role that gender,race, and religious prejudice play in keeping the poor subordinated. The authors of this article suggest three ways in which researchers in marketing could bring their unique expertise to the question of social justice in a global economy: by reinventing the theoretical foundation laid down by thinkers such as Rawls, by documenting and evaluating emergent “feasible fixes” to achieve justice (such as the global resource dividend, cause-related marketing, Fair Trade, and philanthrocapitalism), and by exploring the parameters of the consumption basket that would be minimally required to achieve human capabilities.

Climate change and the cost of conserving species in Madagascar

We examined the cost of conserving species as climate changes using Madagascar as an example. We used a Maxent species distribution model to predict the ranges of 74 plant species endemic to the forests of Madagascar from 2000-2080 in three climate scenarios. We set a conservation target of achieving 10,000 hectares of forest cover for each species, and calculated the cost of achieving this target under each climate scenario. We interviewed natural forest restoration project managers and conducted a literature review to obtain the net present cost per hectare of management actions to maintain or establish forest cover. For each species we added hectares of land from lowest to highest cost per additional year of forest cover until the conservation target was achieved throughout the time period. Climate change was predicted to reduce the size of species’ ranges, the overlap between species’ ranges and existing or planned protected areas, and the overlap between species’ ranges and existing forest. As a result, climate change increased the cost of achieving the conservation target by necessitating successively more costly management actions: additional management within existing protected areas (US$0-60/ha), avoidance of forest degradation (loss of biomass) in community-managed areas ($160-576/ha), avoidance of deforestation in unprotected areas ($252-1069/ha), and establishment of forest on non-forested land within protected areas ($802-2710/ha), in community-managed areas ($962-3226/ha), and in unprotected areas ($1054-3719/ha). Our results suggest that though forest restoration may be required for the conservation of some species as climate changes, it is more cost-effective to maintain existing forest wherever possible.

Informed Consent: Autonomy and Self-Ownership

Using the example of an unconsented mouth swab I criticise the view that an action of this kind taken in itself is wrongful in respect of its being a violation of autonomy. This is so much inasmuch as autonomy merits respect only with regard to ‘critical life choices’. I consider the view that such an action is nevertheless harmful or risks serious harm. I also respond to two possible suggestions: that the action is of a kind that violates autonomy; and, that the class of such actions violates autonomy. I suggest that the action is wrongful in as much as it is a bodily trespass. I consider, and criticise, two ways of understanding how morally I stand to my own body: as owner and as sovereign. In respect of the latter I consider Arthur Ripstein’s recent defence of a sovereignty principle. Finally I criticise an attempt by Joel Feinberg to explain bodily trespass in terms of personal autonomy.