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BACKGROUND: Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain. OBJECTIVE: This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect. METHODS: The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of the success rate of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon microscopic calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication. RESULTS: TRPV1 was found to be an ultrasound-sensitive ion channel. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. CONCLUSIONS: This noninvasive and cell-type-specific neuromodulation approach with the capability to target the deep brain has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.

Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subsequent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dysfunction. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury.

Hua Pan,1 Rohun U Palekar,2 Kirk K Hou,3 John Bacon,2 Huimin Yan,3 Luke E Springer,3 Antonina Akk,3 Lihua Yang,3 Mark J Miller,3 Christine TN Pham,3 Paul H Schlesinger,3 Samuel A Wickline1 1Department of Cardiovascular Sciences, USF Health, Morsani College of Medicine, The USF Health Heart Institute, University of South Florida, Tampa, FL, USA; 2Department of Medicine, Washington University, St Louis, MO, USA; 3Department of Biomedical Engineering, Washington University, St Louis, MO, USA Background: A direct and independent role of inflammation in atherothrombosis was recently highlighted by the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, showing the benefit of inhibiting signaling molecules, eg, interleukins. Accordingly, we sought to devise a flexible platform for preventing the inflammatory drivers at their source to preserve plaque endothelium and mitigate procoagulant risk. Methods: p5RHH-siRNA nanoparticles were formulated through self-assembly processes. The therapeutic efficacy of p5RHH-JNK2 siRNA nanoparticles was evaluated both in vitro and in vivo. Results: Because JNK2 is critical to macrophage uptake of oxidized lipids through scavenger receptors that engender expression of myriad inflammatory molecules, we designed an RNA-silencing approach based on peptide–siRNA nanoparticles (p5RHH-siRNA) that localize to atherosclerotic plaques exhibiting disrupted endothelial barriers to achieve control of JNK2 expression by macrophages. After seven doses of p5RHH-JNK2 siRNA nanoparticles over 3.5 weeks in ApoE-/- mice on a Western diet, both JNK2 mRNA and protein levels were significantly decreased by 26% (P=0.044) and 42% (P=0.042), respectively. Plaque-macrophage populations were markedly depleted and NFκB and STAT3-signaling pathways inhibited by 47% (P

The intestinal lamina propria (LP) contains antigen‐presenting cells with features of dendritic cells and macrophages, collectively referred to as mononuclear phagocytes (MNPs). Association of MNPs with the epithelium is thought to play an important role in multiple facets of intestinal immunity including imprinting MNPs with the ability to induce IgA production, inducing the expression of gut homing molecules on T cells, facilitating the capture of luminal antigens and microbes, and subsequent immune responses in the mesenteric lymph node (MLN). However, the factors promoting this process in the steady state are largely unknown, and in vivo models to test and confirm the importance of LP‐MNP association with the epithelium for these outcomes are unexplored. Evaluation of epithelial expression of chemoattractants in mice where MNP–epithelial associations were impaired suggested CCL20 as a candidate promoting epithelial association. Expression of CCR6, the only known receptor for CCL20, was required for MNPs to associate with the epithelium. LP‐MNPs from CCR6−/− mice did not display defects in acquiring antigen and stimulating T‐cell responses in ex vivo assays or in responses to antigen administered systemically. However, LP‐MNPs from CCR6‐deficient mice were impaired at acquiring luminal and epithelial antigens, inducing IgA production in B cells, inducing immune responses in the MLN, and capturing and trafficking luminal commensal bacteria to the MLN. These findings identify a crucial role for CCR6 in promoting LP‐MNPs to associate with the intestinal epithelium in the steady state to perform multiple functions promoting gut immune homeostasis.

Viral infections of the central nervous system (CNS) are often associated with blood-brain barrier (BBB) disruption, yet the impact of virus replication and immune cell recruitment on BBB integrity are incompletely understood. Using two-photon microscopy, we demonstrate that Venezuelan equine encephalitis virus (VEEV) strain TC83-GFP, a GFP expressing, attenuated strain with a G3A mutation within the 5′ UTR that is associated with increased sensitivity to type I interferons (IFNs), does not directly impact BBB permeability. Following intranasal infection of both wild-type and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1)-deficient mice, which fail to block TC83-specific RNA translation, virus spreads to the olfactory bulb and cortex via migration along axonal tracts of neurons originating from the olfactory neuroepithelium. Global dissemination of virus in the CNS by 2 days post-infection (dpi) was associated with increased BBB permeability in the olfactory bulb, but not in the cortex or hindbrain, where permeability only increased after the recruitment of CX3CR1+ and CCR2+ mononuclear cells on 6 dpi, which corresponded with tight junction loss and claudin 5 redistribution. Importantly, despite higher levels of viral replication, similar results were obtained in IFIT1-deficient mice. These findings indicate that TC83 gains CNS access via anterograde axonal migration without directly altering BBB function and that mononuclear and endothelial cell interactions may underlie BBB disruption during alphavirus encephalitis.

In this study, a multilayer thin film of ITO/VO 2 /TiO 2 was investigated for simultaneous control of the solar and thermal spectra with potential application as an energy-efficient coating for windows in built environments. The functions for these layers were: low emissivity, thermochromism, and anti-reflectance in the visible region. Films were deposited using reactive magnetron sputtering and characterized with scanning electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, UV–vis–NIR spectrophotometry, and Fourier transform infrared spectroscopy. The results demonstrate that relatively high luminous transmittance, low emissivity, and favorable thermochromism can be achieved for a film with a transition temperature centered at 52 °C with a hysteresis width of 18 °C. This shows that an advancement of the previous state of the art can be made by restricting the Scherrer grain size of the VO 2 layer to 92 nm.

Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.

Proper T cell activation is promoted by sustained calcium signaling downstream of the TCR. However, the dynamics of calcium flux after stimulation with an APC in vivo remain to be fully understood. Previous studies focusing on T cell motility suggested that the activation of naive T cells in the lymph node occurs in distinct phases. In phase I, T cells make multiple transient contacts with dendritic cells before entering a phase II, where they exist in stable clusters with dendritic cells. It has been suggested that T cells signal during transient contacts of phase I, but this has never been shown directly. Because time-dependent loss of calcium dyes from cells hampers long-term imaging of cells in vivo after antigenic stimulation, we generated a knock-in mouse expressing a modified form of the Cameleon fluorescence resonance energy transfer reporter for intracellular calcium and examined calcium flux both in vitro and in situ. In vitro, we observed transient, oscillatory, and sustained calcium flux after contact with APC, but these behaviors were not affected by the type of APC or Ag quantity, but were, however, moderately dependent on Ag quality. In vivo, we found that during phase I, T cells exhibit weak calcium fluxes and detectable changes in cell motility. This demonstrates that naive T cells signal during phase I and support the hypothesis that accumulated calcium signals are required to signal the beginning of phase II.

Vanadium(IV) oxide possesses a reversible first-order phase transformation near 68 °C. Potential applications of the material include advanced optical devices and thermochromic smart windows. In this study, vanadium oxide films were grown on three types of glass substrates using reactive DC magnetron sputtering and were then annealed in air. The substrates were characterized with energy-dispersive X-ray spectroscopy, and the films were characterized with X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy, atomic force microscopy, transmission electron microscopy, and UV-Vis-NIR spectrophotometry. The results show that the composition of the substrate has a major impact on the microstructure and optical properties of the deposited films. Sodium (Na) in the glass can undesirably inhibit thermochromism; however, replacing half of the Na with potassium (K) suppresses the Na diffusion and promotes the nucleation of pure VO 2 with superior thermochromic functionality. The improved performance is attributed to the mixed-alkali effect between Na and K. These findings are both scientifically and technologically important since soda (Na 2 O) is an essential flux material in glass products such as windows.

In this study the influence of deposition temperature and a post-deposition annealing process on the optical, electrical, mechanical, and tribological properties of titanium oxide thin films was investigated. Based on high-resolution XPS, it was observed that the films became more metallic as the deposition temperature was raised from 15 to 450 °C. Moreover, the mechanical and tribological properties of the film deposited at 450 °C were at least 50% greater than for the film deposited at 15 °C. After annealing at 450 °C for 30 min in air, the films all became transparent and insulating. However, the annealing process had mixed effects on the mechanical and tribological properties such that the 15 and 250 °C films softened, but the 450 °C film hardened. This mixed trend is attributed to the different as-deposited film stoichiometries. The results show that the coupled effects of deposition temperature and post-deposition annealing are quite complex and that the mechanical properties of TiO2 thin films can be controlled independently of their optical and electrical properties. This is important because TiO2 coatings are often used as the outer-most layers in optical devices.

Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell membrane–associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia/reperfusion injury (IRI), we took advantage of a clinically relevant mouse model of transplant-mediated lung IRI. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient, deficiency in DAP12 protected against pulmonary IRI. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking.

Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200–300 nm perfluorocarbon core nanoparticles (PFC-NP) in ApoE null mouse plaques with [19F] magnetic resonance spectroscopy (MRS). Permeability to PFC-NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization. Markedly accelerated clotting (53.3% decrease in clotting time) was observed in carotid artery preparations of fat-fed mice subjected to photochemical injury as defined by the time to flow cessation. For all mice on and off diet, an inverse linear relationship was observed between the permeability to PFC-NP and accelerated thrombosis (P = 0.02). Translational feasibility for quantifying plaque permeability and vascular damage in vivo was demonstrated with clinical 3 T MRI of PFC-NP accumulating in plaques of atherosclerotic rabbits. These observations suggest that excessive permeability to PFC-NP may indicate prothrombotic risk in damaged atherosclerotic vasculature, which resolves within weeks after dietary therapy.—Palekar, R. U., Jallouk, A. P., Goette, M. J., Chen, J., Myerson, J. W., Allen, J. S., Akk, A., Yang, L., Tu, Y., Miller, M. J., Pham, C. T. N., Wickline, S. A., Pan, H. Quantifying progression and regression of thrombotic risk in experimental atherosclerosis.

This essay uses the work of Jonathan Edwards to trace intellectual, historical, and theoretical connections between eighteenth-century religious conversion in England and New England and later accounts of masochism's Enlightenment philosophical basis. Expanding feminist readings of revival abjection to include racial abjection, I focus on Edwards's account of religious sentiment in a “Personal Narrative” (ca. 1739), A Faithful Narrative of the Surprizing Works of God (1736–37), and Some Thoughts Concerning the Present Revival of Religion in New England (1742). Situating these texts in their philosophical and political contexts, I then use A Treatise Concerning Religious Affections (1746) to show how Edwards's evolving response to revivalist disruptions of hierarchy led him to describe a sentimental structure of desire similar to masochism as a defense against a modern subjectivity that would allow for masochism.

Early immune responses are important in shaping long-term outcomes of human lung transplants. To examine the role of early immune responses in lung rejection and acceptance we developed a method to retransplant mouse lungs. Retransplantation into T cell-deficient hosts showed that for lungs and hearts alloimmune responses occurring within 72 hours of transplantation are reversible. In contrast to hearts, a 72-hour period of immunosuppression with costimulation blockade in primary allogeneic recipients suffices to prevent rejection of lungs upon retransplantation into untreated allogeneic hosts. Long-term lung acceptance is associated with induction of bronchus-associated lymphoid tissue, where Foxp3+ cells accumulate and recipient T cells interact with CD11c+ dendritic cells. Acceptance of retransplanted lung allografts is abrogated by treatment of immunosuppressed primary recipients with anti-CD25 antibodies. Thus, events contributing to lung transplant acceptance are established early in the graft and induction of bronchus-associated lymphoid tissue can be associated with an immune quiescent state.

Two-photon intravital microscopy has substantially broadened our understanding of tissue- and organ-specific differences in the regulation of inflammatory responses. However, little is known about the dynamic regulation of leukocyte recruitment into inflamed heart tissue, largely due to technical difficulties inherent in imaging moving tissue. Here, we report a method for imaging beating murine hearts using intravital 2-photon microscopy. Using this method, we visualized neutrophil trafficking at baseline and during inflammation. Ischemia reperfusion injury induced by transplantation or transient coronary artery ligation led to recruitment of neutrophils to the heart, their extravasation from coronary veins, and infiltration of the myocardium where they formed large clusters. Grafting hearts containing mutant ICAM-1, a ligand important for neutrophil recruitment, reduced the crawling velocities of neutrophils within vessels, and markedly inhibited their extravasation. Similar impairment was seen with the inhibition of Mac-1, a receptor for ICAM-1. Blockade of LFA-1, another ICAM-1 receptor, prevented neutrophil adherence to endothelium and extravasation in heart grafts. As inflammatory responses in the heart are of great relevance to public health, this imaging approach holds promise for studying cardiac-specific mechanisms of leukocyte recruitment and identifying novel therapeutic targets for treating heart disease.

The intestinal immune system is exposed to a mixture of foreign antigens from diet, commensal flora and potential pathogens. Understanding how pathogen-specific immunity is elicited while avoiding inappropriate responses to the background of innocuous antigens is essential for understanding and treating intestinal infections and inflammatory diseases. The ingestion of protein antigen can induce oral tolerance, which is mediated in part by a subset of intestinal dendritic cells (DCs) that promote the development of regulatory T cells. The lamina propria (LP) underlies the expansive single-cell absorptive villous epithelium and contains a large population of DCs (CD11c(+) CD11b(+) MHCII(+) cells) comprised of two predominant subsets: CD103(+) CX(3)CR1(-) DCs, which promote IgA production, imprint gut homing on lymphocytes and induce the development of regulatory T cells, and CD103(-) CX(3)CR1(+) DCs (with features of macrophages), which promote tumour necrosis factor-α (TNF-α) production, colitis, and the development of T(H)17 T cells. However, the mechanisms by which different intestinal LP-DC subsets capture luminal antigens in vivo remains largely unexplored. Using a minimally disruptive in vivo imaging approach we show that in the steady state, small intestine goblet cells (GCs) function as passages delivering low molecular weight soluble antigens from the intestinal lumen to underlying CD103(+) LP-DCs. The preferential delivery of antigens to DCs with tolerogenic properties implies a key role for this GC function in intestinal immune homeostasis.

A new class of thermal protection materials based on a novel organic silicone polymer system, referred to generically as SM8000, was investigated. The composite material undergoes “ceramitization” on exposure to elevated temperatures under solid rocket exhaust plumes. SM8000 converts in situ to an oxidative resistant ceramic material at elevated temperatures. The remaining char forms a tough, abrasion-resistant surface. This paper summarizes the four year research anddevelopment program in refining, testing, anddeveloping this class of silicone polymer matrix composites as thermal protection materials. Composite design, specifically resin and reinforcement selection, composite geometry, ablation testing method development, as well as both prepreg and laminate manufacturing scale-up issues, were considered as an integral part of this research program. Thermal performance of this new class of silicone-based matrix composites exceeds the performance of the conventional phenolic-based matrix composites. A silicone quartz composite and process were developed that could provide a high-quality, flat, uniformpanelmeasuring 2.44 by 1.22mby9.53mm.SM8000 offers one of the best alternative polymer systems to the phenolic system that has been in use for the last 40 years.

Adaptive immunity is initiated in secondary lymphoid tissues when naive T cells recognize foreign antigen presented as MHC-bound peptide on the surface of dendritic cells. Only a small fraction of T cells in the naive repertoire will express T cell receptors specific for a given epitope, but antigen recognition triggers T cell activation and proliferation, thus greatly expanding antigen-specific clones. Expanded T cells can serve a helper function for B cell responses or traffic to sites of infection to secrete cytokines or kill infected cells. Over the past decade, two- photon microscopy of lymphoid tissues has shed important light on T cell development, antigen recognition, cell trafficking and effector functions. These data have enabled the development of sophisticated quantitative and computational models that, in turn, have been used to test hypotheses in silico that would otherwise be impossible or difficult to explore experimentally. Here, we review these models and their principal findings and highlight remaining questions where modeling approaches are poised to advance our understanding of complex immunological systems.

In an accompanying paper, we find specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intraislet dendritic cells bearing the β-cell-peptide-MHC complex. Here, we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. Vascular cell adhesion molecule-1 (VCAM-1) expression was notable in blood vessels, as was intercellular adhesion molecule-1 (ICAM-1). ICAM-1 was also found on β-cells. These expression changes induced the entry of nonspecific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of nonspecific T cells required a chemokine response and VCAM-1 expression by the islets. IFN-γ was important for the early gene expression changes in the islets. By microarray analysis, we detected up-regulation of a group of IFN-inducible genes as early as 8 h post–T-cell transfer. These studies establish that entry of diabetogenic T cells induces a state of receptivity of islets to subsequent immunological insults.

Mind the GAPs: insights into intestinal epithelial barrier maintenance and luminal antigen delivery

The intestinal lymphatic system comprises two noncommunicating lymphatic networks: one containing the lacteals draining the villi and the connecting submucosal lymphatic network and one containing the lymphatics that drain the intestine muscular layer. These systems deliver lymph into a common network of collecting lymphatics originating near the mesenteric border. The intestinal lymphatic system serves vital functions in the regulation of tissue fluid homeostasis, immune surveillance, and the transport of nutrients; conversely, this system is affected by, and directly contributes to, disease processes within the intestine. Recent discoveries of specific lymphatic markers, factors promoting lymphangiogenesis, and factors selectively affecting the development of intestinal lymphatics, hold promise for unlocking the role of lymphatics in the pathogenesis of diseases affecting the intestine and for intestinal lymphatic selective therapies. Vital to progress in understanding how the intestinal lymphatic system functions is the integration of recent advances identifying molecular pathways for lymphatic growth and remodeling with advanced imaging modalities to observe lymphatic function and dysfunction in vivo.

Background & Aims Helicobacter pylori infection increases gastric regulatory T cell (Treg) response, which may contribute to H pylori immune escape. We hypothesize that H pylori directs Treg skewing by way of dendritic cells (DCs) and thus inhibits interleukin-17 + helper T cells (Th17) immunity. Methods Two-photon microscopy was used to locate DCs in gastric lamina propria of mice. The induction of Th17 and Treg responses by bacteria-pulsed murine bone marrow–derived DCs was analyzed by cytokine production and stimulation of T-cell proliferation. The effect of VacA, CagA, transforming growth factor-β (TGF-β), and IL-10 on Th17/Treg balance was assessed. The in vivo significance of Tregs on the H pylori –specific Th17 response and H pylori density was determined by using anti-CD25 neutralizing antibodies to deplete Tregs in mice. Results We showed that mucosal CD11c + DCs are located near the surface of normal gastric epithelium, and their number increased after H pylori infection. Study of the direct interaction of DCs with H pylori showed a Treg-skewed response. The Treg skewing was independent of H pylori VacA and CagA and dependent on TGF-β and IL-10. In vivo Treg skewing by adoptive transfer of H pylori –pulsed DCs reduces the ratio of gastric IL-17/Foxp3 mRNA expressions. The depletion of CD25 + Tregs results in early reduction of H pylori density, which is correlated with enhanced peripheral H pylori –specific Th17, but not Th1, response. Conclusions Overall, our study indicates that H pylori alters the DC-polarized Th17/Treg balance toward a Treg-biased response, which suppresses the effective induction of H pylori –specific Th17 immunity.

I then turned my eyes to the forest and it seemed alive with its sons and daughters. There appeared to be the utmost order and regularity in their encampment and they held all things in common.Oh what a pity that this state of things should change. How much better would it be if the whites would act like a civilized people, and instead of giving my brethren of the woods "rum!" in exchange for their furs, give them food and clothing for themselves and children. If this course were pursued, I believe that God would bless both the whites and natives threefold. . . .It is a great trial for me to be mouth for God.William Apess, A Son of the Forest (1829)1In January of 1836, William Apess, a Pequot, an adopted Mashpee, and a former Methodist preacher, delivered his most celebrated oration, the "Eulogy on King Philip," at the Odeon, a luxurious lecture hall. The hall would later see other liberal social reformers, including Sarah and Angelina Grimke, ascend its stage. Apess was a veteran of New England's reformist public sphere. Since 1833 he had focused his efforts on Mashpee sovereignty, giving regular lectures and sermons in Connecticut and Massachusetts for at least six years. In support of that cause he published two books, delivered several lectures, and organized nonsectarian, multiracial camp meetings where he spoke and preached as the founder and leader of the "Free and United Church." In these pursuits Apess was "much caressed" by Frederick Douglass, William Garrison, and other prominent reformers whose inclination to support Native American political organizing had been frustrated by Cherokee slaveholding. Like Douglass, Garrison, and the Grimkes, Apess's participation in the public sphere of political reform derived from his earlier participation in sectarian preaching, publication, and organizing. While abolitionist, feminist, and other mid-nineteenth-century publics have received welcome attention, the earlier sectarian public spheres from which they sprung have been less thoroughly examined, save as prelude. Recent studies of Apess have begun to offer another narrative. Exploring continuities between Apess's early work as a Methodist preacher and his later participation in New England's public sphere, they persuasively suggest that Methodist practice and rhetoric made significant contributions to Apess's anticolonial critique.2Apess's work in a small network of Methodist reformers indicates that his relationship to Methodism was more complicated, and more central to his anticolonial critique, than most critics suggest. Reformist Methodist rhetoric, worship, and organizing helped structure Apess's understanding of the relationship between labor, race, and religion in the early republic. The world of Methodist reform was not simply a training ground for Apess's subsequent Mashpee organizing. Apess intervened in the development of national and religious identity through notions of race by using reformist Methodist rhetoric and organizing to create an Indian subject capable of full participation in the early republic's urban and print public spheres. Apess did so by modifying the tactics of eighteenth-century Indian Christian writing and anticipating the more militant nineteenth-century rhetoric of Indian resistance.3Apess's 1829 edition of A Son of the Forest uses intemperance as an organizing theme for the white destruction of Indian communities and depicts Indian subjects with the capacity to control bodily drives, emotions, and, most importantly, labor. As the opening epigraph suggests, Apess's service as "mouth for God" is a central metaphor for his writing and publishing as an Indian Christian. The mouth, from which speech issues and drink enters, embodies what Apess calls his "great trial" as a preacher. Characterizing himself as God's instrument, Apess announces the triumph of divine word over corrupt flesh. Reformist Methodist temperance writing directly influenced Apess's work. …

The spleen is an important organ for the host response to blood-borne bacterial infections. Many cell types and cell surface receptors have been shown to play role in the capture and control of bacteria, yet these are often studied individually and a coherent picture has yet to emerge of how various phagocytes collaborate to control bacterial infection. We analyzed the cellular distribution of Listeria monocytogenes (LM) in situ during the early phase of infection. Using an immunohistochemistry approach, five distinct phagocyte populations contained LM after i.v. challenge and accounted for roughly all bacterial signal in tissue sections. Our analysis showed that LM was initially captured by a wide range of phagocytes in the marginal zone (MZ), where the growth of LM appeared to be controlled. The distribution of LM within the macrophage populations changed during the first hours, decreasing in the MZ macrophages, transiently increasing in CD11c+ DC and in CD11b+ cells. After 4–6 hrs LM was transported to the periarteriolar lymphoid sheath (PALS) where the infective foci developed and LM grew exponentially.

In the mammalian gastrointestinal tract, the cell fate decisions that specify the development of multiple, diverse lineages are governed in large part by interactions of stem and early lineage progenitor cells with their microenvironment, or niche. Here, we show that the gastric parietal cell (PC) is a key cellular component of the previously undescribed niche for the gastric epithelial neck cell, the progenitor of the digestive enzyme secreting zymogenic (chief) cell (ZC). Genetic ablation of PCs led to failed patterning of the entire zymogenic lineage: progenitors showed premature expression of differentiated cell markers, and fully differentiated ZCs failed to develop. We developed a separate mouse model in which PCs localized not only to the progenitor niche, but also ectopically to the gastric unit base, which is normally occupied by terminally differentiated ZCs. Surprisingly, these mislocalized PCs did not maintain adjacent zymogenic lineage cells in the progenitor state, demonstrating that PCs, though necessary, are not sufficient to define the progenitor niche. We induced this PC mislocalization by knocking out the cytoskeleton-regulating gene Cd2ap in Mist1(-/-) mice, which led to aberrant E-cadherin localization in ZCs, irregular ZC-ZC junctions, and disruption of the ZC monolayer by PCs. Thus, the characteristic histology of the gastric unit, with PCs in the middle and ZCs in the base, may depend on establishment of an ordered adherens junction network in ZCs as they migrate into the base.

This study investigated the level of congruency between scores on the Self-Directed Search–Form R (J. L. Holland, 1994) and scores from an online instrument, both of which measure Holland types (J. L. Holland, 1985, 1997). A reasonably high level of congruence was found. Implications for career counselors are briefly delineated.

This comparative study examined the degree of congruency between the results of the Self-Directed Search Form E (J. L. Holland, 1990) and an online self-assessment career planning exercise. A relatively high level of congruence was found between the 2 measures. Implications for career counselors and for future research studies are briefly discussed.

The authors examined job satisfaction and workers' perceptions of a nonprofessional occupation using the Position Classification Inventory (PCI; G. D. Gottfredson & J. L. Holland, 1991). Results revealed high job satisfaction scores and suggest that the PCI shows promise as a method of classifying working-class occupations according to J. L. Holland's (1985, 1997) theory.

Career decision making is an important aspect of career choice and career development. This theoretical article explores the relationship between J. L. Holland's (1997) 6 dimensions of personality and individual decision-making styles. Implications for career counselors are also provided.

A pesar de que la admisión temporal de trabajadores en Suiza y Francia decayó precipitadamente después de1986, una nueva generación de políticas para los trabajadores temporales extranjeros de la posguerra fría ha surgido en la Unión Europea. Estas nuevas políticas son modestas. Alemania admite a cientos de miles de trabajadores temporales al año. España admite de 20 mil a 30 mil trabajadores temporales por año, aunque la mayor parte de ellos residen ilegalmente en el país. Los primeros análisis sobre los supuestos trabajadores inmigrantes contratados sugieren que la nueva generación de políticas de trabajadores extranjeros temporales se desviaron como lo hicieron las de la generación de la posguerra hacia 1973. Otras hipótesis de trabajo derivadas de la "sabiduría" de la generación de la posguerra incluyen la expectativa de que las nuevas políticas darán como resultado un significativo e inesperado establecimiento de trabajadores, la socavación de las políticas de control de la migración y la exacerbación de las relaciones bilaterales entre las sociedades receptoras y expulsoras.

The authors examined the degree of congruency found in a sample of 61 college students between a preference for a specific counseling orientation, measured using the Counseling Orientation Scale (COS; L. C. Loesch & R. J. McDavis, 1978), and a dominant Holland type, measured using the Self-Directed Search (SDS; J. L. Holland, 1994). Results revealed a moderate degree of congruency between the 2 scores. Implications of the findings for counselors are discussed.

Two-photon microscopy is providing literal insight into the cellular dynamics of lymphoid organs and, guided by analysis of three-dimensional images, into mechanisms that underlie cell migration and antigen recognition in vivo. This review describes lymphocyte motility and antigen recognition in the native tissue environment and compares these results with a much more extensive literature on lymphocyte motility, signaling, and chemotaxis in vitro. We discuss the in vitro literature on dynamic aspects of lymphocyte motility, chemotaxis, and the response to antigen and present the view that random migration of lymphocytes may drive a stochastic mechanism of antigen recognition in lymphoid organs, rather than being guided by chemotaxis.

The authors, using the recently developed Position Classification Inventory (PCI; G. Gottfredson & J. L. Holland, 1991), examined male and female perceptions of a nonprofessional occupation. Results suggest that the PCI shows promise as a method of classifying occupations according to J. L. Holland's (1997) theory.

Lymphocyte motility is vital for trafficking within lymphoid organs and for initiating contact with antigen-presenting cells. Visualization of these processes has previously been limited to in vitro systems. We describe the use of two-photon laser microscopy to image the dynamic behavior of individual living lymphocytes deep within intact lymph nodes. In their native environment, T cells achieved peak velocities of more than 25 micrometers per minute, displaying a motility coefficient that is five to six times that of B cells. Antigenic challenge changed T cell trajectories from random walks to “swarms” and stable clusters. Real-time two-photon imaging reveals lymphocyte behaviors that are fundamental to the initiation of the immune response.

The author investigated the degree of change in a single client's 3-letter Holland code (J. L. Holland, 1985) over a 10-year period. Results seem to support Holland's theory that personality traits remain relatively stable over time.

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.