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At least three major theistic arguments have a common structure, in which their proponents i) defend the existence of some ultimate, abstract entity and then ii) claim that this abstract thing they have argued for is God. One of these arguments is called the “Third Way.” The conclusion of the Third Way is that a) there exists a being that is itself necessary and that is also the source (or cause) of all other metaphysically necessary beings, and b) this ultimate, necessary being is God. Aquinas’s other arguments, i.e. the First, Second, Fourth, and Fifth Ways, are structured similarly. The abstract entity whose existence is established in a) is not shown to have any personal properties at all. The entity seems strikingly unlike the personal deity whose existence the argument is intended to support. So there is an objection according to which the concept of an ultimate source of necessity is so removed from that of a personal God that the argument fails to support its conclusion. In this dissertation I show that, as a result of some relatively recent developments in modal logic and some associated insights into the nature of meaning and reference, this objection no longer holds.In the first chapter, I argue for the existence of propositions. Propositions are the objects of a person’s beliefs, attitudes, and the conceptual “vehicles” of truth and falsehood; something is true or false if and only if the proposition corresponding to that very thing is true or false. To argue for the existence of propositions, I argue that sentences which seem to refer to propositions cannot be analyzed as other sentences that refer to arguably less abstract entities, such as language types, inscriptions, or other concrete instances of language production. This part of the dissertation involves an analysis of the nature of translation, especially with respect to the translation of direct quotation, as well as some discussion of the semantics of the English word ‘said’.In the second chapter, I then defend what I call a “dirty propositional” account of modal-logic semantics. I do this by arguing that, although worlds are not identical to sets or classes of propositions, for each possible world there are characteristic sets of propositions that correspond to that world. I also argue that any one of a world’s characteristic sets entails every proposition that is true at that world. Appreciating that worlds have characteristic sets allows for an analysis of modal statements that is committed to a minimalistic metaphysics of possible worlds, is not committed to a counterpart theory, and allows us to use sets of propositions to refer to worlds.In the third chapter, I use the semantics for modal logic developed in the second chapter to discuss the medieval, Aristotelian concepts of necessity and possibility that Aquinas uses in the Third Way. In this discussion I show that even though the modal concepts in the argument are not the same as contemporary modal concepts, results from twentieth-century modal logic and philosophy of language are nonetheless relevant to the argument. They show that the so-called “Impersonal Objection” or “Gap Problem” does not apply to the Third Way. More generally, this dissertation shows that the strength of similar objections to Aquinas’s arguments from the concept of a Prime Mover or a First Cause also depends at least partly on the semantic properties of the descriptions that are used to express the concept of a Prime Mover and the concept of a First Cause.

Well-known issues with multicast have prevented the deployment of multicast in 802.11 and other local-area wireless environments. This document offers guidance on known limitations and problems with wireless multicast. Also described are certain multicast enhancement features that have been specified by the IETF and by IEEE 802 for wireless media, as well as some operational choices that can be taken to improve the performace of the network. Finally, some recommendations are provided about the usage and combination of these features and operational choices.

Background Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen administration during desensitization therapy can itself induce allergic responses. Several small molecule drugs and nutraceuticals have been used clinically and experimentally to suppress these allergic responses. Objectives This study sought to optimize drug inhibition of IgE-mediated anaphylaxis. Methods Several agents were tested individually and in combination for ability to suppress IgE-mediated anaphylaxis in conventional mice, FceRIα-humanized mice, and reconstituted immunodeficient mice that have human mast cells and basophils. Hypothermia was the readout for anaphylaxis; therapeutic efficacy was measured by degree of inhibition of hypothermia. Serum mouse mast cell protease 1 level was used to measure extent of mast cell degranulation. Results Histamine receptor 1 (HR1) antagonists, β-adrenergic agonists, and a spleen tyrosine kinase (Syk) inhibitor were best at individually inhibiting IgE-mediated anaphylaxis. A Bruton’s tyrosine kinase (BTK) inhibitor, administered alone, only inhibited hypothermia when FceRI signaling was suboptimal. Combinations of these agents could completely or nearly completely inhibit IgE-mediated hypothermia in these models. Both Syk and BTK inhibition decreased mast cell degranulation, but only Syk inhibition also blocked desensitization. Many other agents that are used clinically and experimentally had little or no beneficial effect. Conclusions Combinations of an HR1 antagonist, a β-adrenergic agonist, and a Syk or a BTK inhibitor protect best against IgE-mediated anaphylaxis, while an HR1 antagonist plus a β-adrenergic agonist ± a BTK antagonist is optimal for inhibiting IgE-mediated anaphylaxis without suppressing desensitization.

A holographic lidar concept established on the Digital Micromirror Mirror (DMD)-based hybrid light modulation is reported, which multiplexes coarse-steering by sawtooth phase modulation and fine-steering by binary amplitude modulation. The hybrid steering is achieved by overlaying displayed Computer-Generated Holograms (CGHs) with a sawtooth blazed grating phase mask, which the blaze angle programmed by synchronized short-pulse illumination of transitioning micromirrors creating the CGHs. The steering principle is demonstrated as a 2D beam steering scheme with a 532 nm visible pulse laser, and implemented into a 905 nm lidar system with a 44° field-of-view, 0.9°×0.4° angular resolution, 7.8 FPS video frame rate, and 1 m detection distance.

This document updates RFC 6775 and RFC 8505 in order to enable proxy services for IPv6 Neighbor Discovery by Routing Registrars called Backbone Routers. Backbone Routers are placed along the wireless edge of a Backbone, and federate multiple wireless links to form a single Multi-Link Subnet.

Small pixel pitch with a large array size is highly anticipated for solid-state lidar transmitter and receiver. We demonstrate 2D beam steering with reduced effective pixel pitch by harnessing transitional state of the mirror array.

Virtual memory (VM) CD8+ T cells are present in unimmunized mice, yet possess T-cell receptors specific for foreign antigens. To date, VM cells have only been characterized in C57BL/6 mice. Here, we assessed the cytokine requirements for VM cells in C57BL/6 and BALB/c mice. As reported previously, VM cells in C57BL/6 mice rely mostly on IL-15 and marginally on IL-4. In stark contrast, VM cells in BALB/c mice rely substantially on IL-4 and marginally on IL-15. Further, NKT cells are the likely source of IL-4, because CD1d-deficient mice on a BALB/c background have significantly fewer VM cells. Notably, this NKT/IL-4 axis contributes to appropriate effector and memory T-cell responses to infection in BALB/c mice, but not in C57BL/6 mice. However, the effects of IL-4 are manifest prior to, rather than during, infection. Thus, cytokine-mediated control of the precursor population affects the development of virus-specific CD8+ T-cell memory. Depending upon the genetic background, different cytokines encountered before infection may influence the subsequent ability to mount primary and memory anti-viral CD8+ T-cell responses.

A digital micromirror device (DMD) based holographic beam steering technique is reported that multiplexes fine-steering binary amplitude gratings with a coarse-steering programmable blazed grating. The angular spatial light modulation (ASLM) technique encodes the spatial pattern of the binary amplitude grating at the same plane as the angular modulation set by a phase map of the DMD-based beam steering technique. The beam steering technique is demonstrated at 532 nm and implemented into a 905 nm lidar system. The results of the lidar system tests are presented, achieving a 44° field-of-view, 0.9°×0.4° (H×V) angular resolution, 1 m max distance, 1.5 kHz sampling, and 7.8 FPS video. Scalability techniques are proposed, including max distance increases to over 100 m.

This specification updates RFC 6775 - 6LoWPAN Neighbor Discovery, to clarify the role of the protocol as a registration technique, simplify the registration operation in 6LoWPAN routers, as well as to provide enhancements to the registration capabilities and mobility detection for different network topologies including the Routing Registrars performing routing for host routes and/or proxy Neighbor Discovery in a low power network.

Background: Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MFs) after cardiac injury. We hypothesized that interfering with FN polymerization or its genetic ablation in fibroblasts would attenuate MF and fibrosis and improve cardiac function after ischemia/reperfusion (I/R) injury. Methods: Mouse and human MFs were used to assess the impact of the FN polymerization inhibitor (pUR4) in attenuating pathological cellular features such as proliferation, migration, extracellular matrix deposition, and associated mechanisms. To evaluate the therapeutic potential of inhibiting FN polymerization in vivo, wild-type mice received daily intraperitoneal injections of either pUR4 or control peptide (III-11C) immediately after cardiac surgery for 7 consecutive days. Mice were analyzed 7 days after I/R to assess MF markers and inflammatory cell infiltration or 4 weeks after I/R to evaluate long-term effects of FN inhibition on cardiac function and fibrosis. Furthermore, inducible, fibroblast-restricted, FN gene–ablated (Tcf21 MerCreMer ; Fn flox ) mice were used to evaluate cell specificity of FN expression and polymerization in the heart. Results: pUR4 administration on activated MFs reduced FN and collagen deposition into the extracellular matrix and attenuated cell proliferation, likely mediated through decreased c-myc signaling. pUR4 also ameliorated fibroblast migration accompanied by increased β1 integrin internalization and reduced levels of phosphorylated focal adhesion kinase protein. In vivo, daily administration of pUR4 for 7 days after I/R significantly reduced MF markers and neutrophil infiltration. This treatment regimen also significantly attenuated myocardial dysfunction, pathological cardiac remodeling, and fibrosis up to 4 weeks after I/R. Last, inducible ablation of FN in fibroblasts after I/R resulted in significant functional cardioprotection with reduced hypertrophy and fibrosis. The addition of pUR4 to the FN-ablated mice did not confer further cardioprotection, suggesting that the salutary effects of inhibiting FN polymerization may be mediated largely through effects on FN secreted from the cardiac fibroblast lineage. Conclusions: Inhibiting FN polymerization or cardiac fibroblast gene expression attenuates pathological properties of MFs in vitro and ameliorates adverse cardiac remodeling and fibrosis in an in vivo model of heart failure. Interfering with FN polymerization may be a new therapeutic strategy for treating cardiac fibrosis and heart failure.

Transforming growth factor β (TGF-β) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-βRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-β-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-βRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls. Emphysematous pathology in LysM(Cre)TGF-βRII(flox/flox) mice is characterized by excessive matrix metalloprotease (MMP) activity, reduced lung elasticity, increased total lung capacity, and dysregulated respiration. Thus, TGF-β effects on myeloid cells suppress helminth immunity as a consequence of restoring lung function after infection.

The repair protein trefoil factor 2 promotes Th2 responses to helminth infection and allergens in part by inducing IL-33., The molecular mechanisms that drive mucosal T helper type 2 (TH2) responses against parasitic helminths and allergens remain unclear. In this study, we demonstrate in mice that TFF2 (trefoil factor 2), an epithelial cell–derived repair molecule, is needed for the control of lung injury caused by the hookworm parasite Nippostrongylus brasiliensis and for type 2 immunity after infection. TFF2 is also necessary for the rapid production of IL-33, a TH2-promoting cytokine, by lung epithelia, alveolar macrophages, and inflammatory dendritic cells in infected mice. TFF2 also increases the severity of allergic lung disease caused by house dust mite antigens or IL-13. Moreover, TFF2 messenger RNA expression is significantly increased in nasal mucosal brushings during asthma exacerbations in children. These experiments extend the biological functions of TFF2 from tissue repair to the initiation and maintenance of mucosal TH2 responses.

IL-4Rα expression on airway smooth muscle cells is sufficient for the development of airway hyperresponsiveness., Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models, and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse versus human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and the relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient but not necessary to induce AHR. Five genes known to promote smooth muscle migration, proliferation, and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle–directed asthma therapeutics.

Alternatively activated macrophages prevent lethal intestinal pathology caused by worm ova in mice infected with the human parasite Schistosoma mansoni through mechanisms that are currently unclear. This study demonstrates that arginase I (Arg I), a major product of IL-4– and IL-13–induced alternatively activated macrophages, prevents cachexia, neutrophilia, and endotoxemia during acute schistosomiasis. Specifically, Arg I-positive macrophages promote TGF-β production and Foxp3 expression, suppress Ag-specific T cell proliferation, and limit Th17 differentiation. S. mansoni-infected Arg I-deficient bone marrow chimeras develop a marked accumulation of worm ova within the ileum but impaired fecal egg excretion compared with infected wild-type bone marrow chimeras. Worm ova accumulation in the intestines of Arg I-deficient bone marrow chimeras was associated with intestinal hemorrhage and production of molecules associated with classical macrophage activation (increased production of IL-6, NO, and IL-12/IL-23p40), but whereas inhibition of NO synthase-2 has marginal effects, IL-12/IL-23p40 neutralization abrogates both cachexia and intestinal inflammation and reduces the number of ova within the gut. Thus, macrophage-derived Arg I protects hosts against excessive tissue injury caused by worm eggs during acute schistosomiasis by suppressing IL-12/IL-23p40 production and maintaining the Treg/Th17 balance within the intestinal mucosa.

Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) β. RELM-β is essential for normal spontaneous expulsion and IL-4–induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC. RELM-β is nontoxic for H. polygyrus in vitro but directly inhibits the ability of worms to feed on host tissues during infection. This decreases H. polygyrus adenosine triphosphate content and fecundity. Importantly, RELM-β–driven immunity does not require T or B cells, alternative macrophage activation, or increased gut permeability. Thus, we demonstrate a novel mechanism for host protection at the mucosal interface that explains how stimulation of epithelial cells by IL-4 and IL-13 contributes to protection against parasitic helminthes that dwell in the intestinal lumen.

The cytokines IL-10 and TGF-β regulate immunity and inflammation. IL-10 is known to suppress the extent of hepatic damage caused by parasite ova during natural infection with Schistosoma mansoni, but the role of TGF-β is less clear. Cytokine blockade studies in mice revealed that anti-IL-10R mAb treatment during acute infection modestly increased cytokine production and liver damage, whereas selective anti-TGF-β mAb treatment had marginal effects. In contrast, mice administered both mAbs developed severe hepatic inflammation, with enlarged, necrotic liver granulomas, cachexia, and >80% mortality by 8 wk postinfection, despite increased numbers of CD4+CD25+Foxp3+ T regulatory cells. Blocking both IL-10 and TGF-β at the onset of egg production also significantly increased IL-4, IL-6, TNF, IFN-γ, and IL-17 production and markedly increased hepatic, peritoneal, and splenic neutrophilia. In contrast, coadministration of anti-IL-10R and TGF-β mAbs had little effect upon parasite ova-induced intestinal pathology or development of alternatively activated macrophages, which are required to suppress intestinal pathology. This suggests that inflammation is controlled during acute S. mansoni infection by two distinct, organ-specific mechanisms: TGF-β and IL-10 redundantly suppress hepatic inflammation while intestinal inflammation is regulated by alternatively activated macrophages.

Computer aided drug design is progressing and playing an increasingly important role in drug discovery. Computational methods are being used to evaluate larger and larger numbers of real and virtual compounds. New methods based on molecular simulations that take protein and ligand flexibility into account also contribute to an ever increasing need for compute time. Computational grids are therefore becoming a critically important tool for modern drug discovery, but can be expensive to deploy and maintain. Here, we describe the low cost implementation of a 165 node, computational grid at Anadys Pharmaceuticals. The grid makes use of the excess computing capacity of desktop computers deployed throughout the company and of outdated desktop computers which populate a central computing grid. The performance of the grid grows automatically with the size of the company and with advances in computer technology. To ensure the uniformity of the nodes in the grid, all computers are running the Linux operating system. The desktop computers run Linux inside MS Windows using coLinux as virtualization software. HYDRA has been used to optimize computational models, for virtual screening and for lead optimization.

A multi-radio device may perform dual-radio handovers in a make-before-break manner, at the price of higher peak-power and more sophisticated isolation of receiver signal from radio frequency (RF) interference. The IEEE 802.21c Task Group has developed a media-independent single radio handover specification to avoid these requirements resulting in smaller battery size and less design complexity, and therefore lower cost. This media-independent handover mechanism also enables signaling between different networks.

Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism. Here, we show that Cdc42 controls polarity, unexpectedly, via its effector WASp. Cdc42 controls WASp activation and its distant localization to the uropod. At the uropod, WASp regulates the reorganization of CD11b integrin into detergent resistant membrane domains; in turn, CD11b recruits the microtubule end binding protein EB1 to capture and stabilize microtubules at the uropod. This organization is necessary to maintain neutrophil polarity during migration and is critical for neutrophil emigration into inflamed lungs. These results suggest unrecognized mechanism of neutrophil polarity in which WASp mediates long-distance control of the uropod by Cdc42 to maintain a proper balance between the pseudopod and the uropod. Our study reveals a new function for WASp in the control of neutrophil polarity via crosstalk between CD11b and microtubules.

In maxillofacial head and neck oncology, tracheostomy is often used to secure the airway, but not without risk. This study compared the existing practice of two units: one where tracheostomy was routinely done with one where overnight intubation was used. From both units we retrospectively analysed 50 consecutive patients who had intraoral resection, neck dissection, and microvascular reconstruction for head and neck cancer. When compared with tracheostomy, overnight intubation resulted in a shorter mean stay in the intensive therapy unit (ITU) (1.4 compared with 3.7 days), a shorter overall hospital stay (12.9 compared with 18.0 days), less time to first oral intake (8.9 compared with 12.8 days), and a lower rate of lower respiratory tract infection (LRTI) (10% compared with 38%). This study supports the discontinuation of routine tracheostomy and the adoption of a more selective practice to improve recovery.

Genome-wide screening and positional cloning have linked neuropeptide S receptor 1 (NPSR1) with asthma and airway hyperresponsiveness. However, the mechanism by which NPSR1 regulates pulmonary responses remains elusive. Because neuropeptide S and its receptor NPSR1 are expressed in brain regions that regulate respiratory rhythm, and Npsr1-deficient mice have impaired stress and anxiety responses, we aimed to investigate whether neuropeptide S and NPSR1 regulate respiratory function through a central-mediated pathway. After neuropeptide S intracerebroventricular administration, respiratory responses of wildtype and Npsr1-deficient mice were monitored by whole-body or invasive plethysmography with or without serial methacholine inhalation. Airway inflammatory and hyperresponsiveness were assessed in allergen-challenged (ovalbumin or Aspergillus fumigatus) Npsr1-deficient mice. Analysis of breathing patterns by whole-body plethysmography revealed that intracerebroventricular neuropeptide S, as compared with the artificial cerebral spinal fluid control, increased respiratory frequency and decreased tidal volume in an NPSR1-dependent manner but did not affect enhanced pause. Following serial methacholine inhalation, intracerebroventricular neuropeptide S increased respiratory frequency in wildtype mice, but not Npsr1-deficient mice, and had no effect on tidal volume. Intracerebroventricular neuropeptide S significantly reduced airway responsiveness to methacholine as measured by whole-body plethysmography. Npsr1 deletion had no impact on airway inflammation or hyperresponsiveness in ovalbumin- or Aspergillus fumigatus-induced experimental asthma. Our results demonstrate that neuropeptide S and NPSR1 regulate respiratory function through a central nervous system-mediated pathway.

The Internet has revolutionized communication, ed- ucation, commerce and information access for its users world- wide. Unfortunately, the lack of copper/fiber infrastructure in the rural areas of the developing world has prevented a large majority of the human population from reaping the benefits of the Internet. While the number of mobile subscribers in the developing world has more than quadrupled in the last five years, the adoption of the Internet has shown a slow growth pattern. Recently, there has been a growing interest in providing Internet access to rural areas by means of inexpensive long distance WiFi mesh networks. However, the expensive Internet uplink and the difficulty in troubleshooting of WiFi mesh networks has hindered their large scale deployment. In this paper, we propose Cell- Share - an architecture that leverages the explosive growth in cellular network penetration in the developing world to provide rural WiFi mesh networks with an on-demand scalable Internet uplink and troubleshooting back-channel using a collaborative mobile phone framework. We implement Cell-Share on Windows Mobile and Android platforms to demonstrate the feasibility of using the infrastructure of cellular data networks to provide a back-channel for network troubleshooting as well as capacity enhancement for rural mesh networks. I. INTRODUCTION The information and communication infrastructure of any region plays a pivotal role in its socio-economic development and can be regarded as one of its greatest assets. With rapid advances in the field of communication technology and infor- mation access over the past few decades, the world has entered the communications age. The growth of the Internet has played an integral role in this information revolution. Unfortunately, this revolution contributed in the development of only a small portion of the human population, confined to the contemporary developed economies of the world and the urban areas of the developing nations, resulting in a "digital divide". A vast majority of the people living in the rural areas of developing and under-developed nations have yet to take advantage of the Internet revolution. Figure 1 highlights the disparity in the availability of electricity, fixed-telephone service and some form of public Internet facility in the village communities of the world, as estimated by the International Telecommunica- tion Union (ITU) - a United Nations agency for Information and Communication Technology (ICT) issues (11).

T cell proliferation and survival are regulated by the cytokine receptor common γ-chain-associated cytokines IL-2, IL-7, and IL-15, while IL-4, another γ-chain-associated cytokine, is thought to primarily affect T cell quality rather than quantity. In contrast, our experiments reveal that endogenously produced IL-4 is a direct, nonredundant, and potent stimulator of CD8+ T cell proliferation in Ag- and pathogen-induced CD8+ T cell responses. These stimulatory effects of IL-4 are observed in both BALB/c and C57BL/6 mice and activate both naive and memory/activated phenotype CD8+ T cells, although the former are stimulated less than are the latter. IL-4 effects are IL-7- and IL-15-independent, but MHC class I-dependent stimulation appears to be required for the mitogenic effect of IL-4 on naive phenotype CD8+ T cells. Thus, endogenously produced IL-4 is an important regulator of quantitative as well as qualitative aspects of T cell immunity.