Jennifer Wang

Background: The intestinal crypt homeostasis is maintained by a combination of growth factors including Wnt, R-Spondin1, Noggin and the epidermal growth factor. In human colorectal cancer, the Wnt pathway is constitutively activated through genetic and epigenetic alterations in as many as 11 genes encoding components of this crypt stem-cell maintenance mechanism. Although the proliferation of colon cancer cells does not require Wnt, it is possible that colon cancer cells can still respond to the crypt growth factors in the colonic microenvironment. A number of studies have shown that epithelial cells behave differently in 3-D versus 2-D cultures. Because the 3-D conditions more closely mimic the in vivo environment, we examined the effects of Wnt and other crypt growth factors on colon cancer cell growth in 3-D culture.Methods: Colon cancer cells were grown in 3-D matrigel supplemented with different combinations of crypt growth factors and colonies were examined for morphology and pathways.Results: When colon cancer cells were cultured in 3-D with EGF, they grew as round spheroid colonies. However, colon cancer cells also grew as flat, disc-like colonies when cultured with EGF plus Wnt, R-Spondin1 and Noggin. Disc colonies were found to have comparable levels of E-cadherin as the spheroid colonies, but showed decreased E-cadherin at the cell-matrix contact sites. Disc colonies also elaborated F-actin rich protrusions at the cell-matrix edge, reminiscent of an invasive phenotype but without the expression of vimentin. These E-cadherin and F-actin alterations were not induced by the four growth factors in 2-D culture. Formation of the disc colonies was inhibited by the knockdown of β-catenin and by protein kinase inhibitors such as gefitinib, imatinib and MK-2206. Furthermore, withdrawal of the crypt growth factors was able to revert the disc colonies to spheroid growth, showing that the invasive phenotype was reversible dependent on the availability of growth factors.Conclusions: These findings show that colon cancer cells remain responsive to the growth factors in the crypt microenvironment and can be induced to undergo morphological transformation in the more physiologically relevant 3-D culture. © 2013 Ludwig et al.; licensee BioMed Central Ltd.

© 2016 American Chemical Society.A tetravalent cerium macrocyclic complex was prepared with an octadentate terephthalamide ligand comprised of hard catecholate donors and characterized in the solution state by spectrophotometric titrations and electrochemistry and in the crystal by X-ray diffraction. The solution-state studies showed that L exhibits a remarkably high affinity toward Ce4+, with log β110 = 61 and ΔG = -348 kJ/mol, compared with log β110 = 32.02 for the analogous Pr3+ complex. In addition, L exhibits an unusual preference for forming CeL4- relative to formation of the analogous actinide complex, ThL4-, which has β110 = 53.7. The extreme stabilization of tetravalent cerium relative to its trivalent state is also evidenced by the shift of 1.91 V in the redox potential of the Ce3+/Ce4+ couple of the complex. The unprecedented behavior prompted an electronic structure analysis using L3- and M5,4-edge X-ray absorption near-edge structure spectroscopies and configuration interaction calculations, which showed that 4f-orbital bonding in CeLK4 has partial covalent character due to ligand-to-metal charge transfer in the ground state. The experimental results are presented in the context of earlier measurements on tetravalent cerium compounds, indicating that the amount of LMCT for CeLK4 is similar to that observed for [Et4N]2[CeCl6] and CeO2 and significantly less than that for the organometallic sandwich compound cerocene, 2Ce. A simple model to rationalize changes in 4f orbital bonding for tri- and tetravalent lanthanide and actinide compounds is also provided.

© 2016 The Royal Society of Chemistry.The electronic structure in the complete series of stable lanthanide sesquioxides, Ln2O3, has been evaluated using oxygen K-edge X-ray absorption spectroscopy with a scanning transmission X-ray microscope. The experimental results agree with recent synthetic, spectroscopic and theoretical investigations that provided evidence for 5d orbital involvement in lanthanide bonding, while confirming the traditional viewpoint that there is little Ln 4f and O 2p orbital mixing. However, the results also showed that changes in the energy and occupancy of the 4f orbitals can impact Ln 5d and O 2p mixing, leading to several different bonding modes for seemingly identical Ln2O3 structures. On moving from left to right in the periodic table, abrupt changes were observed for the energy and intensity of transitions associated with Ln 5d and O 2p antibonding states. These changes in peak intensity, which were directly related to the amounts of O 2p and Ln 5d mixing, were closely correlated to the well-established trends in the chemical accessibility of the 4f orbitals towards oxidation or reduction. The unique insight provided by the O K-edge XAS is discussed in the context of several recent theoretical and physical studies on trivalent lanthanide compounds.

© 2015 Elsevier B.V.This article demonstrates an instrumented mouthguard capable of non-invasively monitoring salivary uric acid levels. The enzyme -modified screen printed electrode system has been integrated onto a mouthguard platform along with anatomically-miniaturized instrumentation electronics featuring a potentiostat, microcontroller, and a Bluetooth Low Energy transceiver. Unlike RFID-based biosensing systems, which require large proximal power sources, the developed platform enables real-time wireless transmission of the sensed information to standard smartphones, laptops, and other consumer electronics for on-demand processing, diagnostics, or storage. The mouthguard biosensor system offers high sensitivity, selectivity, and stability towards uric acid detection in human saliva, covering the concentration ranges for both healthy people and hyperuricemia patients. The new wireless mouthguard biosensor system is able to monitor SUA level in real-time and continuous fashion, and can be readily expanded to an array of sensors for different analytes to enable an attractive wearable monitoring system for diverse health and fitness applications.

© Hsiao et al.; licensee BioMed Central.Background: Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear. Methods: Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12. Results: Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein. Conclusions: Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.

© 2014 American Chemical Society.Attempts to apply artificial nano/micromotors for diverse biomedical applications have inspired a variety of strategies for designing motors with diverse propulsion mechanisms and functions. However, existing artificial motors are made exclusively of synthetic materials, which are subject to serious immune attack and clearance upon entering the bloodstream. Herein we report an elegant approach that turns natural red blood cells into functional micromotors with the aid of ultrasound propulsion and magnetic guidance. Iron oxide nanoparticles are loaded into the RBCs, where their asymmetric distribution within the cells results in a net magnetization, thus enabling magnetic alignment and guidance under acoustic propulsion. The RBC motors display efficient guided and prolonged propulsion in various biological fluids, including undiluted whole blood. The stability and functionality of the RBC motors, as well as the tolerability of regular RBCs to the ultrasound operation, are carefully examined. Since the RBC motors preserve the biological and structural features of regular RBCs, these motors possess a wide range of antigenic, transport, and mechanical properties that common synthetic motors cannot achieve and thus hold considerable promise for a number of practical biomedical uses.

© The Author 2014.Uterine fibroids are the most common solid tumors found in women of reproductive age. It has been reported that deregulation of the mammalian target of rapamycin pathway plays an important role in the etiology of leiomyoma. Here, we investigated the effect of rapamycin, an inhibitor of mTORC1, on the growth of primary fibroid smooth muscle cells and human telomerase reverse transcriptase -transduced and immortalized fSMCs. With the primary fSMCs, a 24-hour treatment with rapamycin was sufficient to trigger a growth arrest that was not reversible upon drug removal. By contrast, the growth inhibitory effect of rapamycin on the hTERT-transduced fSMCs was readily reversible, as these cells resumed proliferation upon the withdrawal of the drug. These results suggest that rapamycin-induced irreversible growth arrest of fSMCs is dependent on the senescence barrier that is abrogated by the ectopic expression of telomerase.

IMPORTANCE: Most evaluations of pay-for-performance incentives have focused on large-group practices. Thus, the effect of P4P in small practices, where many US residents receive care, is largely unknown. Furthermore, whether electronic health records with chronic disease management capabilities support small-practice response to P4P has not been studied. OBJECTIVE: To assess the effect of P4P incentives on quality in EHR-enabled small practices in the context of an established quality improvement initiative. DESIGN, SETTING, AND PARTICIPANTS: A cluster-randomized trial of small primary care clinics in New York City from April 2009 through March 2010. A city program provided all participating clinics with the same EHR software with decision support and patient registry functionalities and quality improvement specialists offering technical assistance. INTERVENTIONS: Incentivized clinicswere paid for each patient whose care met the performance criteria, but they received higher payments for patients with comorbidities, who had Medicaid insurance, or who were uninsured. Quality reports were given quarterly to both the intervention and control groups. MAIN OUTCOMES AND MEASURES: Comparison of differences in performance improvement, from the beginning to the end of the study, between control and intervention clinics for aspirin or antithrombotic prescription, blood pressure control, cholesterol control, and smoking cessation interventions. Mixed-effects logistic regression was used to account for clustering of patients within clinics, with a treatment by time interaction term assessing the statistical significance of the effect of the intervention. RESULTS: Participating clinics had similar baseline characteristics, with a mean of 4592 patients at the intervention group clinics and 3042 at the control group clinics. Intervention clinics had greater adjusted absolute improvement in rates of appropriate antithrombotic prescription, blood pressure control, and in smoking cessation interventions. Intervention clinics performed better on all measures for Medicaid and uninsured patients except cholesterol control, but no differences were statistically significant. CONCLUSIONS AND RELEVANCE: Among small EHR-enabled clinics, a P4P incentive program compared with usual care resulted in modest improvements in cardiovascular care processes and outcomes. Because most proposed P4P programs are intended to remain in place more than a year, further research is needed to determine whether this effect increases or decreases over time. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00884013.

Inspired by early Confucian texts such as the Analects, Mencius, and Xunzi, defenders of Confucian role ethics argue that persons are constituted by their social roles and relationships. However, this has the puzzling implication that persons cannot survive changes in social roles and relationships. This paper proposes ways to understand this claim by appealing to the notions of essence, material constitution, and four-dimensionalism. In particular, it will be suggested that role ethicists should distinguish biological humans from persons and should say either that (i) persons are materially constituted by biological humans, or that (ii) persons are four-dimensional objects that merely overlap with biological humans. There has thus far not been much contact between early Chinese philosophy and contemporary metaphysics in this vein. A secondary goal of this paper is to demonstrate that views in early Chinese philosophy can be examined within frameworks from contemporary metaphysics, and furthermore, that the results include novel theses not yet recognized in contemporary metaphysics.

In the middle of the last century, it was common to explain the notion of necessity in linguistic terms. A necessary truth, it was said, is a sentence whose truth is guaranteed by linguistic rules. Quine famously argued that, on this view, de re modal claims do not make sense. “Porcupettes are porcupines” is necessarily true, but it would be a mistake to say of a particular porcupette that it is necessarily a porcupine, or that it is possibly purple. Linguistic theories of necessity fell out of favour with the publication of Kripke’s Naming and Necessity, and Quine’s arguments were put aside. In her recent book, Norms and Necessity, Amie Thomasson presents her modal normativism, which is an updated version of the mid-century theories just described. Quine’s arguments are thus relevant once again. We recapitulate Quine’s central argument, in the context of modal normativism. We then criticise Amie Thomasson’s discussion of de re modality. We finish by briefly presenting an alternative account of de re modal statements, which is compatible with modal normativism.

There is a puzzle concerning the essences of fundamental entities that arises from considerations about essence, on one hand, and fundamentality, on the other. The Essence-Dependence Link (EDL) says that if x figures in the essence of y, then y is dependent upon x. EDL is prima facie plausible in many cases, especially those involving derivative entities. But consider the property negative charge. A negatively charged object exhibits certain behaviors that a positively charged object does not: it moves away from other negatively charged objects, towards positively charged objects, etc. It is commonly thought that negative charge disposes its bearer to move away from other negatively charged objects, towards positively charged objects, etc. But if negative charge is fundamental, then no other entities—including the property positive charge—can figure in its essence. We thus have a prima facie puzzle: How can we say anything interesting about the essences of fundamental entities without running afoul of EDL? In this paper, I present and discuss the consequences of EDL for the debate between causal essentialists and quidditists about properties, and propose solutions to the puzzle.

ABSTRACT In Making Things Up, Bennett defends an impressive array of theses surrounding the notion of building. My focus is on Bennett’s use of modal recombination principles in her arguments, including in particular the principle that contingent fundamental entities are freely recombinable. I have argued that such principles are motivated by mere intuition, and that we have reasons to reject them. I discuss how worries about modal recombination principles affect three of her key arguments, which concern whether building is necessitating, whether relative fundamentality is primitive, and whether building is fundamental. I argue that while Bennett’s appeal to modal recombination is unjustified, she has other resources available to her in each of the three cases.

Modal primitivists hold that some modal truths are primitively true. They thus seem to face a special epistemological problem: how can primitive modal truths be known? The epistemological objection has not been adequately developed in the literature. I undertake to develop the objection, and then to argue that the best formulation of the epistemological objection targets all realists about modality, rather than the primitivist alone. Furthermore, the moves available to reductionists in response to the objection are also available to primitivists. I conclude by suggesting that extant theories of the epistemology of modality are not sensitive to the question of primitivism versus reductionism.

Many are reluctant to accept primitive modality into their fundamental picture of the world. The worry often traces to this thought: we shouldn't adopt any more primitive - that is, unexplained - notions than we need in order to explain all the features of the world, and primitive modal notions are not needed. I examine one prominent rival to modal primitivism, combinatorialism, and show that in order to account for all the modal features of the world the combinatorialist must adopt two additional primitive notions. My own modal primitivist view takes as primitive the notion of incompatibility between properties or relations. I show how the non-modal notions that the combinatorialist must adopt as primitive may be analyzed using my notion. The upshot is that with respect to the number of primitive notions, my modal primitivist theory comes out ahead.

Dispositionality is a modal notion of a certain sort. When an object is said to have a disposition, we typically understand this to mean that under certain circumstances, the object would behave in a certain way. For instance, a fragile object is disposed to break when dropped onto a concrete surface. It need not actually break - its being fragile has implications that, so to speak, point beyond the actual world. According to dispositionalism, all modal features of the world may be accounted for in terms of its dispositional features. My aim in this paper is to assess the prospects for dispositionalism by examining the most promising theories. Sections 1 and 2 clarify the assumptions and desiderata of a successful dispositionalist theory of modality. Section 3 introduces the principles governing the dispositionalist theories that apparently meet the desiderata. Sections 4 through 6 show that dispositionalism nonetheless faces three problems: while dispositions help account for modal features of the world that are local, diachronic, or gradable, they cannot account for certain modal features of the world that are global, synchronic, or absolute. I end by discussing the costs of preserving dispositionalism.

Modal primitivism is the view that there are modal features of the world which cannot be reduced to the non-modal. Theories which embrace primitive modality are often rejected for reasons of ideological simplicity: the fewer primitive notions a theory invokes, the better. Furthermore, modal primitivism is often associated with the view that all modal features of the world are irreducibly modal, which appears unsystematic and unexplanatory. As a result, many prefer modal reductionism. This work is an articulation and defense of a modal primitivist theory of modality which requires minimal ideology and is systematic and explanatory. On this version of modal primitivism, only some modal features of the world are irreducibly modal—namely, incompatibilities between certain properties or relations. Other modal features of the world are reducible to a combination of primitive incompatibilities and the non-modal features of the world. In chapter 1, I introduce various issues in the metaphysics of modality, giving appropriate background for what follows. My modal primitivist theory of modality is introduced in chapters 2 and 3. In chapter 2, I argue that a well-known modal reductionist theory of modality is not as ideologically innocent as it’s thought to be: modal primitivism has the upper hand with respect to primitive notions. I then introduce the primitive notion of incompatibility and show how this notion can be used to account for de dicto modality, which concerns purely qualitative modal claims. In chapter 3, I present a theory of de re modality, that which concerns modal claims involving particular individuals. Since on this theory the de re is reducible to the de dicto, it requires no more primitive modality than that which appears at the level of the de dicto. I end in chapter 4 by arguing against a rival modal primitivist theory, showing that the primitive notion that it countenances, dispositionality, cannot account for all modal claims.

Actualist counterpart theory replaces David Lewis’s concrete possible worlds and individuals with ersatz worlds and individuals, but retains counterpart theory about de re modality. While intuitively attractive, this view has been rejected for two main reasons: the problem of indiscernibles and the Humphrey objection. I argue that in insisting that ersatz individuals play the same role as Lewisian individuals, actualists commit the particularist fallacy. The actualist should not require stand-ins for every Lewisian individual. Ersatz individuals should instead be construed as representations of actually existing qualitative ways for individuals to be, or qualitative properties individuals can instantiate. This necessitates changes elsewhere. Non-instrumental uses of Kripke semantics and standard counterpart semantics also require stand-ins for particular non-actual individuals. I argue that the actualist should instead adopt a non-standard counterpart semantics that more clearly illuminates the role that actual properties and relations play in explaining de re possibilities and necessities. The result is an intuitive and forceful reply to both the problem of indiscernibles and the Humphrey objection

A fundamental entity is an entity that is ‘ontologically independent’; it does not depend on anything else for its existence or essence. It seems to follow that a fundamental entity is ‘modally free’ in some sense. This assumption, that fundamentality entails modal freedom (or ‘FEMF’ as I shall label the thesis), is used in the service of other arguments in metaphysics. But as I will argue, the road from fundamentality to modal freedom is not so straightforward. The defender of FEMF should provide positive reasons for believing it, especially in light of recent views that are incompatible with it. I examine both direct and indirect routes to FEMF.