Ju Wang

According to radical scepticism, knowledge of the external world is impossible. Transcendental arguments are supposed to be anti-sceptical, but can they provide a satisfying response to radical scepticism? Especially, when radical scepticism is cast as posing a how-possible question, there is a concern that transcendental arguments are neither sufficient nor necessary for answering such question. In light of this worry, I argue that we can take a modest transcendental argument as a stepping stone for a diagnostic anti-sceptical proposal, and I use a Wittgensteinian modest transcendental argument to illustrate my point.

Radical scepticism contends that our knowledge of the external world is impossible. Particularly, radical scepticism can be motivated by the closure principle. Several commentators have noted that a straightforward way to respond to such arguments is via externalist strategies, e.g., Goldman, Greco, Bergmann. However, these externalist strategies are not effective against a slightly weaker form of the argument, a closure principle for rationally grounded knowledge, closureRK.\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${closure}_{RK.}$$\end{document} The sceptical argument, framed around the closureRK\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {closure}_{\mathrm{RK}}$$\end{document} principle, targets rationally grounded knowledge. Although externalist strategies are ineffective against this form of argument, its conclusion can nonetheless be resisted by combining, in a novel way, the resources of Wittgenstein and Davidson. In particular, I argue that the sceptic is assuming an unrestricted way of using the closureRK\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {closure}_{\mathrm{RK}}$$\end{document} principle, which is incorrect. Alternatively, I argue for The Conditionality of Rational Support Thesis, i.e., the thesis that rational support via competent deduction is conditional. In particular, rational support must be provided within an evaluative system in which hinge propositions are presupposed and contentful beliefs are being evaluated. In the end, we can resist the closureRK\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {closure}_{\mathrm{RK }}$$\end{document}-based sceptical argument while retaining the closureRK\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {closure}_{\mathrm{RK}}$$\end{document} principle.

There is a debate on the nature of ignorance in contemporary epistemology. The standard view holds that ignorance is the lack of knowledge, while the new view contends that ignorance is the lack of true belief. Rather than taking a side in this dispute, Pritchard recently offers a new proposal according to which ignorance essentially involves not just the absence of a certain epistemic good, but also an intellectual failing of inquiry. We argue that Pritchard’s new proposal advances the discussion of ignorance by incorporating insight from virtue epistemology, and hence the normative dimension of ignorance is properly noticed. Crucially, ignorance is no longer a mere static cognitive state, but also reflects the quality of inquiry and inquirers’ obligations. However, the new proposal faces two problems. First, current formulation is incomplete so that it cannot ground the epistemic blame that Pritchard requires. More details must be filled in. Second, his view would label all ignorance as normatively negative, and therefore locutions such as virtuous ignorance, blameless ignorance and the positive value of ignorance would be wrong.

Cognitive enhancement has an increasingly wider influence on our life. The main issue that concerns epistemologists is what its epistemological implications are. Adam Carter and Duncan Pritchard argue that cognitive enhancement improves cognitive achievement, but this view faces axiological objections. A worry exists that cognitive enhancement undermines achievements and erodes intellectual character. Crucially, two parties seem to talk past each other because the nature of cognitive enhancement and the value of cognitive enhancement are not clearly distinguished. To end the stand‐off between the two parties, I take insight from Gwen Bradford’s work and argue that, other things being equal, cognitive enhancement either decreases the value of cognitive achievement or undermines cognitive achievement. In the face of this threat, I further submit that we could learn to live with cognitive enhancement in an integrated way so that the lost value can be restored.

© 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.

We report coregistration of near-infrared diffuse optical spectroscopy and magnetic resonance imaging for the study of animal model tumors. A combined broadband steady-state and frequency-domain apparatus was used to determine tissue oxyhemoglobin, deoxyhemoglobin, and water concentration locally in tumors. Simultaneous MRI coregistration provided structural and contrast-enhanced images of the tumor that were correlated with the optical measurements. By use of Monte Carlo simulations, the optically sampled volume was superimposed on the MR images, showing precisely which tissue structure was probed optically. DOS and MRI coregistration measurements were performed on seven rats over 20 days and were separated into three tumor tissue classifications: viable, edematous, and necrotic. A ratio of water concentration to total hemoglobin concentration, as measured optically, was performed for each tissue type and showed values for edematous tissue to be greater than viable tissue. Tissue hemoglobin oxygen saturation also showed a large variation between tissue types: viable tissue had an optically measured StO2 value of 61 ± 5%, whereas StO2 determined for necrotic tissue was 43 ± 6%. © 2003 Optical Society of America.

We present a combined near-infrared diffuse optical spectroscopy and Magnetic Resonance Imaging system for the study of animal model tumors. A combined broad-band steady-state and frequency domain optical spectroscopy apparatus was integrated with the MRI. The physiological properties of tissue rendered by MRI, including vascular volume fraction and water, were compared with chromophore concentrations as determined from the parameters obtained by optical measurements. DOS measurements provided oxyhemoglobin, deoxy-hemoglobin, and water concentration locally in tumors. A method for coregistration of the information obtained by both modalities was developed. Using Monte Carlo simulations, the optically sampled volume was superimposed on the MR images, illustrating which tissue structure was probed optically. Finally, two optical contrast agents, indocyanine green and methylene blue, were employed and their kinetics were measured by DOS system from different locations on the tumor and compared with Gd-DTPA enhancement maps obtained from MRI.

© 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.

Background: The p53 tumor suppressor and its related protein, p73, share a homologous DNA binding domain, and mouse genetics studies have suggested that they have overlapping as well as distinct biological functions. Both p53 and p73 are activated by genotoxic stress to regulate an array of cellular responses. Previous studies have suggested that p53 and p73 independently activate the cellular apoptotic program in response to cytotoxic drugs. The goal of this study was to compare the promoter-binding activity of p53 and p73 at steady state and after genotoxic stress induced by hydroxyurea. Results: We employed chromatin immunoprecipitation, the NimbleGen promoter arrays and a model-based algorithm for promoter arrays to identify promoter sequences enriched in anti-p53 or anti-p73 immunoprecipitates, either before or after treatment with hydroxyurea, which increased the expression of both p53 and p73 in the human colon cancer cell line HCT116-3. We calculated a model-based algorithm for promoter array score for each promoter and found a significant correlation between the promoter occupancy profiles of p53 and p73. We also found that after hydroxyurea treatment, the p53-bound promoters were still bound by p73, but p73 became associated with additional promoters that that did not bind p53. In particular, we showed that hydroxyurea induces the binding of p73 but not p53 to the promoter of MLH3, which encodes a mismatch repair protein, and causes an up-regulation of the MLH3 mRNA. Conclusion: These results suggest that hydroxyurea exerts differential effects on the promoter-binding functions of p53 and p73 and illustrate the power of model-based algorithm for promoter array in the analyses of promoter occupancy profiles of highly homologous transcription factors. © 2009 Huang et al; licensee BioMed Central Ltd.

Background: High throughput screens with RNA interference technology enable loss-of-function analyses of gene activities in mammalian cells. While the construction of genome-scale shRNA libraries has been successful, results of large-scale screening of those libraries can be difficult to analyze because of the relatively high noise levels and the fact that not all shRNAs in a library are equally effective in silencing gene expression. Results: We have screened a library consisting of 43,828 shRNAs directed against 8,500 human genes for functions that are necessary in cell detachment induced by a constitutively activated c-Abl tyrosine kinase. To deal with the issues of noise and uncertainty of knockdown efficiencies, we employed an analytical strategy that combines quantitative data analysis with biological knowledge, i.e. Gene Ontology and pathway information, to increase the power of the RNAi screening technique. Using this strategy we found 16 candidate genes to be involved in Abl-induced disruption of cell adhesion, and verified that the knockdown of IL6ST is associated with enhanced cell attachment. Conclusion: Our results suggest that the power of genome-wide quantitative shRNA screens can be significantly increased when analyzed using a systems biology-based approach to identify functional gene networks. © 2008 Huang et al; licensee BioMed Central Ltd.

In contemporary epistemology, sceptical arguments are motivated either by the closure principle or the underdetermination principle. Therefore, it is very important to figure out the structure of the sceptical argument before coming up with an anti-sceptic strategy. With a review of the debate on the relationship between the two principles from Anthony Brueckner to Kevin McCain, it is argued that while maintaining the weak closed justification , closure and underdetermination are not logically equivalent. As a result, two independent responses are needed to answer the sceptical problem satisfactorily. Also, in order to secure a philosophically significant notion of justification and evidence, reasons are given to hold WCJ*, as opposed to rejecting it. This understanding of the sceptical argument would help to focus the real challenge of scepticism

In this paper, I attempt to show how Davidson’s anti-sceptical argument can respond to the closureRK-based radical scepticism. My approach will focus on the closureRK principle rather than the possibility that our beliefs could be massively wrong. I first review Davidson’s principle of charity and the triangulation argument, and then I extract his theory on content of a belief. According to this theory, content of a belief is determined by its typical cause and other relevant beliefs. With this constraint on content, I argue that doubt must be local. Furthermore, since one cannot rationally believe that one’s commitment to the cause of beliefs could be false, our commitment to the denial of a sceptical hypothesis is not a knowledge-apt belief. Therefore, the closureRK principle is not applicable to rational evaluations of this commitment. As a result, the closureRK-based sceptical argument fails while the closureRK principle remains.