bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of IL-17, IL-23 and Their Receptors in Minor Salivary Glands of Patients with Primary Sjögren's Syndrome
Authors: Mieliauskaite Diana , Dumalakiene Irena , Rugiene Rita , Mackiewicz Zygmunt
Published: January 2012

The main purpose of this study was to determine the expression of interleukins-17/-23 (ILs-17/-23) and receptors of interleukins-17/-23 (IL-17R, IL-23R) in minor salivary glands (MSGs) of patients with primary Sjögren's syndrome (pSS). Expression of IL-17, IL-23 and receptors of IL-17/-23 was analyzed in MSGs from 25 patients with pSS, 25 patients with probable preclinical pSS, and 25 patients with nonautoimmune sicca syndrome by immunohistochemistry. Comparison of the expression of IL-17, IL-23 and receptors of IL-17, IL-23 in MSG of patients with pSS with probable preclinical pSS, and with nonautoimmune sicca syndrome showed significant differences between three groups. However, the expression of IL-17, IL-23 and receptors of IL-17/-23 in MSG was comparable in pSS and probable preclinical pSS patients. We did not find correlation between the expression of IL-17 and IL-23 and of IL-17R and IL-23R in patients with pSS. These results demonstrate an involvement of IL-17/-23 system in the early pSS pathogenesis.
On the Max‐Type Equation xn+1 = max {1/xn, Anxn−1} with a Period‐Two Parameter
Authors: Yalçınkaya İbrahim
Published: January 2012

We study the behavior of the well‐defined solutions of the max type difference equation xn+1 = max {1/xn, Anxn−1}, n=0,1,…, where the initial conditions are arbitrary nonzero real numbers and {An} is a period‐two sequence of real numbers with An ∈ [0, ∞).
Study of Carbon Nanotube-Substrate Interaction
Authors: Soares Jaqueline S. , Jorio Ado
Published: January 2012

Environmental effects are very important in nanoscience and nanotechnology. This work reviews the importance of the substrate in single-wall carbon nanotube properties. Contact with a substrate can modify the nanotube properties, and such interactions have been broadly studied as either a negative aspect or a solution for developing carbon nanotube-based nanotechnologies. This paper discusses both theoretical and experimental studies where the interaction between the carbon nanotubes and the substrate affects the structural, electronic, and vibrational properties of the tubes.
Positive and Nondecreasing Solutions to an m‐Point Boundary Value Problem for Nonlinear Fractional Differential Equation
Authors: Cabrera I. J. , Harjani J. , Sadarangani K. B.
Published: January 2012

We are concerned with the existence and uniqueness of a positive and nondecreasing solution for the following nonlinear fractional m‐point boundary value problem: , where denotes the standard Riemann‐Liouville fractional derivative, f : [0,1]×[0, ∞)→[0, ∞) is a continuous function, ai ≥ 0 for i = 1,2, …, m − 2, and 0 < ξ1 < ξ2 < ⋯<ξm−2 < 1. Our analysis relies on a fixed point theorem in partially ordered sets. Some examples are also presented to illustrate the main results.
MAC Protocols Used by Wireless Sensor Networks and a General Method of Performance Evaluation
Authors: Kabara Joseph , Calle Maria
Published: January 2012

Many researchers employ IEEE802.15.4 as communication technology for wireless sensor networks (WSNs). However, medium access control (MAC) layer requirements for communications in wireless sensor networks (WSNs) vary because the network is usually optimized for specific applications. Thus, one particular standard will hardly be suitable for every possible application. Two general categories of MAC techniques exist: contention based and schedule based. This paper explains these two main approaches and includes examples of each one. The paper concludes with a unique performance analysis and comparison of benefits and limitations of each protocol with respect to WSNs.
Online Parallel Machine Scheduling to Maximize the Number of Early Jobs
Authors: Zheng Feifeng , Liu Ming , Chu Chengbin , Xu Yinfeng
Published: January 2012

We study a maximization problem: online scheduling on m identical machines to maximize the number of early jobs. The problem is online in the sense that all jobs arrive over time. Each job′s characteristics, such as processing time and due date, become known at its arrival time. We consider the preemption-restart model, in which preemption is allowed, while once a job is restarted, it loses all the progress that has been made on this job so far. If in some schedule a job is completed before or at its due date, then it is called early (or on time). The objective is to maximize the number of early jobs. For m identical machines, we prove an upper bound 1 − (1/2m) of competitive ratio and show that ECT (earliest completion time) algorithm is 1/2‐competitive.
Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology
Authors: Gao Jin , Chang Yong S. , Jallal Bahija , Viner Jaye
Published: January 2012

Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic effects that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. As a result, compounds targeting the IGF axis have become an area of intense preclinical and clinical research for cancer therapeutics. The IGF axis is intimately involved with the insulin-signaling pathway because of their close homologies. This homology may explain hurdles encountered in the clinical development of IGF-targeted therapies, such as less-than-expected antitumor efficacy that may arise from compensatory increases in the activity of insulin receptor isoform A (IR-A), in response to IGF-I receptor (IGF-IR) inhibition and perturbations in glucose homeostasis, arising from the inhibition of insulin receptor isoform B (IR-B) activity. In this brief review, we compare differentiating factors that characterize the 3 major classes of IGF-targeting compounds: therapeutic antibodies that target IGF-IR, small molecule tyrosine kinase inhibitors that inhibit kinase activities of IGF-IR and IR, and antibodies that target IGF ligands. Cancer Res; 72(1); 3–12. ©2012 AACR.
Opposing Effects of Pigment Epithelium–Derived Factor on Breast Cancer Cell versus Neuronal Survival: Implication for Brain Metastasis and Metastasis-Induced Brain Damage
Authors: Fitzgerald Daniel P. , Subramanian Preeti , Deshpande Monika , Graves Christian , Gordon Ira , Qian Yongzhen , Snitkovsky Yeva , Liewehr David J. , Steinberg Seth M. , Paltán-Ortiz José D. , Herman Mary M. , Camphausen Kevin , Palmieri Diane , Becerra S. Patricia , Steeg Patricia S.
Published: January 2012

Brain metastases are a significant cause of morbidity and mortality for patients with cancer, yet preventative and therapeutic options remain an unmet need. The cytokine pigment epithelium–derived factor (PEDF) is downregulated in resected human brain metastases of breast cancer compared with primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here, we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a prosurvival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish PEDF as both a metastatic suppressor and a neuroprotectant in the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences. Cancer Res; 72(1); 144–53. ©2012 AACR.
BRAF Inhibitors for the Treatment of Metastatic Melanoma: Clinical Trials and Mechanisms of Resistance
Authors: Alcalá Alexander Marzuka , Flaherty Keith T.
Published: January 2012

The efficacy of selective BRAF inhibitors has now been established in the 50% of patients with metastatic melanoma whose tumors harbor activating mutations. However, for the vast majority of patients, responses persist for less than a year. In extensive preclinical investigations, researchers have focused on potential resistance mechanisms with the hope of identifying treatment strategies that can overcome resistance. Preliminary results suggest that reactivation of the mitogen-activated protein kinase (MAPK) pathway by several BRAF-independent mechanisms is the predominant pattern. However, MAPK pathway–independent mechanisms also seem to play a potential role. More definitive cataloging of resistance mechanisms in patients' tumor samples is needed as combination regimens are being readied for clinical evaluation. Clin Cancer Res; 18(1); 33–9. ©2012 AACR.
Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale
Authors: Komlodi-Pasztor Edina , Sackett Dan L. , Fojo Antonio Tito
Published: January 2012

Although they have been advocated with an understandable enthusiasm, mitosis-specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosis-specific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise. Clin Cancer Res; 18(1); 51–63. ©2012 AACR.
Drug Development: Portals of Discovery
Authors: Bates Susan E. , Amiri-Kordestani Laleh , Giaccone Giuseppe
Published: January 2012

A British humorist said, “There is much to be said for failure. It is much more interesting than success.” This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf–mutated melanoma and crizotinib for non–small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer. Clin Cancer Res; 18(1); 23–32. ©2012 AACR.
Elusive Extranuclear Estrogen Receptors in Breast Cancer
Authors: Levin Ellis R.
Published: January 2012

Estrogen receptors at the plasma membrane and cytoplasm have been difficult to detect in breast cancer specimens. New imaging approaches are needed to determine the percentage of cancers expressing extranuclear estrogen receptors and their impact on cancer biology and treatment. Clin Cancer Res; 18(1); 6–8. ©2012 AACR.
Dose-dependent effect of early antiplatelet therapy in acute ischaemic stroke
Authors: Overbeck Ursula , Endres Heinz G. , Krogias Christos , Neubauer Horst , Meves Saskia H.
Published: January 2012

Antiplatelet agents are essential in treating patients with acute ischaemic stroke (AIS) to prevent recurrent ischaemic events. The aim of this study was to evaluate the effectiveness of early antiplatelet therapy with different aspirin (ASA) dosages in patients with AIS. This observational study included 454 patients with AIS in whom antiplatelet treatment was initiated. The antiplatelet effect was determined by whole blood aggregometry within 48 hours after antplatelet therapy was initiated. An impedance change exceeding 0 Ω after stimulation with arachidonic acid was defined as ASA low response (ALR) and ≥5 Ω in ADP-stimulated specimen as clopidogrel LR. Of the study group 53.5% patients were treated with 200 mg ASA orally, 27.5% with 500 mg ASA intravenously, 8.6% with 100 mg ASA orally, and 7.7% with 75 mg clopidogrel. A dose-dependent antiplatelet effect of ASA treatment was found: 18.4% of patients with 500 mg ASA intravenously were ALR, in contrast to 32.5% on 200 mg and 35.9% on 100 mg ASA orally. Clopidogrel treatment without a loading dose resulted in a high proportion of LR (45.7%). Using the propensity score method revealed a three times higher risk for ALR for patients treated with ASA 200 mg [odds ratio 2.99 (1.55–5.79)] compared to treatment with ASA 500 mg. In conclusion, initiating antiplatelet therapy in patients with AIS resulted in a dose-dependent insufficient platelet inhibitory effect. Our findings suggest using a loading dose of 500 mg ASA intravenously as this seems to be favourable when a sufficient early platelet inhibitory effect is wanted.

ClinicalTrials.gov Identifier: NCT01273935
Culture and Social Support Provision
Authors: Chen Jacqueline M. , Kim Heejung S. , Mojaverian Taraneh , Morling Beth
Published: January 2012

The present research examined cultural differences in the type and frequency of support provided as well as the motivations underlying these behaviors. Study 1, an open-ended survey, asked participants about their social interactions in the past 24 hours and found that European Americans reported providing emotion-focused support more frequently than problem-focused support, whereas Japanese exhibited the opposite pattern. Study 2, a closed-ended questionnaire study, found that, in response to the close other’s big stressor, European Americans provided more emotion-focused support whereas Japanese provided equivalent amounts of emotion-focused and problem-focused support. In addition, Study 2 examined motivational explanations for these differences. Social support provision was motivated by the goal of closeness and increasing recipient self-esteem among European Americans, but only associated with the motive for closeness among Japanese. These studies illustrate the importance of considering cultural context and its role in determining the meaning and function of various support behaviors.
The ‘promise’ of three methods of word association analysis to L2 lexical research
Authors: Zareva Alla , Wolter Brent
Published: January 2012

The present study is an attempt to empirically test and compare the results of three methods of word association (WA) analysis. Two of the methods – namely, associative commonality and nativelikeness, and lexico-syntactic patterns of associative organization – have been traditionally used in both first language (L1) and second language (L2) associative research and the third one – collocational aspect of associative responses – is a more recent perspective on associative connections. The central assumption behind the study is that each method captures a different aspect of language users’ lexical organization and, in that, their findings may paint a different picture of how the L1 and L2 lexicons compare as proficiency increases. At the same time, the sensitivity of each method to reflect differences related to proficiency may also point to their potential as a research and assessment tool.

Three equal size groups of participants ( N = 180) at different proficiency levels – native speakers (NSs), second language (L2) advanced and intermediate learners of English – completed a familiarity and a WA test in writing. The tests contained 36 items equated for lexical class (nouns, verbs, and adjectives) and frequency of occurrence (high, mid, and low). The participants’ WAs generated to familiar vocabulary were analysed in three different ways, following the methods of analysis practiced by each of the three traditions under investigation. In the main, the results showed that examining the lexico-syntactic patterns of associative organization as well as the collocational aspect of associative links are two more ‘promising’ ways of looking at WAs than examining them with respect to their nativelike associative commonality.
Direct mapping of acoustics to phonology: On the lexical encoding of front rounded vowels in L1 English– L2 French acquisition
Authors: Darcy Isabelle , Dekydtspotter Laurent , Sprouse Rex A , Glover Justin , Kaden Christiane , McGuire Michael , Scott John HG
Published: January 2012

It is well known that adult US-English-speaking learners of French experience difficulties acquiring high /y/–/u/ and mid /œ/–/ɔ/ front vs. back rounded vowel contrasts in French. This study examines the acquisition of these French vowel contrasts at two levels: phonetic categorization and lexical representations. An ABX categorization task (for details, see Section IV) revealed that both advanced and intermediate learners categorized /œ/ vs. /ɔ/ and /y/ vs. /u/ differently from native speakers of French, although performance on the /y/–/u/ contrast was more accurate than on the /œ/–/ɔ/ contrast in all contexts. On a lexical decision task with repetition priming, advanced learners and native speakers produced no (spurious) response time (RT) facilitations for /y/–/u/ and /œ/–/ɔ/ minimal pairs; however, in intermediate learners, the decision for a word containing /y/ was speeded by hearing an otherwise identical word containing /u/ (and vice versa), suggesting that /u/ and /y/ are not distinguished in lexical representations. Thus, while it appears that advanced learners encoded the /y/–/u/ and /œ/–/ɔ/ contrasts in the phonological representations of lexical items, they gained no significant benefit on the categorization task. This dissociation between phonological representations and phonetic categorization challenges common assumptions about their relationship and supports a novel approach we label ‘direct mapping from acoustics to phonology’ (DMAP).
Short research note: The Beginning Spanish Lexicon: A web-based interface to calculate phonological similarity among Spanish words in adults learning Spanish as a foreign language
Authors: Vitevitch Michael S. , Stamer Melissa K. , Kieweg Douglas
Published: January 2012

A number of resources provide psycholinguistic researchers with information about the words that the typical child or adult knows in a variety of languages. What is currently not available is a resource that provides information about the words that a typical adult learning a foreign language knows. We created such a resource for Spanish: The Beginning Spanish Lexicon. The present report describes the words contained in this web-accessible resource, and the information about those words provided by the interface. This information is freely accessible at: http://www.people.ku.edu/~mvitevit/BegSpanLex.html
That’s not so different from the: Definite and demonstrative descriptions in second language acquisition
Authors: Ionin Tania , Baek Soondo , Kim Eunah , Ko Heejeong , Wexler Kenneth
Published: January 2012

This article investigates how adult Korean-speaking learners of English interpret English definite descriptions ( the book, the books) and demonstrative descriptions ( that book, those books). Korean lacks articles, but has demonstratives, and it is hypothesized that transfer leads learners to (initially) equate definites with demonstratives. Following J Hawkins (1991) , Roberts (2002) and Wolter (2006) , it is assumed that definite and demonstrative descriptions have the same central semantics of uniqueness, but differ in the domain relative to which uniqueness is computed: while the book denotes the unique book in the discourse, that book denotes the unique book in the immediately salient situation. A written elicited production task and a picture-based comprehension task are used to examine whether Korean-speaking learners of English are aware of this distinction. The results indicate that learners distinguish definites and demonstratives, but not as strongly as native English speakers; low-proficiency learners are particularly likely to interpret definite descriptions analogously to demonstrative descriptions, in both tasks. These results pose interesting conceptual and methodological questions for further research into the second language acquisition of article semantics.
“Mind” in ancient Japanese: The primitive perception of its existence
Authors: Sasaki Ken-ichi
Published: January 2012

What I am planning to write for Diogenes is an essay of elucidating the original meaning of “kokoro” in ancient Japanese.

“Kokoro” is regarded as corresponding to mind in English; for example, we call philosophy of mind “philosophy of kokoro”. We can compare English with French in order to notice the problem concerning this notion. While we say in English “mind-body problem”, in French we call the problem (or rather “l’union”) of “l’âme et du corps”. But there are many cases where “mind” is translated with “l’esprit”. We can already ask the question from where comes this ambiguity. Much the more in Japanese.

I should explain how the philosophical terms are constructed in Japanese. When we say philosophy tout court in Japan, that means the Western philosophy or philosophy in the Western style. Most of its technical terms were made as translation from the Western languages, and when we dare to translate the Western words, the most usual way is to use Chinese characters that are ideograms. In ordinary Japanese, terms originating from Chinese are mixed into its vocabulary. We feel certain “difference” in such words, especially in technical terms borrowed from the Western languages: such is the case of philosophical terms. But “kokoro” is not such a translated word, but an original Japanese word. So personally I feel that this word sounds slightly strange as a philosophical term.

That is the motive of this paper of mine: I wish to conceive the original meaning of “kokoro” in its originating stage. I consult mainly Manyô-shû, ancient anthology of poem established about the mid 8th Century.
From Complex System to Integrative Science
Authors: Ikeda Yoshiaki
Published: January 2012

This paper aims to introduce my thought as an “anti”-Logocentrism. To begin with, I would like to point out two aspects of this theme. First, even if philosophical thinking is essentially based on logical form, it is sometimes exposed to illogicality. But this illogicality is meaningful. Second, it has to do with differences between Western and my thought. The former respects rational thinking and follows strictly formal logic. It is true that we cannot think without rationality, but when, for example, we deal with complex systems, we cannot follow the law of excluded middle because of the contradictory effects that coexist in interfaces which emerge in complex systems.

In terms of complex systems, it is not acceptable to choose only one possibility and to deny the other. It is not uncommon to see such ambiguous situations, but we often overlook them. These situations are, however, not as disordered as we think, and they can be accepted as they actually are. I refer to such thinking as “passive thinking”. In this way, there are two types of philosophical thinking. One is rational thinking, and the other is passive thinking. The latter stays often in contradiction without following logical form, which occurs in interfaces in complex systems. In such cases, we cannot think rationally, because contradictory effects coexist there. Furthermore, we find there something whole new, namely, “emergent property”; that is just what passive thinking deals with. Since early times, Japanese have attached more importance to passive thinking.
Philosophy of Nothingness and Process Theology
Authors: Tanaka Yutaka
Published: January 2012

This paper discusses the two representative philosophers of the Kyoto School, Kitaro Nishida and Hajime Tanabe from the perspective of process theology and the Buddhist-Christian dialogue in Japan.

The first chapter explicates Nishida’s concept of “pure experience” in comparison with William James’ radical empiricism and with Kant’s dualism of sense and reason. Pure experience in Nishida’s sense is neither a passive reception of objective sense-data given before subjective mental operations, nor the raw material of experience which must be given “form” by experiencing subject. It is nothing but metaphysically ultimate activity from which both the experiencing subject and the whole range of the experienced objects from sense-perception to intellectual intuition emerge as its self-unfolding.

The second and third chapters discuss the two key concepts of process theology, “concrescence” and “the extensive continuum” with a special reference to the Mahayana Buddhist concept of “emptiness (sunyata)” and “dependent arising (pratityasamutpada)”. Nishida’s tripartite concept of topos, i.e. a topos of relative being, a topos of relative nothingness, and the topos of absolute nothingness will be applied to process theology in order to explicate the relation of two ultimates in Whitehead’s metaphysics, i.e. the relation of God as the religious ultimate to creativity as the metaphysical ultimate.

The fourth and fifth chapters discuss Hajime Tanabe as a critical successor of Nishida’s philosophy of Nothingness. Tanabe is more akin to Whitehead than to Nishida in that Tanabe reformulates Nishida’s concept of Nothingness from the temporal perspective of a finite human existence related essentially to “species” or “society” in the historical world. Tanabe transforms the unity of contradictories in the logic of topos into the contrasted opposites in the historical process of becoming, which involves novelty and discontinuous leaps at points of historical crisis. For him history has become “the overall Koan” in which the metaphysical topology of static being is to be superseded by the innovative principle of nothingness in the historical world.
Acting-Intuition and Pathos in Nishida and Miki: For the Invisible of the Post-Hiroshima Age, or Irradiated Bodies and Power
Authors: Kazashi Nobuo
Published: January 2012

One of the hallmarks of Kitaro Nishida (1870-1945) and the Kyoto School formed around him is their emphatic endeavor to reconsider perennial philosophical questions from what they called the “stand of the acting-self.” In this paper we begin by bringing into relief the contemporary significance of Nishida’s pioneering notions – such as “logic of place,” “acting-intuition,” and “historical body” – by relating them to some kindred meditations by James, Merleau-Ponty, and Heidegger. Along the way, we call into question some shortcomings that we consider inherent in these philosophical perspectives – with special attention to their expression in the thought of Nishida’s disciple, Kiyoshi Miki, who sought to advance his master’s thought critically under the headings of “dialectics of logos and pathos” and “formative imagination.” Then, we discuss some issues regarding inhuman weapons – particularly the so-called DU (depleted uranium) weapons, which we regard as the “nuclear shadow” – in order to illustrate the aspects of human reality to which Nishida and Miki failed to give adequate consideration. In particular, we examine the destructive capabilities of our “technological bodies” and the reality of the often invisible “pathos of others” – especially in times of war – which ultimately is ours as well.
The Birth of Ehiyehlogy: Beyond Buddhist Thought and Ontotheology
Authors: Miyamoto Hisao
Published: January 2012

In this article it is proposed to go beyond ontotheology, which has been seen as the start of totalitarian thought and totalitarianism. In order to do this and find the key to interpretation the author refers to narratology and Hayatology or Ehiyehlogy (a variety of Hebrew ontology). From the nar-ratological viewpoint he analyses and interpretes the following Old Testament texts: Abraham’s story and the narrative of the Exodus under the guidance of Moses.

By means of this narratological analysis the author identifies in these Old Testament texts Hebrew ontological thought, that is, Ehiyehlogy. He therefore sets out some features of the Hebrew being (hayâh and ehyeh) in the following respects:

i.

it is an ecstatic becoming and differentiates;

ii.

this ecstasy has an intentionality focused on the other;

iii.

this intentionality tends towards creation of a community;

iv.

intervention by such a being (hayâh or ehyeh) articulates time, the historical kairos;

v.

this articulation takes the concrete form of an alliance;

vi.

the Hebrew being acts through being incarnate in people (prophets, sages, writers who wrote for Abraham, Moses or others, etc.).

Taken together, these features of the being make up an ontology which has an open identity and is made manifest in the narrative identity that is not monopolistic but polyphonic, that is, in little stories or anonymous, marginal characters, or else people resisting totalitarianism.

This Ehiyehlogy is supported not only by studying the Hebrew text but also by Buddhist inspiration, which emphasizes the relativity aspect rather than the substantial one. Hence, by building up Ehiyehlogy the author looks onto overcoming the totalitarian nature of contemporary civilization and look for the possibility of coexistence.
Valproic Acid Phase Shifts the Rhythmic Expression of PERIOD2::LUCIFERASE
Authors: Johansson Anne-Sofie , Brask Johan , Owe-Larsson Björn , Hetta Jerker , Lundkvist Gabriella B.S.
Published: January 2012

Valproic acid (VPA) is an anticonvulsant used to treat bipolar disorder, a psychiatric disease associated with disturbances in circadian rhythmicity. Little is known about how VPA affects circadian rhythms. The authors cultured tissues containing the master brain pacemaker for circadian rhythmicity, the suprachiasmatic nuclei (SCN), and skin fibroblasts from transgenic PERIOD2::LUCIFERASE (PER2::LUC) mice and studied the effect of VPA on the circadian PER2::LUC rhythm by measuring bioluminescence. VPA (1 mM) significantly phase advanced the PER2::LUC rhythm when applied at a time point corresponding to the lowest (trough, ~ZT 0) PER2::LUC expression but phase delayed the PER2::LUC rhythm when the drug was administered at the time of highest (peak, ~ZT 12) protein expression. In addition, it significantly increased the overall amplitude of PER2::LUC oscillations at time points at or close to ZT 12 but had no effect on period. Real-time PCR analyses on mouse and human fibroblasts revealed that expressions of other clock genes were increased after 2 h treatment with VPA. Because VPA is known to inhibit histone deacetylation, the authors treated cultures with an established histone deacetylation inhibitor, trichostatin A (TSA; 20 ng/mL), to compare the effect of VPA and TSA on molecular rhythmicity. They found that TSA had similar effects on the PER2::LUC rhythm as VPA. Furthermore, VPA and TSA significantly increased acetylation on histone H3 but in comparison little on histone H4. Lithium is another commonly used treatment for bipolar disorder. Therefore, the authors also studied the impact of lithium chloride (LiCl; 10 mM) on the PER2::LUC rhythm. LiCl delayed the phase, but in contrast to VPA and TSA, LiCl lengthened the PER2::LUC period and had no effect on histone acetylation. These results demonstrate that VPA can delay or advance the phase, as well as increase the amplitude, of the PERIOD2::LUCIFERASE rhythm depending on the circadian time of application. Furthermore, the authors show that LiCl delays the phase and lengthens the period of the PER2::LUC rhythm, confirming previous reports on circadian lithium effects. These different molecular effects may underlie differential chronotherapeutic effects of VPA and lithium.
Genetic Interaction of Per1 and Dec1/2 in the Regulation of Circadian Locomotor Activity
Authors: Bode Brid , Shahmoradi Ali , Rossner Moritz J. , Oster Henrik
Published: January 2012

In mammals, 24-h rhythms are controlled by a hierarchical system of endogenous clocks, with a circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus that synchronizes peripheral oscillators throughout the body. The molecular clock machinery is regulated by interlocked transcriptional translational feedback loops (TTLs). The core TTL includes the transcriptional modulators PER (1-3) and CRY (1/2) that feed back on their own expression by interaction with CLOCK/BMAL1. An accessory loop involving the transcription factors DEC1 and DEC2 has been described that also impinges on CLOCK/BMAL1-mediated transactivation. In Drosophila, the DEC ortholog CWO shows synergistic activity to PER. This prompted the authors to analyze PER1-DEC interaction in the mammalian SCN. They generated Per1/Dec double and triple mutant mice to monitor activity rhythms under entrained and free-running conditions. Furthermore, they analyzed expression of the clock genes Per2, Rev-Erbα, and Bmal1 in wild-type and Per1/Dec mutant SCN by in situ hybridization. The experiments reveal a critical role for Per1-Dec interaction in regulating activity phase under entrained conditions. In constant darkness, a synergistic function for Per1 and Dec1/2 in period regulation was found, correlating with disrupted clock gene mRNA levels in the SCN. Luciferase reporter gene assays indicate an activatory function of DECs on Bmal1 expression. Together, the results suggest a partially redundant and bidirectional regulatory function for the 2 Dec genes in the TTL and a conservation of Per-Dec (Cwo) synergism between vertebrate and invertebrate clocks.
The Circadian Clock, Light, and Cryptochrome Regulate Feeding and Metabolism in Drosophila
Authors: Seay Daniel J. , Thummel Carl S.
Published: January 2012

Recent studies in mammals have demonstrated a central role for the circadian clock in maintaining metabolic homeostasis. In spite of these advances, however, little is known about how these complex pathways are coordinated. Here, we show that fundamental aspects of the circadian control of metabolism are conserved in the fruit fly Drosophila. We assay feeding behavior and basic metabolite levels in individual flies and show that, like mammals, Drosophila display a rapid increase in circulating sugar following a meal, which is subsequently stored in the form of glycogen. These daily rhythms in carbohydrate levels are disrupted in clock mutants, demonstrating a critical role for the circadian clock in the postprandial response to feeding. We also show that basic metabolite levels are coordinated in a clock-dependent manner and that clock function is required to maintain lipid homeostasis. By examining feeding behavior, we show that flies feed primarily during the first 4 hours of the day and that light suppresses a late day feeding bout through the cryptochrome photoreceptor. These studies demonstrate that central aspects of feeding and metabolism are dependent on the circadian clock in Drosophila. Our work also uncovers novel roles for light and cryptochrome on both feeding behavior and metabolism.
Endothelial-monocyte activating polypeptide II disrupts alveolar epithelial type II to type I cell transdifferentiation
Authors: Chen Yao , Legan Susan K , Mahan Anne , Thornton Janet , Xu Haiming , Schwarz Margaret A
Published: January 2012

Background

Distal alveolar morphogenesis is marked by differentiation of alveolar type (AT)-II to AT-I cells that give rise to the primary site of gas exchange, the alveolar/vascular interface. Endothelial-Monocyte Activating Polypeptide (EMAP) II, an endogenous protein with anti-angiogenic properties, profoundly disrupts distal lung neovascularization and alveolar formation during lung morphogenesis, and is robustly expressed in the dysplastic alveolar regions of infants with Bronchopulmonary dysplasia. Determination as to whether EMAP II has a direct or indirect affect on ATII→ATI trans-differentiation has not been explored.

Method

In a controlled nonvascular environment, an in vitro model of ATII→ATI cell trans-differentiation was utilized to demonstrate the contribution that one vascular mediator has on distal epithelial cell differentiation.

Results

Here, we show that EMAP II significantly blocked ATII→ATI cell transdifferentiation by increasing cellular apoptosis and inhibiting expression of ATI markers. Moreover, EMAP II-treated ATII cells displayed myofibroblast characteristics, including elevated cellular proliferation, increased actin cytoskeleton stress fibers and Rho-GTPase activity, and increased nuclear:cytoplasmic volume. However, EMAP II-treated cells did not express the myofibroblast markers desmin or αSMA.

Conclusion

Our findings demonstrate that EMAP II interferes with ATII → ATI transdifferentiation resulting in a proliferating non-myofibroblast cell. These data identify the transdifferentiating alveolar cell as a possible target for EMAP II's induction of alveolar dysplasia.
RAD tag sequencing as a source of SNP markers in Cynara cardunculus L
Authors: Scaglione Davide , Acquadro Alberto , Portis Ezio , Tirone Matteo , Knapp Steven J , Lanteri Sergio
Published: January 2012

Background

The globe artichoke (Cynara cardunculus L. var. scolymus) genome is relatively poorly explored, especially compared to those of the other major Asteraceae crops sunflower and lettuce. No SNP markers are in the public domain. We have combined the recently developed restriction-site associated DNA (RAD) approach with the Illumina DNA sequencing platform to effect the rapid and mass discovery of SNP markers for C. cardunculus.

Results

RAD tags were sequenced from the genomic DNA of three C. cardunculus mapping population parents, generating 9.7 million reads, corresponding to ~1 Gbp of sequence. An assembly based on paired ends produced ~6.0 Mbp of genomic sequence, separated into ~19,000 contigs (mean length 312 bp), of which ~21% were fragments of putative coding sequence. The shared sequences allowed for the discovery of ~34,000 SNPs and nearly 800 indels, equivalent to a SNP frequency of 5.6 per 1,000 nt, and an indel frequency of 0.2 per 1,000 nt. A sample of heterozygous SNP loci was mapped by CAPS assays and this exercise provided validation of our mining criteria. The repetitive fraction of the genome had a high representation of retrotransposon sequence, followed by simple repeats, AT-low complexity regions and mobile DNA elements. The genomic k-mers distribution and CpG rate of C. cardunculus, compared with data derived from three whole genome-sequenced dicots species, provided a further evidence of the random representation of the C. cardunculus genome generated by RAD sampling.

Conclusion

The RAD tag sequencing approach is a cost-effective and rapid method to develop SNP markers in a highly heterozygous species. Our approach permitted to generate a large and robust SNP datasets by the adoption of optimized filtering criteria.
Risk groups defined by Recursive Partitioning Analysis of patients with colorectal adenocarcinoma treated with colorectal resection
Authors: Chang Yun-Jau , Chen Li-Ju , Chang Yao-Jen , Chung Kuo-Piao , Lai Mei-Shu
Published: January 2012

Background

To define different prognostic groups of surgical colorectal adenocarcinoma patients derived from recursive partitioning analysis (RPA).

Methods

Ten thousand four hundred ninety four patients with colorectal adenocarcinoma underwent colorectal resection from Taiwan Cancer Database during 2003 to 2005 were included in this study. Exclusion criteria included those patients with stage IV disease or without number information of lymph nodes. For the definition of risk groups, the method of classification and regression tree was performed. Main primary outcome was 5-year cancer-specific survival.

Results

We identified six prognostic factors for cancer-specific survival, resulting in seven terminal nodes. Four risk groups were defined as following: Group 1 (mild risk, 1,698 patients), Group 2 (moderate risk, 3,129 patients), Group 3 (high risk, 4,605 patients) and Group 4 (very high risk, 1,062 patients). The 5-year cancer-specific survival for Group 1, 2, 3, and 4 was 86.6%, 62.7%, 55.9%, and 36.6%, respectively (p < 0.001). Hazard ratio of death was 2.13, 5.52 and 10.56 (95% confidence interval 1.74-2.60, 4.58-6.66 and 8.66-12.9, respectively) times for Group 2, 3, and 4 as compared to Group 1. The predictive capability of these grouping was also similar in terms of overall and progression-free survival.

Conclusion

The use of RPA offered an alternative grouping method that could predict the survival of patients who underwent surgery for colorectal adenocarcinoma.
High content live cell imaging for the discovery of new antimalarial marine natural products
Authors: Cervantes Serena , Stout Paige E , Prudhomme Jacques , Engel Sebastian , Bruton Matthew , Cervantes Michael , Carter David , Tae-Chang Young , Hay Mark E , Aalbersberg William , Kubanek Julia , Le Roch Karine G
Published: January 2012

Background

The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum.

Methods

A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.

Results

Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.

Conclusion

Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.
A systematic review of economic evaluations of interventions to tackle cardiovascular disease in low- and middle-income countries
Authors: Suhrcke Marc , Boluarte Till A , Niessen Louis
Published: January 2012

Background

Low-and middle-income countries are facing both a mounting burden of cardiovascular disease (CVD) as well as severe resource constraints that keep them from emulating some of the extensive strategies pursued in high-income countries. There is thus an urgency to identify and implement those interventions that help reap the biggest reductions of the CVD burden, given low resource levels. What are the interventions to combat CVDs that represent good "value for money" in low-and middle-income countries? This study reviews the evidence-base on economic evaluations of interventions located in those countries.

Methods

We conducted a systematic literature review of journal articles published until 2009, based on a comprehensive key-word based search in generic and specialized electronic databases, accompanied by manual searches of expert databases. The search strategy consisted of freetext and MeSH terms related to economic evaluation and cardiovascular disease. Two independent reviewers verified fulfillment of inclusion criteria and extracted study characteristics.

Results

Thirty-three studies met the selection criteria. We find a growing research interest, in particular in most recent years, if from a very low baseline. Most interventions fall under the category primary prevention, as opposed to case management or secondary prevention. Across the spectrum of interventions, pharmaceutical strategies have been the predominant focus, and, taken at face value, these show significant positive economic evidence, specifically when compared to the counterfactual of no interventions. Only a few studies consider non-clinical interventions, at population level. Almost half of the studies have modelled the intervention effectiveness based on existing risk-factor information and effectiveness evidence from high-income countries.

Conclusion

The cost-effectiveness evidence on CVD interventions in developing countries is growing, but remains scarce, and is biased towards pharmaceutical interventions. While the burden of cardiovascular disease is growing in these countries, future research should put greater emphasis on non-clinical interventions than has hitherto been the case. Significant differences in outcome measures and methodologies prohibit a direct ranking of the interventions by their degree of cost-effectiveness. Considerable caution should be exercised when transferring effectiveness estimates from developed countries for the purpose of modelling cost-effectiveness in developing countries. New local CVD risk factor and intervention follow-up studies are needed. Some pharmaceutical strategies appear cost-effective while clarifications are needed on the diagnostic approach in single high-risk factor vs. absolute risk targeting, the role of patient compliance, and the potential public health consequences of large-scale medicalization.