bluuebunny/crossref_metadata_2025 huggingface dataset:
The self-inhibited structure of full-length PCSK9 at 1.9 Å reveals structural homology with resistin within the C-terminal domain
Authors: Hampton Eric N. , Knuth Mark W. , Li Jun , Harris Jennifer L. , Lesley Scott A. , Spraggon Glen
Published: September 2007

Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) are strongly associated with levels of low-density lipoprotein cholesterol in the blood plasma and, thereby, occurrence or resistance to atherosclerosis and coronary heart disease. Despite this importance, relatively little is known about the biology of PCSK9. Here, the crystal structure of a full-length construct of PCSK9 solved to 1.9-Å resolution is presented. The structure contains a fully folded C-terminal cysteine-rich domain (CRD), showing a distinct structural similarity to the resistin homotrimer, a small cytokine associated with obesity and diabetes. This structural relationship between the CRD of PCSK9 and the resistin family is not observed in primary sequence comparisons and strongly suggests a distant evolutionary link between the two molecules. This three-dimensional homology provides insight into the function of PCSK9 at the molecular level and will help to dissect the link between PCSK9 and CHD.
Monitoring of lipid storage in
Caenorhabditis elegans
using coherent anti-Stokes Raman scattering (CARS) microscopy
Authors: Hellerer Thomas , Axäng Claes , Brackmann Christian , Hillertz Per , Pilon Marc , Enejder Annika
Published: September 2007

Better understanding of the fundamental mechanisms behind metabolic diseases requires methods to monitor lipid stores on single-cell level
in vivo
. We have used
Caenorhabditis elegans
as a model organism to demonstrate the limitations of fluorescence microscopy for imaging of lipids compared with coherent anti-Stokes Raman scattering (CARS) microscopy, the latter allowing chemically specific and label-free imaging in living organisms. CARS microscopy was used to quantitatively monitor the impact of genetic variations in metabolic pathways on lipid storage in 60 specimens of
C. elegans
. We found that the feeding-defective mutant
pha-3
contained a lipid volume fraction one-third of that found in control worms. In contrast, mutants (
daf-2
,
daf-4
dauer) with deficiencies in the insulin and transforming growth factors (IGF and TGF-β) signaling pathways had lipid volume fractions that were 1.4 and 2 times larger than controls, respectively. This was observed as an accumulation of small-sized lipid droplets in the hypodermal cells, hosting as much as 40% of the total lipid volume in contrast to the 9% for the wild-type larvae. Spectral CARS microscopy measurements indicated that this is accompanied by a shift in the ordering of the lipids from gel to liquid phase. We conclude that the degree of hypodermal lipid storage and the lipid phase can be used as a marker of lipid metabolism shift. This study shows that CARS microscopy has the potential to become a sensitive and important tool for studies of lipid storage mechanisms, improving our understanding of phenomena underlying metabolic disorders.
The small interfering RNA production pathway is required for shoot meristem initiation in rice
Authors: Nagasaki Hiroshi , Itoh Jun-ichi , Hayashi Katsunobu , Hibara Ken-ichiro , Satoh-Nagasawa Namiko , Nosaka Misuzu , Mukouhata Motohiro , Ashikari Motoyuki , Kitano Hidemi , Matsuoka Makoto , Nagato Yasuo , Sato Yutaka
Published: September 2007

The shoot apical meristem (SAM) is a group of stem cells that are responsible for plant development. Mutations in rice
SHOOTLESS2
(
SHL2
),
SHL4/SHOOT ORGANIZATION2
(
SHO2
), and
SHO1
cause complete deletion or abnormal formation of the SAM. In this study we showed that defects in SAM formation in
shl
mutants are associated with the loss of expression of the homeodomain–leucine zipper (
HD-ZIPIII
) family genes. Rice
SHL2
,
SHL4/SHO2
, and
SHO1
encoded orthologues of
Arabidopsis
RNA-dependent RNA polymerase 6, ARGONAUTE (AGO) 7, and DICER-like 4, respectively, whose mutations affect leaf development through the trans-acting siRNA (ta-siRNA) pathway. This suggested that the ta-siRNA pathway regulates the critical step of SAM formation during rice embryogenesis. The gain-of-function experiment by the ectopic expression of
SHL4
resulted in reduced accumulation of an microRNA,
miR166
, and partial adaxialization of leaves, supporting a role for the ta-siRNA pathway in the maintenance of leaf polarity as previously reported in maize. Analysis of the spatiotemporal expression patterns of
HD-ZIPIII
and
miR166
in wild-type and
shl
mutant embryos suggested that the loss of
HD-ZIPIII
expression in the SAM region of the developing embryo is the result of ectopic expression of
miR166
. Our analysis of
shl
mutants demonstrated that
HD-ZIPIII
expression regulated by
miR166
is sensitive to the ta-siRNA pathway during SAM formation in rice embryogenesis.
Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity
Authors: Van Damme Philip , Bogaert Elke , Dewil Maarten , Hersmus Nicole , Kiraly Dora , Scheveneels Wendy , Bockx Ilse , Braeken Dries , Verpoorten Nathalie , Verhoeven Kristien , Timmerman Vincent , Herijgers Paul , Callewaert Geert , Carmeliet Peter , Van Den Bosch Ludo , Robberecht Wim
Published: September 2007

Influx of Ca2+ions through α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to neuronal damage in stroke, epilepsy, and neurodegenerative disorders such as ALS. The Ca2+permeability of AMPA receptors is largely determined by the glutamate receptor 2 (GluR2) subunit, receptors lacking GluR2 being permeable to Ca2+ions. We identified a difference in GluR2 expression in motor neurons from two rat strains, resulting in a difference in vulnerability to AMPA receptor-mediated excitotoxicity bothin vitroandin vivo. Astrocytes from the ventral spinal cord were found to mediate this difference in GluR2 expression in motor neurons. The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptor-mediated excitotoxicity. These results reveal a mechanism through which astrocytes influence neuronal functioning in health and disease.
The effect of climate variations on the dynamics of pasture–livestock interactions under cooperative and noncooperative management
Authors: Brekke Kjell Arne , Øksendal Bernt , Stenseth Nils Chr.
Published: September 2007

It is well known from Hardin's “Tragedy of the Commons” [Hardin G (1968)
Science
162:1243–1248] that, if open access is allowed, overgrazing typically results. Hardin, and most authors of the subsequent literature, adopted a static view of the underlying ecosystem. Here we extend this tragedy of the commons to consider the dynamics of the involved ecosystem as well. We consider a general model that allows for a variable carrying capacity of the pastures (due to variation in precipitation) and a stimulating effect on plant growth due to grazing. Our analysis further emphasizes the tragedy; in addition to overgrazing, the ecosystem may approach limit cycles. Thus, unless the pastoralists are able to coordinate themselves, the human capability of long-term planning will generally not stabilize the system. Although numerical optimization shows that a cooperative optimum would yield a high and stable harvest, the open-access system may produce limit cycles, in which even the peak harvest may be below the stable cooperative optimal harvest. Such fluctuations cause both losses in biomass production and utility losses. Our dynamic analysis also demonstrates that, in the absence of cooperation between herders, too much rain in an otherwise dry area might (temporally) destabilize the ecological grazing system through overstocking, subsequently leading to further overgrazing (which will be observed in, but not caused by, the typically dry conditions of landscapes where pastoralism is practiced). In short, through this study we have brought time (and temporal dynamics) into the Hardin's tragedy of the commons and show that the tragedy might be profoundly worsened.
Centromere identity is specified by a single centromeric nucleosome in budding yeast
Authors: Furuyama Suzanne , Biggins Sue
Published: September 2007

Chromosome segregation ensures that DNA is equally divided between daughter cells during each round of cell division. The centromere (CEN) is the specific locus on each chromosome that directs formation of the kinetochore, the multiprotein complex that interacts with the spindle microtubules to promote proper chromosomal alignment and segregation during mitosis. CENs are organized into a specialized chromatin structure due to the incorporation of an essential CEN-specific histone H3 variant (CenH3) in the centromeric nucleosomes of all eukaryotes. Consistent with its essential role at the CEN, the loss or up-regulation of CenH3 results in mitotic defects. Despite the requirement for CenH3 in CEN function, it is unclear how CenH3 nucleosomes structurally organize centromeric DNA to promote formation of the kinetochore. To address this issue, we developed a modified chromatin immunoprecipitation approach to analyze the number and position of CenH3 nucleosomes at the budding yeast CEN. Using this technique, we show that yeast CENs have a single CenH3 nucleosome positioned over the CEN-determining elements. Therefore, a single CenH3 nucleosome forms the minimal unit of centromeric chromatin necessary for kinetochore assembly and proper chromosome segregation.
Facile O-atom insertion into CC and CH bonds by a trinuclear copper complex designed to harness a singlet oxene
Authors: Chen Peter P.-Y. , Yang Richard B.-G. , Lee Jason C.-M. , Chan Sunney I.
Published: September 2007

Two trinuclear copper [Cu
I
Cu
I
Cu
I
(L)]
1+
complexes have been prepared with the multidentate ligands (L) 3,3′-(1,4-diazepane-1,4-diyl)bis(1-((2-(dimethylamino)ethyl)(methyl)amino)propan-2-ol) (7-Me) and (3,3′-(1,4-diazepane-1,4-diyl)bis(1-((2-(diethylamino) ethyl)(ethyl) amino)propan-2-ol) (7-Et) as models for the active site of the particulate methane monooxygenase (pMMO). The ligands were designed to form the proper spatial and electronic geometry to harness a “singlet oxene,” according to the mechanism previously suggested by our laboratory. Consistent with the design strategy, both [Cu
I
Cu
I
Cu
I
(L)]
1+
reacted with dioxygen to form a putative bis(μ
3
-oxo)Cu
II
Cu
II
Cu
III
species, capable of facile O-atom insertion across the central C

C bond of benzil and 2,3-butanedione at ambient temperature and pressure. These complexes also catalyze facile O-atom transfer to the C

H bond of CH
3
CN to form glycolonitrile. These results, together with our recent biochemical studies on pMMO, provide support for our hypothesis that the hydroxylation site of pMMO contains a trinuclear copper cluster that mediates C

H bond activation by a singlet oxene mechanism.
Das einfache Eins-Werden des Menschen und Gottes bei Meister Eckhart und Hegel
Authors: Beriaschwili Mamuka
Published: September 2007

This essay examines the becoming-one of man and God in the thought of Meister Eckhart and G. W. F. Hegel. It holds that the seemingly moral category of love is elevated to the onto-gnoseological dimension of the One itself in its fullness. In this very work which is love and at the same time is God Himself, God loves all things not as created, but rather inasmuch as they are created in God. This absolute process of becoming is brought to perfection when empirical space and time are overcome – a transcendence expressed by Eckhart as the ‹nun› of eternal presence.
Metaphysik und konstruierende Vernunft
Authors: Krieger Gerhard
Published: September 2007

This essay investigates the extent to which the notion of the subject provides access to medieval metaphysics. Historically, this question involves the relation of nominalism to the Cartesian cogito, with regard to which it is possible to speak of a certain continuity in view of the paradigmatically explanatory function of the notion of the I. Against this background, it is maintained that the notion of the subject provides access to medieval metaphysics insofar as the notion of the I belongs to the notion of the subject. Medieval metaphysics and constructive reason can be mediated with one another to the extent that reason in its constructive significance is connected with the notion of the I.
Maître Théodoric, averroïste d’Erfurt du XIVe siècle
Authors: Kuksewicz Zdzisław
Published: September 2007

We know of three commentaries on Aristotle by Theodoricus de Magdeburg: The Quaestiones super De physica, the Quaestiones super De substantia orbis, and the Quaestiones super De anima. This paper presents an analysis of some of Thedoricus’ s questions with regard to three main topics: (1) Matter and Substance, (2) God (Quaestiones super De physica, super De substantia orbis), and (3) Man and Soul (Quaestiones super De anima). The investigation of the first two works – and of the first two topics respectively – starts with an assessment of their contents. It turns out, however, that Super De physica scarcely differs from Super De substantia orbis and that the few differences are rather superficial. Theodoricus’ s Super De anima mainly expounds the theory of the intellect. The analysis concentrates on his role in the debates with other Latin Averroists such as John of Jandun. It is evident that Theodoricus, even in his disagreement with other philosophers, essentially relies on Averroistic thought; but he also strikes out in new directions. These two characteristics of his philosophy – consistency and originality – mark him as an outstanding thinker in the tradition of Latin Averroism.
Metaphysical Speculation and its Applicability to a Mode of Living
Authors: Harding Brian
Published: September 2007

This paper argues that Boethius’ De Consolatione Philosophiae presents theoretical metaphysical speculation as having a direct bearing on the life of the metaphysician. Boethius accomplishes this through his depiction of Lady Philosophy’s ‘therapy’ wherein complex metaphysical arguments are utilized to pull Boethius out of his depression, returning him to what she calls his true self. I begin the paper by contextualizing this discussion in terms of the debate as to whether or not the ‘philosophic life’ of pagan antiquity is present in medieval thought. I then turn to a discussion of the therapeutic metaphysical arguments of Lady Philosophy and their effects on Boethius’ mental and emotional state. I conclude the essay by listing some questions raised and directions for further study.
What’s in a name? Students of William of Champeaux on the vox significativa
Authors: Cameron Margaret
Published: September 2007

William of Champeaux (1170-1121) is best known as Peter Abelard’s teacher and the proponent of realism of universals. In recent years, many works on the linguistic liberal arts – grammar, dialectic and rhetoric – have been attributed to him. However, at least in the case of the dialectical commentaries, these attributions have been hastily made and are probably incorrect. The commentaries themselves, correctly situated in the time and place when Abelard and William worked at Notre Dame, nonetheless deserve close attention. The commentaries on Aristotle’s De interpretatione are examined here: in them we find a new theory of signification which developed as a critical response to William of Champeaux’s view of the vox significativa, as well as an important clue to the origins of the doctrine of the proprietates terminorum.
'Getting Organized'
Authors: Pöchhacker Franz
Published: September 2007

Based on a broad definition of the concept of community interpreting, the paper gives an overview of the development of community-based interpreting as a profession since the 1960s. Reviewing both the field of sign language interpreting and spoken-language community interpreting in the context of migration, major elements in the process of professionalization are described with reference to selected examples. The overall picture is one of great diversity of approaches, constraints and responses to the challenge of intra-social interpreting needs throughout the world, shaped by the variable interplay of factors like the existence of legal provisions, institutional arrangements for interpreter service delivery, an authority-driven or profession-based system of accreditation or certification more or less specifying standards of practice and professional ethics, training programs within (or outside) the established public system of higher education, and a professional organization more or less inclusive of various types of interpreting activity. Typically, interpreting services 'get organized' (by institutions or community agencies) before practitioners get organized to shape their professional terms of reference, and much progress in the evolution of community interpreting is still to be made.
Islands and LF-movement in Greek sluicing
Authors:   Merchant
Published: September 2007

This paper investigates the interaction of island insensitivities and form-identity effects in sluicing, and examines the consequences of these for the architecture of ellipsis resolution. On the basis of a number of novel facts from Greek, it is argued that current approaches, both PF-deletion and LF-copying, are inadequate. The present data instead motivate a revised LF-copying approach which relies on the scoping movement of indefinites at LF and þ-chain uniformity.
Greek dialects in Asia Minor: Accentuation in Pontic and Cappadocian
Authors: Kooij Jan G. , Revithiadou Anthi
Published: September 2007

In this paper, we discuss the relation between morphological structure and prosodic form in two Greek dialects of Asia Minor: Pontic and Cappadocian. Both dialects underwent a change at all levels of grammar under the influence of Turkish. Emphasis is on the gradual transition from fusional to agglutinative morphology displayed primarily by several dialectal groups of Cappadocian. We show that this morphological development had a profound impact on the accentual behavior of the dialects in question. A comparative analysis of both dialectal groups sheds light on some interesting aspects of the phonology-morphology interface such as the relation between type of morphology and mode of accentuation.
‘Subject’ and EPP in Greek: The discontinuous subject hypothesis
Authors: Philippaki-Warburton Irene , Spyropoulos Vassilios
Published: September 2007

In the present study we examine the notion ‘subject’ in finite clauses in Greek, a null-subject language, and we investigate the connection between the rich morphological marking of subject-agreement on the verb and the definition of this notion. We propose that ‘subject’ in Greek should be analysed as a discontinuous element which consists of a null nominal element in the SpecTP position satisfying the Extended Projection Principle (EPP), associated with a

pro

at the relevant theta-position inside the VP. We argue that this analysis has not only the theoretical advantage of maintaining the universally strong value of EPP, but also, perhaps more importantly, the descriptive advantage of providing a satisfactory explanation for a number of apparent idiosyncrasies of Greek constructions.
Politeness and formulaicity: Evidence from Cypriot Greek
Authors: Terkourafi Marina
Published: September 2007

In Brown and Levinson’s politeness theory, the degree of indirectness of an utterance is presumed to be commensurate with the sum of the variables of Distance, Power and Ranking of an imposition. This claim was tested with reference to a corpus of spontaneous requests from Cypriot Greek. It emerged that, rather than motivating the choice of a ‘generic’ politeness strategy corresponding to a certain degree of indirectness, particular combinations of values of extra-linguistic variables (such as sex, age and social class of interlocutors, relationship between them, setting) tend to co-occur with particular combinations of the values of linguistic variables (type of verb, subjective modality, number/person). It is proposed that the latter combinations constitute formulae accessed during the production/interpretation of polite discourse in a holistic manner alongside perceivable features of the extra-linguistic context.
Modern Greek dialects: A preliminary classification
Authors: Trudgill Peter
Published: September 2007

Although there are many works on individual Modern Greek dialects, there are very few overall descriptions, classifications, or cartographical representations of Greek dialects available in the literature. This paper discusses some possible reasons for these lacunae, having to do with dialect methodology, and Greek history and geography. It then moves on to employ the work of Kontossopoulos and Newton in an attempt to arrive at a more detailed classification of Greek dialects than has hitherto been attempted, using a small number of phonological criteria, and to provide a map, based on this classification, of the overall geographical configuration of Greek dialects.
Accounts of the count–mass distinction
Authors: Joosten Frank
Published: September 2007

Summary

The issue of what is usually, but also misleadingly called the count–
mass distinction, i.e. the distinction between nouns that can be counted (e.g. a car, two cars, many cars) and nouns that cannot (e.g. *a sand, *two sands, *many sands, sand, much sand), has been addressed and accounted for in different ways. This paper gives a critical survey of four main theoretical views on the distinction and points out that each of them is problematic in some way. It is argued that that the count–mass distinction should not be reduced to an exclusively grammatical, ontological, semantic, or contextual issue. A proper characterisation of the distinction can only be given if its multidimensional character is fully acknowledged and if parameters such as basic count- or masshood, degree of lexicalisation, conceptualisation, and (non-)arbitrariness are taken into account.
Locatif spatial initial et position du sujet nominal
Authors: Fuchs Catherine
Published: September 2007

This contribution is devoted to the study of French « locative inversion » structures X V S (Sur la cheminée trônent deux chandeliers). It is argued that such structures are specific, and cannot be derived from X S V structures (Sur la cheminée, deux chandeliers trônent), since the syntactic relation between X and V is different — X being in the scope of the predicate in the former case, but not in the latter. Furthermore, the two structures cannot be considered, on the semantic level, as paraphrases deriving from a unique underlying representation, since the semantic values and interpretations attributed to the verbal item differ ; whereas on the pragmatic level, each construction enters a different type of discourse setting. Thus a formal theory is outsketched, based on a topological approach of word ordering in the process of utterance construction, which accounts for the specificity of the above mentioned structures.
The grammaticalization of adjectives of identity and difference in English and Dutch
Authors: Breban Tine
Published: September 2007

This article deals with adjectives of general comparison in English and Dutch, more particularly, with the core adjectives expressing identity and difference in both languages. These are, for identity, English same and identical and Dutch zelfde and identiek, and, for difference, English other and different and their Dutch counterparts ander, verschillend and verscheiden. Throughout, the contrastive description offered will be based on the analysis of corpus examples of these nine adjectives and on the quantification of their distinct uses. In the first place, I will investigate whether the grammaticalization claim made about English adjectives of comparison in Breban (2002) and Breban and Davidse (forthcoming) also applies to Dutch adjectives of comparison. According to this claim, the English adjectives of identity and difference have two distinct types of uses, fully lexical uses and textual — referential and cohesive — uses which are connected as points of departure and result of a process of grammaticalization. I will show that the same grammaticalization process characterizes the semantics of Dutch adjectives of identity and difference, which hence provides an additional, comparative, argument in support of the grammaticalization hypothesis. Secondly, I will, by elaborating the grammaticalization interpretation descriptively, propose a systematic overview of similarities and differences in the semantics of the English and Dutch adjectives of identity and difference. I will focus first on the different degrees of grammaticalization manifested by the English and Dutch adjectives. I will then investigate in what way the various meaning distinctions resulting from the grammaticalization process are distributed over the adjectives in both languages. This will give us some insight into the overall way in which the core adjectives of identity and difference are organized semantically in English and Dutch.
A new role for narrative in variationist sociolinguistics
Authors: Johnstone Barbara
Published: September 2007

Labov and Waletzky’s (1997[1967]) path-breaking description of “narrative syntax” arose in the context of variationist sociolinguistic research, and narrative continues to be an important source of data for variationist’ work. In most of this work, however, narrative is not the object of study. Variationist sociolinguists are interested in the structure and function of sounds, words, and phrases found in narrative data, but they have not typically asked how the structure and function of narrative itself might bear on the questions about linguistic variation and language change that define their field. Here I suggest that close attention to the structure and function of narrative can, in fact, shed light on a topic of central interest to variationists, namely vernacular norm-formation. I argue that narratives about encounters with linguistic difference help create shared orientations to particular sets of nonstandard linguistic features and link them with region, class, and other sources of identity. I further suggest that narrative functions particularly well as a vehicle for language-ideological differentiation (Gal & Irvine, 1995) of this sort.
Thinking big with small stories in narrative and identity analysis
Authors: Georgakopoulou Alexandra
Published: September 2007

Narrative research is frequently described as a rich and diverse enterprise, yet the kinds of narrative data that it bases itself on present a striking consensus: they are autobiographical in kind (i.e., about non-shared, personal experience, single past events). In this paper, I put forth a case for under-represented narrative data which I collectively call (following Bamberg 2004a, b; also Georgakopoulou & Bamberg, 2005) “small stories” (partly literally, partly metaphorically). My aim is to flesh small stories out, to urge for the sort of systematic research that will establish connections between their interactional features and their sites of engagement and finally to consider the implications of their inclusion in narrative research for identity analysis (as the main agenda of much of narrative research). I will thus propose small stories research as a “new” narrative turn that can provide a needed meeting point for narrative analysis and narrative inquiry.
Stories: Big or small
Authors: Bamberg Michael
Published: September 2007

This article is a pledge that we actually should care about the differences between what has recently been coined ‘small’ versus ‘big’ stories because they represent very different approaches to narrative inquiry. In the attempt to pull other contributions of this special issue into the debate between small and big, I argue that the small story approach is able to theoretically and methodologically enrich traditional narrative inquiry — not in a peaceful, complementary fashion, but by more radically re-positioning big story approaches as grounded in dialogical/discursive approaches such as small story research.
The self-telling body
Authors: Charon Rita
Published: September 2007

This essay will examine some of the narrative practices emerging in the health care professions — medicine, nursing, social work, and psychotherapy. We have always, of course, understood that the most fertile and clinically salient information we derive about patients comes from listening to them talking about their illnesses. Nonetheless, medicine’s recent past is marked by not so much a suspicion of as a dismissal of word in diagnosing and treating disease. Of late, medicine (and because I am a doctor, I will limit myself to thinking about medicine in the essay) has found sustenance from such fields as trauma studies, oral history, and testimony work. Finally, we are coming around to understanding that our tasks include the duty to bear witness as others tell of trauma and loss.The narrative practice of medicine — or, as I have come to say, the practice of narrative medicine — unites a host of neighboring concerns and approaches. Historically, medicine came into the narrative realms through qualitative social science, especially sociolinguistics, as a means to represent and comprehend the conversations that take place between doctors and patients. Such scholars as Elliot Mishler, Richard Frankel, Catherine Riessman, and Candice West really altered medical practice by making medical discourse amenable to inspection and then analysis. Around the same time, we also turned to literary texts and ways of thinking that help us to enter the worlds of patients, see others’ experience from their perspectives, greet the metaphorical as well as the factual power of words, and be moved by what we hear. Oddly, then, medical practice became a bridge between the qualitative social sciences and literary theory, letting us, from the inside, see how very similar are the efforts of the sociologist examining discourse and the novelist creating it.We doctors feel great good fortune in having the ultimate objective correlative — what might be captivating but ethereal theorizing becomes as practical and concrete and earthy as can be by virtue of being about somebody’s body — particularly somebody’s ailing body. What extreme pleasure that my thinking complicated thoughts and being attuned to the complex ways of language can translate into control of my patients’ blood sugar or relief of their migraines or diagnosis of their coronary artery disease. Narrative medicine becomes, in the end, a heady, brainy, compassionate, corporeal practice that can heal the patient and nourish the doctor at the same time — by virtue of the talk.
Induction of Cellular Senescence by Insulin-like Growth Factor Binding Protein-5 through a p53-dependent Mechanism
Authors: Kim Kwang Seok , Seu Young Bae , Baek Suk-Hwan , Kim Mi Jin , Kim Keuk Jun , Kim Jung Hye , Kim Jae-Ryong
Published: September 2007

The insulin-like growth factor (IGF) signaling pathway plays a crucial role in the regulation of cell growth, differentiation, apoptosis, and aging. IGF-binding proteins (IGFBPs) are important members of the IGF axis. IGFBP-5 is up-regulated during cellular senescence in human dermal fibroblasts and endothelial cells, but the function of IGFBP-5 in cellular senescence is unknown. Here we show that IGFBP-5 plays important roles in the regulation of cellular senescence. Knockdown of IGFBP-5 in old human umbilical endothelial cells (HUVECs) with IGFBP-5 micro-RNA lentivirus caused partial reduction of a variety of senescent phenotypes, such as changes in cell morphology, increases in cell proliferation, and decreases in senescence-associated β-galactosidase (SA-β-gal) staining. In addition, treatment with IGFBP-5 protein or up-regulation of IGFBP-5 in young cells accelerates cellular senescence, as confirmed by cell proliferation and SA-β-gal staining. Premature senescence induced by IGFBP-5 up-regulation in young cells was rescued by knockdown of p53, but not by knockdown of p16. Furthermore, atherosclerotic arteries exhibited strong IGFBP-5–positive staining along intimal plaques. These results suggest that IGFBP-5 plays a role in the regulation of cellular senescence via a p53-dependent pathway and in aging-associated vascular diseases.
Preventing the Degradation of Mps1 at Centrosomes Is Sufficient to Cause Centrosome Reduplication in Human Cells
Authors: Kasbek Christopher , Yang Ching-Hui , Yusof Adlina Mohd , Chapman Heather M. , Winey Mark , Fisk Harold A.
Published: September 2007

Supernumerary centrosomes promote the assembly of abnormal mitotic spindles in many human tumors. In human cells, overexpression of the cyclin-dependent kinase (Cdk)2 partner cyclin A during a prolonged S phase produces extra centrosomes, called centrosome reduplication. Cdk2 activity protects the Mps1 protein kinase from proteasome-mediated degradation, and we demonstrate here that Mps1 mediates cyclin A-dependent centrosome reduplication. Overexpression of cyclin A or a brief proteasome inhibition increases the centrosomal levels of Mps1, whereas depletion of Cdk2 leads to the proteasome-dependent loss of Mps1 from centrosomes only. When a Cdk2 phosphorylation site within Mps1 (T468) is mutated to alanine, Mps1 cannot accumulate at centrosomes or participate in centrosome duplication. In contrast, phosphomimetic mutations at T468 or deletion of the region surrounding T468 prevent the proteasome-dependent removal of Mps1 from centrosomes in the absence of Cdk2 activity. Moreover, cyclin A-dependent centrosome reduplication requires Mps1, and these stabilizing Mps1 mutations cause centrosome reduplication, bypassing cyclin A. Together, our data demonstrate that the region surrounding T468 contains a motif that regulates the accumulation of Mps1 at centrosomes. We suggest that phosphorylation of T468 attenuates the degradation of Mps1 at centrosomes and that preventing this degradation is necessary and sufficient to cause centrosome reduplication in human cells.
A Single MAPKKK Regulates the Hog1 MAPK Pathway in the Pathogenic FungusCandida albicans
Authors: Cheetham Jill , Smith Deborah A. , da Silva Dantas Alessandra , Doris Kathryn S. , Patterson Miranda J. , Bruce Catherine R. , Quinn Janet
Published: September 2007

The Hog1 mitogen-activated protein kinase (MAPK) plays a central role in stress responses in the human pathogen Candida albicans. Here, we have investigated the MAPK kinase kinase (MAPKKK)-dependent regulation of the pathway. In contrast to the Hog1 pathway in Saccharomyces cerevisiae, which is regulated by three MAPKKKs (Ssk2, Ssk22, and Ste11), our results demonstrate that Hog1 in C. albicans is regulated by a single MAPKKK Ssk2. Deletion of SSK2 results in comparable stress and morphological phenotypes exhibited by hog1Δ cells, and Ssk2 is required for the stress-induced phosphorylation and nuclear accumulation of Hog1, and for Hog1-dependent gene expression. Furthermore, phenotypes associated with deletion of SSK2 can be circumvented by expression of a phosphomimetic mutant of the MAPKK Pbs2, indicating that Ssk2 regulates Hog1 via activation of Pbs2. In S. cerevisiae, the Hog1 pathway is also regulated by the MAPKKK Ste11. However, we can find no connection between Ste11 and the regulation of Hog1 in C. albicans. Furthermore, expression of a chimeric Pbs2 protein containing the Ste11-dependent regulatory region of S. cerevisiae Pbs2, fails to stimulate Ste11-dependent stress signaling in C. albicans. Collectively, our data show that Ssk2 is the sole MAPKKK to relay stress signals to Hog1 in C. albicans and that the MAPK signaling network in C. albicans has diverged significantly from the corresponding network in S. cerevisiae.
Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals
Authors: Guo Wei-hui , Wang Yu-li
Published: September 2007

Recent studies suggest that mechanical signals mediated by the extracellular matrix play an essential role in various physiological and pathological processes; yet, how cells respond to mechanical stimuli remains elusive. Using live cell fluorescence imaging, we found that actin filaments, in association with a number of focal adhesion proteins, including zyxin and vasodilator-stimulated phosphoprotein, undergo retrograde fluxes at focal adhesions in the lamella region. This flux is inversely related to cell migration, such that it is amplified in fibroblasts immobilized on micropatterned islands. In addition, the flux is regulated by mechanical signals, including stretching forces applied to flexible substrates and substrate stiffness. Conditions favoring the flux share the common feature of causing large retrograde displacements of the interior actin cytoskeleton relative to the substrate anchorage site, which may function as a switch translating mechanical input into chemical signals, such as tyrosine phosphorylation. In turn, the stimulation of actin flux at focal adhesions may function as part of a feedback mechanism, regulating structural assembly and force production in relation to cell migration and mechanical load. The retrograde transport of associated focal adhesion proteins may play additional roles in delivering signals from focal adhesions to the interior of the cell.
Transducers: an emerging probabilistic framework for modeling indels on trees
Authors: Bradley Robert K. , Holmes Ian
Published: September 2007

Contact:  ihh@berkeley.edu
Multiple spaced seeds for homology search
Authors: Ilie Lucian , Ilie Silvana
Published: September 2007

Motivation: Homology search finds similar segments between two biological sequences, such as DNA or protein sequences. The introduction of optimal spaced seeds in PatternHunter has increased both the sensitivity and the speed of homology search, and it has been adopted by many alignment programs such as BLAST. With the further improvement provided by multiple spaced seeds in PatternHunterII, Smith–Waterman sensitivity is approached at BLASTn speed. However, computing optimal multiple spaced seeds was proved to be NP-hard and current heuristic algorithms are all very slow (exponential).

Results: We give a simple algorithm which computes good multiple seeds in polynomial time. Due to a completely different approach, the difference with respect to the previous methods is dramatic. The multiple spaced seed of PatternHunterII, with 16 weight 11 seeds, was computed in 12 days. It takes us 17 s to find a better one. Our approach changes the way of looking at multiple spaced seeds.

Contact:  ilie@csd.uwo.ca
Identification of potential HIV-1 targets of minocycline
Authors: Jenwitheesuk Ekachai , Samudrala Ram
Published: September 2007

Summary: Minocycline, a broad spectrum antibiotic, has been discovered to have inhibitory activity against HIV-1 in vitro, but the targets inhibited are unknown. We used a docking with dynamics protocol developed by us to predict the binding affinities of minocycline against seven active sites of five HIV-1 proteins to putatively identify the potential target(s) of minocycline. The results indicate that minocycline has the highest predicted binding affinity against HIV-1 integrase.

Contact:  ram@compbio.washington.edu
Structure-based calculation of drug efficiency indices
Authors: Hetényi Csaba , Maran Uko , García-Sosa Alfonso T. , Karelson Mati
Published: September 2007

Motivation: The efficiency indices (EI's) have been derived from the experimental binding affinities of drug candidates to macromolecules. These ‘two-in-one’ measures include information on both pharmacodynamics and pharmacokinetics of the candidate molecules. The time-consuming experimental measurement of binding affinities of extensive molecule libraries may become a bottle-neck of large scale generation and application of EI's.

Results: To overcome this limitation, structure-based calculation of new EI's is introduced using the modified free energy function of the popular program package AutoDock. The results are validated on experimental binding data of biochemical systems such as potent inhibitors bound to β-secretase, a key enzyme of Alzheimer's disease and various drug–protein complexes. Application of new EI's is tested. Thermodynamics of EI's and their role in virtual high - throughput screening of drugs and in the development of docking programs are discussed.

Contact:  csabahete@yahoo.com

Supplementary information: Accompanies this manuscript on the publisher's web site.
Phylocomposer and phylodirector: analysis and visualization of transducer indel models
Authors: Holmes Ian
Published: September 2007

Summary: Finite-state string transducers are probabilistic tools similar to Hidden Markov Models that can be systematically extended to large number of sequences related by indel and substitution processes on phylogenetic trees. The number of states in such models grows exponentially with the number of nodes in the tree, with the consequence that even quite small trees can be difficult to analyze or visualize. Here, we present two tools, phylocomposer and phylodirector, for working with string transducers. The former tool implements previously described composition algorithms for extending transducers to arbitrary tree topologies, while the latter generates short animations for arbitrary input alignments and phylogenetic trees, illustrating the state path through the composed transducer.

Availability: Phylocomposer and phylodirector are freely available at http://biowiki.org/PhyloComposer and http://biowiki.org/PhyloDirector

Contact:  ihh@berkeley.edu
Assessment of population size and migration routes of silver eel in the River Rhine based on a 2-year combined mark-recapture and telemetry study
Authors: Breteler Jan Klein , Vriese Tim , Borcherding Jost , Breukelaar André , Jörgensen Lothar , Staas Stefan , de Laak Gerard , Ingendahl Detlev
Published: September 2007

Klein Breteler, J., Vriese, T., Borcherding, J., Breukelaar, A., Jörgensen, L., Staas, S., de Laak, G., and Ingendahl, D. 2007. Assessment of population size and migration routes of silver eel in the River Rhine based on a 2-year combined mark-recapture and telemetry study. – ICES Journal of Marine Science, 64: 1450–1456. More than 3000 female silver eels >50 cm were marked and released in the River Rhine at Cologne in 2004 and 2005, and more than 4000 and 6000 per year, respectively, were checked for marks in the different Rhine branches close to the sea. Migration pathways of downstream-migrating eels were also tracked by telemetry from the point of release (300–350 km from the sea, depending on the migration route) through the three main branches of the Rhine (Waal, Nederrijn + Lek, IJssel + Lake IJsselmeer) to the sea. Downstream migration to the sea took from <2 d to more than a year, but was generally in October and November of the year of release. Most successful migrators seemed to find their way to the sea via the Nieuwe Waterweg rather than via Lake IJsselmeer or Haringvliet. Some 23% of released eels of the 2004 cohort and 15% of the 2005 cohort made it to the sea in less than 2 years. The telemetry data suggest that the Nederrijn + Lek watercourse, the only location where hydropower stations have been built in the lower Rhine system, might be important for downstream migration of eels only in the years with greater discharges, suggesting that management measures should concentrate on the Waal and downstream sections to improve spawning escapement of the silver eel population of the Rhine system.
Impedance Cardiography: A Comparison of Cardiac Output vs Waveform Analysis for Assessing Left Ventricular Systolic Dysfunction
Authors: DeMarzo Arthur P. , Kelly Russell F. , Calvin James E.
Published: September 2007

Early detection of asymptomatic left ventricular systolic dysfunction (LVSD) is beneficial in managing heart failure. Recent studies have cast doubt on the usefulness of cardiac output as an indicator of LVSD. In impedance cardiography (ICG), the dZ/dt waveform has a systolic wave called the E wave. This study looked at measurements of the amplitude and area of the E wave compared with ICG‐derived cardiac output, stroke volume, cardiac index, and stroke index as methods of assessing LVSD. ICG data were obtained from patients (n=26) admitted to a coronary care unit. Clinical LVSD severity was stratified into 4 groups (none, mild, moderate, and severe) based on echocardiography data and standard clinical assessment by a cardiologist blinded to ICG data. Statistical analysis showed that the E wave amplitude and area were better indicators of the level of LVSD than cardiac output, stroke volume, cardiac index, or stroke index. ICG waveform analysis has potential as a simple point‐of‐care test for detecting LVSD in asymptomatic patients at high risk for developing heart failure and for monitoring LVSD in patients being treated for heart failure.
Real‐time PCR detection systems for Flavescence dorée and Bois noir phytoplasmas in grapevine: comparison with conventional PCR detection and application in diagnostics
Authors: Hren M. , Boben J. , Rotter A. , Kralj P. , Gruden K. , Ravnikar M.
Published: September 2007

A new real‐time PCR detection system was developed for grapevine yellows (GY) using TaqMan minor groove binder probes and including two amplicons for group‐specific detection of Flavescence dorée (FD) and Bois noir (BN) phytoplasmas, plus a universal phytoplasma amplicon. FD and BN amplicons were designed to amplify species‐specific genomic DNA fragments and the universal amplicon to amplify the 16S ribosomal DNA region. Efficiency of PCR amplification, limit of detection, range of linearity and dynamic range were assessed for all three amplicons. The specificity of detection systems was tested on several other isolates of phytoplasmas and bacteria and on healthy field grapevine and insect samples. No cross‐reactivity with other phytoplasma strains, plant or insect DNA was detected. The assay was compared with conventional PCR on more than 150 field grapevine, insect and field bindweed samples. Real‐time PCR showed higher sensitivity as phytoplasmas were detected in several PCR‐negative and in all PCR‐positive samples. A data‐mining analysis of results from both detection approaches also favoured real‐time PCR over conventional PCR diagnostics. The developed procedure for detection of phytoplasmas in grapevine also included amplification of plant DNA co‐extracted with phytoplasmic DNA, providing additional quality control for the DNA extraction and PCR amplification for each sample. The newly developed assay is a reliable, specific and sensitive method easily applicable to high‐throughput diagnosis of GY.
The evolution of helping and harming on graphs: the return of the inclusive fitness effect
Authors: LEHMANN L. , KELLER L. , SUMPTER D. J. T.
Published: September 2007

Evolutionary graph theory has been proposed as providing new fundamental rules for the evolution of co‐operation and altruism. But how do these results relate to those of inclusive fitness theory? Here, we carry out a retrospective analysis of the models for the evolution of helping on graphs of Ohtsuki et al. [Nature (2006) 441, 502] and Ohtsuki & Nowak [Proc. R. Soc. Lond. Ser. B Biol. Sci (2006) 273, 2249]. We show that it is possible to translate evolutionary graph theory models into classical kin selection models without disturbing at all the mathematics describing the net effect of selection on helping. Model analysis further demonstrates that costly helping evolves on graphs through limited dispersal and overlapping generations. These two factors are well known to promote relatedness between interacting individuals in spatially structured populations. By allowing more than one individual to live at each node of the graph and by allowing interactions to vary with the distance between nodes, our inclusive fitness model allows us to consider a wider range of biological scenarios leading to the evolution of both helping and harming behaviours on graphs.