bluuebunny/crossref_metadata_2025 huggingface dataset:
Worker caste polymorphism has a genetic basis in
Acromyrmex
leaf-cutting ants
Authors: Hughes William O. H. , Sumner Seirian , Van Borm Steven , Boomsma Jacobus J.
Published: August 2003

Division of labor is fundamental to the success of all societies. The most
striking examples are the physically polymorphic worker castes in social
insects with clear morphological adaptations to different roles. These
polymorphic worker castes have previously been thought to be a classic example
of nongentically controlled polymorphism, being mediated entirely by
environmental cues. Here we show that worker caste development in the
leaf-cutting ant
Acromyrmex echinatior
has a significant genetic
component. Individuals of different patrilines within the same colony differ
in their propensities to develop into minor or major workers. The mechanism
appears to be plastic, with caste destiny resulting from interplay between
nurture and nature. Unlike the few other recently discovered examples of a
genetic influence on caste determination, the present result does not relate
to any rare or exceptional circumstances, such as interspecific hybridization.
The results suggest that a significant role of genetics may have been
overlooked in our understanding of other complex polymorphisms of social
insects.
Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension
Authors: Bonnet Sébastien , Dumas-de-La-Roque Eric , Bégueret Hugues , Marthan Roger , Fayon Michael , Dos Santos Pierre , Savineau Jean-Pierre , Baulieu Etienne-Emile
Published: August 2003

Pulmonary artery (PA) hypertension was studied in a chronic
hypoxic-pulmonary hypertension model (7–21 days) in the rat. Increase in
PA pressure (measured by catheterism), cardiac right ventricle hypertrophy
(determined by echocardiography), and PA remodeling (evaluated by histology)
were almost entirely prevented after oral dehydroepiandrosterone (DHEA)
administration (30 mg/kg every alternate day). Furthermore, in hypertensive
rats, oral administration, or intravascular injection (into the jugular vein)
of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA
reduced the level of intracellular calcium (measured by
microspectrofluorimetry). The effect of DHEA appears to involve a large
conductance Ca
2+
-activated potassium channel
(BK
Ca
)-dependent stimulatory mechanism, at both function and
expression levels (isometric contraction and Western blot), via a
redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be
involved because the antagonist 4-amino-pyridine blocked part of the DHEA
effect. The possible pathophysiological and therapeutic significance of the
results is discussed.
The ATP-waiting conformation of rotating F
1
-ATPase revealed by single-pair fluorescence resonance energy transfer
Authors: Yasuda Ryohei , Masaike Tomoko , Adachi Kengo , Noji Hiroyuki , Itoh Hiroyasu , Kinosita Kazuhiko
Published: August 2003

F
1
-ATPase is an ATP-driven rotary motor in which a rod-shaped
γ subunit rotates inside a cylinder made of
α
3
β
3
subunits. To elucidate the conformations
of rotating F
1
, we measured fluorescence resonance energy transfer
(FRET) between a donor on one of the three βs and an acceptor on γ
in single F
1
molecules. The yield of FRET changed stepwise at low
ATP concentrations, reflecting the stepwise rotation of γ. In the
ATP-waiting state, the FRET yields indicated a γ position ≈40°
counterclockwise (= direction of rotation) from that in the crystal structures
of mitochondrial F
1
, suggesting that the crystal structures mimic a
metastable state before product release.
Short interfering RNA-mediated interference of gene expression and viral DNA accumulation in cultured plant cells
Authors: Vanitharani Ramachandran , Chellappan Padmanabhan , Fauquet Claude M.
Published: August 2003

Gene silencing mediated by double-stranded RNA is a sequence-specific RNA
degradation mechanism highly conserved in eukaryotes that serves as an
antiviral defense pathway in both plants and
Drosophila
. Short
interfering RNAs (siRNAs), the 21- to 23-nt double-stranded intermediates of
this natural defense mechanism, are becoming powerful tools for reducing gene
expression and countering viral infection in a variety of mammalian cells.
Here we report the use of siRNAs to target reporter gene expression and viral
DNA accumulation in cultured plant cells. Transient expression of reporter
genes encoding either GFP or red fluorescent protein from
Discosoma
was specifically reduced by 58% and 47%, respectively, at 24 h after
codelivery of cognate siRNAs in BY2 protoplasts. In contrast to mammalian
systems, the siRNA-induced silencing of GFP expression was transitive as
indicated by the presence of siRNAs representing parts of the target RNA
outside the region homologous to the triggering siRNA. Codelivery of an siRNA
designed to target the mRNA encoding the replication-associated protein (AC1)
of the geminivirus African cassava mosaic virus (ACMV) from Cameroon blocked
AC1 mRNA accumulation by ≈91% and inhibited accumulation of the ACMV
genomic DNA by ≈66% at 36 and 48 h after transfection. As with
siRNA-induced reporter gene silencing, the siRNA targeting ACMV AC1 was
specific and did not affect the replication of East African cassava mosaic
Cameroon virus. This report demonstrates the occurrence of siRNA-mediated
suppression of gene expression in cultured plant cells and that siRNA can
interfere with and suppress accumulation of a nuclear-replicated DNA
virus.
Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin
Authors: Faccio Roberta , Novack Deborah V. , Zallone Alberta , Ross F. Patrick , Teitelbaum Steven L.
Published: August 2003

The β3 integrin cytoplasmic domain, and specifically S752, is critical for integrin localization and osteoclast (OC) function. Because growth factors such as macrophage colony–stimulating factor and hepatocyte growth factor affect integrin activation and function via inside-out signaling, a process requiring the β integrin cytoplasmic tail, we examined the effect of these growth factors on OC precursors. To this end, we retrovirally expressed various β3 integrins with cytoplasmic tail mutations in β3-deficient OC precursors. We find that S752 in the β3 cytoplasmic tail is required for growth factor–induced integrin activation, cytoskeletal reorganization, and membrane protrusion, thereby affecting OC adhesion, migration, and bone resorption. The small GTPases Rho and Rac mediate cytoskeletal reorganization, and activation of each is defective in OC precursors lacking a functional β3 subunit. Activation of the upstream mediators c-Src and c-Cbl is also dependent on β3. Interestingly, although the FAK-related kinase Pyk2 interacts with c-Src and c-Cbl, its activation is not disrupted in the absence of functional β3. Instead, its activation is dependent upon intracellular calcium, and on the β2 integrin. Thus, the β3 cytoplasmic domain is responsible for activation of specific intracellular signals leading to cytoskeletal reorganization critical for OC function.
Microtubules are the only structural constituent of the spindle apparatus required for induction of cell cleavage
Authors: Alsop G. Bradley , Zhang Dahong
Published: August 2003

Structural constituents of the spindle apparatus essential for cleavage induction remain undefined. Findings from various cell types using different approaches suggest the importance of all structural constituents, including asters, the central spindle, and chromosomes. In this study, we systematically dissected the role of each constituent in cleavage induction in grasshopper spermatocytes and narrowed the essential one down to bundled microtubules. Using micromanipulation, we produced “cells” containing only asters, a truncated central spindle lacking both asters and chromosomes, or microtubules alone. We show that furrow induction occurs under all circumstances, so long as sufficient microtubules are present. Microtubules, as the only spindle structural constituent, undergo dramatic, stage-specific reorganizations, radiating toward cell cortex in “metaphase,” disassembling in “anaphase,” and bundling into arrays in “telophase.” Furrow induction usually occurs at multisites around microtubule bundles, but only those induced by sustained bundles ingress. We suggest that microtubules, regardless of source, are the only structural constituent of the spindle apparatus essential for cleavage furrow induction.
Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes
Authors: Bache Kristi G. , Brech Andreas , Mehlum Anja , Stenmark Harald
Published: August 2003

Hrs and the endosomal sorting complexes required for transport, ESCRT-I, -II, and -III, are involved in the endosomal sorting of membrane proteins into multivesicular bodies and lysosomes or vacuoles. The ESCRT complexes are also required for formation of intraluminal endosomal vesicles and for budding of certain enveloped RNA viruses such as HIV. Here, we show that Hrs binds to the ESCRT-I subunit Tsg101 via a PSAP motif that is conserved in Tsg101-binding viral proteins. Depletion of Hrs causes a reduction in membrane-associated ESCRT-I subunits, a decreased number of multivesicular bodies and an increased size of late endosomes. Even though Hrs mainly localizes to early endosomes and Tsg101 to late endosomes, the two proteins colocalize on a subpopulation of endosomes that contain lyso-bisphosphatidic acid. Overexpression of Hrs causes accumulation of Tsg101 on early endosomes and prevents its localization to late endosomes. We conclude that Hrs mediates the initial recruitment of ESCRT-I to endosomes and, thereby, indirectly regulates multivesicular body formation.
Vps27 recruits ESCRT machinery to endosomes during MVB sorting
Authors: Katzmann David J. , Stefan Christopher J. , Babst Markus , Emr Scott D.
Published: August 2003

Down-regulation (degradation) of cell surface proteins within the lysosomal lumen depends on the function of the multivesicular body (MVB) sorting pathway. The function of this pathway requires the class E vacuolar protein sorting (Vps) proteins. Of the class E Vps proteins, both the ESCRT-I complex (composed of the class E proteins Vps23, 28, and 37) and Vps27 (mammalian hepatocyte receptor tyrosine kinase substrate, Hrs) have been shown to interact with ubiquitin, a signal for entry into the MVB pathway. We demonstrate that activation of the MVB sorting reaction is dictated largely through interactions between Vps27 and the endosomally enriched lipid species phosphatidylinositol 3-phosphate via the FYVE domain (Fab1, YGL023, Vps27, and EEA1) of Vps27. ESCRT-I then physically binds to Vps27 on endosomal membranes via a domain within the COOH terminus of Vps27. A peptide sequence in this domain, PTVP, is involved in the function of Vps27 in the MVB pathway, the efficient endosomal recruitment of ESCRT-I, and is related to a motif in HIV-1 Gag protein that is capable of interacting with Tsg101, the mammalian homologue of Vps23. We propose that compartmental specificity for the MVB sorting reaction is the result of interactions of Vps27 with phosphatidylinositol 3-phosphate and ubiquitin. Vps27 subsequently recruits/activates ESCRT-I on endosomes, thereby facilitating sorting of ubiquitinated MVB cargoes.
HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein
Authors: Pornillos Owen , Higginson Daniel S. , Stray Kirsten M. , Fisher Robert D. , Garrus Jennifer E. , Payne Marielle , He Gong-Ping , Wang Hubert E. , Morham Scott G. , Sundquist Wesley I.
Published: August 2003

The HIV-1 Gag protein recruits the cellular factor Tsg101 to facilitate the final stages of virus budding. A conserved P(S/T)AP tetrapeptide motif within Gag (the “late domain”) binds directly to the NH2-terminal ubiquitin E2 variant (UEV) domain of Tsg101. In the cell, Tsg101 is required for biogenesis of vesicles that bud into the lumen of late endosomal compartments called multivesicular bodies (MVBs). However, the mechanism by which Tsg101 is recruited from the cytoplasm onto the endosomal membrane has not been known. Now, we report that Tsg101 binds the COOH-terminal region of the endosomal protein hepatocyte growth factor–regulated tyrosine kinase substrate (Hrs; residues 222–777). This interaction is mediated, in part, by binding of the Tsg101 UEV domain to the Hrs 348PSAP351 motif. Importantly, Hrs222–777 can recruit Tsg101 and rescue the budding of virus-like Gag particles that are missing native late domains. These observations indicate that Hrs normally functions to recruit Tsg101 to the endosomal membrane. HIV-1 Gag apparently mimics this Hrs activity, and thereby usurps Tsg101 and other components of the MVB vesicle fission machinery to facilitate viral budding.
A mutant heterodimeric myosin with one inactive head generates maximal displacement
Authors: Kad Neil M. , Rovner Arthur S. , Fagnant Patricia M. , Joel Peteranne B. , Kennedy Guy G. , Patlak Joseph B. , Warshaw David M. , Trybus Kathleen M.
Published: August 2003

Each of the heads of the motor protein myosin II is capable of supporting motion. A previous report showed that double-headed myosin generates twice the displacement of single-headed myosin (Tyska, M.J., D.E. Dupuis, W.H. Guilford, J.B. Patlak, G.S. Waller, K.M. Trybus, D.M. Warshaw, and S. Lowey. 1999. Proc. Natl. Acad. Sci. USA. 96:4402–4407). To determine the role of the second head, we expressed a smooth muscle heterodimeric heavy meromyosin (HMM) with one wild-type head, and the other locked in a weak actin-binding state by introducing a point mutation in switch II (E470A). Homodimeric E470A HMM did not support in vitro motility, and only slowly hydrolyzed MgATP. Optical trap measurements revealed that the heterodimer generated unitary displacements of 10.4 nm, strikingly similar to wild-type HMM (10.2 nm) and approximately twice that of single-headed subfragment-1 (4.4 nm). These data show that a double-headed molecule can achieve a working stroke of ∼10 nm with only one active head and an inactive weak-binding partner. We propose that the second head optimizes the orientation and/or stabilizes the structure of the motion-generating head, thereby resulting in maximum displacement.
Peroxisome Proliferator–activated Receptors α and γ Down-regulate Allergic Inflammation and Eosinophil Activation
Authors: Woerly Gaetane , Honda Kohei , Loyens Marc , Papin Jean-Paul , Auwerx Johan , Staels Bart , Capron Monique , Dombrowicz David
Published: August 2003

Allergic asthma is characterized by airway hyperresponsiveness, eosinophilia, and mucus accumulation and is associated with increased IgE concentrations. We demonstrate here that peroxisome proliferator–activated receptors (PPARs), PPAR-α and PPAR-γ, which have been shown recently to be involved in the regulation of various cell types within the immune system, decrease antigen-induced airway hyperresponsiveness, lung inflammation, eosinophilia, cytokine production, and GATA-3 expression as well as serum levels of antigen-specific IgE in a murine model of human asthma. In addition, we demonstrate that PPAR-α and -γ are expressed in eosinophils and their activation inhibits in vitro chemotaxis and antibody-dependent cellular cytotoxicity. Thus, PPAR-α and -γ (co)agonists might be of therapeutic interest for the regulation of allergic or inflammatory reactions by targeting both regulatory and effector cells involved in the immune response.
A Conduit System Distributes Chemokines and Small Blood-borne Molecules through the Splenic White Pulp
Authors: Nolte Martijn A. , Beliën Jeroen A.M. , Schadee-Eestermans Inge , Jansen Wendy , Unger Wendy W.J. , van Rooijen Nico , Kraal Georg , Mebius Reina E.
Published: August 2003

Access to the splenic white pulp is restricted to lymphocytes and dendritic cells. Here we show that movement of molecules from the blood into these confined areas is also limited. Large molecules, such as bovine serum albumin (68 kD), immunoglobulin G (150 kD), and 500 kD dextran are unable to enter the white pulp, whereas smaller blood-borne molecules can directly permeate this compartment. The distribution is restricted to a stromal network that we refer to as the splenic conduit system. The small lumen of the conduit contains collagen fibers and is surrounded in the T cell areas by reticular fibroblasts that express ER-TR7. It also contains the chemokine CCL21. Conversely, in B cell follicles the B cell–attracting chemokine CXCL13 was found to be associated with the conduit and absence of ER-TR7+ fibroblasts. These results show heterogeneity of reticular fibroblasts that enfold the conduit system and suggest that locally produced chemokines are transported through and presented on this reticular network. Therefore, the conduit plays a role in distribution of both blood-borne and locally produced molecules and provides a framework for directing lymphocyte migration and organization of the splenic white pulp.
Toll-like Receptor 9–mediated Recognition of Herpes Simplex Virus-2 by Plasmacytoid Dendritic Cells
Authors: Lund Jennifer , Sato Ayuko , Akira Shizuo , Medzhitov Ruslan , Iwasaki Akiko
Published: August 2003

Plasmacytoid dendritic cells (pDCs) have been identified as a potent secretor of the type I interferons (IFNs) in response to CpG as well as several viruses. In this study, we examined the molecular mechanism of virus recognition by pDCs. First, we demonstrated that the CD11c+Gr-1intB220+ pDCs from mouse bone marrow secreted high levels of IFN-α in response to either live or UV-inactivated Herpes simplex virus-2 (HSV-2). Next, we identified that IFN-α secretion by pDCs required the expression of the adaptor molecule MyD88, suggesting the involvement of a Toll-like receptor (TLR) in HSV-2 recognition. To test whether a TLR mediates HSV-2–induced IFN-α secretion from pDCs, various knockout mice were examined. These experiments revealed a clear requirement for TLR9 in this process. Further, we demonstrated that purified HSV-2 DNA can trigger IFN-α secretion from pDCs and that inhibitory CpG oligonucleotide treatment diminished HSV-induced IFN-α secretion by pDCs in a dose-dependent manner. The recognition of HSV-2 by TLR9 was mediated through an endocytic pathway that was inhibited by chloroquine or bafilomycin A1. The strict requirement for TLR9 in IFN-α secretion was further confirmed by the inoculation of HSV-2 in vivo. Therefore, these results demonstrate a novel mechanism whereby the genomic DNA of a virus can engage TLR9 and result in the secretion of IFN-α by pDCs.
Differentiation of Effector/Memory Vδ2 T Cells and Migratory Routes in Lymph Nodes or Inflammatory Sites
Authors: Dieli Francesco , Poccia Fabrizio , Lipp Martin , Sireci Guido , Caccamo Nadia , Di Sano Caterina , Salerno Alfredo
Published: August 2003

Vδ2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and mount both immediate effector functions and memory responses after microbial infection. However, how Vδ2 T cells mediate different facets of a memory response remains unknown. Here, we show that the expression of CD45RA and CD27 antigens defines four subsets of human Vδ2 T cells with distinctive compartmentalization routes. Naive CD45RA+CD27+ and memory CD45RA−CD27+ cells express lymph node homing receptors, abound in lymph nodes, and lack immediate effector functions. Conversely, memory CD45RA−CD27− and terminally differentiated CD45RA+CD27− cells, which express receptors for homing to inflamed tissues, are poorly represented in the lymph nodes while abounding at sites of inflammation, and display immediate effector functions. These observations and additional in vitro experiments indicate a lineage differentiation pattern for human Vδ2 T cells that generates naive cells circulating in lymph nodes, effector/memory cells patrolling the blood, and terminally differentiated effector cells residing in inflamed tissues.
γδ T Cells Provide an Early Source of Interferon γ in Tumor Immunity
Authors: Gao Yunfei , Yang Wancai , Pan Meng , Scully Eileen , Girardi Michael , Augenlicht Leonard H. , Craft Joe , Yin Zhinan
Published: August 2003

Interferon (IFN)-γ is necessary for tumor immunity, however, its initial cellular source is unknown. Because γδ T cells primarily produce this cytokine upon activation, we hypothesized that they would provide an important early source of IFN-γ in tumor immunosurveillance. To address this hypothesis, we first demonstrated that γδ T cell–deficient mice had a significantly higher incidence of tumor development after challenge with a chemical carcinogen methylcholanthrene (MCA) or inoculation with the melanoma cell line B16. In wild-type mice, γδ T cells were recruited to the site of tumor as early as day 3 after inoculation, followed by αβ T cells at day 5. We then used bone marrow chimeras and fetal liver reconstitutions to create mice with an intact γδ T cell repertoire but one that was specifically deficient in the capacity to produce IFN-γ. Such mice had a higher incidence of tumor development, induced either with MCA or by inoculation of B16 melanoma cells, compared with mice with IFN-γ–competent γδ T cells. Moreover, genetic deficiency of γδ T cells resulted in impaired IFN-γ production by tumor antigen-triggered αβ T cell upon immunization with tumor lysate. These results demonstrate that γδ T cells can play a necessary role in tumor immunity through provision of an early source of IFN-γ that in turn may regulate the function of tumor-triggered αβ T cells.
A Philosophy of Science for the Twenty-First Century
Authors: Kourany Janet A.
Published: August 2003

Two major reasons feminists are concerned with science relate to science's social effects: that science can be a powerful ally in the struggle for equality for women; and that all too frequently science has been a generator and perpetuator of inequality. This concern with the social effects of science leads feminists to a different mode of appraising science from the purely epistemic one prized by most contemporary philosophers of science. The upshot, I suggest, is a new program for philosophy of science, a program for a socially responsible philosophy of science.
A New Program for Philosophy of Science?
Authors: Giere Ronald N.
Published: August 2003

I contend that Janet Kourany's “A Philosophy of Science for the Twenty-First Century” contains three levels of projects: (1) a naturalistic project, (2) a critical project, and (3) a political project. The naturalistic project is already well established. The critical project is less valued and less established within the profession, but seems a worthy and achievable goal. The political project, I argue, takes one outside the professional pursuit of the philosophy of science. The critical project encompasses both the evaluation of scientific research programs and of empirical conclusions. I contend that the former is widely acknowledged as legitimate while the latter is unacceptable.
Reply to Giere
Authors: Kourany Janet A.
Published: August 2003

In his “A New Program for Philosophy of Science?”, Ronald Giere expresses qualms regarding the critical and political projects I advocate for philosophy of science—that the critical project assumes an underdetermination absent from actual science, and the political project takes us outside the professional pursuit of philosophy of science. In reply I contend that the underdetermination the critical project assumes does occur in actual science, and I provide a variety of examples to support this. And I contend that the political project requires no more than what other academic fields even in science studies are already providing.
The Evolution of Altruism: The Sober/Wilson Model
Authors: Gildenhuys Peter
Published: August 2003

In what follows, I critique the interpretation that Sober and Wilson offer of their group selection model in Unto Others. Sober and Wilson mistakenly claim that their model operates as an example of Simpson's paradox and defend an interpretation of their model according to which groups are operated upon by natural selection. In the place of their interpretation, I offer one that parallels the mathematical calculation of the model's outcome and does not depend on the postulation of a force of group selection or a value for group fitness.
Discussion: Species Are Individuals—Or Are They?
Authors: Reydon Thomas A. C.
Published: August 2003

Recently Coleman and Wiley presented a new defense of the species-are-individuals thesis, based on an analysis of the use of binomial species names by biologists. Here I point out some problems in their defense and I argue that although in some domains of biological science species are best understood as individuals, Coleman and Wiley fail to establish that this is true for the whole of biology.
Is the World Really “Dappled”? A Response to Cartwright's Charge against “Cross-Wise Reduction”
Authors: Ruphy Stéphanie
Published: August 2003

Nancy Cartwright's charge against horizontal reductionism leads to a claim about how the world is, namely “dappled.” By proposing a simple thought-experiment, I show that Cartwright's division of the world into “nomological” machines and “messy” systems for which no law applies is meaningless. The thought-experiment shows that for a system, having the property of being a nomological machine depends on what kind of questions you ask about it. No metaphysical conclusion about the world being unruly or not can be drawn from a division that is question-dependent. Moreover, I argue that this predicament undermines Cartwright's attempt to provide an illustration of how bad metaphysics of science translates into bad scientific methodologies and policies.
Fodor on Cognition, Modularity, and Adaptationism
Authors: Okasha Samir
Published: August 2003

This paper critically examines Jerry Fodor's latest attacks on evolutionary psychology. Contra Leda Cosmides and John Tooby, Fodor argues (i) there is no reason to think that human cognition is a Darwinian adaptation in the first place, and (ii) there is no valid inference from adaptationism about the mind to massive modularity. However, Fodor maintains (iii) that there is a valid inference in the converse direction, from modularity to adaptationism, but (iv) that the language module is an exception to the validity of this inference. I explore Fodor's arguments for each of these claims, and the interrelations between them. I argue that Fodor is incorrect on point (i), correct on point (ii), partially correct on point (iii), and incorrect on point (iv). Overall, his critique fails to show that adopting a broadly Darwinian approach to cognition is intellectually indefensible.
Systems of Visual Identification in Neuroscience: Lessons from Epistemic Logic
Authors: Hintikka Jaakko , Symons John
Published: August 2003

The following analysis shows how developments in epistemic logic can play a nontrivial role in cognitive neuroscience. We argue that the striking correspondence between two modes of identification, as distinguished in the epistemic context, and two cognitive systems distinguished by neuroscientific investigation of the visual system (the “where” and “what” systems) is not coincidental, and that it can play a clarificatory role at the most fundamental levels of neuroscientific theory.
Simulated Experiments: Methodology for a Virtual World
Authors: Winsberg Eric
Published: August 2003

This paper examines the relationship between simulation and experiment. Many discussions of simulation, and indeed the term “numerical experiments,” invoke a strong metaphor of experimentation. On the other hand, many simulations begin as attempts to apply scientific theories. This has lead many to characterize simulation as lying between theory and experiment. The aim of the paper is to try to reconcile these two points of view—to understand what methodological and epistemological features simulation has in common with experimentation, while at the same time keeping a keen eye on simulation's ancestry as a form of scientific theorizing. In so doing, it seeks to apply some of the insights of recent work on the philosophy of experiment to an aspect of theorizing that is of growing philosophical interest: the construction of local models.
Foundations of Statistical Mechanics—Two Approaches
Authors: Leeds Stephen
Published: August 2003

This paper is a discussion of David Albert's approach to the foundations of classical statistical menchanics. I point out a respect in which his account makes a stronger claim about the statistical mechanical probabilities than is usually made, and I suggest what might be motivation for this. I outline a less radical approach, which I attribute to Boltzmann, and I give some reasons for thinking that this approach is all we need, and also the most we are likely to get. The issue between the two accounts turns out to be one about the explanatory role probabilities play in statistical mechanics.
Fulling Non-uniqueness and the Unruh Effect: A Primer on Some Aspects of Quantum Field Theory
Authors: Arageorgis Aristidis , Earman John , Ruetsche Laura
Published: August 2003

We discuss the intertwined topics of Fulling non-uniqueness and the Unruh effect. The Fulling quantization, which is in some sense the natural one for an observer uniformly accelerated through Minkowski spacetime to adopt, is often heralded as a quantization of the Klein-Gordon field which is both physically relevant and unitarily inequivalent to the standard Minkowski quantization. We argue that the Fulling and Minkowski quantizations do not constitute a satisfactory example of physically relevant, unitarily inequivalent quantizations, and indicate what it would take to settle the open question of whether a satisfactory example exists. A popular gloss on the Unruh effect has it that an observer uniformly accelerated through the Minkowski vacuum experiences a thermal flux of Rindler quanta. Taking the Unruh effect, so glossed, to establish that the notion of particle must be relativized to a reference frame, some would use it to demote the particle concept from fundamental status. We explain why technical results do not support the popular gloss and why the attempted demotion of the particle concept is both unsuccessful and unnecessary. Fulling non-uniqueness and the Unruh effect merit attention despite these negative verdicts because they provide excellent vehicles for illustrating key concepts of quantum field theory and for probing foundational issues of considerable philosophical interest.
Two Theorems on Invariance and Causality
Authors: Cartwright Nancy
Published: August 2003

In much recent work, invariance under intervention has become a hallmark of the correctness of a causal-law claim. Despite its importance this thesis generally is either simply assumed or is supported by very general arguments with heavy reliance on examples, and crucial notions involved are characterized only loosely. Yet for both philosophical analysis and practicing science, it is important to get clear about whether invariance under intervention is or is not necessary or sufficient for which kinds of causal claims. Furthermore, we need to know what counts as an intervention and what invariance is. In this paper I offer explicit definitions of two different kinds for the notions intervention, invariance, and causal correctness. Then, given some natural and relatively uncontroversial assumptions, I prove two distinct sets of theorems showing that invariance is indeed a mark of causality when the concepts are appropriately interpreted.
Bayesianism, Quo Vadis? —Critical Notice: David Corfield and Jon Williamson (eds.), Foundations of Bayesianism
Authors: Risse Mathias
Published: August 2003

This is a review essay about David Corfield and Jon Williamson's anthology Foundations of Bayesianism. Taken together, the fifteen essays assembled in the book assess the state of the art in Bayesianism. Such an assessment is timely, because decision theory and formal epistemology have become disciplines that are no longer taught on a routine basis in good philosophy departments. Thus we need to ask: Quo vadis, Bayesianism? The subjects of the articles include Bayesian group decision theory, approaches to the concept of probability, Bayesian approaches in the philosophy of mathematics, reflections on the relationship between causation and probability, the Independence axiom, and a range of criticisms of Bayesianism, among other subjects. While critical of some of the arguments presented in the articles, this review recommends Corfield and Williamson's volume to anyone who is trying to stay abreast of Bayesian research.
Pathways to Biomedical Discovery
Authors: Thagard Paul
Published: August 2003

A biochemical pathway is a sequence of chemical reactions in a biological organism. Such pathways specify mechanisms that explain how cells carry out their major functions by means of molecules and reactions that produce regular changes. Many diseases can be explained by defects in pathways, and new treatments often involve finding drugs that correct those defects. This paper presents explanation schemas and treatment strategies that characterize how thinking about pathways contributes to biomedical discovery. It discusses the significance of pathways for understanding the nature of diseases, explanations, and theories.
Last Will and Testament: Stephen Jay Gould's The Structure of Evolutionary Theory
Authors: Sterelny Kim
Published: August 2003

I outline Gould's conception of evolutionary theory and his ways of contrasting it with contemporary Darwinism; a contemporary Darwinism that focuses on the natural selection of individual organisms. Gould argues for a hierarchical conception of the living world and of the evolutionary processes that have built that living world: organisms are built from smaller components (genes, cells) and are themselves components of groups, populations, species, lineages. Selection, drift and constraint are important to all of these levels of biological organization, not just that of individual organisms. Moreover, both drift and constraint are more important than orthodoxy supposes. While having some sympathy for both of these lines of argument, I argue that they are more problematic than Gould supposes, and that he understates the power and the heterogeneity of orthodox conceptions of life's evolution.
Character Individuation in Phylogenetic Inference
Authors: Richards Richard
Published: August 2003

Ontological questions in biology have typically focused on the nature of species: what are species; how are they identified and individuated? There is an analogous, but much neglected concern: what are characters; how are they identified and individuated? Character individuation is significant because biological systematics relies on a parsimony principle to determine phylogeny and classify taxa, and the parsimony principle is usually interpreted to favor the phylogenetic hypothesis that requires the fewest changes in characters. But no character individuation principle identified so far is adequate. For biological systematics we need a better way of conceiving characters.
Fit and Diversity: Explaining Adaptive Evolution
Authors: Walsh Denis M.
Published: August 2003

According to a prominent view of evolutionary theory, natural selection and the processes of development compete for explanatory relevance. Natural selection theory explains the evolution of biological form insofar as it is adaptive. Development is relevant to the explanation of form only insofar as it constrains the adaptation-promoting effects of selection. I argue that this view of evolutionary theory is erroneous. I outline an alternative, according to which natural selection explains adaptive evolution by appeal to the statistical structure of populations, and development explains the causes of adaptive evolution at the level of individuals. Only together can a statistical theory of selection and a mechanical theory of development explain why populations of organisms comprise individuals that are adapted to their conditions of existence.
Effective Complexity as a Measure of Information Content
Authors: McAllister James W.
Published: August 2003

Murray Gell-Mann has proposed the concept of effective complexity as a measure of information content. The effective complexity of a string of digits is defined as the algorithmic complexity of the regular component of the string. This paper argues that the effective complexity of a given string is not uniquely determined. The effective complexity of a string admitting a physical interpretation, such as an empirical data set, depends on the cognitive and practical interests of investigators. The effective complexity of a string as a purely formal construct, lacking a physical interpretation, is either close to zero, or equal to the string's algorithmic complexity, or arbitrary, depending on the auxiliary criterion chosen to pick out the regular component of the string. Because of this flaw, the concept of effective complexity is unsuitable as a measure of information content.
How to Design Galilean Fall Experiments in Economics
Authors: Boumans Marcel
Published: August 2003

In the social sciences we hardly can create laboratory conditions, we only can try to find out which kinds of experiments Nature has carried out. Knowledge about Nature's designs can be used to infer conditions for reliable predictions. This problem was explicitly dealt with in Haavelmo's (1944) discussion of autonomous relationships, Friedman's (1953) as-if methodology, and Simon's (1961) discussions of nearly-decomposable systems. All three accounts take Marshallian partitioning as starting point, however not with a sharp ceteris paribus razor but with the blunt knife of negligibility assumptions. As will be shown, in each account reflection on which influences are negligible, for what phenomena and for how long, played a central role.
Quantum Decoherence and the Approach to Equilibrium
Authors: Hemmo Meir , Shenker Orly
Published: August 2003

We discuss a recent proposal by Albert (1994a; 1994b; 2000, ch. 7) to recover thermodynamics on a purely dynamical basis, using the quantum theory of the collapse of the wave function by Ghirardi, Rimini, and Weber (1986). We propose an alternative way to explain thermodynamics within no-collapse interpretations of quantum mechanics. Our approach relies on the standard quantum mechanical models of environmental decoherence of open systems (e.g., Joos and Zeh 1985; Zurek and Paz 1994). This paper presents the two approaches and discusses their advantages. The problems faced by both approaches will be discussed in a sequel (Hemmo and Shenker 2003).
Undecidability inRn: Riddled Basins, the KAM Tori, and the Stability of the Solar System
Authors: Parker Matthew W.
Published: August 2003

Some have suggested that certain classical physical systems have undecidable long-term behavior, without specifying an appropriate notion of decidability over the reals. We introduce such a notion,decidability in μ(or d-μ) for any measureμ,which is particularly appropriate for physics and in some ways more intuitive than Ko's (1991)recursive approximability(r.a.). For Lebesgue measureλ,d-λimplies r.a. Sets with positiveλ-measure that are sufficiently “riddled” with holes are never d-λbut are often r.a. This explicates Sommerer and Ott's (1996) claim of uncomputable behavior in a system with riddled basins of attraction. Furthermore, it clarifies speculations that the stability of the solar system (and similar systems) may be undecidable, for the invariant tori established by KAM theory form sets that are not d-λ.
The Philosophy of Chemistry Reformulating Itself: Nalni Bhushan and Stuart Rosenfeld's Of Minds and Molecules: New Philosophical Perspectives on Chemistry
Authors: Vollmer S.H.
Published: August 2003

Philosophers of chemistry, following the lead of physicists, have been slow to realize that molecular descriptions issuing from quantum mechanics in the absence of chemical theory are fatally flawed. In the wake of this realization, new topics have begun to unfold—including new metaphysical issues, new concerns about the philosophy of chemistry's place in the philosophy of science, and new accounts of how properties are observed, inferred, and presented. A recent collection of essays, Of Minds and Molecules: New Philosophical Perspectives on Chemistry edited by Nalini Bhushan and Stuart Rosenfeld, reveals what some of these new issues are and suggests new directions for the philosophy of chemistry.
Response to Vollmer's Review of Minds and Molecules
Authors: Scerri Eric
Published: August 2003

I present a response to Vollmer's review of the book Of Minds and Molecules, and especially her comments on my own article therein. This provides an opportunity to discuss two central ideas in the philosophy of chemistry. These are the distinction between elements as simple substances (element-1) and elements as basic substances (element-2) and Paneth's proposed intermediate position for philosophy of chemistry. The response also discusses the question of isotopes in relationship to the nature of the elements and their classification as well as the philosophical status of atomic orbitals.
A Bayesian Account of the Virtue of Unification
Authors: Myrvold Wayne C.
Published: August 2003

A Bayesian account of the virtue of unification is given. On this account, the ability of a theory to unify disparate phenomena consists in the ability of the theory to render such phenomena informationally relevant to each other. It is shown that such ability contributes to the evidential support of the theory, and hence that preference for theories that unify the phenomena need not, on a Bayesian account, be built into the prior probabilities of theories.
Dappled Theories in a Uniform World
Authors: Sklar Lawrence
Published: August 2003

It has been argued, most trenchantly by Nancy Cartwright, that the diversity of the concepts and regularities we actually use to describe nature and predict and explain its behavior leaves us with no reason to believe that our foundational physical theories actually “apply” outside of delicately contrived systems within the laboratory. This paper argues that, diversity of method notwithstanding, there is indeed good reason to think that the foundational laws of physics are universal in their scope.
Transcription from an upstream promoter controls methylation signaling from an inverted repeat of endogenous genes inArabidopsis
Authors: Melquist Stacey , Bender Judith
Published: August 2003

In plants, replication of RNAviruses and RNAfrom highly transcribed transgenes can trigger DNA methylation. These systems accumulate diced small RNA(smRNA) products of double-stranded RNA(dsRNA) precursors, but it is not known which RNAspecies directs methylation. The methylatedPAItryptophan biosynthetic genes inArabidopsisallow the study of methylation signals for endogenous genes with lower expression levels. ThePAIgenes are arranged as a tandem inverted repeat plus two singlet genes at unlinked loci. Here we show that the predominantPAItranscript initiates at a novel unmethylated promoter that lies upstream of one of the inverted repeatPAIgenes. Suppressed transcription from the upstream promoter using transgene-directed silencing reduces methylation on the singletPAIgenes, but not on the inverted repeat, consistent with an RNAmethylation signal. RNAgel blots detect normalPAItranscripts and dsRNA read-through species, but not diced smRNAs, suggesting that either precursor dsRNAs or subdetectable levels of smRNAs, below the threshold to effectively degradePAItranscripts, serve as thePAImethylation signal. Thus, the lower expression endogenous gene system allows dissection of a RNA-directed methylation pathway distinct from RNA degradation pathways.
Control of cell number byDrosophilaFOXO: downstream and feedback regulation of the insulin receptor pathway
Authors: Puig Oscar , Marr Michael T. , Ruhf M. Laure , Tjian Robert
Published: August 2003

TheDrosophilainsulin receptor (dInR) regulates cell growth and proliferation through the dPI3K/dAkt pathway, which is conserved in metazoan organisms. Here we report the identification and functional characterization of theDrosophilaforkhead-related transcription factor dFOXO, a key component of the insulin signaling cascade. dFOXO is phosphorylated by dAkt upon insulin treatment, leading to cytoplasmic retention and inhibition of its transcriptional activity. Mutant dFOXO lacking dAkt phosphorylation sites no longer responds to insulin inhibition, remains in the nucleus, and is constitutively active. dFOXO activation in S2 cells induces growth arrest and activates two key players of the dInR/dPI3K/dAkt pathway: the translational regulator d4EBP and the dInR itself. Induction of d4EBP likely leads to growth inhibition by dFOXO, whereas activation of dInR provides a novel transcriptionally induced feedback control mechanism. Targeted expression of dFOXO in fly tissues regulates organ size by specifying cell number with no effect on cell size. Our results establish dFOXO as a key transcriptional regulator of the insulin pathway that modulates growth and proliferation.
Mechanism of p38 MAP kinase activation in vivo
Authors: Brancho Deborah , Tanaka Nobuyuki , Jaeschke Anja , Ventura Juan-Jose , Kelkar Nyaya , Tanaka Yoshinori , Kyuuma Masanao , Takeshita Toshikazu , Flavell Richard A. , Davis Roger J.
Published: August 2003

The p38 mitogen-activated protein kinase (MAPK) is activated in vitro by three different protein kinases: MKK3, MKK4, and MKK6. To examine the relative roles of these protein kinases in the mechanism of p38 MAP kinase activation in vivo, we examined the effect of disruption of the murineMkk3, Mkk4, andMkk6genes on the p38 MAPK signaling pathway. We show that MKK3 and MKK6are essential for tumor necrosis factor-stimulated p38 MAPK activation. In contrast, ultraviolet radiation-stimulated p38 MAPK activation was mediated by MKK3, MKK4, and MKK6. Loss of p38 MAPK activation in the mutant cells was associated with defects in growth arrest and increased tumorigenesis. These data indicate that p38 MAPK is regulated by the coordinated and selective actions of three different protein kinases in response to cytokines and exposure to environmental stress.
Public private partnerships: an introduction
Authors: Broadbent Jane , Laughlin Richard
Published: August 2003

Public private partnerships (PPPs) are a recent extension of what has now become well known as the “new public management” agenda for changes in the way public services are provided. PPPs involve organisations whose affiliations lie in respectively the public and private sectors working together in partnership to provide public services. This special issue of the Accounting, Auditing & Accountability Journal explores this new development, which, in its most advanced form, is contained in the UK’s Private Finance Initiative (PFI) but is now spreading across the world in multiple forms. This introduction provides an overview of this development as well as an outline of the seven papers that make up this special issue. These seven papers are divided into two parts – the first four looking at different aspects of PFI and the latter three providing three country‐based (from the USA, New Zealand and Australia) studies of PFI/PPP. Many questions about the nature, regulation, pre‐decision analysis and post‐project evaluation are addressed in these papers but many research questions remain unanswered, as this Introduction makes plain.