bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid changes in life-history characteristics of a long-lived temperate reef fish
Authors: Ziegler Philippe E. , Lyle Jeremy M. , Haddon Malcolm , Ewing Graeme P.
Published: December 2007

Banded morwong, Cheilodactylus spectabilis, a long-lived sedentary temperate reef fish, has undergone rapid changes in its growth and maturity characteristics along the east coast of Tasmania, Australia. Over a period of 10 years, growth of young males and females has consistently accelerated, such that in 2005, 3-year-old fish were up to 40 mm or 13% longer compared with 1996, and age at 50% maturity for females had declined from 4 to 3 years. The magnitude and speed of the observed changes were unexpected given the species’ longevity (maximum age of over 95 years). The underlying mechanisms for the changes remain unclear but density-dependent responses to changes in population size and age composition, possibly mediated through reduced competition for shelter and intra-specific interactions, may have been contributing factors. Increasing sea surface temperatures over part of the period of change does not appear to have been a major driver and a genetic response to fishing seems unlikely. Notwithstanding any uncertainty, C. spectabilis populations have become more productive in recent years, challenging the general approach towards stock assessment where life-history characteristics are assumed to remain stable across contrasting levels of stock abundance and environmental conditions.
Towards a unique and transmissible vaccine against myxomatosis and rabbit haemorrhagic disease for rabbit populations
Authors: Angulo Elena , Bárcena Juan
Published: December 2007

Currently available vaccines against myxomatosis and rabbit hemorrhagic disease virus (RHDV) are not suited to immunise wild rabbit populations, as vaccines need to be delivered individually by conventional veterinary practices. As an alternative approach, research in Spain has focused on the development of a transmissible vaccine. A recombinant virus has been constructed based on a naturally attenuated myxoma virus (MV) field strain, expressing the RHDV capsid protein (VP60). Following inoculation of rabbits, the recombinant virus (MV-VP60) induced specific antibody responses against MV and RHDV, conferring protection against lethal challenges with both viruses. Furthermore, the recombinant MV-VP60 virus showed a limited horizontal transmission capacity, either by direct contact or in a flea-mediated process, promoting immunisation of contact uninoculated animals. Efficacy and safety of the vaccine have been extensively evaluated under laboratory conditions and in a limited field trial. The development of the transmissible vaccine strategy and the steps being taken to obtain the marketing authorisation for the vaccine in the European Union are presented in this review.
Prospects for fertility control in the European rabbit (Oryctolagus cuniculus) using myxoma virus-vectored immunocontraception
Authors: van Leeuwen B. H. , Kerr P. J.
Published: December 2007

Research over the last 15 years has examined whether fertility control can reduce overabundant rabbit populations and whether an effective immunocontraceptive agent can be developed and delivered. The results of this research indicate that for fertility control to have an environmental impact at least 80% of females will need to be infertile and that this infertility will need to be permanent. Epidemiological studies suggest that this level of infertility may be very difficult to obtain with a recombinant myxoma virus because of competition with field strains of virus. Research with laboratory rabbits using recombinant myxoma virus to deliver an immunocontraceptive antigen demonstrated that it was possible to obtain the required level of infertility using rabbit zona pellucida C as an antigen. However, only ~50% of animals remained infertile in the medium term. Further research on delivery vector and antigen selection would be needed to produce a practical immunocontraceptive virus for laboratory testing. Such a virus would then need to be optimised for transmissibility before it would be suitable for field testing.
Pest or prized possession? Genetically modified biocontrol from an international perspective
Authors: Henderson Wendy R. , Murphy Elaine C.
Published: December 2007

This article provides an overview of current research, regulations and international issues concerning genetically modified (GM) organisms for use as biological controls of vertebrates. There is increasing interest in using biotechnology to solve vertebrate pest problems around the world. A major issue lies in the fact that individual countries focusing on internal problems of pest management may overlook the potential of transborder entry. Animals considered a pest in one country may well be prized possessions in another, and research and management strategies should consider the adverse effects of biocontrol agents entering the ‘wrong’ country. There is a wealth of guidance in the form of national and international regulations and ethics guidelines. However, current legislation and agreements may not be adequate to ensure that all risks of GM biocontrols, particularly disseminating agents, have been considered from an international perspective. Major issues include concerns of transboundary movement, non-target effects and the need for an international body to consult with and regulate the use of GM biocontrols. We live in a finite and interconnected world: it is vital that impacts of potential control strategies are assessed at a local and international level, and from social, environmental and economic perspectives.
Replacement of Iγ3 germ-line promoter by Iγ1 inhibits class-switch recombination to IgG3
Authors: Oruc Zeliha , Boumédiène Ahmed , Le Bert Marc , Khamlichi Ahmed Amine
Published: December 2007

Class-switch recombination (CSR) enables IgM-producing B cells to switch to the production of IgG, IgE, and IgA. The process requires germ-line (GL) transcription that initiates from promoters upstream of switch (S) sequences and is regulated by the 3′ regulatory region (3′RR) located downstream of the Ig heavy chain (IgH) locus. How the 3′RR effect its long-range activation is presently unclear. We generated a mouse line in which Iγ3 GL promoter was replaced by Iγ1. We found that GL transcription could initiate from the inserted Iγ1 promoter and was induced by increased concentrations of IL-4 and that the transcripts were normally spliced. However, when compared with GL transcripts derived from the endogenous Iγ1 promoter in the same stimulation conditions, those from the inserted Iγ1 promoter were less abundant. CSR to Cγ3 was abrogated bothin vivoandin vitro. The results strongly suggest that the endogenous Iγ1 promoter insulates the inserted Iγ1 from the long-range activating effect of the 3′RR. The implications of our findings are discussed in light of the prominent models of long-distance activation in complex loci.
Activation mechanism of a noncanonical RNA-dependent RNA polymerase
Authors: Garriga Damià , Navarro Aitor , Querol-Audí Jordi , Abaitua Fernando , Rodríguez José F. , Verdaguer Núria
Published: December 2007

Two lineages of viral RNA-dependent RNA polymerases (RDRPs) differing in the organization (canonical vs. noncanonical) of the palm subdomain have been identified. Phylogenetic analyses indicate that both lineages diverged at a very early stage of the evolution of the enzyme [Gorbalenya AE, Pringle FM, Zeddam JL, Luke BT, Cameron CE, Kalmakoff J, Hanzlik TN, Gordon KH, Ward VK (2002)
J Mol Biol
324:47–62]. Here, we report the x-ray structure of a noncanonical birnaviral RDRP, named VP1, in its free form, bound to Mg
2+
ions, and bound to a peptide representing the polymerase-binding motif of the regulatory viral protein VP3. The structure of VP1 reveals that the noncanonical connectivity of the palm subdomain maintains the geometry of the catalytic residues found in canonical polymerases but results in a partial blocking of the active site cavity. The VP1–VP3 peptide complex shows a mode of polymerase activation in which VP3 binding promotes a conformational change that removes the steric blockade of the VP1 active site, facilitating the accommodation of the template and incoming nucleotides for catalysis. The striking structural similarities between birnavirus (dsRNA) and the positive-stranded RNA picornavirus and calicivirus RDRPs provide evidence supporting the existence of functional and evolutionary relationships between these two virus groups.
Soj (ParA) DNA binding is mediated by conserved arginines and is essential for plasmid segregation
Authors: Hester Christina M. , Lutkenhaus Joe
Published: December 2007

Soj is a member of the ParA family of ATPases involved in plasmid and chromosomal segregation. It binds nonspecifically and cooperatively to DNA although the function of this binding is unknown. Here, we show that mutation of conserved arginine residues that map to the surface of
Bacillus subtilis
Soj caused only minimal effects on nucleotide-dependent dimerization but had dramatic effects on DNA binding. Using a model plasmid partitioning system in
Escherichia coli
, we find that Soj DNA-binding mutants are deficient in plasmid segregation. The location of the arginines on the Soj structure explains why DNA binding depends on dimerization and was used to orient the Soj dimer on the DNA, revealing the axis of Soj polymerization. The arginine residues are conserved among other chromosomal homologues, including the ParAs from
Caulobacter crescentus
,
Pseudomonas aeruginosa
,
Pseudomonas putida
,
Streptomyces coelicolor
, and chromosome I of
Vibrio cholerae
indicating that DNA binding is a common feature of members of this family.
Glass transition and rheological redundancy in F-actin solutions
Authors: Semmrich Christine , Storz Tobias , Glaser Jens , Merkel Rudolf , Bausch Andreas R. , Kroy Klaus
Published: December 2007

The unique mechanical performance of animal cells and tissues is attributed mostly to their internal biopolymer meshworks. Its perplexing universality and robustness against structural modifications by drugs and mutations is an enigma in cell biology and provides formidable challenges to materials science. Recent investigations could pinpoint highly universal patterns in the soft glassy rheology and nonlinear elasticity of cells and reconstituted networks. Here, we report observations of a glass transition in semidilute F-actin solutions, which could hold the key to a unified explanation of these phenomena. Combining suitable rheological protocols with high-precision dynamic light scattering, we can establish a remarkable rheological redundancy and trace it back to a highly universal exponential stretching of the single-polymer relaxation spectrum of a “glassy wormlike chain.” By exploiting the ensuing generalized time-temperature superposition principle, the time domain accessible to microrheometry can be extended by several orders of magnitude, thus opening promising new metrological opportunities.
Individual faces elicit distinct response patterns in human anterior temporal cortex
Authors: Kriegeskorte Nikolaus , Formisano Elia , Sorger Bettina , Goebel Rainer
Published: December 2007

Visual face identification requires distinguishing between thousands of faces we know. This computational feat involves a network of brain regions including the fusiform face area (FFA) and anterior inferotemporal cortex (aIT), whose roles in the process are not well understood. Here, we provide the first demonstration that it is possible to discriminate cortical response patterns elicited by individual face images with high-resolution functional magnetic resonance imaging (fMRI). Response patterns elicited by the face images were distinct in aIT but not in the FFA. Individual-level face information is likely to be present in both regions, but our data suggest that it is more pronounced in aIT. One interpretation is that the FFA detects faces and engages aIT for identification.
Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis
Authors: Ardi Veronica C. , Kupriyanova Tatyana A. , Deryugina Elena I. , Quigley James P.
Published: December 2007

Several lines of evidence have implicated matrix metalloproteinase 9 (MMP-9) as a protease inducing an angiogenic switch critical for tumor progression. Among MMP-9-expressing cell types, including cancer cells and tumor-associated leukocytes, inflammatory neutrophils appear to provide an important source of MMP-9 for tumor angiogenesis. However, delivery of MMP-9 by neutrophils has not been mechanistically linked to its catalytic activity at the angiogenic site. By using a modified angiogenic model, allowing for a direct analysis of exogenously added cells and their products in collagen onplants grafted on the chorioallantoic membrane of the chicken embryo, we demonstrate that intact human neutrophils and their granule contents are highly angiogenic. Furthermore, purified neutrophil MMP-9, isolated from the released granules as a zymogen (proMMP-9), constitutes a distinctly potent proangiogenic moiety inducing angiogenesis at subnanogram levels. The angiogenic response induced by neutrophil proMMP-9 required activation of the tissue inhibitor of metalloproteinases (TIMP)-free zymogen and the catalytic activity of the activated enzyme. That the high angiogenic potency of neutrophil proMMP-9 is associated with its unique TIMP-free status was confirmed when a generated and purified stoichiometric complex of neutrophil proMMP-9 with TIMP-1 failed to induce angiogenesis. Recombinant human proMMP-9, operationally free of TIMP-1, also induced angiogenesis at subnanomolar levels, but lost its proangiogenic potential when stoichiometrically complexed with TIMP-1. Similar proMMP-9/TIMP-1 complexes, but naturally produced by human monocytic U937 cells and HT-1080 fibrosarcoma cells, did not stimulate angiogenesis. These findings provide biochemical evidence that infiltrating neutrophils, in contrast to other cell types, deliver a potent proangiogenic moiety, i.e., the unencumbered TIMP-free MMP-9.
Estimation of multiple transmission rates for epidemics in heterogeneous populations
Authors: Cook Alex R. , Otten Wilfred , Marion Glenn , Gibson Gavin J. , Gilligan Christopher A.
Published: December 2007

One of the principal challenges in epidemiological modeling is to parameterize models with realistic estimates for transmission rates in order to analyze strategies for control and to predict disease outcomes. Using a combination of replicated experiments, Bayesian statistical inference, and stochastic modeling, we introduce and illustrate a strategy to estimate transmission parameters for the spread of infection through a two-phase mosaic, comprising favorable and unfavorable hosts. We focus on epidemics with local dispersal and formulate a spatially explicit, stochastic set of transition probabilities using a percolation paradigm for a susceptible–infected (S–I) epidemiological model. The S–I percolation model is further generalized to allow for multiple sources of infection including external inoculum and host-to-host infection. We fit the model using Bayesian inference and Markov chain Monte Carlo simulation to successive snapshots of damping-off disease spreading through replicated plant populations that differ in relative proportions of favorable and unfavorable hosts and with time-varying rates of transmission. Epidemiologically plausible parametric forms for these transmission rates are compared by using the deviance information criterion. Our results show that there are four transmission rates for a two-phase system, corresponding to each combination of infected donor and susceptible recipient. Knowing the number and magnitudes of the transmission rates allows the dominant pathways for transmission in a heterogeneous population to be identified. Finally, we show how failure to allow for multiple transmission rates can overestimate or underestimate the rate of spread of epidemics in heterogeneous environments, which could lead to marked failure or inefficiency of control strategies.
Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step
Authors: Adermark Louise , Lovinger David M.
Published: December 2007

Endocannabinoids (eCBs) mediate short- and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies have suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it is not known whether this release process occurs automatically upon eCB synthesis or whether it is regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM11 and UCM707, but did not require activation of metabotropic glutamate receptors,
l
-calcium channels, nitric oxide, voltage-activated Na
+
channels, or intracellular calcium. Application of the CB
1
R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB
1
receptor by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. These findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.
MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression
Authors: Lee Daniel Y. , Deng Zhaoqun , Wang Chia-Hui , Yang Burton B.
Published: December 2007

MicroRNAs are single-stranded RNA of 18–24 nt expressed endogenously that play important roles in cancer development. Here, we show that expression of
miR-378
enhances cell survival, reduces caspase-3 activity, and promotes tumor growth and angiogenesis. Proteomic analysis indicates reduced expression of suppressor of fused (Sufu), a potential target of
miR-378
, which was confirmed
in vitro
and
in vivo
. Expression of a luciferase construct containing the target site in Sufu was repressed when cotransfected with
miR-378
. Transfection of a Sufu construct reversed the effect of
miR-378
, suggesting an important role for
miR-378
in tumor cell survival. We also discovered that
miR-378
targets Fus-1. Expression of luciferase constructs harboring the target sites in Fus-1 was repressed by
miR-378
. Fus-1 constructs with or without its 3′ UTR were also generated. Cotransfection experiments showed that the presence of
miR-378
repressed Fus-1 expression. Suppression of Fus-1 expression by siRNA against Fus-1 enhanced cell survival. Transfection of the Fus-1 construct reversed the function of
miR-378
in cell survival. Our results suggest that
miR-378
transfection enhanced cell survival, tumor growth, and angiogenesis through repression of the expression of two tumor suppressors, Sufu and Fus-1.
Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory
Authors: Zhang Ying , Bertolino Alessandro , Fazio Leonardo , Blasi Giuseppe , Rampino Antonio , Romano Raffaella , Lee Mei-Ling T. , Xiao Tao , Papp Audrey , Wang Danxin , Sadée Wolfgang
Published: December 2007

Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect ofDRD2variants remains ambiguous. We measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of theDRD2locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studiedDRD2variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproducedin vitroby using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. Our results identify regulatoryDRD2polymorphisms that modify mRNA expression and splicing and working memory pathways.
The Na
+
/I
−
symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate
Authors: Dohán Orsolya , Portulano Carla , Basquin Cécile , Reyna-Neyra Andrea , Amzel L. Mario , Carrasco Nancy
Published: December 2007

The Na
+
/I
−
symporter (NIS) is a key plasma membrane protein that mediates active I
−
uptake in the thyroid, lactating breast, and other tissues with an electrogenic stoichiometry of 2 Na
+
per I
−
. In the thyroid, NIS-mediated I
−
uptake is the first step in the biosynthesis of the iodine-containing thyroid hormones, which are essential early in life for proper CNS development. In the lactating breast, NIS mediates the translocation of I
−
to the milk, thus supplying this essential anion to the nursing newborn. Perchlorate (ClO
4
−
) is a well known competitive inhibitor of NIS. Exposure to food and water contaminated with ClO
4
−
is common in the U.S. population, and the public health impact of such exposure is currently being debated. To date, it is still uncertain whether ClO
4
−
is a NIS blocker or a transported substrate of NIS. Here we show
in vitro
and
in vivo
that NIS actively transports ClO
4
−
, including ClO
4
−
translocation to the milk. A simple mathematical fluxes model accurately predicts the effect of ClO
4
−
transport on the rate and extent of I
−
accumulation. Strikingly, the Na
+
/ ClO
4
−
transport stoichiometry is electroneutral, uncovering that NIS translocates different substrates with different stoichiometries. That NIS actively concentrates ClO
4
−
in maternal milk suggests that exposure of newborns to high levels of ClO
4
−
may pose a greater health risk than previously acknowledged because ClO
4
−
would thus directly inhibit the newborns' thyroidal I
−
uptake.
Single-vesicle imaging reveals that synaptic vesicle exocytosis and endocytosis are coupled by a single stochastic mode
Authors: Balaji J. , Ryan T. A.
Published: December 2007

The nature of synaptic vesicle recycling at nerve terminals has been a subject of considerable debate for >35 years. Here, we report the use of an optical strategy that allows the exocytosis and retrieval of synaptic components to be tracked in real time at single-molecule sensitivity in living nerve terminals. This approach has allowed us to examine the recycling of synaptic vesicles in response to single action potentials. Our results show that, after exocytosis, individual synaptic vesicles are retrieved by a stochastic process with an exponential distribution of delay times, with a mean time of ≈14 s. We propose that evidence for fast endocytosis, such as that proposed to support the presence of kiss-and-run, is likely explained by the stochastic nature of a slower process.
Life history trade-offs explain the evolution of human pygmies
Authors: Migliano Andrea Bamberg , Vinicius Lucio , Lahr Marta Mirazón
Published: December 2007

Explanations for the evolution of human pygmies continue to be a matter of controversy, recently fuelled by the disagreements surrounding the interpretation of the fossil homininHomo floresiensis. Traditional hypotheses assume that the small body size of human pygmies is an adaptation to special challenges, such as thermoregulation, locomotion in dense forests, or endurance against starvation. Here, we present an analysis of stature, growth, and individual fitness for a large population of Aeta and a smaller one of Batak from the Philippines and compare it with data on other pygmy groups accumulated by anthropologists for a century. The results challenge traditional explanations of human pygmy body size. We argue that human pygmy populations and adaptations evolved independently as the result of a life history tradeoff between the fertility benefits of larger body size against the costs of late growth cessation, under circumstances of significant young and adult mortality. Human pygmies do not appear to have evolved through positive selection for small stature—this was a by-product of selection for early onset of reproduction.
Highly permeable polymeric membranes based on the incorporation of the functional water channel protein Aquaporin Z
Authors: Kumar Manish , Grzelakowski Mariusz , Zilles Julie , Clark Mark , Meier Wolfgang
Published: December 2007

The permeability and solute transport characteristics of amphiphilic triblock-polymer vesicles containing the bacterial water-channel protein Aquaporin Z (AqpZ) were investigated. The vesicles were made of a block copolymer with symmetric poly-(2-methyloxazoline)-poly-(dimethylsiloxane)-poly-(2-methyloxazoline) (PMOXA
15
-PDMS
110
-PMOXA
15
) repeat units. Light-scattering measurements on pure polymer vesicles subject to an outwardly directed salt gradient in a stopped-flow apparatus indicated that the polymer vesicles were highly impermeable. However, a large enhancement in water productivity (permeability per unit driving force) of up to ≈800 times that of pure polymer was observed when AqpZ was incorporated. The activation energy (
E
a
) of water transport for the protein-polymer vesicles (3.4 kcal/mol) corresponded to that reported for water-channel-mediated water transport in lipid membranes. The solute reflection coefficients of glucose, glycerol, salt, and urea were also calculated, and indicated that these solutes are completely rejected. The productivity of AqpZ-incorporated polymer membranes was at least an order of magnitude larger than values for existing salt-rejecting polymeric membranes. The approach followed here may lead to more productive and sustainable water treatment membranes, whereas the variable levels of permeability obtained with different concentrations of AqpZ may provide a key property for drug delivery applications.
A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases
Authors: Fedorov Oleg , Marsden Brian , Pogacic Vanda , Rellos Peter , Müller Susanne , Bullock Alex N. , Schwaller Juerg , Sundström Michael , Knapp Stefan
Published: December 2007

Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333′531, a PKCβ inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333′531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients.
Molecular identification of bacteria in bronchoalveolar lavage fluid from children with cystic fibrosis
Authors: Harris J. Kirk , De Groote Mary Ann , Sagel Scott D. , Zemanick Edith T. , Kapsner Robert , Penvari Churee , Kaess Heidi , Deterding Robin R. , Accurso Frank J. , Pace Norman R.
Published: December 2007

Culture of bronchoalveolar lavage fluid (BALF) is the gold standard for detection of pathogens in the lower airways in cystic fibrosis (CF). However, current culture results do not explain all clinical observations in CF, including negative culture results during pulmonary exacerbation and inflammation in the absence of pathogens. We hypothesize that organisms not routinely identified by culture occur in the CF airway and may contribute to disease. To test this hypothesis we used a culture-independent molecular approach, based on use of rRNA sequence analysis, to assess the bacterial composition of BALF from children with CF and disease controls (DC). Specimens from 42 subjects (28 CF) were examined, and ≈6,600 total clones were screened to identify 121 species of bacteria. In general, a single rRNA type dominated clone libraries from CF specimens, but not DC. Thirteen CF subjects contained bacteria that are not routinely assessed by culture. In four CF subjects, candidate pathogens were identified and include the anaerobe
Prevotella denticola
, a
Lysobacter
sp., and members of the
Rickettsiales
. The presumptive pathogens
Tropheryma whipplei
and
Granulicatella elegans
were identified in cases from the DC group. The presence of unexpected bacteria in CF may explain inflammation without documented pathogens and consequent failure to respond to standard treatment. These results show that molecular techniques provide a broader perspective on airway bacteria than do routine clinical cultures and thus can identify targets for further clinical evaluation.
Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation
Authors: Salio Mariolina , Speak Anneliese O. , Shepherd Dawn , Polzella Paolo , Illarionov Petr A. , Veerapen Natacha , Besra Gurdyal S. , Platt Frances M. , Cerundolo Vincenzo
Published: December 2007

Invariant natural killer T (
i
NKT) cells are a subset of nonconventional T cells recognizing endogenous and/or exogenous glycolipid antigens in the context of CD1d molecules. It remains unclear whether innate stimuli can modify the profile of endogenous lipids recognized by
i
NKT cells on the surface of antigen-presenting cells (APCs). We report that activation of human APCs by Toll-like receptor ligands (TLR-L) modulates the lipid biosynthetic pathway, resulting in enhanced recognition of CD1d-associated lipids by
i
NKT cells, as defined by IFN-γ secretion. APC-derived soluble factors further increase CD1d-restricted
i
NKT cell activation. Finally, using soluble tetrameric
i
NKT T cell receptors (TCR) as a staining reagent, we demonstrate specific up-regulation of CD1d-bound ligand(s) on TLR-mediated APC maturation. The ability of innate stimuli to modulate the lipid profile of APCs resulting in
i
NKT cell activation and APC maturation underscores the role of
i
NKT cells in assisting priming of antigen-specific immune responses.
Sequence of late molecular events in the activation of rhodopsin
Authors: Knierim Bernhard , Hofmann Klaus Peter , Ernst Oliver P. , Hubbell Wayne L.
Published: December 2007

Activation of the G protein-coupled receptor rhodopsin involves both the motion of transmembrane helix 6 (TM6) and proton exchange events. To study how these activation steps relate to each other, spin-labeled rhodopsin in solutions of dodecyl maltoside was used so that time-resolved TM6 motion and proton exchange could each be monitored as a function of pH and temperature after an activating light flash. The results reveal that the motion of TM6 is not synchronized with deprotonation of the Schiff base that binds the chromophore to the protein but is an order of magnitude slower at 30°C. However, TM6 motion and the uptake of a proton from solution in the neutral pH range follow the same time course. Importantly, the motion of TM6 is virtually independent of pH, as is Schiff base deprotonation under the conditions used, whereas proton uptake titrates with a pK of 6.5. This finding shows that proton uptake is a consequence rather than a cause of helix motion. Activated rhodopsin binds to and subsequently activates the cognate G protein, transducin. It has been shown that peptides derived from the C terminus of the transducin α-subunit mimic in part binding of the intact G protein. These peptides are found to bind to rhodopsin after TM6 movement, resulting in the release of protons. Collectively, the data suggest the following temporal sequence of events involved in activation: (i) internal Schiff base proton transfer; (ii) TM6 movement; and (iii) proton uptake from solution and binding of transducin.
Repopulation of adult and neonatal mice with human hepatocytes: A chimeric animal model
Authors: Bissig Karl-Dimiter , Le Tam T. , Woods Niels-Bjarne , Verma Inder M.
Published: December 2007

We report the successful transplantation of human hepatocytes in immunodeficient, fumarylacetoacetate hydrolase-deficient (fah
−/−
) mice. Engraftment occurs over the entire liver acinus upon transplantation. A few weeks after transplantation, increasing concentrations of human proteins (e.g., human albumin and human C3a) can be measured in the blood of the recipient mouse. No fusion between mouse and human hepatocytes can be detected. Three months after transplantation, up to 20% of the mouse liver is repopulated by human hepatocytes, and sustained expression of lentiviral vector transduced gene can be observed. We further report the development of a hepatocyte transplantation method involving a transcutaneous, intrahepatic injection in neonatal mice. Human hepatocytes engraft over the entire injected lobe with an expansion pattern similar to those observed with intrasplenic transplantation.
Causal Depth, Theoretical Appropriateness, and Individualism in Psychology
Authors: Wilson Robert A.
Published: December 2007

Individualists claim that wide explanations in psychology are problematic. I argue that wide psychological explanations sometimes have greater explanatory power than individualistic explanations. The aspects of explanatory power I focus on arecausal depthandtheoretical appropriateness.Reflection on the depth and appropriateness of other wide explanations of behavior, such as evolutionary explanations, clarifies why wide psychological explanations sometimes have more causal depth and theoretical appropriateness than narrow psychological explanations. I also argue for the rejection of eliminative materialism.
The Statistical Character of Evolutionary Theory
Authors: Horan Barbara L.
Published: December 2007

This paper takes a critical look at the idea that evolutionary theory is a statistical theory. It argues that despite the strong instrumental motivation for statistical theories, they are not necessary to explain deterministic systems. Biological evolution is fundamentally a result of deterministic processes. Hence, a statistical theory is not necessary for describing the evolutionary forces of genetic drift and natural selection, nor is it needed for describing the fitness of organisms. There is a computational advantage to the statistical theory of population genetics, but population genetics succeeds only by eliminating causes from its account of evolutionary change.
Causal Independence
Authors: Kvart Igal
Published: December 2007

In Kvart (1991a), I discussed the analysis of causal relevance presented in A Theory of Counterfactuals (1986) (and first in 1975). I explained there in what respect the notion captured by the analysis of Kvart (1986) is a mere approximation to the requisite notion of causal relevance. In this paper I present another analysis of causal relevance, devoid of the shortcoming of its predecessor.

The present analysis of causal relevance is, again, grounded in a chancelike notion of objective probability. The correlative notion of causal independence is analyzed as holding in case there is a so-called causal impact series, which is defined here. The basic notions used for this analysis are the notion of a differentiator, which upsets an equiprobability case, and that of a blocker, which restores it.
Genes Made Molecular
Authors: Waters C. Kenneth
Published: December 2007

This paper investigates what molecular biology has done for our understanding of the gene. I base a new account of the gene concept of classical genetics on theclassical dogmathat gene differences cause phenotypic differences. Although contemporary biologists often think of genes in terms of this concept, molecular biology provides a second way to understand genes. I clarify this second way by articulating amolecular gene concept.This concept unifies our understanding of the molecular basis of a wide variety of phenomena, including the phenomena that classical genetics explains in terms of gene differences causing phenotypic differences.
Some Problems with the Linnaean Hierarchy
Authors: Ereshefsky Marc
Published: December 2007

Most biologists use the Linnaean system for constructing classifications of the organic world. The Linnaean system, however, has lost its theoretical basis due to the shift in biology from creationist and essentialist tenets to evolutionary theory. As a result, the Linnaean system is both cumbersome and ontologically vacuous. This paper illustrates the problems facing the Linnaean system, and ends with a brief introduction to an alternative approach to biological classification.
The Cognitive Structure of Scientific Theories
Authors: Giere Ronald N.
Published: December 2007

This paper explores a new reason for preferring a model-theoretic approach to understanding the nature of scientific theories. Identifying the models in philosophers' model-theoretic accounts of theories with the concepts in cognitive scientists' accounts of categorization suggests a structure to families of models far richer than has commonly been assumed. Using classical mechanics as an example, it is argued that families of models may be “mapped” as an array with “horizontal” graded structures, multiply hierarchical “vertical” structures, and local “radial” structures. These structures promise important implications for how scientific theories are learned and used in actual scientific practice.
Stronger Evidence
Authors: Achinstein Peter
Published: December 2007

According to a standard account of evidence, one piece of information is stronger evidence for an hypothesis than is another iff the probability of the hypothesis on the one is greater than it is on the other. This condition, I argue, is neither necessary nor sufficient because various factors can strengthen the evidence for an hypothesis without increasing (and even decreasing) its probability. Contrary to what probabilists claim, I show that this obtains even if a probability function can take these evidential factors into account in ways they suggest and yield a unique probability value. Nor will the problem be solved by appealing to second-order probabilities.
Accessibility, Kinds, and Laws: A Structural Explication
Authors: Mormann Thomas
Published: December 2007

“Accessibility” is a crucial concept of possible worlds semantics. The simplest approach to accessibility is the “magical theory” that construes this relation as analogous to spatial or temporal relations. In this paper I give a nonmagical structural account of the accessibility relation that can be used to give a necessitarian account of kinds and laws. Laws are characterized in a structural way as stable invariants of the world's gestalt. Finally, I point out how the structural approach can be embedded in a general representational theory of modality.
Representation and the Imperfect Ideal
Authors: Wallis Charles
Published: December 2007

This paper examines the nomic covariationist strategy of using idealization to define representation. While the literature has focused upon the possibility of defining ideal conditions for perception, I argue that nomic covariationist appeals to idealization are pseudoscientific and contrary to a foundational and empirically well-supported methodological presupposition in cognitive science. Moreover, one major figure in this camp fails to come to grips with its role and its problems in mainstream science. Thus he forwards a false dichotomy of the sciences and treats idealization as a blank check written by scientists on an unknown bank. Finally, I consider and reject alternative formulations of the nomic covariationist's idealization strategy.
Scientific Abstraction and the Realist Impulse
Authors: Bunzl Martin
Published: December 2007

In a series of important papers, A. Fine has developed and defended the view that the proper reading of scientific practice is neither realist nor antirealist. Instead, he argues that realism and antirealism both add something extra to a core position which is neither. In this discussion I reexamine his claim in the light of some criticisms. Fine's position contains an important insight, but to draw that point out requires shifting the way in which Fine poses the argument. I do so by examining an argument by H. Stein.
Sober on Brandon on Screening-Off and the Levels of Selection
Authors: Brandon Robert N. , Antonovics Janis , Burian Richard , Carson Scott , Cooper Greg , Davies Paul Sheldon , Horvath Christopher , Mishler Brent D. , Richardson Robert C. , Smith Kelly , Thrall Peter
Published: December 2007

Sober (1992) has recently evaluated Brandon's (1982, 1990; see also 1985, 1988) use of Salmon's (1971) concept of screening-off in the philosophy of biology. He critiques three particular issues, each of which will be considered in this discussion.
Darwin Meets the Logic of Decision: Correlation in Evolutionary Game Theory
Authors: Skyrms Brian
Published: December 2007

The proper treatment of correlation in evolutionary game theory has unexpected connections with recent philosophical discussions of the theory of rational decision. The Logic of Decision (Jeffrey 1983) provides the correct framework for correlated evolutionary game theory and a variant of “ratifiability” is the appropriate generalization of “evolutionarily stable strategy”. The resulting theory unifies the treatment of correlation due to kin, population viscosity, detection, signaling, reciprocal altruism, and behavior-dependent contexts. It is shown that (1) a strictly dominated strategy may be selected, and (2) under conditions of perfect correlation a strictly efficient strategy must be selected.
A Critical Review of Philosophical Work on the Units of Selection Problem
Authors: Sober Elliott , Wilson David Sloan
Published: December 2007

The evolutionary problem of the units of selection has elicited a good deal of conceptual work from philosophers. We review this work to determine where the issues now stand.
Two Concepts of Constraint: Adaptationism and the Challenge from Developmental Biology
Authors: Amundson Ron
Published: December 2007

The so-called “adaptationism” of mainstream evolutionary biology has been criticized from a variety of sources. One, which has received relatively little philosophical attention, is developmental biology. Developmental constraints are said to be neglected by adaptationists. This paper explores the divergent methodological and explanatory interests that separate mainstream evolutionary biology from its embryological and developmental critics. It will focus on the concept of constraint itself; even this central concept is understood differently by the two sides of the dispute.
Normality as a Biological Concept
Authors: Wachbroit Robert
Published: December 2007

The biological sciences employ a concept of normality that must be distinguished from statistical or value concepts. The concept of normality is presupposed in the standard explications of biological functions, and it is crucial to the strategy of explanation by approximations in, for example, physiology. Nevertheless, this concept of normality does not seem to be captured in the language of physics. Thus attempts at explaining the methodological relationship between the biological sciences and the physical sciences by concentrating only on the concept of biological function cannot go very far. An analysis of the concept of normality is also necessary.
Reductionism and the Unification Theory of Explanation
Authors: Jones Todd
Published: December 2007

P. Kitcher's unification theory of explanation appears to endorse a reductionistic view of scientific explanation that is inconsistant with scientific practice. In this paper, I argue that this appearance is illusory. The existence of multiply realizable generalizations enable the unification theory to also count many high-level accounts as explanatory.
Hard and Soft Accidental Uniformities
Authors: Flichman Eduardo H.
Published: December 2007

I discuss some aspects of the epistemological distinction between laws of nature and accidental uniformities. In order that the exposition be self-contained I briefly provide a taxonomy proposed in another work for statements that appear in a scientific theory. Once this taxonomy has been presented I attempt to prove two very different types of accidental uniformities: hard and soft. The distinction is fundamental because the latter have frequently been confused with laws of nature. I try to justify why I believe that these statements are accidental uniformities and not laws of nature.
Phenomenotechnique in Historical Perspective: Its Origins and Implications for Philosophy of Science
Authors: Castelão-Lawless Teresa
Published: December 2007

This article provides an overview of the historical and philosophical context from which originated G. Bachelard's concept of “phenomenotechnique”. It analyzes why phenomenotechnique is crucial for science studies. By incorporating the concept of phenomenotechnique into Hacking's and Galison's models of science, I argue that we can avoid the radicalism of both while also preventing the analysis of scientific practices from collapsing into the interpretive frames mandated by social constructivists.
For Pluralism and Against Realism About Species
Authors: Stanford P. Kyle
Published: December 2007

I argue for accepting a pluralist approach to species, while rejecting the realism about species espoused by P. Kitcher and a number of other philosophers of biology. I develop an alternative view of species concepts as divisions of organisms into groups for study which are relative to the systematic explanatory interests of biologists at a particular time. I also show how this conception resolves a number of difficult puzzles which plague the application of particular species concepts.
Bayesianism and Diverse Evidence
Authors: Wayne Andrew
Published: December 2007

A common methodological adage holds that diverse evidence better confirms a hypothesis than does the same amount of similar evidence. Proponents of Bayesian approaches to scientific reasoning such as Horwich, Howson and Urbach, and Earman claim to offer both a precise rendering of this maxim in probabilistic terms and an explanation of why the maxim should be part of the methodological canon of good science. This paper contends that these claims are mistaken and that, at best, Bayesian accounts of diverse evidence are crucially incomplete. This failure should lend renewed force to a long-neglected global worry about Bayesian approaches.
Are Physical Properties Dispositions?
Authors: Reeder Nick
Published: December 2007

Averill (1990) argues that not every property is a disposition. I claim here that his reasoning is faulty, suffering at one point from a logical error and at other points from an inadequate account of counterfactuals.