bluuebunny/crossref_metadata_2025 huggingface dataset:
Faceting ionic shells into icosahedra via electrostatics
Authors: Vernizzi Graziano , Olvera de la Cruz Monica
Published: November 2007

Shells of various viruses and other closed packed structures with spherical topology exhibit icosahedral symmetry because the surface of a sphere cannot be tiled without defects, and icosahedral symmetry yields the most symmetric configuration with the minimum number of defects. Icosahedral symmetry is different from icosahedral-shaped structures, which include some large viruses, cationic–anionic vesicles, and fullerenes. We present a faceting mechanism of ionic shells into icosahedral shapes that breaks icosahedral symmetry resulting from different arrangements of the charged components among the facets. These self-organized ionic structures may favor the formation of flat domains on curved surfaces. We show that icosahedral shapes without rotational symmetry can have lower energy than spheres with icosahedral symmetry caused by preferred bending directions in the planar ionic lattice. The ability to create icosahedral shapes without icosahedral symmetry may lead to the design of new functional materials. The electrostatically driven faceting mechanism we present here suggests that we can design faceted polyhedra with diverse symmetries by coassembling oppositely charged molecules of different stoichiometric ratios.
The relative importance of directional change, random walks, and stasis in the evolution of fossil lineages
Authors: Hunt Gene
Published: November 2007

The nature of evolutionary changes recorded by the fossil record has long been controversial, with particular disagreement concerning the relative frequency of gradual change versus stasis within lineages. Here, I present a large-scale, statistical survey of evolutionary mode in fossil lineages. Over 250 sequences of evolving traits were fit by using maximum likelihood to three evolutionary models: directional change, random walk, and stasis. Evolution in these traits was rarely directional; in only 5% of fossil sequences was directional evolution the most strongly supported of the three modes of change. The remaining 95% of sequences were divided nearly equally between random walks and stasis. Variables related to body size were significantly less likely than shape traits to experience stasis. This finding is in accord with previous suggestions that size may be more evolutionarily labile than shape and is consistent with some but not all of the mechanisms proposed to explain evolutionary stasis. In general, similar evolutionary patterns are observed across other variables, such as clade membership and temporal resolution, but there is some evidence that directional change in planktonic organisms is more frequent than in benthic organisms. The rarity with which directional evolution was observed in this study corroborates a key claim of punctuated equilibria and suggests that truly directional evolution is infrequent or, perhaps more importantly, of short enough duration so as to rarely register in paleontological sampling.
Cell adhesion and cortex contractility determine cell patterning in the
Drosophila
retina
Authors: Käfer Jos , Hayashi Takashi , Marée Athanasius F. M. , Carthew Richard W. , Graner François
Published: November 2007

Because of the resemblance of many epithelial tissues to densely packed soap bubbles, it has been suggested that surface minimization, which drives soap bubble packing, could be governing cell packing as well. We test this by modeling the shape of the cells in a
Drosophila
retina ommatidium. We use the observed configurations and shapes in wild-type flies, as well as in flies with different numbers of cells per ommatidia, and mutants with cells where E- or N-cadherin is either deleted or misexpressed. We find that surface minimization is insufficient to model the experimentally observed shapes and packing of the cells based on their cadherin expression. We then consider a model in which adhesion leads to a surface increase, balanced by cell cortex contraction. Using the experimentally observed distributions of E- and N-cadherin, we simulate the packing and cell shapes in the wild-type eye. Furthermore, by changing only the corresponding parameters, this model can describe the mutants with different numbers of cells or changes in cadherin expression.
A self-consistent theory for graphene transport
Authors: Adam Shaffique , Hwang E. H. , Galitski V. M. , Das Sarma S.
Published: November 2007

We demonstrate theoretically that most of the observed transport properties of graphene sheets at zero magnetic field can be explained by scattering from charged impurities. We find that, contrary to common perception, these properties are not universal but depend on the concentration of charged impurities
n
imp
. For dirty samples (250 × 10
10
cm
−2
<
n
imp
< 400 × 10
10
cm
−2
), the value of the minimum conductivity at low carrier density is indeed 4
e
2
/
h
in agreement with early experiments, with weak dependence on impurity concentration. For cleaner samples, we predict that the minimum conductivity depends strongly on
n
imp
, increasing to 8
e
2
/
h
for
n
imp
≈ 20 × 10
10
cm
−2
. A clear strategy to improve graphene mobility is to eliminate charged impurities or use a substrate with a larger dielectric constant.
Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism
Authors: Mosconi Lisa , Brys Miroslaw , Switalski Remigiusz , Mistur Rachel , Glodzik Lidia , Pirraglia Elizabeth , Tsui Wai , De Santi Susan , de Leon Mony J.
Published: November 2007

Having a parent affected with late-onset Alzheimer's disease (AD) is a risk factor for developing AD among cognitively normal subjects. We examined whether cognitively normal subjects with a parental family history of AD show cerebral metabolic rate of glucose (CMRglc) reductions consistent with AD as compared with those without a family history and whether there are parent gender effects. Forty-nine 50- to 80-year-old normal subjects were examined who received clinical, neuropsychological, and 2-[
18
F]fluoro-2-deoxy-
d
-glucose–positron emission tomography examinations, including 16 subjects with a maternal (FHm) and eight with a paternal (FHp) family history of AD and 25 with no family history (FH
−
). FH groups were comparable for demographic and neuropsychological measures. As compared with both FH
−
and FHp groups, FHm subjects showed CMRglc reductions in the same regions as clinically affected AD patients, involving the posterior cingulate cortex/precuneus, parietotemporal and frontal cortices, and medial temporal lobes (
P
< 0.05, corrected for multiple comparisons). These effects remained significant after accounting for possible risk factors for AD, including age, gender, education, apolipoprotein E genotype, and subjective memory complaints. No CMRglc differences were found between FHp and FH
−
subjects. This study shows a relationship between reduced CMRglc in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals.
Simpler mode of inheritance of transcriptional variation in maleDrosophila melanogaster
Authors: Wayne Marta L. , Telonis-Scott Marina , Bono Lisa M. , Harshman Larry , Kopp Artyom , Nuzhdin Sergey V. , McIntyre Lauren M.
Published: November 2007

Sexual selection drives faster evolution in males. The X chromosome is potentially an important target for sexual selection, because hemizygosity in males permits accumulation of alleles, causing tradeoffs in fitness between sexes. Hemizygosity of the X could cause fundamentally different modes of inheritance between the sexes, with more additive variation in males and more nonadditive variation in females. Indeed, we find that genetic variation for the transcriptome is primarily additive in males but nonadditive in females. As expected, these differences are more pronounced on the X chromosome than the autosomes, but autosomal loci are also affected, possibly because of X-linked transcription factors. These differences may be of evolutionary significance because additive variation responds quickly to selection, whereas nonadditive genetic variation does not. Thus, hemizygosity of the X may underlie much of the faster male evolution of the transcriptome and potentially other phenotypes. Consistent with this prediction, genes that are additive in males and nonadditive in females are overrepresented among genes responding to selection for increased mating speed.
The developmental selector
AS1
is an evolutionarily conserved regulator of the plant immune response
Authors: Nurmberg Pedro L. , Knox Kirsten A. , Yun Byung-Wook , Morris Peter C. , Shafiei Reza , Hudson Andrew , Loake Gary J.
Published: November 2007

The MYB-related gene
ASYMMETRIC LEAVES 1
(
AS1
) and its orthologs have an evolutionarily conserved role in specification of leaf cell identity. AS1 is expressed in leaf founder cells, where it functions as a heterodimer with the structurally unrelated AS2 proteins to repress activity of
KNOTTED 1-like homeobox
(
KNOX
) genes. AS1 therefore confines
KNOX
activity to the shoot apical meristem, where it promotes stem cell function through the regulation of phytohormone activities. Here, we show that loss-of-function mutations in
AS1
unexpectedly convey heightened protection against necrotrophic fungi. AS1 operates as a negative regulator of inducible resistance against these pathogens by selectively binding to the promoters of genes controlled by the immune activator, jasmonic acid (JA), damping the defense response. In contrast, AS1 is a positive regulator of salicylic acid (SA)-independent extracellular defenses against bacterial pathogens. Neither the absence of
AS2
nor
ERECTA
function, which enhances the morphological phenotype of
as1
, nor the conditional or constitutive expression of
KNOX
genes impacted disease resistance. Thus, the function of AS1 in responses to phytopathogens is independent of its AS2-associated role in development. Loss of function in the
AS1
orthologs
PHAN
in
Antirrhinum majus
and
NSPHAN
in
Nicotiana sylvestris
produced pathogen-response phenotypes similar to
as1
plants, and therefore the defense function of
AS1
is evolutionarily conserved in plant species with a divergence time of ≈125 million years.
A quantum-chemical picture of hemoglobin affinity
Authors: Alcantara R. E. , Xu C. , Spiro T. G. , Guallar V.
Published: November 2007

Understanding the molecular mechanism of hemoglobin cooperativity remains an enduring challenge. Protein forces that control ligand affinity are not directly accessible by experiment. We demonstrate that computational quantum mechanics/molecular mechanics methods can provide reasonable values of ligand binding energies in Hb, and of their dependence on allostery. About 40% of the binding energy differences between the relaxed state and tense state quaternary structures result from strain induced in the heme and its ligands, especially in one of the pyrrole rings. The proximal histidine also contributes significantly, in particular, in the α-chains. The remaining energy difference resides in protein contacts, involving residues responsible for locking the quaternary changes. In the α-chains, the most important contacts involve the FG corner, at the “hinge” region of the α
1
β
2
quaternary interface. The energy differences are spread more evenly among the β-chain residues, suggesting greater flexibility for the β- than for the α-chains along the quaternary transition. Despite this chain differentiation, the chains contribute equally to the relaxed substitute state energy difference. Thus, nature has evolved a symmetric response to the quaternary structure change, which is a requirement for maximum cooperativity, via different mechanisms for the two kinds of chains.
Dynamical quorum sensing: Population density encoded in cellular dynamics
Authors: De Monte Silvia , d'Ovidio Francesco , Danø Sune , Sørensen Preben Graae
Published: November 2007

Mutual synchronization by exchange of chemicals is a mechanism for the emergence of collective dynamics in cellular populations. General theories exist on the transition to coherence, but no quantitative, experimental demonstration has been given. Here, we present a modeling and experimental analysis of cell-density-dependent glycolytic oscillations in yeast. We study the disappearance of oscillations at low cell density and show that this phenomenon occurs synchronously in all cells and not by desynchronization, as previously expected. This study identifies a general scenario for the emergence of collective cellular oscillations and suggests a quorum-sensing mechanism by which the cell density information is encoded in the intracellular dynamical state.
A recurrent inversion on the eutherian X chromosome
Authors: Cáceres Mario ,   National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program, Sullivan Robert T. , Thomas James W.
Published: November 2007

Chromosomal inversions have an important role in evolution, and an increasing number of inversion polymorphisms are being identified in the human population. The evolutionary history of these inversions and the mechanisms by which they arise are therefore of significant interest. Previously, a polymorphic inversion on human chromosome Xq28 that includes the
FLNA
and
EMD
loci was discovered and hypothesized to have been the result of nonallelic homologous recombination (NAHR) between near-identical inverted duplications flanking this region. Here, we carried out an in-depth study of the orthologous region in 27 additional eutherians and report that this inversion is not specific to humans, but has occurred independently and repeatedly at least 10 times in multiple eutherian lineages. Moreover, inverted duplications flank the
FLNA–EMD
region in all 16 species for which high-quality sequence assemblies are available. Based on detailed sequence analyses, we propose a model in which the observed inverted duplications originated from a common duplication event that predates the eutherian radiation. Subsequent gene conversion homogenized the duplications, thereby providing a continuous substrate for NAHR that led to the recurrent inversion of this segment of the genome. These results provide an extreme example in support of the evolutionary breakpoint reusage hypothesis and point out that some near-identical human segmental duplications may, in fact, have originated >100 million years ago.
Bimolecular complementation reveals that glycoproteins gB and gH/gL of herpes simplex virus interact with each other during cell fusion
Authors: Atanasiu Doina , Whitbeck J. Charles , Cairns Tina M. , Reilly Brigid , Cohen Gary H. , Eisenberg Roselyn J.
Published: November 2007

Herpes simplex virus entry into cells requires four glycoproteins, gB, gD, gH, and gL. Binding of gD to one of its receptors triggers steps requiring the core fusion proteins, gB and the gH/gL heterodimer. There is evidence that gH/gL initiates hemifusion of cells, but whether this complex interacts physically with gB to cause complete fusion is unknown. We used bimolecular complementation (BiMC) of enhanced yellow fluorescent protein (EYFP) to detect glycoprotein interactions during cell–cell fusion. The N- or C-terminal half of EYFP was fused to the C terminus of gD, gB, and gH to form six chimeric proteins (Dn, Dc, Bn, Bc, Hn, and Hc). BiMC was detected by confocal microscopy. Receptor-bearing (C10) cells cotransfected with Dn and Bc or Dn, Hc, and untagged gL exhibited EYFP fluorescence, indicative of interactions between gD and gB and between gD and gH/gL. EYFP complementation did not occur in cells transfected with gL, Bc, and Hn. However, when gD was coexpressed with these other three proteins, cell–cell fusion occurred and the syncytia exhibited bright EYFP fluorescence. To separate glycoprotein expression from fusion, we transfected C10 cells with gL, Bc, and Hn for 20 h and then added soluble gD to trigger fusion. We detected fluorescent syncytia within 10 min, and both their number and size increased with exposure time to gD. Thus, when gD binds its receptor, the core fusion machinery is triggered to form a multiprotein complex as a step in fusion and possibly virus entry.
Crystal structure of measles virus hemagglutinin provides insight into effective vaccines
Authors: Hashiguchi Takao , Kajikawa Mizuho , Maita Nobuo , Takeda Makoto , Kuroki Kimiko , Sasaki Kaori , Kohda Daisuke , Yanagi Yusuke , Maenaka Katsumi
Published: November 2007

Measles still remains a major cause of childhood morbidity and mortality worldwide. Measles virus (MV) vaccines are highly successful, but the mechanism underlying their efficacy has been unclear. Here we report the crystal structure of the MV attachment protein, hemagglutinin, responsible for MV entry. The receptor-binding head domain exhibits a cubic-shaped β-propeller structure and forms a homodimer. N-linked sugars appear to mask the broad regions and cause the two molecules forming the dimer to tilt oppositely toward the horizontal plane. Accordingly, residues of the putative receptor-binding site, highly conserved among MV strains, are strategically positioned in the unshielded area of the protein. These conserved residues also serve as epitopes for neutralizing antibodies, ensuring the serological monotype, a basis for effective MV vaccines. Our findings suggest that sugar moieties in the MV hemagglutinin critically modulate virus–receptor interaction as well as antiviral antibody responses, differently from sugars of the HIV gp120, which allow for immune evasion.
The shoot meristem identity gene
TFL1
is involved in flower development and trafficking to the protein storage vacuole
Authors: Sohn Eun Ju , Rojas-Pierce Marcela , Pan Songqin , Carter Clay , Serrano-Mislata Antonio , Madueño Francisco , Rojo Enrique , Surpin Marci , Raikhel Natasha V.
Published: November 2007

Plants are unique in their ability to store proteins in specialized protein storage vacuoles (PSVs) within seeds and vegetative tissues. Although plants use PSV proteins during germination, before photosynthesis is fully functional, the roles of PSVs in adult vegetative tissues are not understood. Trafficking pathways to PSVs and lytic vacuoles appear to be distinct. Lytic vacuoles are analogous evolutionarily to yeast and mammalian lysosomes. However, it is unclear whether trafficking to PSVs has any analogy to pathways in yeast or mammals, nor is PSV ultrastructure known in
Arabidopsis
vegetative tissue. Therefore, alternative approaches are required to identify components of this pathway. Here, we show that an
Arabidopsis thaliana
mutant that disrupts PSV trafficking identified
TERMINAL FLOWER 1
(
TFL1
), a shoot meristem identity gene. The
tfl1-19/mtv5
(for “modified traffic to the vacuole”) mutant is specifically defective in trafficking of proteins to the PSV. TFL1 localizes to endomembrane compartments and colocalizes with the putative δ-subunit of the AP-3 adapter complex. Our results suggest a developmental role for the PSV in vegetative tissues.
Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E
Authors: Huang Hua , Chen Yan , Ye Jin
Published: November 2007

Hepatitis C virus (HCV) is a single-stranded positive-sense RNA virus of the Flaviviridae family. HCV-infected hepatocytes are known to produce reactive oxygen species (ROS), which initiate lipid peroxidation, a reaction that converts polyunsaturated fatty acids, such as arachidonate, into reactive carbonyls that inactivate proteins. To study the effect of lipid peroxidation on HCV replication, we administered arachidonate to Huh7 cells that harbor an HCV replicon (Huh7-K2040 cells). After incubation in medium supplemented with arachidonate but deprived of lipid-soluble antioxidants, the cellular amount of malondialdehyde (MDA), a product of lipid peroxidation, increased markedly in Huh7-K2040 cells but not in parental Huh7 cells that do not harbor an HCV replicon. This increase was followed by a sharp reduction (>95%) in HCV RNA. Both of these events were prevented when cells were treated with vitamin E, a lipid-soluble antioxidant. After prolonged incubation of Huh7-K2040 cells with arachidonate in the absence of lipid-soluble antioxidants, the amount of MDA decreased after the reduction in the amount of HCV RNA. Thus, in the presence of arachidonate and in the absence of lipid-soluble antioxidants, HCV replication induces lipid peroxidation that reduces the amount of HCV RNA. Our results provide a mechanism for the previous observation that polyunsaturated fatty acids inhibit HCV replication [Kapadia SB, Chisari FV (2005)
Proc Natl Acad Sci USA
102:2561–2566], and they suggest that these agents may be effective in inhibiting HCV replication
in vivo
.
The process of mRNA–tRNA translocation
Authors: Frank Joachim , Gao Haixiao , Sengupta Jayati , Gao Ning , Taylor Derek J.
Published: November 2007

In the elongation cycle of translation, translocation is the process that advances the mRNA–tRNA moiety on the ribosome, to allow the next codon to move into the decoding center. New results obtained by cryoelectron microscopy, interpreted in the light of x-ray structures and kinetic data, allow us to develop a model of the molecular events during translocation.
Evolution of heteromeric nitrilase complexes in Poaceae with new functions in nitrile metabolism
Authors: Jenrich Roland , Trompetter Inga , Bak Søren , Olsen Carl Erik , Møller Birger Lindberg , Piotrowski Markus
Published: November 2007

Members of the nitrilase 4 (NIT4) family of higher plants catalyze the conversion of β-cyanoalanine to aspartic acid and asparagine, a key step in cyanide detoxification. Grasses (Poaceae) possess two different NIT4 homologs (NIT4A and NIT4B), but none of the recombinant Poaceae enzymes analyzed showed activity with β-cyanoalanine, whereas protein extracts of the same plants clearly posses this activity.
Sorghum bicolor
contains three NIT4 isoforms
Sb
NIT4A,
Sb
NIT4B1, and
Sb
NIT4B2. Individually, each isoform does not possess enzymatic activity whereas the heteromeric complexes
Sb
NIT4A/B1 and
Sb
NIT4A/B2 hydrolyze β-cyanoalanine with high activity. In addition, the
Sb
NIT4A/B2 complex accepts additional substrates, the best being 4-hydroxyphenylacetonitrile. Corresponding NIT4A and NIT4B isoforms from other Poaceae species can functionally complement the sorghum isoforms in these complexes. Site-specific mutagenesis of the active site cysteine residue demonstrates that hydrolysis of β-cyanoalanine is catalyzed by the NIT4A isoform in both complexes whereas hydrolysis of 4-hydroxyphenylacetonitrile occurs at the NIT4B2 isoform. 4-Hydroxyphenylacetonitrile was shown to be an
in vitro
breakdown product of the cyanogenic glycoside dhurrin, a main constituent in
S. bicolor
. The results indicate that the
Sb
NIT4A/B2 heterocomplex plays a key role in an endogenous turnover of dhurrin proceeding via 4-hydroxyphenylacetonitrile and thereby avoiding release of toxic hydrogen cyanide. The operation of this pathway would enable plants to use cyanogenic glycosides as transportable and remobilizable nitrogenous storage compounds. Through combinatorial biochemistry and neofunctionalizations, the small family of nitrilases has gained diverse biological functions in nitrile metabolism.
The Parkinson's disease gene DJ-1 is also a key regulator of stroke-induced damage
Authors: Aleyasin Hossein , Rousseaux Maxime W. C. , Phillips Maryam , Kim Raymond H. , Bland Ross J. , Callaghan Steve , Slack Ruth S. , During Matthew J. , Mak Tak W. , Park David S.
Published: November 2007

Recent evidence has indicated that common mechanisms play roles among multiple neurological diseases. However, the specifics of these pathways are not completely understood. Stroke is caused by the interruption of blood flow to the brain, and cumulative evidence supports the critical role of oxidative stress in the ensuing neuronal death process. DJ-1 (
PARK7
) has been identified as the gene linked to early-onset familial Parkinson's disease. Currently, our work also shows that DJ-1 is central to death in both
in Vitro
and
in Vivo
models of stroke. Loss of DJ-1 increases the sensitivity to excitotoxicity and ischemia, whereas expression of DJ-1 can reverse this sensitivity and indeed provide further protection. Importantly, DJ-1 expression decreases markers of oxidative stress after stroke insult
in Vivo
, suggesting that DJ-1 protects through alleviation of oxidative stress. Consistent with this finding, we demonstrate the essential role of the oxidation-sensitive cysteine-106 residue in the neuroprotective activity of DJ-1 after stroke. Our work provides an important example of how a gene seemingly specific for one disease, in this case Parkinson's disease, also appears to be central in other neuropathological conditions such as stroke. It also highlights the important commonalities among differing neuropathologies.
Growth inhibition of non-small-cell lung carcinoma by BN/GRP antagonist is linked with suppression of K-Ras, COX-2, and pAkt
Authors: Hohla Florian , Schally Andrew V. , Kanashiro Celia A. , Buchholz Stefan , Baker Benjamin , Kannadka Chandrika , Moder Angelika , Aigner Elmar , Datz Christian , Halmos Gabor
Published: November 2007

Bombesin (BN) or gastrin-releasing peptide (GRP) can stimulate the growth of neoplasms such as breast cancer and small-cell lung carcinoma (SCLC). Antagonists of BN/GRP have been shown to inhibit these cancers. We evaluated whether antagonists of BN/GRP can suppress the growth of human non-SCLC (NSCLC) xenografted into nude mice. The effect of the administration of BN/GRP antagonist RC-3940-II on the growth of H460 and A549 NSCLC cell lines orthotopically xenografted into the intrapulmonary interstitium was examined. Protein levels of K-Ras, COX-2, Akt/pAkt, WT p53, Erk1/2, and lung resistance-related protein (LRP) in tumors were analyzed by Western blot analaysis, and receptors for BN/GRP were investigated by radioligand-binding studies. The effect of RC-3940-II on the proliferation of H460 and A549 cells
in vitro
was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays. High-affinity receptors for BN/GRP were found on tumors. Treatment with RC-3940-II significantly (
P
< 0.001) inhibited growth of H460 and A549 NSCLC xenografts by 30–50% and led to an improved performance status, compared with controls. In H460 NSCLC, the antitumor effect was associated with a significant (
P
< 0.001) reduction in protein levels of K-Ras, COX-2, pAkt, and pERK1/2 and with a major augmentation in the expression of WT p53, compared with controls. In A549 NSCLC, pAkt and LRP were significantly down-regulated. Our findings demonstrate the efficacy of BN/GRP antagonist RC-3940-II for the treatment of NSCLC. The suppression of K-Ras, COX-2, pAkt, and LRP, as well as the up-regulation of WT p53 might contribute to the antitumor action of BN/GRP antagonists.
Empowerment-Based Research Methods: A 10-Year Approach to Enhancing Indigenous Social and Emotional Wellbeing
Authors: Tsey Komla , Wilson Andrew , Haswell-Elkins Melissa , Whiteside Mary , McCalman Janya , Cadet-James Yvonne , Wenitong Mark
Published: November 2007

Objectives: This paper describes a research program that has operationalized the links between empowerment at personal/family, group/organizational and community/structural levels and successful mechanisms to address Indigenous social and emotional wellbeing issues such as family violence and abuse, suicide prevention and incarceration.

Methods: A two-pronged approach, involving the Family Wellbeing Empowerment Program and Participatory Action Research, was used to enhance the capacity of program participants and their communities to take greater charge of issues affecting their health and wellbeing.

Results: Key program outcomes include an enhancement of participants’ sense of self worth, resilience, problem-solving ability, ability to address immediate family difficulties as well as belief in the mutability of the social environment. There is also evidence of increasing capacity to address wider structural issues such as poor school attendance rates, the critical housing shortage, endemic family violence, alcohol and drug misuse, chronic disease, and over-representation of Indigenous men in the criminal justice system. Participants are also breaking new ground in areas such as values-based Indigenous workforce development and organizational change, as well as issues about contemporary Indigenous spirituality.

Conclusions: The use of a long-term (10-year) community research strategy focussing directly on empowerment has demonstrated the power of this approach to facilitate Indigenous people's capacity to regain social and emotional wellbeing and begin to rebuild the social norms of their families and community.
Enhancing the Accessibility of Public Mental Health Services in Queensland to Meet the Needs of Deaf People From an Indigenous Australian or Culturally and Linguistically Diverse Background
Authors: Denman Lara
Published: November 2007

Objective: The aim of this paper was to identify the accessibility barriers that deaf people from an Indigenous Australian or culturally and linguistically diverse background encounter when attempting to access public mental health services in Queensland.

Method: Consultation with key stakeholders was undertaken.

Results: Many of the barriers that deter deaf Indigenous Australians from accessing public mental health services in Queensland, in addition to preventing them from having access to the same continuum of care available to hearing English-speaking people were identified.

Conclusions: Deaf Indigenous Australians encounter significant barriers when they seek to access public mental health services in Queensland. If these barriers are to be dissolved to ensure access to the same continuum of mental health care available to hearing English-speaking then a series of education and training, research and resource strategies need to be further addressed.
Ca2+-dependent Calmodulin Binding to FcRn Affects Immunoglobulin G Transport in the Transcytotic Pathway
Authors: Dickinson Bonny L. , Claypool Steven M. , D'Angelo June A. , Aiken Martha L. , Venu Nanda , Yen Elizabeth H. , Wagner Jessica S. , Borawski Jason A. , Pierce Amy T. , Hershberg Robert , Blumberg Richard S. , Lencer Wayne I.
Published: November 2007

The Fcγ receptor FcRn transports immunoglobulin G (IgG) so as to avoid lysosomal degradation and to carry it bidirectionally across epithelial barriers to affect mucosal immunity. Here, we identify a calmodulin-binding site within the FcRn cytoplasmic tail that affects FcRn trafficking. Calmodulin binding to the FcRn tail is direct, calcium-dependent, reversible, and specific to residues comprising a putative short amphipathic α-helix immediately adjacent to the membrane. FcRn mutants with single residue substitutions in this motif, or FcRn mutants lacking the cytoplasmic tail completely, exhibit a shorter half-life and attenuated transcytosis. Chemical inhibitors of calmodulin phenocopy the mutant FcRn defect in transcytosis. These results suggest a novel mechanism for regulation of IgG transport by calmodulin-dependent sorting of FcRn and its cargo away from a degradative pathway and into a bidirectional transcytotic route.
Independent component analysis for the extraction of reliable protein signal profiles from MALDI-TOF mass spectra
Authors: Mantini Dante , Petrucci Francesca , Del Boccio Piero , Pieragostino Damiana , Di Nicola Marta , Lugaresi Alessandra , Federici Giorgio , Sacchetta Paolo , Di Ilio Carmine , Urbani Andrea
Published: November 2007

Motivation: Independent component analysis (ICA) is a signal processing technique that can be utilized to recover independent signals from a set of their linear mixtures. We propose ICA for the analysis of signals obtained from large proteomics investigations such as clinical multi-subject studies based on MALDI-TOF MS profiling. The method is validated on simulated and experimental data for demonstrating its capability of correctly extracting protein profiles from MALDI-TOF mass spectra.

Results: The comparison on peak detection with an open-source and two commercial methods shows its superior reliability in reducing the false discovery rate of protein peak masses. Moreover, the integration of ICA and statistical tests for detecting the differences in peak intensities between experimental groups allows to identify protein peaks that could be indicators of a diseased state. This data-driven approach demonstrates to be a promising tool for biomarker-discovery studies based on MALDI-TOF MS technology.

Availability: The MATLAB implementation of the method described in the article and both simulated and experimental data are freely available at http://www.unich.it/proteomica/bioinf/.

Contact:  a.urbani@unich.it
vbmp: Variational Bayesian Multinomial Probit Regression for multi-class classification in R
Authors: Lama Nicola , Girolami Mark
Published: November 2007

Summary: vbmp is an R package for Gaussian Process classification of data over multiple classes. It features multinomial probit regression with Gaussian Process priors and estimates class posterior probabilities employing fast variational approximations to the full posterior. This software also incorporates feature weighting by means of Automatic Relevance Determination. Being equipped with only one main function and reasonable default values for optional parameters, vbmp combines flexibility with ease of usage as is demonstrated on a breast cancer microarray study.

Availability: The R library vbmp implementing this method is part of Bioconductor and can be downloaded from http://www.dcs.gla.ac.uk/~girolami

Contact:  nicola.lama@unina2.it

Supplementary information: Supplementary data are available at http://www.dcs.gla.ac.uk/~girolami
MetaNetter: inference and visualization of high-resolution metabolomic networks
Authors: Jourdan Fabien , Breitling Rainer , Barrett Michael P. , Gilbert David
Published: November 2007

Summary: We present a Cytoscape plugin for the inference and visualization of networks from high-resolution mass spectrometry metabolomic data. The software also provides access to basic topological analysis. This open source, multi-platform software has been successfully used to interpret metabolomic experiments and will enable others using filtered, high mass accuracy mass spectrometric data sets to build and analyse networks.

Availability:  http://compbio.dcs.gla.ac.uk/fabien/abinitio/abinitio.html

Contact:  Fabien.Jourdan@toulouse.inra.fr

Supplementary information:  http://compbio.dcs.gla.ac.uk/fabien/abinitio/doc/Supplementary.pdf
Kernel approaches for genic interaction extraction
Authors: Kim Seonho , Yoon Juntae , Yang Jihoon
Published: November 2007

Motivation: Automatic knowledge discovery and efficient information access such as named entity recognition and relation extraction between entities have recently become critical issues in the biomedical literature. However, the inherent difficulty of the relation extraction task, mainly caused by the diversity of natural language, is further compounded in the biomedical domain because biomedical sentences are commonly long and complex. In addition, relation extraction often involves modeling long range dependencies, discontiguous word patterns and semantic relations for which the pattern-based methodology is not directly applicable.

Results: In this article, we shift the focus of biomedical relation extraction from the problem of pattern extraction to the problem of kernel construction. We suggest four kernels: predicate, walk, dependency and hybrid kernels to adequately encapsulate information required for a relation prediction based on the sentential structures involved in two entities. For this purpose, we view the dependency structure of a sentence as a graph, which allows the system to deal with an essential one from the complex syntactic structure by finding the shortest path between entities. The kernels we suggest are augmented gradually from the flat features descriptions to the structural descriptions of the shortest paths. As a result, we obtain a very promising result, a 77.5 F-score with the walk kernel on the Language Learning in Logic (LLL) 05 genic interaction shared task.

Availability: The used algorithms are free for use for academic research and are available from our Web site http://mllab.sogang.ac.kr/∼shkim/LLL05.tar.gz.

Contact:  shkim@lex.yonsei.ac.kr
A Kampo Medicine, Boi‐ogi‐to, Inhibits Obesity in Ovariectomized Rats
Authors: Yamakawa Jun-ichi , Moriya Junji , Takahashi Takashi , Ishige Atsushi , Motoo Yoshiharu , Yoshizaki Fumihiko , Kanda Tsugiyasu
Published: November 2007

In women facing menopause, end of menstrual activity is accompanied by lower levels of estrogen and gradual weight gain. Postmenopausal weight gain sounds an alarm for women′s health and may lead to hyperlipidemia, a lipid increase and glucose intolerance. These phenomena are connected to lifestyle‐related diseases such as hypertension, type II diabetes mellitus, arteriosclerosis and metabolic syndrome, making it essential to prevent weight gain in women. A Kampo medicine, Boi‐ogi‐to, is traditionally used to treat obese conditions, but the mechanism has not yet been investigated. In this experiment, we tested the antiobesity properties of Boi‐ogi‐to in ovariectomized rats by measuring changes of serum cytokine levels and adipocytokines in fat cells. After treatment with this extract for 6 weeks (20‐week‐old rats), we found that there was a significant weight decrease in rats treated with Boi‐ogi‐to as compared with that in the control group. Serum tumor necrosis factor (TNF)‐α levels increased significantly in a dose‐dependent manner. Gene expression of adipose tissue in uterus also dose dependently showed a significant increase of TNF‐α levels, suggesting that secretion of TNF‐α by fat cells might play a role in the ability of Boi‐ogi‐to to inhibit weight gain. While peroxisome proliferators‐activated receptor‐γ and adiponectin levels did not show a significant difference as compared with those in the control, levels of mRNA expression showed a tendency to increase dose dependently. Resistin did not show any significant change. These results suggest that Boi‐ogi‐to might be useful for the prevention of obesity that occurs in women with reduction of estrogen.
Collaborative Governance in Theory and Practice
Authors: Ansell Chris , Gash Alison
Published: November 2007

Over the past few decades, a new form of governance has emerged to replace adversarial and managerial modes of policy making and implementation. Collaborative governance, as it has come to be known, brings public and private stakeholders together in collective forums with public agencies to engage in consensus-oriented decision making. In this article, we conduct a meta-analytical study of the existing literature on collaborative governance with the goal of elaborating a contingency model of collaborative governance. After reviewing 137 cases of collaborative governance across a range of policy sectors, we identify critical variables that will influence whether or not this mode of governance will produce successful collaboration. These variables include the prior history of conflict or cooperation, the incentives for stakeholders to participate, power and resources imbalances, leadership, and institutional design. We also identify a series of factors that are crucial within the collaborative process itself. These factors include face-to-face dialogue, trust building, and the development of commitment and shared understanding. We found that a virtuous cycle of collaboration tends to develop when collaborative forums focus on “small wins” that deepen trust, commitment, and shared understanding. The article concludes with a discussion of the implications of our contingency model for practitioners and for future research on collaborative governance.
Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells
Authors: Garcia Susana M. , Casanueva M. Olivia , Silva M. Catarina , Amaral Margarida D. , Morimoto Richard I.
Published: November 2007

Protein homeostasis maintains proper intracellular balance by promoting protein folding and clearance mechanisms while minimizing the stress caused by the accumulation of misfolded and damaged proteins. Chronic expression of aggregation-prone proteins is deleterious to the cell and has been linked to a wide range of conformational disorders. The molecular response to misfolded proteins is highly conserved and generally studied as a cell-autonomous process. Here, we provide evidence that neuronal signaling is an important modulator of protein homeostasis in post-synaptic muscle cells. In a forward genetic screen in Caenorhabditis elegans for enhancers of polyglutamine aggregation in muscle cells, we identified unc-30, a neuron-specific transcription factor that regulates the synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). We used additional sensors of protein conformational states to show that defective GABA signaling or increased acetylcholine (ACh) signaling causes a general imbalance in protein homeostasis in post-synaptic muscle cells. Moreover, exposure to GABA antagonists or ACh agonists has a similar effect, which reveals that toxins that act at the neuromuscular junction are potent modifiers of protein conformational disorders. These results demonstrate the importance of intercellular communication in intracellular homeostasis.
The neurohormone orexin stimulates hypoxia-inducible factor-1 activity
Authors: Sikder Devanjan , Kodadek Thomas
Published: November 2007

Orexin A and Orexin B (also known as hypocretins) are neuropeptides that bind two related G-coupled protein receptors (OXR1 and OXR2) and thus induce wakefulness, food consumption, and locomotion. Conversely, deletion of the orexin gene in mice produces a condition similar to canine and human narcolepsy. Despite the central importance of the orexin system in regulating wakefulness and feeding behavior, little is known about the downstream signaling mechanisms that achieve these effects. In this study, genomics techniques are used to probe this question and reveal that orexin activates the hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor whose pathogenic role in stimulating angiogenesis in hypoxic tumors has been the focus of intense investigation. Orexin-stimulated HIF-1 activity is due to both increased HIF-1α gene transcription and a down-regulation of von Hippel-Lindau (VHL), the E3 ubiquitin ligase that mediates the turnover of HIF-1 via the ubiquitin–proteasome pathway. Orexin-mediated activation of HIF-1 results in increased glucose uptake and higher glycolytic activity, as expected from studies of hypoxic cells. However, orexin receptor-expressing cells somehow override the HIF-1-mediated preference for funneling pyruvate into anaerobic glycolysis and instead favor ATP production through the tricarboxylic acid cycle and oxidative phosphorylation. These findings implicate HIF-1 as an important transcription factor in the hormone-mediated regulation of hunger and wakefulness.
Pin1 modulates RNA polymerase II activity during the transcription cycle
Authors: Xu Yu-Xin , Manley James L.
Published: November 2007

The C-terminal domain of the RNA polymerase (RNAP) II largest subunit (CTD) plays a critical role in coordinating multiple events in pre-mRNA transcription and processing. Previously we reported that the peptidyl prolyl isomerase Pin1 modulates RNAP II function during the cell cycle. Here we provide evidence that Pin1 affects multiple aspects of RNAP II function via its regulation of CTD phosphorylation. Using chromatin immunoprecipitation (ChIP) assays with CTD phospho-specific antibodies, we confirm that RNAP II displays a dynamic association with specific genes during the cell cycle, preferentially associating with transcribed genes in S phase, while disassociating in M phase in a matter that correlates with changes in CTD phosphorylation. Using inducible Pin1 cell lines, we show that Pin1 overexpression is sufficient to release RNAP II from chromatin, which then accumulates in a hyperphosphorylated form in nuclear speckle-associated structures. In vitro transcription assays show that Pin1 inhibits transcription in nuclear extract, while an inactive Pin1 mutant in fact stimulates it. Several assays indicate that the inhibition largely reflects Pin1 activity during transcription initiation and not elongation, suggesting that Pin1 modulates CTD phosphorylation, and RNAP II activity, during an early stage of the transcription cycle.
A novel class of bacteria-induced small RNAs in Arabidopsis
Authors: Katiyar-Agarwal Surekha , Gao Shang , Vivian-Smith Adam , Jin Hailing
Published: November 2007

Small RNAs, including microRNAs (miRNAs) and small interfering RNAs (siRNAs), are essential regulatory molecules of many cellular processes. Arabidopsis has at least three classes of endogenous siRNAs—chromatin-associated siRNAs, trans-acting siRNAs (tasiRNAs), and natural antisense transcript (NAT)-associated siRNAs (nat-siRNAs)—all 20–25 nucleotides (nt) in length. Here, we identified a novel class of small RNAs, long siRNAs (lsiRNAs), which are 30–40 nt and share many common features with known siRNAs. The lsiRNAs identified so far are induced by pathogen infection or under specific growth conditions. One of the lsiRNAs, AtlsiRNA-1, is generated from SRRLK/AtRAP NAT pair and specifically induced by the bacterium Pseudomonas syringae carrying effector avrRpt2. Recently, 25- to 31-nt PIWI-interacting RNAs (piRNAs) and repeat-associated siRNAs (rasiRNAs) were identified in animal germline cells. In contrast to the biogenesis of piRNAs/rasiRNAs, which is dicer independent and requires PIWI subfamily proteins, generation of AtlsiRNA-1 requires DCL1, DCL4, and the ARGONAUTE subfamily protein AGO7. It also depends on HYL1, HEN1, HST1, RDR6, and Pol IV. Induction of AtlsiRNA-1 silences AtRAP, which encodes a RAP-domain protein involved in disease resistance. Our further analysis implies that AtlsiRNA-1 may destabilize target mRNA through decapping and XRN4-mediated 5′-to-3′ degradation.
Riboswitch-dependent gene regulation and its evolution in the plant kingdom
Authors: Bocobza Samuel , Adato Avital , Mandel Tali , Shapira Michal , Nudler Evgeny , Aharoni Asaph
Published: November 2007

Riboswitches are natural RNA sensors that affect gene control via their capacity to bind small molecules. Their prevalence in higher eukaryotes is unclear. We discovered a post-transcriptional mechanism in plants that uses a riboswitch to control a metabolic feedback loop through differential processing of the precursor RNA 3′ terminus. When cellular thiamin pyrophosphate (TPP) levels rise, metabolite sensing by the riboswitch located in TPP biosynthesis genes directs formation of an unstable splicing product, and consequently TPP levels drop. When transformed in plants, engineered TPP riboswitches can act autonomously to modulate gene expression. In an evolutionary perspective, a TPP riboswitch is also present in ancient plant taxa, suggesting that this mechanism is active since vascular plants emerged 400 million years ago.