bluuebunny/crossref_metadata_2025 huggingface dataset:
Facilitation of murine cardiac L-type Ca
v
1.2 channel is modulated by Calmodulin kinase II–dependent phosphorylation of S1512 and S1570
Authors: Blaich Anne , Welling Andrea , Fischer Stefanie , Wegener Jörg Werner , Köstner Katharina , Hofmann Franz , Moosmang Sven
Published: May 2010

Activity-dependent means of altering calcium (Ca
2
+
) influx are assumed to be of great physiological consequence, although definitive tests of this assumption have only begun to emerge. Facilitation and inactivation offer two opposing, activity-dependent means of altering Ca
2+
influx via cardiac Ca
v
1.2 calcium channels. Voltage- and frequency-dependent facilitation of Ca
v
1.2 has been reported to depend on Calmodulin (CaM) and/or the activity of Calmodulin kinase II (CaMKII). Several sites within the cardiac L-type calcium channel complex have been proposed as the targets of CaMKII. Here, we generated mice with knockin mutations of α
1
1.2 S1512 and S1570 phosphorylation sites [sine facilitation (SF) mice]. Homocygote SF mice were viable and reproduced in a Mendelian ratio. Voltage-dependent facilitation in ventricular cardiomyocytes carrying the SF mutation was decreased from 1.58- to 1.18-fold. The CaMKII inhibitor KN-93 reduced facilitation to 1.28 in control cardiomyocytes. SF mutation negatively shifted the voltage-dependent inactivation and slowed recovery from inactivation, thereby making fewer channels available for activation. Telemetric ECG recordings at different heart rates showed that QT time decreased significantly more in SF than in control mice at higher rates. Our results strongly support the notion that CaMKII-dependent phosphorylation of Cav1.2 at S1512 and S1570 mediates Ca
2+
current facilitation in the murine heart.
Multiple
GAL
pathway gene clusters evolved independently and by different mechanisms in fungi
Authors: Slot Jason C. , Rokas Antonis
Published: May 2010

A notable characteristic of fungal genomes is that genes involved in successive steps of a metabolic pathway are often physically linked or clustered. To investigate how such clusters of functionally related genes are assembled and maintained, we examined the evolution of gene sequences and order in the galactose utilization (
GAL
) pathway in whole-genome data from 80 diverse fungi. We found that
GAL
gene clusters originated independently and by different mechanisms in three unrelated yeast lineages. Specifically, the
GAL
cluster found in
Saccharomyces
and
Candida
yeasts originated through the relocation of native unclustered genes, whereas the
GAL
cluster of
Schizosaccharomyces
yeasts was acquired through horizontal gene transfer from a
Candida
yeast. In contrast, the
GAL
cluster of
Cryptococcus
yeasts was assembled independently from the
Saccharomyces
/
Candida
and
Schizosaccharomyces GAL
clusters and coexists in the
Cryptococcus
genome with unclustered
GAL
paralogs. These independently evolved
GAL
clusters represent a striking example of analogy at the genomic level. We also found that species with
GAL
clusters exhibited significantly higher rates of
GAL
pathway loss than species with unclustered
GAL
genes. These results suggest that clustering of metabolic genes might facilitate fungal adaptation to changing environments both through the acquisition and loss of metabolic capacities.
Circuit topology for synchronizing neurons in spontaneously active networks
Authors: Takahashi Naoya , Sasaki Takuya , Matsumoto Wataru , Matsuki Norio , Ikegaya Yuji
Published: May 2010

Spike synchronization underlies information processing and storage in the brain. But how can neurons synchronize in a noisy network? By exploiting a high-speed (500–2,000 fps) multineuron imaging technique and a large-scale synapse mapping method, we directly compared spontaneous activity patterns and anatomical connectivity in hippocampal CA3 networks ex vivo. As compared to unconnected pairs, synaptically coupled neurons shared more common presynaptic neurons, received more correlated excitatory synaptic inputs, and emitted synchronized spikes with approximately 10
7
times higher probability. Importantly, common presynaptic parents per se synchronized more than unshared upstream neurons. Consistent with this, dynamic-clamp stimulation revealed that common inputs alone could not account for the realistic degree of synchronization unless presynaptic spikes synchronized among common parents. On a macroscopic scale, network activity was coordinated by a power-law scaling of synchronization, which engaged varying sets of densely interwired (thus highly synchronized) neuron groups. Thus, locally coherent activity converges on specific cell assemblies, thereby yielding complex ensemble dynamics. These segmentally synchronized pulse packets may serve as information modules that flow in associatively parallel network channels.
Functional feedback from mushroom bodies to antennal lobes in the
Drosophila
olfactory pathway
Authors: Hu Aiqun , Zhang Wei , Wang Zuoren
Published: May 2010

Feedback plays important roles in sensory processing. Mushroom bodies are believed to be involved in olfactory learning/memory and multisensory integration in insects. Previous cobalt-labeling studies have suggested the existence of feedback from the mushroom bodies to the antennal lobes in the honey bee. In this study, the existence of functional feedback from
Drosophila
mushroom bodies to the antennal lobes was investigated through ectopic expression of the ATP receptor P2X
2
in the Kenyon cells of mushroom bodies. Activation of Kenyon cells induced depolarization in projection neurons and local interneurons in the antennal lobes in a nicotinic receptor-dependent manner. Activation of Kenyon cell axons in the βγ-lobes in the mushroom body induced more potent responses in the antennal lobe neurons than activation of Kenyon cell somata. Our results indicate that functional feedback from Kenyon cells to projection neurons and local interneurons is present in
Drosophila
and is likely mediated by the βγ-lobes. The presence of this functional feedback from the mushroom bodies to the antennal lobes suggests top-down modulation of olfactory information processing in
Drosophila
.
Multiscale modeling of diffusion in the early
Drosophila
embryo
Authors: Sample Christine , Shvartsman Stanislav Y.
Published: May 2010

We developed a multiscale approach for the computationally efficient modeling of morphogen gradients in the syncytial
Drosophila
embryo, a single cell with multiple dividing nuclei. By using a homogenization technique, we derived a coarse-grained model with parameters that are explicitly related to the geometry of the syncytium and kinetics of nucleocytoplasmic shuttling. One of our main results is an accurate analytical approximation for the effective diffusivity of a morphogen molecule as a function of the nuclear density. We used this expression to explore the dynamics of the Bicoid morphogen gradient, a signal that patterns the anterior-posterior axis of the embryo. A similar approach can be used to analyze the dynamics of all three maternal morphogen gradients in
Drosophila
.
A viral assembly factor promotes AAV2 capsid formation in the nucleolus
Authors: Sonntag Florian , Schmidt Kristin , Kleinschmidt Jürgen A.
Published: May 2010

The volume available in icosahedral virus capsids limits the size of viral genomes. To overcome this limitation, viruses have evolved strategies to increase their coding capacity by using more than one ORF while keeping the genome length constant. The assembly of virus capsids requires the coordinated interaction of a large number of subunits to generate a highly ordered structure in which the viral genome can be enclosed. To understand this process, it is essential to know which viral and nonviral components are involved in the assembly reaction. Here, we show that the adeno-associated virus (AAV) encodes a protein required for capsid formation by means of a nested, alternative ORF of the
cap
gene. Translation is initiated at a nonconventional translation start site, resulting in the expression of a protein with a calculated molecular weight of 23 kDa. This protein, designated assembly-activating protein (AAP), is localized in the host cell nucleolus, where AAV capsid morphogenesis occurs. AAP targets newly synthesized capsid proteins to this organelle and in addition fulfils a function in the assembly reaction itself. Sequence analysis suggests that also all other species of the genus Dependovirus encode a homologous protein in their
cap
gene. The arrangement of different ORFs that encode capsid proteins and an assembly factor within the same mRNA facilitates a timely coordinated expression of the components involved in the assembly process.
Ancient origin of the integrin-mediated adhesion and signaling machinery
Authors: Sebé-Pedrós Arnau , Roger Andrew J. , Lang Franz B. , King Nicole , Ruiz-Trillo Iñaki
Published: May 2010

The evolution of animals (metazoans) from their unicellular ancestors required the emergence of novel mechanisms for cell adhesion and cell–cell communication. One of the most important cell adhesion mechanisms for metazoan development is integrin-mediated adhesion and signaling. The integrin adhesion complex mediates critical interactions between cells and the extracellular matrix, modulating several aspects of cell physiology. To date this machinery has been considered strictly metazoan specific. Here we report the results of a comparative genomic analysis of the integrin adhesion machinery, using genomic data from several unicellular relatives of Metazoa and Fungi. Unexpectedly, we found that core components of the integrin adhesion complex are encoded in the genome of the apusozoan protist
Amastigomonas
sp., and therefore their origins predate the divergence of Opisthokonta, the clade that includes metazoans and fungi. Furthermore, our analyses suggest that key components of this apparatus have been lost independently in fungi and choanoflagellates. Our data highlight the fact that many of the key genes that had formerly been cited as crucial for metazoan origins have a much earlier origin. This underscores the importance of gene cooption in the unicellular-to-multicellular transition that led to the emergence of the Metazoa.
Analysis of factorial time-course microarrays with application to a clinical study of burn injury
Authors: Zhou Baiyu , Xu Weihong , Herndon David , Tompkins Ronald , Davis Ronald , Xiao Wenzhong , Wong Wing Hung ,   Inflammation and Host Response to Injury Program, Toner Mehmet , Warren H. Shaw , Schoenfeld David A. , Rahme Laurence , McDonald-Smith Grace P. , Hayden Douglas , Mason Philip , Fagan Shawn , Yu Yong-Ming , Cobb J. Perren , Remick Daniel G. , Mannick John A. , Lederer James A. , Gamelli Richard L. , Silver Geoffrey M. , West Michael A. , Shapiro Michael B. , Smith Richard , Camp David G. , Qian Weijun , Storey John , Mindrinos Michael , Tibshirani Rob , Lowry Stephen , Calvano Steven , Chaudry Irshad , West Michael A. , Cohen Mitchell , Moore Ernest E. , Johnson Jeffrey , Moldawer Lyle L. , Baker Henry V. , Efron Philip A. , Balis Ulysses G.J. , Billiar Timothy R. , Ochoa Juan B. , Sperry Jason L. , Miller-Graziano Carol L. , De Asit K. , Bankey Paul E. , Finnerty Celeste C. , Jeschke Marc G. , Minei Joseph P. , Arnoldo Brett D. , Hunt John L. , Horton Jureta , Cobb J. Perren , Brownstein Bernard , Freeman Bradley , Maier Ronald V. , Nathens Avery B. , Cuschieri Joseph , Gibran Nicole , Klein Matthew , O’Keefe Grant
Published: May 2010

Time-course microarray experiments are capable of capturing dynamic gene expression profiles. It is important to study how these dynamic profiles depend on the multiple factors that characterize the experimental condition under which the time course is observed. Analytic methods are needed to simultaneously handle the time course and factorial structure in the data. We developed a method to evaluate factor effects by pooling information across the time course while accounting for multiple testing and nonnormality of the microarray data. The method effectively extracts gene-specific response features and models their dependency on the experimental factors. Both longitudinal and cross-sectional time-course data can be handled by our approach. The method was used to analyze the impact of age on the temporal gene response to burn injury in a large-scale clinical study. Our analysis reveals that 21% of the genes responsive to burn are age-specific, among which expressions of mitochondria and immunoglobulin genes are differentially perturbed in pediatric and adult patients by burn injury. These new findings in the body’s response to burn injury between children and adults support further investigations of therapeutic options targeting specific age groups. The methodology proposed here has been implemented in R package “TANOVA” and submitted to the Comprehensive R Archive Network at
http://www.r-project.org/
. It is also available for download at
http://gluegrant1.stanford.edu/TANOVA/
.
Chemical structure, network topology, and porosity effects on the mechanical properties of Zeolitic Imidazolate Frameworks
Authors: Tan Jin Chong , Bennett Thomas D. , Cheetham Anthony K.
Published: May 2010

The mechanical properties of seven zeolitic imidazolate frameworks (ZIFs) based on five unique network topologies have been systematically characterized by single-crystal nanoindentation studies. We demonstrate that the elastic properties of ZIF crystal structures are strongly correlated to the framework density and the underlying porosity. For the systems considered here, the elastic modulus was found to range from 3 to 10 GPa, whereas the hardness property lies between 300 MPa and 1.1 GPa. Notably, these properties are superior to those of other metal–organic frameworks (MOFs), such as MOF-5. In substituted imidazolate frameworks, our results show that their mechanical properties are mainly governed by the rigidity and bulkiness of the substituted organic linkages. The framework topology and the intricate pore morphology can also influence the degree of mechanical anisotropy. Our findings present the previously undescribed structure-mechanical property relationships pertaining to hybrid open frameworks that are important for the design and application of new MOF materials.
Isolation, expression analysis, and functional characterization of the first antidiuretic hormone receptor in insects
Authors: Paluzzi Jean-Paul , Park Yoonseong , Nachman Ronald J. , Orchard Ian
Published: May 2010

Diuresis following blood-gorging in
Rhodnius prolixus
is the major process leading to the transmission of Chagas’ disease. We have cloned the cDNA of the first receptor known to be involved in an antidiuretic strategy in insects, a strategy that prevents diuresis. This receptor belongs to the insect CAPA receptor family known in other insects to be activated by peptides encoded within the
capability
gene. We characterize the expression profile in fifth-instars and find expression is localized to the alimentary canal. Highest transcript levels are found in Malpighian tubules and the anterior midgut, which are known targets of the antidiuretic hormone, RhoprCAPA-α2. Two transcripts were identified,
capa-r1
and
capa-r2
; however, the latter encodes an atypical G protein-coupled receptor lacking a region ranging between the first and second transmembrane domain. Our heterologous expression assay revealed the expressed
capa-r1
receptor is activated by RhoprCAPA-α2 (EC
50
= 385nM) but not by RhoprCAPA-α1. Structural analogs of the inactive RhoprCAPA-α1 were capable of activating the expressed
capa-r1
receptor, confirming the importance of the C-terminal consensus sequence common to CAPA-related peptides. In addition, this receptor has some sensitivity to the pyrokinin-related peptide, RhoprCAPA-αPK1, but with an efficacy ≈40-fold less than RhoprCAPA-α2. Other peptides belonging to the PRXamide superfamily were inactive on the
capa-r1
receptor. Taken together, the neuroendocrinological relevance of this receptor in facilitating the antidiuretic strategy in
R. prolixus
may make this receptor a useful target for development of agonists or antagonists that could help influence the transmission of Chagas’ disease that occurs during diuresis in this medically important insect-disease vector.
Tissue-specific p19
Arf
regulation dictates the response to oncogenic K-ras
Authors: Young Nathan P. , Jacks Tyler
Published: May 2010

The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the
Ink4a/Arf
locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras
G12D
in vivo has not been examined. Using compound mutant mice containing the

Arf
GFP

reporter and the spontaneously activating

K-ras
LA2

allele, we have uncovered dramatic tissue specificity of K-ras
G12D
-dependent p19
Arf
up-regulation. Lung tumors, which can arise in the presence of functional p19
Arf
, rarely display p19
Arf
induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19
Arf
-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of
Ink4a/Arf
as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19
Arf
induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.
Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice
Authors: Kakoki Masao , Sullivan Kelli A. , Backus Carey , Hayes John M. , Oh Sang Su , Hua Kunjie , Gasim Adil M. H. , Tomita Hirofumi , Grant Ruriko , Nossov Sarah B. , Kim Hyung-Suk , Jennette J. Charles , Feldman Eva L. , Smithies Oliver
Published: May 2010

An insertion polymorphism of the angiotensin-I converting enzyme gene (
ACE
) is common in humans and the higher expressing allele is associated with an increased risk of diabetic complications. The
ACE
polymorphism does not significantly affect blood pressure or angiotensin II levels, suggesting that the kallikrein-kinin system partly mediates the effects of the polymorphism. We have therefore explored the influence of lack of both bradykinin receptors (B1R and B2R) on diabetic nephropathy, neuropathy, and osteopathy in male mice heterozygous for the Akita diabetogenic mutation in the insulin 2 gene (
Ins2
). We find that all of the detrimental phenotypes observed in Akita diabetes are enhanced by lack of both B1R and B2R, including urinary albumin excretion, glomerulosclerosis, glomerular basement membrane thickening, mitochondrial DNA deletions, reduction of nerve conduction velocities and of heat sensation, and bone mineral loss. Absence of the bradykinin receptors also enhances the diabetes-associated increases in plasma thiobarbituric acid-reactive substances, mitochondrial DNA deletions, and renal expression of fibrogenic genes, including transforming growth factor beta1, connective tissue growth factor, and endothelin-1. Thus, lack of B1R and B2R exacerbates diabetic complications. The enhanced renal injury in diabetic mice caused by lack of B1R and B2R may be mediated by a combination of increases in oxidative stress, mitochondrial DNA damage and over expression of fibrogenic genes.
Superconducting high-pressure phases of disilane
Authors: Jin Xilian , Meng Xing , He Zhi , Ma Yanming , Liu Bingbing , Cui Tian , Zou Guangtian , Mao Ho-kwang
Published: May 2010

High-pressure structures of disilane (Si
2
H
6
) are investigated extensively by means of first-principles density functional theory and a random structure-searching method. Three metallic structures with
P
-1,
Pm
-3
m
, and
C
2/
c
symmetries are found, which are more stable than those of XY
3
-type candidates under high pressure. Enthalpy calculations suggest a remarkably wide decomposition (Si and H
2
) pressure range below 135 GPa, above which three metallic structures are stable. Perturbative linear-response calculations for
Pm
-3
m
disilane at 275 GPa show a large electron-phonon coupling parameter
λ
of 1.397 and the resulting superconducting critical temperature beyond the order of 10
2
 K.
Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus
Authors: Savitsky David A. , Yanai Hideyuki , Tamura Tomohiko , Taniguchi Tadatsugu , Honda Kenya
Published: May 2010

Interferon regulatory factor (IRF) 5 is a key transcription factor for the activation of innate immune responses downstream of Toll-like receptor signaling. Based on recent genetic analyses, IRF5 is a focus for its potential involvement in systemic lupus erythematosus (SLE), although how IRF5 contributes to SLE is uncertain. In this study, we demonstrate a requirement for IRF5 in the development of murine SLE via its role in B lymphocytes. We show that antinuclear autoantibodies and Ig glomerular deposits, hallmarks of SLE, are absent in

Irf5
−/−

mice challenged to develop SLE by pristane injection. In particular, production of autoantibodies of the IgG2a subtype, the most prominent isotype in inducing autoimmunity, requires IRF5. Finally, we provide evidence for the critical role of this transcription factor in the secretion of pathogenic antibodies through its direct control of class switch recombination of the γ2a locus. By demonstrating a B-cell-intrinsic role, this study places IRF5 in a context that may have implications for understanding the pathogenesis of human SLE.
A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism
Authors: Chen Wei , Zhang Xiaoting , Birsoy Kivanc , Roeder Robert G.
Published: May 2010

As conventional transcriptional factors that are activated in diverse signaling pathways, nuclear receptors play important roles in many physiological processes that include energy homeostasis. The MED1 subunit of the Mediator coactivator complex plays a broad role in nuclear receptor-mediated transcription by anchoring the Mediator complex to diverse promoter-bound nuclear receptors. Given the significant role of skeletal muscle, in part through the action of nuclear receptors, in glucose and fatty acid metabolism, we generated skeletal muscle-specific
Med1
knockout mice. Importantly, these mice show enhanced insulin sensitivity and improved glucose tolerance as well as resistance to high-fat diet–induced obesity. Furthermore, the white muscle of these mice exhibits increased mitochondrial density and expression of genes specific to type I and type IIA fibers, indicating a fast-to-slow fiber switch, as well as markedly increased expression of the brown adipose tissue-specific
UCP
-1 and
Cidea
genes that are involved in respiratory uncoupling. These dramatic results implicate MED1 as a powerful suppressor in skeletal muscle of genetic programs implicated in energy expenditure and raise the significant possibility of therapeutical approaches for metabolic syndromes and muscle diseases through modulation of MED1–nuclear receptor interactions.
Role of CaMKIIδ phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure
Authors: Kushnir Alexander , Shan Jian , Betzenhauser Matthew J. , Reiken Steven , Marks Andrew R.
Published: May 2010

The force frequency relationship (FFR), first described by Bowditch 139 years ago as the observation that myocardial contractility increases proportionally with increasing heart rate, is an important mediator of enhanced cardiac output during exercise. Individuals with heart failure have defective positive FFR that impairs their cardiac function in response to stress, and the degree of positive FFR deficiency correlates with heart failure progression. We have identified a mechanism for FFR involving heart rate dependent phosphorylation of the major cardiac sarcoplasmic reticulum calcium release channel/ryanodine receptor (RyR2), at Ser2814, by calcium/calmodulin–dependent serine/threonine kinase–δ (CaMKIIδ). Mice engineered with an RyR2-S2814A mutation have RyR2 channels that cannot be phosphorylated by CaMKIIδ, and exhibit a blunted positive FFR. Ex vivo hearts from RyR2-S2814A mice also have blunted positive FFR, and cardiomyocytes isolated from the RyR2-S2814A mice exhibit impaired rate-dependent enhancement of cytosolic calcium levels and fractional shortening. The cardiac RyR2 macromolecular complexes isolated from murine and human failing hearts have reduced CaMKIIδ levels. These data indicate that CaMKIIδ phosphorylation of RyR2 plays an important role in mediating positive FFR in the heart, and that defective regulation of RyR2 by CaMKIIδ-mediated phosphorylation is associated with the loss of positive FFR in failing hearts.
Life-history connections to rates of aging in terrestrial vertebrates
Authors: Ricklefs Robert E.
Published: May 2010

The actuarial senescence (i.e., the rate of increase in adult mortality with age) was related to body mass, development period, and age at sexual maturity across 124 taxonomic families of terrestrial vertebrates. Model selection based on Akaike's information criterion values adjusted for small size showed that the rate of aging decreases with increasing body mass, gestation period, age at maturity, and possession of flight. Among families of mammals, actuarial senescence was related to extrinsic mortality rate (standardized regression coefficient = 0.215), gestation period (−0.217), and age at maturity (−0.553). Although rate of aging in birds also was related to the embryo development period, birds grow several times more rapidly than mammals, and therefore, the connection between rate of early development and rate of aging is unclear. The strong vertebrate-wide relationship between rate of aging, or life span, and age at maturity can be explained by density-dependent feedback of adult survival rate on the recruitment of young individuals into the breeding population. Thus, age at maturity seems to reflect extrinsic mortality, which, in turn, influences selection on mechanisms that postpone physiological and actuarial senescence. Because rate of embryo development influences rate of aging independently of the age at maturity, in a statistical sense, the evolutionary diversification of development and aging seem to be connected in both birds and mammals; however, the linking mechanisms are not known.
Predicting Recidivism in Sex Offenders Using the SVR-20: The Contribution of Age-at-release
Authors: Barbaree HowardE. , Langton CalvinM. , Blanchard Ray , Boer DouglasP.
Published: May 2010

Sex offenders (N = 468) were released from custody and recidivism outcome was recorded. The Sexual Violence Risk-20 (SVR-20) was scored for each offender and the relationship between age-at-release and SVR-20 item and total scores was examined. SVR-20 total scores were not correlated with age-at-release (r = .-057). SVR-20 scores were combined with a score representing the age of the offender at their release from custody. On the basis of ROC analysis, predictive accuracy was significantly enhanced when age-atrelease was included in the risk score. We suggest that the SVR-20, and perhaps other similar risk instruments, could be improved by including age-at-release information. We discuss the possibility that the advantage obtained by empirical actuarial instruments may be due in part to their close relation with age-at-release.
Gender Differences in Violent Outcome and Risk Assessment in Adolescent Offenders After Residential Treatment
Authors: Lodewijks HennyP. B. , de Ruiter Corine , Doreleijers TheoA. H.
Published: May 2010

In light of the increase of violence in female adolescents during the past few decades, not only preventive, but also remedial strategies are important to mitigate this trend. Once high-risk female adolescents enter the juvenile justice system, it is important to be able to use reliable and valid instruments to predict reoffending. However, only a few studies have focused on risk assessment specifically addressing female adolescents. This prospective study examined gender differences in violent recidivism over an average follow-up period of 18 months after discharge, making use of the Dutch version of the Structured Assessment of Violence Risk in Youth (SAVRY). The SAVRY was coded for 35 female adolescents and a comparison sample of 47 male adolescents on the basis of file information before their release. The juvenile court had referred all these juveniles to a juvenile justice facility, because of violent offending and severe behavioral problems. Data on recidivism were retrieved from the Identification Service System of the National Police Services. Significant differences were found between the two gender groups on a number of SAVRY items. The predictive validity of the SAVRY for violent recidivism was good for girls (AUC = .85) and for boys (AUC = .82). However, false positives for girls were found more frequently than for boys. Implications for gender specific risk assessment and risk management in clinical practice are discussed.
Diagnostic Comorbidity in Psychotic Offenders and Their Criminal History: A Review of the Literature
Authors: Goethals KrisR. , Vorstenbosch EllenC.W. , van Marle HjalmarJ.C
Published: May 2010

There is growing evidence that there is a relationship between a psychotic disorder and violent behavior. Diagnostic comorbidity of a psychotic disorder with substance abuse, a personality disorder or psychopathy increases the likelihood of violence. The aim of this review is to examine the literature about the relationship between a psychotic disorder and violence, and about comorbidity of a psychotic disorder with substance abuse, a personality disorder and/or psychopathy. A search of www.PubMed.com and www.PsychInfo.com for the period 1990–2006 yielded 1942 articles. Ultimately, however, only 73 articles remained after eliminating those on irrelevant topics. Results showed that the roles of substance abuse, the presence of a personality disorder, or a high score on the revised psychopathy checklist are confirmed as important risk factors by many authors. This review revealed a high degree of agreement that possible comorbidity in schizophrenic offenders should be mentioned routinely in scientific research as it has an essential effect on the development of the offender's illness.
The Predictive Validity of the PCL:SV Among a Swiss Prison Population
Authors: Endrass Jérôme , Rossegger Astrid , Frischknecht Andreas , Noll Thomas , Urbaniok Frank
Published: May 2010

Recent studies have found mixed results for the ability of the PCL:SV to predict in-prison violence. The purpose of this study was to evaluate the accuracy of the PCL:SV for predicting in-prison violence in Switzerland. Method: PCL:SV scores were assessed from a sample of 114 prisoners sentenced to at least 10 months in prison for sexual or violent offenses. Results: Significant effect sizes for verbal aggressive behavior were found for sexual offenders. No significant results were found in a sample of violent offenders. No significant results were found for physical violence in any subgroup. Discussion: The results suggest only a limited degree of accuracy for the PCL:SV in predicting intramural aggressive behavior for the sample used in this study.
Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells
Authors: Poulin Lionel Franz , Salio Mariolina , Griessinger Emmanuel , Anjos-Afonso Fernando , Craciun Ligia , Chen Ji-Li , Keller Anna M. , Joffre Olivier , Zelenay Santiago , Nye Emma , Le Moine Alain , Faure Florence , Donckier Vincent , Sancho David , Cerundolo Vincenzo , Bonnet Dominique , Reis e Sousa Caetano
Published: May 2010

In mouse, a subset of dendritic cells (DCs) known as CD8α+ DCs has emerged as an important player in the regulation of T cell responses and a promising target in vaccination strategies. However, translation into clinical protocols has been hampered by the failure to identify CD8α+ DCs in humans. Here, we characterize a population of human DCs that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8α+ DCs in phenotype and function. We describe the presence of such cells in the spleens of humans and humanized mice and report on a protocol to generate them in vitro. Like mouse CD8α+ DCs, human DNGR-1+ BDCA3hi DCs express Necl2, CD207, BATF3, IRF8, and TLR3, but not CD11b, IRF4, TLR7, or (unlike CD8α+ DCs) TLR9. DNGR-1+ BDCA3hi DCs respond to poly I:C and agonists of TLR8, but not of TLR7, and produce interleukin (IL)-12 when given innate and T cell–derived signals. Notably, DNGR-1+ BDCA3+ DCs from in vitro cultures efficiently internalize material from dead cells and can cross-present exogenous antigens to CD8+ T cells upon treatment with poly I:C. The characterization of human DNGR-1+ BDCA3hi DCs and the ability to grow them in vitro opens the door for exploiting this subset in immunotherapy.
Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells
Authors: Bachem Annabell , Güttler Steffen , Hartung Evelyn , Ebstein Frédéric , Schaefer Michael , Tannert Astrid , Salama Abdulgabar , Movassaghi Kamran , Opitz Corinna , Mages Hans W. , Henn Volker , Kloetzel Peter-Michael , Gurka Stephanie , Kroczek Richard A.
Published: May 2010

In recent years, human dendritic cells (DCs) could be subdivided into CD304+ plasmacytoid DCs (pDCs) and conventional DCs (cDCs), the latter encompassing the CD1c+, CD16+, and CD141+ DC subsets. To date, the low frequency of these DCs in human blood has essentially prevented functional studies defining their specific contribution to antigen presentation. We have established a protocol for an effective isolation of pDC and cDC subsets to high purity. Using this approach, we show that CD141+ DCs are the only cells in human blood that express the chemokine receptor XCR1 and respond to the specific ligand XCL1 by Ca2+ mobilization and potent chemotaxis. More importantly, we demonstrate that CD141+ DCs excel in cross-presentation of soluble or cell-associated antigen to CD8+ T cells when directly compared with CD1c+ DCs, CD16+ DCs, and pDCs from the same donors. Both in their functional XCR1 expression and their effective processing and presentation of exogenous antigen in the context of major histocompatibility complex class I, human CD141+ DCs correspond to mouse CD8+ DCs, a subset known for superior antigen cross-presentation in vivo. These data define CD141+ DCs as professional antigen cross-presenting DCs in the human.
On decomposition numbers with Jantzen filtration of cyclotomic 𝑞-Schur algebras
Authors: Wada Kentaro
Published: May 2010

Let

S

(
Λ
)

\mathscr {S}(\varLambda )

be the cyclotomic

q
q

-Schur algebra associated to the Ariki-Koike algebra

H

n
,
r

\mathscr {H}_{n,r}

, introduced by Dipper, James and Mathas. In this paper, we consider

v
v

-decomposition numbers of

S

(
Λ
)

\mathscr {S}(\varLambda )

, namely decomposition numbers with respect to the Jantzen filtrations of Weyl modules. We prove, as a

v
v

-analogue of the result obtained by Shoji and Wada, a product formula for

v
v

-decomposition numbers of

S

(
Λ
)

\mathscr {S}(\varLambda )

, which asserts that certain

v
v

-decomposition numbers are expressed as a product of

v
v

-decomposition numbers for various cyclotomic

q
q

-Schur algebras associated to Ariki-koike algebras

H

n
i

,

r
i

\mathscr {H}_{n_i,r_i}

of smaller rank. Moreover, we prove a similar formula for

v
v

-decomposition numbers of

H

n
,
r

\mathscr {H}_{n,r}

by using a Schur functor.
Increased Genomic Copy Number of DEFA1/DEFA3 Is Associated with Susceptibility to Severe Sepsis in Chinese Han Population
Authors: Chen QiXing , Hakimi Matthew , Wu ShuiJing , Jin Yue , Cheng BaoLi , Wang HaiHong , Xie GuoHao , Ganz Tomas , Linzmeier Rose M. , Fang XiangMing
Published: May 2010

Background

Human neutrophil peptides 1-3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1-3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis.

Methods

This case-control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 were detected.

Results

The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 x 10, odds ratio 2.77, 95% confidence interval 1.85-4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 x 10, odds ratio 2.66, 95% confidence interval 1.69-4.19). This established association was replicated in a second age- and gender-matched case-control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11-3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively).

Conclusions

DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.
Prognostic Implications of Asymptomatic Left Ventricular Dysfunction in Patients Undergoing Vascular Surgery
Authors: Flu Willem-Jan , van Kuijk Jan-Peter , Hoeks Sanne E. , Kuiper Ruud , Schouten Olaf , Goei Dustin , Elhendy Abdou , Verhagen Hence J. M. , Thomson Ian R. , Bax Jeroen J. , Fleisher Lee A. , Poldermans Don
Published: May 2010

Background

The prognostic value of heart failure symptoms on postoperative outcome is well acknowledged in perioperative guidelines. The prognostic value of asymptomatic left ventricular (LV) dysfunction remains unknown. This study evaluated the prognostic implications of asymptomatic LV dysfunction in vascular surgery patients assessed with routine echocardiography.

Methods

Echocardiography was performed preoperatively in 1,005 consecutive vascular surgery patients. Systolic LV dysfunction was defined as LV ejection fraction less than 50%. Ratio of mitral-peak velocity during early and late filling, pulmonary vein flow, and deceleration time was used to diagnose diastolic LV dysfunction. Troponin-T measurements and electrocardiograms were performed routinely perioperatively. Multivariate regression analyses evaluated the relation between LV function and the study endpoints, 30-day cardiovascular events, and long-term cardiovascular mortality.

Results

Left ventricular dysfunction was diagnosed in 506 (50%) patients of which 80% were asymptomatic. In open vascular surgery (n = 649), both asymptomatic systolic and isolated diastolic LV dysfunctions were associated with 30-day cardiovascular events (odds ratios 2.3, 95% confidence interval [CI] 1.4-3.6 and 1.8, 95% CI 1.1-2.9, respectively) and long-term cardiovascular mortality (hazard ratios 4.6, 95% CI 2.4-8.5 and 3.0, 95% CI 1.5-6.0, respectively). In endovascular surgery (n = 356), only symptomatic heart failure was associated with 30-day cardiovascular events (odds ratio 1.8, 95% CI 1.1-2.9) and long-term cardiovascular mortality (hazard ratio 10.3, 95% CI 5.4-19.3).

Conclusions

This study demonstrated that asymptomatic LV dysfunction is predictive for 30-day and long-term cardiovascular outcome in open vascular surgery patients. These data suggest that preoperative risk stratification should include not only solely heart failure symptoms but also routine preoperative echocardiography to risk stratify open vascular surgery patients.
Diet and food partitioning between juveniles of mutton Lutjanus analis, dog Lutjanus jocu and lane Lutjanus synagris snappers (Perciformes: Lutjanidae) in a mangrove‐fringed estuarine environment
Authors: Pimentel C. R. , Joyeux J.‐C.
Published: May 2010

Diet of juvenile mutton Lutjanus analis, dog Lutjanus jocu and lane Lutjanus synagris snappers were studied in the tropical Brazilian estuarine system of the Piraquê‐açú and Piraquê‐mirim Rivers to determine how these species share the resources in this restricted space. The three species prey principally upon Peracarida (L. synagris: relative importance index IRIc = 29%), Natantia (L. analis and L. synagris: IRIc = 39 and 38%, respectively), Reptantia (L. analis and L. jocu: IRIc = 28 and 43%, respectively) and Teleostei (L. jocu: IRIc = 24%). The three species use estuaries as nursery habitats but food overlap was not biologically significant due to a combination of interspecific differences in size, spatial distribution, microhabitat preferences and seasonal patterns of abundance and prey choice. Large marine protected areas incorporating essential habitats for all life stages are suggested to be the best tool for the management of these economically important species.
Interactive effects of food quality, temperature and rearing time on condition of juvenile black bream Acanthopagrus butcheri
Authors: Walther B. D. , Elsdon T. S. , Gillanders B. M.
Published: May 2010

A laboratory experiment was conducted to determine the interactive effects of temperature and diet on condition indices of juvenile black bream Acanthopagrus butcheri, reared for time periods ranging from 2 to 42 days. After fish were reared for varying periods, growth, morphometric (Fulton's K) and biochemical [RNA:DNA (R:D) ratios] indices were measured. Fulton's K responded primarily to temperature, with progressive decrease in condition over time for fish reared at high temperatures. In contrast, R:D ratios were primarily affected by diet composition, with the highest values observed for fish reared on fish‐based diets as opposed to vegetable‐based diets. Significant effects of rearing time were also observed for Fulton's K and R:D ratios, as were some interactive treatment effects. In addition, Fulton's K and R:D ratios were not significantly correlated, perhaps due to the different periods of time integrated by each index or their relative sensitivity to lipid and protein deposition. These results highlight the complex responses of these condition indices to environmental variables and nutritional status.
Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells
Authors: Naka Kazuhito , Hoshii Takayuki , Hirao Atsushi
Published: May 2010

Although discovery of the tyrosine kinase inhibitor (TKI) imatinib mesylate has significantly improved the prognosis of chronic myeloid leukemia (CML) patients, a rare population of CML stem cells is known to be resistant to TKI therapy, causing recurrence of CML. However, recent progress in CML stem cell biology may present a novel therapeutic avenue for CML patients. In this review, we focus on mechanisms used by CML stem cells to maintain TKI‐resistance. Comprehensive approaches including mouse genetics, prospective identification of CML stem cells, and syngenic transplantation techniques have identified several key molecules or signaling pathways, including hedgehog (Hh)/Smo, promyelocytic leukemia (PML), 5‐lipoxygenase (5‐LO), and forkhead box class O (FOXO), that function in CML stem cell maintenance. Inhibiting some of these factors in combination with TKI administration successfully antagonized resistance of CML stem cells to TKI therapy, resulting in efficient eradication of leukemia cells in vivo. Thus, development of methods that sensitize CML stem cells to TKI therapy may lead to novel therapies to treat CML patients. (Cancer Sci 2010)
In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases
Authors: Daruwalla Jurstine , Nikfarjam Mehrdad , Greish Khaled , Malcontenti‐Wilson Cathy , Muralidharan Vijayaragavan , Christophi Chris , Maeda Hiroshi
Published: May 2010

Pirarubicin is a derivative of doxorubicin with improved intracellular uptake and reduced cardiotoxicity. We have prepared a micellar formulation of pirarubicin using styrene‐maleic acid copolymer (SMA) of mean molecular weight of 1.2 kDa, which exhibits a mean diameter of 248 nm in solution. Being a macromolecule, SMA‐pirarubicin micelles exhibit excellent tumor targeting capacity due to the enhanced permeability and retention (EPR) effect. Here we report the antitumor activity of SMA‐pirarubicin micelles on human colon and breast cancer cell lines in vitro, and a murine liver metastasis model in vivo. Metastatic tumor microvasculature, necrosis, apoptosis, proliferation, and survival were also investigated using immunohistochemistry for Ki‐67, active caspase‐3, and CD34, respectively. Drug cytotoxicity in vitro was assessed using MTT (3‐[4,5‐dimethyl‐2‐thiazolyl]‐2, 5‐diphenyl‐2H‐tetrazolium bromide) assay. In vivo, SMA‐pirarubicin was administered at 100, 150, or 200 mg/kg (pirarubicin equivalent). Tumor microvasculature was also assessed using scanning electron microscopy. Styrene‐maleic acid copolymer (SMA)‐pirarubicin micelles were toxic against human colorectal and breast cancer cells in vitro. IC50 was at or below 1 μM, free pirarubicin equivalent. In vivo, SMA‐pirarubicin at 100 mg/kg reduced tumor volume by 80% and achieved a survival rate of 93% at 40 days after tumor inoculation. Styrene‐maleic acid copolymer (SMA)‐pirarubicin micelles demonstrated potent antitumor activity in this liver metastases model, contributing to prolonged survival. Histological examination of tumor nodules showed significant reduction and proliferation of tumor cells (>90%). The present results suggest that investigation of the effect of multiple dosing at later time points to further improve survival is warranted. (Cancer Sci 2010)
5αDH‐DOC (5α‐dihydro‐deoxycorticosterone) activates androgen receptor in castration‐resistant prostate cancer
Authors: Uemura Motohide , Honma Seijiro , Chung Suyoun , Takata Ryo , Furihata Mutsuo , Nishimura Kazuo , Nonomura Norio , Nasu Yasutomo , Miki Tsuneharu , Shuin Taro , Fujioka Tomoaki , Okuyama Akihiko , Nakamura Yusuke , Nakagawa Hidewaki
Published: May 2010

Prostate cancer often relapses during androgen‐depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration‐resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5α‐dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5α‐steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5αDH‐steroids to search for novel products of 5α‐steroid reductases, and identified 11‐deoxycorticosterone (DOC) as a novel substrate for 5α‐steroid reductases in CRPCs. 11‐Deoxycorticosterone (DOC) and 5α‐dihydro‐deoxycorticosterone (5αDH‐DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5α‐steroid reductase (SRD5A1) could convert from DOC to 5αDH‐DOC. Sensitive liquid chromatography‐tandem mass spectrometric analysis detected 5αDH‐DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5αDH‐DOC and other products of 5α‐steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration. (Cancer Sci 2010)