bluuebunny/crossref_metadata_2025 huggingface dataset:
Disruption of the NHR4 domain structure in AML1-ETO abrogates SON binding and promotes leukemogenesis
Authors: Ahn Eun-Young , Yan Ming , Malakhova Oxana A. , Lo Miao-Chia , Boyapati Anita , Ommen Hans Beier , Hines Robert , Hokland Peter , Zhang Dong-Er
Published: October 2008

AML1-ETO is generated from t(8;21)(q22;q22), which is a common form of chromosomal translocation associated with development of acute myeloid leukemia (AML). Although full-length AML1-ETO alone fails to promote leukemia because of its detrimental effects on cell proliferation, an alternatively spliced isoform, AML1-ETO9a, without its C-terminal NHR3/NHR4 domains, strongly induces leukemia. However, full-length AML1-ETO is a major form of fusion product in many t(8;21) AML patients, suggesting additional molecular mechanisms of t(8;21)-related leukemogenesis. Here, we report that disruption of the zinc-chelating structure in the NHR4 domain of AML1-ETO by replacing only one critical amino acid leads to rapid onset of leukemia, demonstrating that the NHR4 domain with the intact structure generates inhibitory effects on leukemogenesis. Furthermore, we identified SON, a DNA/RNA-binding domain containing protein, as a novel NHR4-interacting protein. Knock-down of SON by siRNA resulted in significant growth arrest, and disruption of the interaction between AML1-ETO and endogenous SON rescued cells from AML1-ETO-induced growth arrest, suggesting that SON is an indispensable factor for cell growth, and AML1-ETO binding to SON may trigger signals inhibiting leukemogenesis. In t(8;21) AML patient-derived primary leukemic cells and cell lines, abnormal cytoplasmic localization of SON was detected, which may keep cells proliferating in the presence of full-length AML1-ETO. These results uncovered the crucial role of the NHR4 domain in determination of cellular fate during AML1-ETO-associated leukemogenesis.
β-Arrestin 2 is required for lysophosphatidic acid-induced NF-κB activation
Authors: Sun Jiyuan , Lin Xin
Published: October 2008

Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-κB. Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-κB is not fully defined. In this work, we found that β-arrestin 2, but not β-arrestin 1, is required for LPA-induced NF-κB activation and interlukin-6 expression. Mechanistically, we found that β-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-κB activation, suggesting that β-arrestin 2 may recruit CARMA3 to LPA receptors. Although β-arrestin 2 deficiency did not affect LPA-induced IKKα/β phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKKα/β activation but not for the inducible phosphorylation of IKKα/β. Together, our results provide the genetic evidence that β-arrestin 2 serves as a positive regulator in NF-κB signaling pathway by connecting CARMA3 to GPCRs.
Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target
Authors: Kita Takeshi , Hata Yasuaki , Arita Ryoichi , Kawahara Shuhei , Miura Muneki , Nakao Shintaro , Mochizuki Yasutaka , Enaida Hiroshi , Goto Yoshinobu , Shimokawa Hiroaki , Hafezi-Moghadam Ali , Ishibashi Tatsuro
Published: October 2008

Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-β is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-β is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-β's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-β2 (
r
= 0.82,
P
< 0.0001). PDR or PVR vitreous promoted expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-β blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted α-SMA organization, but it did not affect its vitreal expression.
In vivo
, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-β in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-β and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.
Predataxis behavior inMyxococcus xanthus
Authors: Berleman James E. , Scott Jodie , Chumley Tatiana , Kirby John R.
Published: October 2008

Spatial organization of cells is important for both multicellular development and tactic responses to a changing environment. We find that the social bacterium,Myxococcus xanthusutilizes a chemotaxis (Che)-like pathway to regulate multicellular rippling during predation of other microbial species. Tracking of GFP-labeled cells indicates directed movement ofM. xanthuscells during the formation of rippling wave structures. Quantitative analysis of rippling indicates that ripple wavelength is adaptable and dependent on prey cell availability. Methylation of the receptor, FrzCD is required for this adaptation: afrzFmethyltransferase mutant is unable to construct ripples, whereas afrzGmethylesterase mutant forms numerous, tightly packed ripples. Both thefrzFandfrzGmutant strains are defective in directing cell movement through prey colonies. These data indicate that the transition to an organized multicellular state during predation inM. xanthusrelies on the tactic behavior of individual cells, mediated by a Che-like signal transduction pathway.
Inhibition of Thr-55 phosphorylation restores p53 nuclear localization and sensitizes cancer cells to DNA damage
Authors: Cai Xin , Liu Xuan
Published: October 2008

The p53 tumor suppressor induces cell growth arrest and apoptosis in response to DNA damage. Because these functions are achieved largely by the transcriptional properties of p53, nuclear localization of the protein is essential. Indeed, the tumors with aberrant cytoplasmic localization of wild-type p53 often exhibit an impaired response to DNA damage. In this study, we report that Thr-55 phosphorylation induces the association of p53 with the nuclear export factor CRM1, leading to p53 nuclear export. We further show that MDM2 also promotes the CRM1-p53 association and Thr-55 phosphorylation is required for this process. Interestingly, inhibition of Thr-55 phosphorylation by a dietary flavonoid, apigenin, specifically blocks the CRM1-p53 association, restores p53 nuclear localization, and sensitizes tumor cells with cytoplasm localized wild-type p53 to DNA damage. These data provide insights into the regulation of p53 nuclear localization by post-translational modification and suggest an avenue for targeted therapy for cancers caused by aberrant cytoplasm localization of wild-type p53.
Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development
Authors: Newbern Jason , Zhong Jian , Wickramasinghe Rasika S. , Li Xiaoyan , Wu Yaohong , Samuels Ivy , Cherosky Natalie , Karlo J. Colleen , O'Loughlin Brianne , Wikenheiser Jamie , Gargesha Madhusudhana , Doughman Yong Qiu , Charron Jean , Ginty David D. , Watanabe Michiko , Saitta Sulagna C. , Snider William D. , Landreth Gary E.
Published: October 2008

Disrupted ERK1/2 (
MAPK3
/
MAPK1
) MAPK signaling has been associated with several developmental syndromes in humans; however, mutations in
ERK1
or
ERK2
have not been described. We demonstrate haplo-insufficient ERK2 expression in patients with a novel ≈1 Mb micro-deletion in distal 22q11.2, a region that includes
ERK2
. These patients exhibit conotruncal and craniofacial anomalies that arise from perturbation of neural crest development and exhibit defects comparable to the DiGeorge syndrome spectrum. Remarkably, these defects are replicated in mice by conditional inactivation of
ERK2
in the developing neural crest. Inactivation of upstream elements of the ERK cascade (
B-Raf
and
C-Raf, MEK1
and
MEK2
) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. Our findings demonstrate that mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway and suggest that the craniofacial and cardiac outflow tract defects observed in patients with a distal 22q11.2 micro-deletion are explained by deficiencies in neural crest autonomous ERK2 signaling.
Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase
Authors: Muller Alexander J. , Sharma Madhav D. , Chandler Phillip R. , DuHadaway James B. , Everhart Mary E. , Johnson Burles A. , Kahler David J. , Pihkala Jeanene , Soler Alejandro Peralta , Munn David H. , Prendergast George C. , Mellor Andrew L.
Published: October 2008

Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs. The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN DCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/IL-1 signaling adaptor MyD88, and on cellular stress responses to amino acid withdrawal by means of the integrated stress response kinase GCN2. Consistent with the hypothesis that T cell suppressive, IDO
+
pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation. Thus, IDO is a key immunosuppressive factor that facilitates tumor progression in this setting of chronic inflammation driven by repeated topical PMA exposure.
Prediction of human miRNAs using tissue-selective motifs in 3′ UTRs
Authors: Chang Yao-Ming , Juan Hsueh-Fen , Lee Tzu-Ying , Chang Ya-Ya , Yeh Yao-Ming , Li Wen-Hsiung , Shih Arthur Chun-Chieh
Published: October 2008

MicroRNAs (miRNAs) play an important role in posttranscriptional regulation of genes. We developed a method to predict human miRNAs without requiring cross-species conservation. We first identified lowly/moderately expressed tissue-selective genes using EST data and then identified overrepresented motifs of seven nucleotides in the 3′ UTRs of these genes. Using these motifs as potential target sites of miRNAs, we recovered more than two-thirds of the known human miRNAs. We then used those motifs that did not match any known human miRNA seed region to infer novel miRNAs. We predicted 36 new human miRNA genes with 44 mature forms and 4 novel alternative mature forms of 2 known miRNA genes when a stringent criterion was used and many more novel miRNAs when a less stringent criterion was used. We tested the expression of 11 predicted miRNAs in three human cell lines and found 5 of them expressed in all three cell lines and 1 expressed in one cell line. We selected 2 of them, P-2 and P-27–5p, to do functional validation, using their mimics and inhibitors and using both luciferase assay and Western blotting. These experiments provided strong evidence that both P-2 and P-27–5p are novel miRNAs and that
CREB
3
L
3, which encodes cAMP-responsive element binding protein 3-like 3, is a target gene of P-2, whereas
LAMB
3, which encodes laminin β3, is a target gene of P-27–5p.
Absence from work and emotional stress in women undergoing IVF or ICSI: An analysis of IVF‐related absence from work in women and the contribution of general and emotional factors
Authors: BOUWMANS CLAZIEN A.M. , LINTSEN BEA A.M.E. , AL MAIWEN , VERHAAK CHRIS M. , EIJKEMANS RENÉ J.C. , HABBEMA J. DIK F. , BRAAT DIDI D.M. , HAKKAART‐VAN ROIJEN LEONA
Published: October 2008

Objective. To assess productivity losses due to absence from work during in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment and to describe the pattern of IVF‐related absence from work. Additionally, the influence of general and psychological variables on IVF‐related absence from work was analyzed. Design. Prospective cohort study. Setting. Eight IVF hospitals participated in the study. Sample. Women undergoing their first treatment with IVF/ICSI. Methods. The Health and Labour Questionnaire (HLQ) was used to estimate the costs of IVF‐related absence from work (n = 384). Diaries were used to collect background information and reasons for IVF‐related absence. Psychological data were derived using the Spielberger State and Trait Anxiety Inventory (STAI), the Beck Depression Inventory for Primary Care (BDI‐PC) and the Inventory Social Relations and the Illness Cognition Questionnaire. Regression analyses were performed using two models, one without and one with psychological data, to assess the impact of the different variables on IVF‐related absence from work. Main outcome measure. IVF‐related absence from work and the costs of productivity losses due to IVF/ICSI per treatment. Results. Overall absence from work during IVF/ICSI treatment was on average 33 hours, of which 23 hours were attributed to IVF/ICSI. Costs of productivity losses due to IVF/ICSI were €596 per woman. Significant predictors of IVF‐related absence from work were the number of hours of paid work, age and self‐reported physical and/or emotional problems due to IFV treatment. Conclusions. Women experiencing emotional complaints and women with physical complaints due to IVF/ICSI reported significantly more IVF‐related absence from work.
Uterus transplantation in the rat: Model development, surgical learning and morphological evaluation of healing
Authors: WRANNING CAIZA A. , AKHI SHAMINA N. , KURLBERG GÖRAN , BRÄNNSTRÖM MATS
Published: October 2008

Objective. Experimental uterus transplantation is a growing research field with the aim to develop a treatment for women with absolute uterus factor infertility. The potential risks of surgery and immunosuppressive treatment involved in uterus transplantation need to be identified and minimized in appropriate animal models before clinical trials commence. The aim of the present study was to develop and evaluate a model for uterus transplantation in the rat that can be reproduced and used in future studies concerning critical aspects of uterine function after transplantation. Design. Animal study. Setting. University Hospital. Sample. Uterine tissue sampled at different post‐operative time points after non‐rejecting uterus transplantation in rats. Methods. Adult, virgin female rats of inbred Lewis strain served as donors and recipients of uterine transplants. Two individuals with no previous microsurgical training performed the transplantations and learning curves were recorded. When transplant survival exceeded 70% for both surgeons, 15 animals were transplanted and grafted uteri were evaluated at 1, 7 and 21 days after surgery by assessment of morphology and enumeration of infiltrating neutrophilic granulocytes. Main outcome measures. Animal survival, graft survival, surgery times, uterine morphology, enumeration of infiltrating neutrophilic granulocytes. Results. Both surgeons gained the necessary microsurgical skills needed to achieve above 70% transplant survival at a similar rate. The signs of post‐operative inflammation on day one after transplantation were minor and further reduced at later time points. Conclusion. A reproducible model for uterus transplantation in the rat was developed, which can be used in future studies concerning uterine function after allogenic transplantation.
Critical roles of VEGF‐C‐VEGF receptor 3 in reconnection of the collecting lymph vessels in mice
Authors: IKOMI FUMITAKA , KAWAI YOSHIKO , NAKAYAMA JUN , OGIWARA NAOKO , SASAKI KATSUNORI , MIZUNO RISUKE , OHHASHI TOSHIO
Published: October 2008

Molecular mechanisms of reconnection of collecting lymph vessels were analyzed by using murine popliteal prenodal lymph vessels. At 1 and 2 weeks after being divided by cutting the lymph vessel, lymphatic reconnection was frequently observed accompanied by mesh‐like lymphatic channels. Electron microscopic study also showed a monolayer of endothelial cells in the newly developed lymph vessels. Smooth muscle markers were immunofluorescently demonstrated in the wall of the new vessels. At 1 week after the procedure of cutting, augmented expressions of VEGF receptors 1, 2 and 3 were found immunohistochemically at the site of the reconnected lymph vessels. The expression of mRNA for VEGF receptor 3 was enhanced at 5 days and 1 week in small pieces of the tissues containing the reconnected lymph vessels, compared with that in the corresponding tissues obtained with sham operated ones. The administration of VEGF‐C at the cutting site of the collecting lymph vessel significantly increased the rate of the reconnected lymph vessels, whereas additional treatment with Flt4/Fc chimera protein significantly reduced the rate of the reconnected ones. These results suggest that activation of VEGF‐C‐VEGF receptor 3 has critical roles in reconnection of the collecting lymph vessels in adult mice.
Aggressive assembly of pyrosequencing reads with mates
Authors: Miller Jason R. , Delcher Arthur L. , Koren Sergey , Venter Eli , Walenz Brian P. , Brownley Anushka , Johnson Justin , Li Kelvin , Mobarry Clark , Sutton Granger
Published: October 2008

Motivation: DNA sequence reads from Sanger and pyrosequencing platforms differ in cost, accuracy, typical coverage, average read length and the variety of available paired-end protocols. Both read types can complement one another in a ‘hybrid’ approach to whole-genome shotgun sequencing projects, but assembly software must be modified to accommodate their different characteristics. This is true even of pyrosequencing mated and unmated read combinations. Without special modifications, assemblers tuned for homogeneous sequence data may perform poorly on hybrid data.

Results: Celera Assembler was modified for combinations of ABI 3730 and 454 FLX reads. The revised pipeline called CABOG (Celera Assembler with the Best Overlap Graph) is robust to homopolymer run length uncertainty, high read coverage and heterogeneous read lengths. In tests on four genomes, it generated the longest contigs among all assemblers tested. It exploited the mate constraints provided by paired-end reads from either platform to build larger contigs and scaffolds, which were validated by comparison to a finished reference sequence. A low rate of contig mis-assembly was detected in some CABOG assemblies, but this was reduced in the presence of sufficient mate pair data.

Availability: The software is freely available as open-source from http://wgs-assembler.sf.net under the GNU Public License.

Contact:  jmiller@jcvi.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
MS-specific noise model reveals the potential of iTRAQ in quantitative proteomics
Authors: Hundertmark C. , Fischer R. , Reinl T. , May S. , Klawonn F. , Jänsch L.
Published: October 2008

Motivation: Mass spectrometry (MS) data are impaired by noise similar to many other analytical methods. Therefore, proteomics requires statistical approaches to determine the reliability of regulatory information if protein quantification is based on ion intensities observed in MS.

Results: We suggest a procedure to model instrument and workflow-specific noise behaviour of iTRAQ™ reporter ions that can provide regulatory information during automated peptide sequencing by LC-MS/MS. The established mathematical model representatively predicts possible variations of iTRAQ™ reporter ions in an MS data-dependent manner. The model can be utilized to calculate the robustness of regulatory information systematically at the peptide level in so-called bottom-up proteome approaches. It allows to determine the best fitting regulation factor and in addition to calculate the probability of alternative regulations. The result can be visualized as likelihood curves summarizing both the quantity and quality of regulatory information. Likelihood curves basically can be calculated from all peptides belonging to different regions of proteins if they are detected in LC-MS/MS experiments. Therefore, this approach renders excellent opportunities to detect and statistically validate dynamic post-translational modifications usually affecting only particular regions of the whole protein. The detection of known phosphorylation events at protein kinases served as a first proof of concept in this study and underscores the potential for noise models in quantitative proteomics.

Contact:  lothar.jaensch@helmholtz-hzi.de; f.klawonn@fh-wolfenbuettel.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Weight Loss in Animals and Humans Treated with “Weighlevel”, a Combination of Four Medicinal Plants Used in Traditional Arabic and Islamic Medicine
Authors: Said Omar , Saad Bashar , Fulder Stephen , Khalil Khaled , Kassis Eli
Published: October 2008

Weighlevel, a mixture of extract of four plants used in traditional Arabic and Islamic medicine as well as in European herbal medicine, was prepared and assessed for its safety and efficacy in weight loss. Leaves of Alchemilla vulgaris, Olea europaea and Mentha longifolia L., as well as seeds of Cuminum cyminum, were used. Cultured human fibroblasts treated with Weighlevel did not exhibit any sign of toxicity as evidenced by lactate dehydrogenase release. These results were confirmed in experimental studies on rats where an LD50 of 15.3 g kg−1 was observed. Significant antioxidant properties were seen at very low concentrations of Weighlevel (10 μg ml−1) as measured by the lipid peroxidation method. Progressive and significant weight loss was observed in chickens given this mixture weekly for 4 weeks compared with controls. Furthermore, a 3‐fold increase in the thermogenesis was seen in rat interscapular brown adipose tissue following exposure to different concentrations of Weighlevel extract as determined by measurement of increased oxygen consumption. In addition, a clinical study was carried out among 80 human volunteers with a body mass index (BMI) of 30.67 ± 2.14 kg m−2. All 80 subjects were asked to continue their usual diet but to eat only three main meals daily and to take one Weighlevel tablet 30 min before each meal. Fourteen subjects were excluded for not following the protocol, and 66 subjects were all evaluated for efficacy and tolerability of Weighlevel monthly for 3 months. Weighlevel was well tolerated by all subjects, and no side effects were reported. A progressive and significant weight loss was seen in these subjects during the whole study period. Higher levels of weight loss were seen in people with BMI of 25–30 kg m−2 (overweight) compared to people with BMI >30 kg m−2 (obese). The BMI was reduced after 3 months from 28.5 ± 1.2 and 32.1 ± 1.8 kg m−2 to 24.5 ± 1.4 and 27.5 ± 2.2 kg m−2 in overweight and obese group, respectively. Results indicate safety, tolerability and efficacy of Weighlevel.
Horse mackerel (Trachurus trachurus) stomach fullness off Portugal: index calibration and spatio-temporal variations in feeding intensity
Authors: Garrido Susana , Murta Alberto G. , Moreira Ana , Ferreira Maria João , Angélico Maria Manuel
Published: October 2008

Garrido, S., Murta, A. G., Moreira, A., Ferreira, M. J., and Angélico, M. M. 2008. Horse mackerel (Trachurus trachurus) stomach fullness off Portugal: index calibration and spatio-temporal variations in feeding intensity. – ICES Journal of Marine Science, 65: 1662–1669. An index for stomach fullness used in the routine biological sampling of horse mackerel from Portuguese waters was calibrated about the correspondent stomach mass. The fullness scale comprises four levels (1, empty; 2, <50% filled; 3, >50% filled; 4, bursting) that are easily attributed to whole stomachs during the sampling process. Significant differences were found among the four levels of the fullness scale in their relative stomach masses, indicating that the index can be used for the semi-quantitative analysis of feeding intensity in this species. The fullness index was applied to study spatio-temporal variations in horse mackerel feeding off the Portuguese coast, using data collected from 1985 to 2006 on commercial vessels and research cruises. There was no significant difference in feeding intensity between sexes. Smaller horse mackerel and those in the resting stage of reproduction fed more intensively than larger and spawning fish. Feeding intensities of fish from the southern and northwest coasts of Portugal were greater than for those captured along the southwest coast. Horse mackerel feeding intensity was greater at dawn and varied seasonally, being higher during spring and autumn and lower during winter. Interannual variation in feeding intensity of horse mackerel captured along the west coast of Portugal revealed a significant but slight decrease in recent years.
Lexical Cohesion Analysis of Political Speech
Authors: Klebanov Beata Beigman , Diermeier Daniel , Beigman Eyal
Published: October 2008

This article presents a novel automatic method of text analysis aimed at discovering patterns of lexical cohesion in political speech. The unit of analysis are groups of words with related meanings; the software is based on the results of a multiperson annotation experiment that captures reliably identified connections between words in a text. We illustrate the advantages of such a representation by juxtaposing results of a detailed hand-made analysis of Margaret Thatcher's rhetoric with analysis based on the automatically detected groups of words. We both corroborate previous findings regarding Thatcher's rhetorical tools and illuminate additional elements thereof. We suggest that lexical cohesion analysis is a promising technique to bridge the gap between quantitative and qualitative analyses of text as political material, by establishing units that are both robust enough to enable comprehensive coverage and coherent enough to support direct interpretation.
Coding Disaggregated Intrastate Conflict: Machine Processing the Behavior of Substate Actors Over Time and Space
Authors: Shellman Stephen M.
Published: October 2008

This article describes a new machine-coded event data set specifically designed to study the spatially, temporally, and tactically disaggregated actions of multiple state and nonstate actors in a systematic fashion. The project develops an extensive set of dictionaries for multiple actors and employs a new coding scheme to organize information on such actors and their behavior. The author describes the machine content-analysis methods used to collect the data and the newly developed coding scheme.
Constraint-based network model of pathogen–immune system interactions
Authors: Thakar Juilee , Saadatpour-Moghaddam Assieh , Harvill Eric T. , Albert Réka
Published: October 2008

Pathogenic bacteria such as
Bordetella bronchiseptica
modulate host immune responses to enable their establishment and persistence; however, the immune response is generally successful in clearing these bacteria. Here, we model the dynamic outcome of the interplay between host immune components and
B. bronchiseptica
virulence factors. The model extends our previously published interaction network of
B. bronchiseptica
and includes the existing experimental information on the relative timing of IL10 and IFNγ activation in the form of qualitative inequalities. The current model improves the previous one in two directions: (i) by augmenting the network with new nodes with specific function in T helper cell differentiation and effector mechanisms and (ii) by using a dynamic approach that allows us to quantify node states and mechanisms revealed to be important from our previous model. The model makes predictions about the time scales of each process, the activity thresholds of each node and novel regulatory interactions. For example, the model predicts that the activity threshold of IL4 is higher than that of IL12 and that pro-inflammatory cytokines regulate the activity of Th2 cells. Some of these predictions are supported by the literature, and many can serve as targets of future experiments.
Seabird-driven shifts in Arctic pond ecosystems
Authors: Michelutti Neal , Keatley Bronwyn E , Brimble Samantha , Blais Jules M , Liu Huijun , Douglas Marianne S.V , Mallory Mark L , Macdonald Robie W , Smol John P
Published: October 2008

Migratory animals such as seabirds, salmon and whales can transport large quantities of nutrients across ecosystem boundaries, greatly enriching recipient food webs. As many of these animals biomagnify contaminants, they can also focus pollutants at toxic levels. Seabirds arguably represent the most significant biovectors of nutrients and contaminants from the ocean to the land, given their sheer numbers and global distribution. However, long-term census data on seabirds are rare. Using palaeolimnological proxies, we show that a colony of Arctic seabirds has experienced climate-induced population increases in recent decades. We then document increasing concentrations of contaminants, including polychlorinated biphenyls and cadmium, in pond sediments that are linked to biotransport by seabirds. Our findings suggest that climate-related shifts in global seabird populations will have the unexpected consequence of restructuring coastal ecosystems.
Analysis of atrial fibrillation: from electrocardiogram signal processing to clinical management
Authors: Sörnmo Leif , Stridh Martin , Husser Daniela , Bollmann Andreas , Olsson S. Bertil
Published: October 2008

The analysis of atrial fibrillation in non-invasive ECG recordings has received considerable attention in recent years, spurring the development of signal processing techniques for more advanced characterization of the atrial waveforms than previously available. The present paper gives an overview of different approaches to the extraction of atrial activity in the ECG and to the characterization of the resulting atrial signal with respect to its spectral properties. So far, the repetition rate of the atrial waves is the most studied parameter and its significance in clinical management is briefly considered, including the identification of pathomechanisms and prediction of therapy efficacy.
Cardiac repolarization analysis using the surface electrocardiogram
Authors: Pueyo Esther , Martínez Juan Pablo , Laguna Pablo
Published: October 2008

Sudden cardiac death (SCD) is a challenging health problem in the western world. Analysis of cardiac repolarization from the electrocardiogram (ECG) provides valuable information for stratifying patients according to their risk of suffering from arrhythmic events that could end in SCD, as well as for assessing efficacy of antiarrhythmic therapies. In this paper, we start by exploring the cellular basis of ECG repolarization waveforms under both normal and pathological conditions. We then describe basic preprocessing steps that need to be accomplished on the ECG signal before extracting repolarization indices. A comprehensive review of techniques aimed to characterize spatial or temporal repolarization dispersion is provided, together with a summary of their usefulness for clinical risk stratification. Techniques that describe spatial dispersion of repolarization are based on either differences in repolarization duration or T-wave loop morphology. Techniques that evaluate temporal dispersion of repolarization include the analysis of QT interval adaptation to heart rate changes, QT interval and T-wave variability, and T-wave alternans.
Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event
Authors: Rudd M. Katharine , Endicott RaeLynn M. , Friedman Cynthia , Walker Megan , Young Janet M. , Osoegawa Kazutoyo ,   NISC Comparative Sequencing Program, de Jong Pieter J. , Green Eric D. , Trask Barbara J.
Published: October 2008

Subtelomeres are concentrations of interchromosomal segmental duplications capped by telomeric repeats at the ends of chromosomes. The nature of the segments shared by different sets of human subtelomeres reflects their high rate of recent interchromosomal exchange. Here, we characterize the rearrangements incurred by the 15q subtelomere after it arose from a chromosome fission event in the common ancestor of great apes. We used FISH, sequencing of genomic clones, and PCR to map the breakpoint of this fission and track the fate of flanking sequence in human, chimpanzee, gorilla, orangutan, and macaque genomes. The ancestral locus, a cluster of olfactory receptor (OR) genes, lies internally on macaque chromosome 7. Sequence originating from this fission site is split between the terminus of 15q and the pericentromere of 14q in the great apes. Numerous structural rearrangements, including interstitial deletions and transfers of material to or from other subtelomeres, occurred subsequent to the fission, such that each species has a unique 15q structure and unique collection of ORs derived from the fission locus. The most striking rearrangement involved transfer of at least 200 kb from the fission-site region to the end of chromosome 4q, where much still resides in chimpanzee and gorilla, but not in human. This gross structural difference places the subtelomeric defect underlying facioscapulohumeral muscular dystrophy (FSHD) much closer to the telomere in human 4q than in the hybrid 4q–15q subtelomere of chimpanzee.
Finding and Comparing Syntenic Regions among Arabidopsis and the Outgroups Papaya, Poplar, and Grape: CoGe with Rosids
Authors: Lyons Eric , Pedersen Brent , Kane Josh , Alam Maqsudul , Ming Ray , Tang Haibao , Wang Xiyin , Bowers John , Paterson Andrew , Lisch Damon , Freeling Michael
Published: October 2008

In addition to the genomes of Arabidopsis (Arabidopsis thaliana) and poplar (Populus trichocarpa), two near-complete rosid genome sequences, grape (Vitis vinifera) and papaya (Carica papaya), have been recently released. The phylogenetic relationship among these four genomes and the placement of their three independent, fractionated tetraploidies sum to a powerful comparative genomic system. CoGe, a platform of multiple whole or near-complete genome sequences, provides an integrative Web-based system to find and align syntenic chromosomal regions and visualize the output in an intuitive and interactive manner. CoGe has been customized to specifically support comparisons among the rosids. Crucial facts and definitions are presented to clearly describe the sorts of biological questions that might be answered in part using CoGe, including patterns of DNA conservation, accuracy of annotation, transposability of individual genes, subfunctionalization and/or fractionation of syntenic gene sets, and conserved noncoding sequence content. This précis of an online tutorial, CoGe with Rosids (http://tinyurl.com/4a23pk), presents sample results graphically.
Transforming a Fructan:Fructan 6G-Fructosyltransferase from Perennial Ryegrass into a Sucrose:Sucrose 1-Fructosyltransferase
Authors: Lasseur Bertrand , Schroeven Lindsey , Lammens Willem , Le Roy Katrien , Spangenberg German , Manduzio Hélène , Vergauwen Rudy , Lothier Jérémy , Prud'homme Marie-Pascale , Van den Ende Wim
Published: October 2008

Fructosyltransferases (FTs) synthesize fructans, fructose polymers accumulating in economically important cool-season grasses and cereals. FTs might be crucial for plant survival under stress conditions in species in which fructans represent the major form of reserve carbohydrate, such as perennial ryegrass (Lolium perenne). Two FT types can be distinguished: those using sucrose (S-type enzymes: sucrose:sucrose 1-fructosyltransferase [1-SST], sucrose:fructan 6-fructosyltransferase) and those using fructans (F-type enzymes: fructan:fructan 1-fructosyltransferase [1-FFT], fructan:fructan 6G-fructosyltransferase [6G-FFT]) as preferential donor substrate. Here, we report, to our knowledge for the first time, the transformation of an F-type enzyme (6G-FFT/1-FFT) into an S-type enzyme (1-SST) using perennial ryegrass 6G-FFT/1-FFT (Lp6G-FFT/1-FFT) and 1-SST (Lp1-SST) as model enzymes. This transformation was accomplished by mutating three amino acids (N340D, W343R, and S415N) in the vicinity of the active site of Lp6G-FFT/1-FFT. In addition, effects of each amino acid mutation alone or in combination have been studied. Our results strongly suggest that the amino acid at position 343 (tryptophan or arginine) can greatly determine the donor substrate characteristics by influencing the position of the amino acid at position 340. Moreover, the presence of arginine-343 negatively affects the formation of neofructan-type linkages. The results are compared with recent findings on donor substrate selectivity within the group of plant cell wall invertases and fructan exohydrolases. Taken together, these insights contribute to our knowledge of structure/function relationships within plant family 32 glycosyl hydrolases and open the way to the production of tailor-made fructans on a larger scale.
Replication of Nonautonomous Retroelements in Soybean Appears to Be Both Recent and Common
Authors: Wawrzynski Adam , Ashfield Tom , Chen Nicolas W.G. , Mammadov Jafar , Nguyen Ashley , Podicheti Ram , Cannon Steven B. , Thareau Vincent , Ameline-Torregrosa Carine , Cannon Ethalinda , Chacko Ben , Couloux Arnaud , Dalwani Anita , Denny Roxanne , Deshpande Shweta , Egan Ashley N. , Glover Natasha , Howell Stacy , Ilut Dan , Lai Hongshing , del Campo Sara Martin , Metcalf Michelle , O'Bleness Majesta , Pfeil Bernard E. , Ratnaparkhe Milind B. , Samain Sylvie , Sanders Iryna , Ségurens Béatrice , Sévignac Mireille , Sherman-Broyles Sue , Tucker Dominic M. , Yi Jing , Doyle Jeff J. , Geffroy Valérie , Roe Bruce A. , Maroof M.A. Saghai , Young Nevin D. , Innes Roger W.
Published: October 2008

Retrotransposons and their remnants often constitute more than 50% of higher plant genomes. Although extensively studied in monocot crops such as maize (Zea mays) and rice (Oryza sativa), the impact of retrotransposons on dicot crop genomes is not well documented. Here, we present an analysis of retrotransposons in soybean (Glycine max). Analysis of approximately 3.7 megabases (Mb) of genomic sequence, including 0.87 Mb of pericentromeric sequence, uncovered 45 intact long terminal repeat (LTR)-retrotransposons. The ratio of intact elements to solo LTRs was 8:1, one of the highest reported to date in plants, suggesting that removal of retrotransposons by homologous recombination between LTRs is occurring more slowly in soybean than in previously characterized plant species. Analysis of paired LTR sequences uncovered a low frequency of deletions relative to base substitutions, indicating that removal of retrotransposon sequences by illegitimate recombination is also operating more slowly. Significantly, we identified three subfamilies of nonautonomous elements that have replicated in the recent past, suggesting that retrotransposition can be catalyzed in trans by autonomous elements elsewhere in the genome. Analysis of 1.6 Mb of sequence from Glycine tomentella, a wild perennial relative of soybean, uncovered 23 intact retroelements, two of which had accumulated no mutations in their LTRs, indicating very recent insertion. A similar pattern was found in 0.94 Mb of sequence from Phaseolus vulgaris (common bean). Thus, autonomous and nonautonomous retrotransposons appear to be both abundant and active in Glycine and Phaseolus. The impact of nonautonomous retrotransposon replication on genome size appears to be much greater than previously appreciated.
RETARDED PALEA1 Controls Palea Development and Floral Zygomorphy in Rice
Authors: Yuan Zheng , Gao Shan , Xue Da-Wei , Luo Da , Li Lan-Tian , Ding Shu-Yan , Yao Xuan , Wilson Zoe A. , Qian Qian , Zhang Da-Bing
Published: October 2008

Poaceae, one of the largest flowering plant families in angiosperms, evolved distinct inflorescence and flower morphology diverging from eudicots and other monocots. However, the mechanism underlying the specification of flower morphology in grasses remains unclear. Here we show that floral zygomorphy along the lemma-palea axis in rice (Oryza sativa) is partially or indirectly determined by the CYCLOIDEA (CYC)-like homolog RETARDED PALEA1 (REP1), which regulates palea identity and development. The REP1 gene is only expressed in palea primordium during early flower development, but during later floral stages is radially dispersed in stamens and the vascular bundles of the lemma and palea. The development of palea is significantly retarded in the rep1 mutant and its palea has five vascular bundles, which is similar to the vascular pattern of the wild-type lemma. Furthermore, ectopic expression of REP1 caused the asymmetrical overdifferentiation of the palea cells, altering their floral asymmetry. This work therefore extends the function of the TCP gene family members in defining the diversification of floral morphology in grasses and suggests that a common conserved mechanism controlling floral zygomorphy by CYC-like genes exists in both eudicots and the grasses.
Root System Architecture inArabidopsisGrown in Culture Is Regulated by Sucrose Uptake in the Aerial Tissues
Authors: MacGregor Dana R. , Deak Karen I. , Ingram Paul A. , Malamy Jocelyn E.
Published: October 2008

This article presents a detailed model for the regulation of lateral root formation in Arabidopsis thaliana seedlings grown in culture. We demonstrate that direct contact between the aerial tissues and sucrose in the growth media is necessary and sufficient to promote emergence of lateral root primordia from the parent root. Mild osmotic stress is perceived by the root, which then sends an abscisic acid–dependent signal that causes a decrease in the permeability of aerial tissues; this reduces uptake of sucrose from the culture media, which leads to a repression of lateral root formation. Osmotic repression of lateral root formation in culture can be overcome by mutations that cause the cuticle of a plant's aerial tissues to become more permeable. Indeed, we report here that the previously described lateral root development2 mutant overcomes osmotic repression of lateral root formation because of a point mutation in Long Chain Acyl-CoA Synthetase2, a gene essential for cutin biosynthesis. Together, our findings (1) impact the interpretation of experiments that use Arabidopsis grown in culture to study root system architecture; (2) identify sucrose as an unexpected regulator of lateral root formation; (3) demonstrate mechanisms by which roots communicate information to aerial tissues and receive information in turn; and (4) provide insights into the regulatory pathways that allow plants to be developmentally plastic while preserving the essential balance between aboveground and belowground organs.
NIP6;1 Is a Boric Acid Channel for Preferential Transport of Boron to Growing Shoot Tissues inArabidopsis
Authors: Tanaka Mayuki , Wallace Ian S. , Takano Junpei , Roberts Daniel M. , Fujiwara Toru
Published: October 2008

Boron (B) in soil is taken up by roots through NIP5;1, a boric acid channel, and is loaded into the xylem by BOR1, a borate exporter. Here, the function of Arabidopsis thaliana NIP6;1, the most similar gene to NIP5;1, was studied. NIP6;1 facilitates the rapid permeation of boric acid across the membrane but is completely impermeable to water. NIP6;1 transcript accumulation is elevated in response to B deprivation in shoots but not in roots. NIP6;1 promoter–β-glucuronidase is predominantly expressed in nodal regions of shoots, especially the phloem region of vascular tissues. Three independently identified T-DNA insertion lines for the NIP6;1 gene exhibited reduced expansion of young rosette leaves only under low-B conditions. B concentrations are reduced in young rosette leaves but not in the old leaves of these mutants. Taken together, these data strongly suggest that NIP6;1 is a boric acid channel required for proper distribution of boric acid, particularly among young developing shoot tissues. We propose that NIP6;1 is involved in xylem–phloem transfer of boric acid at the nodal regions and that the water-tight property of NIP6;1 is important for this function. It is proposed that during evolution, NIP5;1 and NIP6;1 were diversified in terms of both the specificity of their expression in plant tissues and their water permeation properties, while maintaining their ability to be induced under low B and their boric acid transport activities.
Conditional Repression of AUXIN BINDING PROTEIN1 Reveals That It Coordinates Cell Division and Cell Expansion during Postembryonic Shoot Development inArabidopsisand Tobacco
Authors: Braun Nils , Wyrzykowska Joanna , Muller Philippe , David Karine , Couch Daniel , Perrot-Rechenmann Catherine , Fleming Andrew J.
Published: October 2008

AUXIN BINDING PROTEIN1 (ABP1) has long been characterized as a potentially important mediator of auxin action in plants. Analysis of the functional requirement for ABP1 during development was hampered because of embryo lethality of the null mutant in Arabidopsis thaliana. Here, we used conditional repression of ABP1 to investigate its function during vegetative shoot development. Using an inducible cellular immunization approach and an inducible antisense construct, we showed that decreased ABP1 activity leads to a severe retardation of leaf growth involving an alteration in cell division frequency, an altered pattern of endocycle induction, a decrease in cell expansion, and a change in expression of early auxin responsive genes. In addition, local repression of ABP1 activity in the shoot apical meristem revealed an additional role for ABP1 in cell plate formation and cell shape. Moreover, cells at the site of presumptive leaf initiation were more sensitive to ABP1 repression than other regions of the meristem. This spatial context-dependent response of the meristem to ABP1 inactivation and the other data presented here are consistent with a model in which ABP1 acts as a coordinator of cell division and expansion, with local auxin levels influencing ABP1 effectiveness.