bluuebunny/crossref_metadata_2025 huggingface dataset:
LORENTZ VIOLATION DISPERSION RELATION AND ITS APPLICATION
Authors: XIAO ZHI , MA BO-QIANG
Published: March 2009

We derive a modified dispersion relation (MDR) in the Lorentz violation extension of the quantum electrodynamics (QED) sector in the standard model extension (SME) framework. Based on the extended Dirac equation and corresponding MDR, we observe the resemblance of the Lorentz violation coupling to spin–gravity coupling. We also develop a neutrino oscillation mechanism induced by the presence of nondiagonal terms of Lorentz violation couplings in two-flavor space in a two-spinor formalism by explicitly assuming neutrinos to be Marjorana fermions. We also obtain a very stringent bound (∽ 10-25) on one of the Lorentz violation parameters by applying the MDR to the ultrahigh energy cosmic ray (UHECR) problem.
CONFINEMENT EFFECT AS A RESULT OF SPONTANEOUS BREAKING OF SCALE INVARIANCE
Authors: KOROVER I. , GUENDELMAN E. I.
Published: March 2009

In this paper the consequences of introducing spontaneous symmetry breaking of scale invariance through a scale that is obtained from the integration of the equations of motion of four index field strengths are studied. Confinement is obtained for all values of this constant of integration. For negative values two point charges have a potential energy that grows linearly with distance, but they can be arbitrarily far apart (although this is costly from the point of view of energy). For positive values of the integration constant, there is no possibility of separating charges too far apart; at a certain point a new charge of opposite sign has to be added to form a neutral system that cannot be bigger that a critical size. We discuss this using different methods, including some developed by Adler and Piran. In addition, we discuss a few alternative effective actions that are similar and that also give confinement.
ON SOME SIMILARITIES AND DIFFERENCES BETWEEN FRACTIONAL PROBABILITY DENSITY SIGNED MEASURE OF PROBABILITY AND QUANTUM PROBABILITY
Authors: JUMARIE GUY
Published: March 2009

A probability density of fractional (or fractal) order is defined by the probability increment pr{x < X ≤ x+dx} = pα(x)(dx)α, 0 < α < 1, and appears to be quite suitable to deal with random variables defined in a fractal space. Combining this definition with the fractional Taylor's series [Formula: see text] denotes the Mittag–Leffler function) provided by the modified Riemann–Liouville derivative, one can expand a probability calculus parallel to the standard one. This approach could be considered as a framework for the derivation of some space fractional partial differential diffusion equations in coarse-grained spaces. It is shown firstly that there is some relation between fractional probability and signed measure of probability, and secondly that when α = 1/2, there is some identity between this fractal probability and quantum probability. Shortly, a wavefunction could be thought of as a fractal probability density of order 1/2. One exhibits further relations with possibility theory and relative information. Lastly, one arrives at a new informational entropy based on the inverse of the Mittag–Leffler function.
MAGNETIC, ELECTRIC AND EQUILIBRIUM PROPERTIES OF YBa2Cu3-x(PO4)xO7-δ HIGH TEMPERATURE SUPERCONDUCTING SYSTEM
Authors: URIBE LAVERDE M. A. , LANDÍNEZ TÉLLEZ D. A. , ROA-ROJAS J.
Published: March 2009

The new YBa 2 Cu 3-x( PO 4)x O 7-δ (x = 0; 0.03; 0.06; 0.09; 0.12) superconducting material was synthesized by the standard solid state reaction recipe. X-ray diffraction results show the effective substitution of copper for phosphate and also show no evidence of any impurity related with phosphate content. Resistivity, DC magnetization and heat capacity measurements reveal a superconducting transition for all samples with a maximum critical temperature up to 97 K, corresponding to the x = 0.03 sample. For higher doping values, the critical temperature decreases in an approximately linear response. In agreement with the charge transfer model, the critical temperature decreases with the carrier density. For x = 0.03, the critical temperature shows a rise up due to an approximation to the optimum density which separates over-doped and under-doped regimes. The maximum critical temperature achieved is one of the highest ever seen for the 123-type superconductors.
Genome-Wide Views of Chromatin Structure
Authors: Rando Oliver J. , Chang Howard Y.
Published: March 2009

Eukaryotic genomes are packaged into a nucleoprotein complex known as chromatin, which affects most processes that occur on DNA. Along with genetic and biochemical studies of resident chromatin proteins and their modifying enzymes, mapping of chromatin structure in vivo is one of the main pillars in our understanding of how chromatin relates to cellular processes. In this review, we discuss the use of genomic technologies to characterize chromatin structure in vivo, with a focus on data from budding yeast and humans. The picture emerging from these studies is the detailed chromatin structure of a typical gene, where the typical behavior gives insight into the mechanisms and deep rules that establish chromatin structure. Important deviation from the archetype is also observed, usually as a consequence of unique regulatory mechanisms at special genomic loci. Chromatin structure shows substantial conservation from yeast to humans, but mammalian chromatin has additional layers of complexity that likely relate to the requirements of multicellularity such as the need to establish faithful gene regulatory mechanisms for cell differentiation.
Mechanisms of Endocytosis
Authors: Doherty Gary J. , McMahon Harvey T.
Published: March 2009

Endocytic mechanisms control the lipid and protein composition of the plasma membrane, thereby regulating how cells interact with their environments. Here, we review what is known about mammalian endocytic mechanisms, with focus on the cellular proteins that control these events. We discuss the well-studied clathrin-mediated endocytic mechanisms and dissect endocytic pathways that proceed independently of clathrin. These clathrin-independent pathways include the CLIC/GEEC endocytic pathway, arf6-dependent endocytosis, flotillin-dependent endocytosis, macropinocytosis, circular doral ruffles, phagocytosis, and trans-endocytosis. We also critically review the role of caveolae and caveolin1 in endocytosis. We highlight the roles of lipids, membrane curvature-modulating proteins, small G proteins, actin, and dynamin in endocytic pathways. We discuss the functional relevance of distinct endocytic pathways and emphasize the importance of studying these pathways to understand human disease processes.
Smaller organ mass with greater age, except for heart
Authors: He Qing , Heshka Stanley , Albu Jeanine , Boxt Lawrence , Krasnow Norman , Elia Marinos , Gallagher Dympna
Published: March 2009

Autopsy/cadaver data indicate that many organs and tissues are smaller in the elderly compared with young adults; however, in vivo data are lacking. The aim of this study was to determine whether the mass of specific high-metabolic-rate organs is different with increasing age, using MRI. Seventy-five healthy women (41 African-Americans and 34 Caucasians, age range 19–88 yr) and 36 men (8 African-Americans and 28 Caucasians, age range 19–84 yr) were studied. MRI-derived in vivo measures of brain, heart, kidneys, liver, and spleen were acquired. Left ventricular mass (LVM) was measured by either echocardiography or cardiac gated MRI. Total body fat mass and fat-free mass (FFM) were measured with a whole body dual-energy X-ray absorptiometry (DXA) scanner. Multiple regression analysis was used to investigate the association between the organ mass and age after adjustment for weight and height (or DXA measures of FFM), race, sex, and interactions among these variable. No statistically significant interaction was found among age, sex, and race in any regression model. Significant negative relationships between organ mass and age were found for brain ( P < 0.0001), kidneys ( P = 0.01), liver ( P = 0.001), and spleen ( P < 0.0001). A positive relationship between LVM and age was found after adjustment for FFM ( P = 0.037). These findings demonstrate that age has a significant effect on brain, kidneys, liver, spleen, and heart mass. The age effect was independent of race and sex.
Evolution of Brain Tumor and Stability of Geometric Invariants
Authors: Tawbe K. , Cotton F. , Vuillon L.
Published: March 2009

This paper presents a method to reconstruct and to calculate geometric invariants on brain tumors. The geometric invariants considered in the paper are the volume, the area, the discrete Gauss curvature, and the discrete mean curvature. The volume of a tumor is an important aspect that helps doctors to make a medical diagnosis. And as doctors seek a stable calculation, we propose to prove the stability of some invariants. Finally, we study the evolution of brain tumor as a function of time in two or three years depending on patients with MR images every three or six months.
Agent-Oriented Privacy-Based Information Brokering Architecture for Healthcare Environments
Authors: Masaud-Wahaishi Abdulmutalib , Ghenniwa Hamada
Published: March 2009

Healthcare industry is facing a major reform at all levels—locally, regionally, nationally, and internationally. Healthcare services and systems become very complex and comprise of a vast number of components (software systems, doctors, patients, etc.) that are characterized by shared, distributed and heterogeneous information sources with varieties of clinical and other settings. The challenge now faced with decision making, and management of care is to operate effectively in order to meet the information needs of healthcare personnel. Currently, researchers, developers, and systems engineers are working toward achieving better efficiency and quality of service in various sectors of healthcare, such as hospital management, patient care, and treatment. This paper presents a novel information brokering architecture that supports privacy-based information gathering in healthcare. Architecturally, the brokering is viewed as a layer of services where a brokering service is modeled as an agent with a specific architecture and interaction protocol that are appropriate to serve various requests. Within the context of brokering, we model privacy in terms of the entities ability to hide or reveal information related to its identities, requests, and/or capabilities. A prototype of the proposed architecture has been implemented to support information-gathering capabilities in healthcare environments using FIPA-complaint platform JADE.
Synthesis, Structure, Electrochemistry, and Cytotoxic Properties of Ferrocenyl Ester Derivatives
Authors: Gao Li Ming , Hernández Ramón , Matta Jaime , Meléndez Enrique
Published: March 2009

A series of ferrocenyl ester complexes, varying the lipophilic character of the pendant groups, was prepared and characterized by spectroscopic and analytical methods. The syntheses of Fe(C5H4CO2CH3)2, Fe(CpCOOCH3) (CpCOO
CH2CH3), and
Fe(CpCOOCH2CH3)2 are reported. The solid-state structure of Fe(C5H4CO2CH3)2 has been determined by X-ray crystallography. Fe(C5H4CO2CH3)2 has the cyclopentadienyl rings virtually in an eclipsed conformation with the pendant groups not completely opposite to each other. Cyclic voltammetry characterization showed that the functionalized ferrocenes oxidize at potentials, Epa, higher than ferrocene as a result of the electro withdrawing effect of the pendant groups on the cyclopentadienyl ligand. The cytotoxicities of Fe(C5H4CO2CH2CH2OH)2, Fe(C5H4CO2CH2CH=CH2)2, Fe(C5H4CO2CH3)2, Fe(CpCOOCH3)(CpCOOCH2CH3), and Fe(CpCOOCH2CH3)2 in colon cancer HT-29 and breast cancer MCF-7 cell lines were measured by the MTT biological viability assay and compared to ferrocene and ferrocenium. Fe(C5H4CO2CH2CH=CH2)2 showed the best IC50 values, 180(10)  μM for HT-29 and 190(30)  μM for MCF-7 cell lines, with cytotoxicities similar to ferrocenium. The cytotoxic data suggest that as we increase the lipophilic character of the functionalized ferrocene, the cytotoxicity improves approaching to the cytotoxic activity of ferrocenium.
Modulation of CXCR4, CXCL12, and Tumor Cell Invasion Potential In Vitro by Phytochemicals
Authors: Hsu Erin L. , Chen Natalie , Westbrook Aya , Wang Feng , Zhang Ruixue , Taylor Robert T. , Hankinson Oliver
Published: March 2009

CXCR4 is a chemokine receptor frequently overexpressed on primary tumor cells. Organs to which these cancers metastasize secrete CXCL12, the unique ligand for CXCR4, which stimulates invasion and metastasis to these sites. Similar to our previous work with the chemoprotective phytochemical, 3,3′-diindolylmethane (DIM), we show here that genistein also downregulates CXCR4 and CXCL12 and subsequently lowers the migratory and invasive potentials of breast and ovarian cancer cells. Moreover, genistein and DIM elicit a significantly greater cumulative effect in lowering CXCR4 and CXCL12 levels than either compound alone. Our data suggest a novel mechanism for the protective effects of phytochemicals against cancer progression and indicate that in combination, these compounds may prove even more efficacious.
Leukocyte Count and Incidence of Hospitalizations Due to Heart Failure
Authors: Engström Gunnar , Melander Olle , Hedblad Bo
Published: March 2009

Background—

Leukocyte concentration in blood is a classical marker of systemic inflammation. Whether high leukocyte counts are associated with incidence of heart failure (HF) is unknown. This population-based study explored whether the leukocyte concentrations were associated with incidence of hospitalizations due to HF.

Methods and results—

Leukocyte counts were measured in 16 940 men from the general population (mean age 44 years) without history of myocardial infarction or stroke. Incidence of hospitalizations due to HF (primary diagnosis) was monitored over 23 years of follow-up, in relation to quartiles of leukocytes. Subjects with myocardial infarction during follow-up were censored in the main analysis. During the follow-up, 436 men were hospitalized due to HF. Incidence of HF hospitalizations was increased in men with high leukocyte counts. After adjustments for confounding factors, the adjusted hazards ratio (HR, 95% CI) for HF hospitalization was 1.00 (reference), 1.26 (0.93 to 1.7), 1.24 (0.91 to 1.7), and 1.73 (1.3 to 2.3), respectively, for men with leukocytes in the 1st, 2nd, 3rd, and 4th (highest) quartiles (trend,
P
<0.001). This relationship was consistent in smokers and nonsmokers and in men with and without hypertension, respectively.

Conclusion—

High leukocyte counts in middle-aged men were associated with increased long-term incidence of HF hospitalizations.
Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage
Authors: Gautier Emmanuel L. , Huby Thierry , Witztum Joseph L. , Ouzilleau Betty , Miller Elizabeth R. , Saint-Charles Flora , Aucouturier Pierre , Chapman M. John , Lesnik Philippe
Published: March 2009

Background—

Because apoptotic cell clearance appears to be defective in advanced compared with early atherosclerotic plaques, macrophage apoptosis may differentially affect plaque progression as a function of lesion stage.

Methods and Results—

We first evaluated the impact of targeted protection of macrophages against apoptosis at both early and advanced stages of atherosclerosis. Increased resistance of macrophages to apoptosis in early atherosclerotic lesions was associated with increased plaque burden; in contrast, it afforded protection against progression to advanced lesions. Conversely, sustained induction of apoptosis in lesional macrophages of advanced lesions resulted in a significant increase in lesion size. Such enhanced lesion size occurred as a result not only of apoptotic cell accumulation but also of elevated chemokine expression and subsequent intimal recruitment of circulating monocytes.

Conclusions—

Considered together, our data suggest that macrophage apoptosis is atheroprotective in fatty streak lesions, but in contrast, defective clearance of apoptotic debris in advanced lesions favors arterial wall inflammation and enhanced recruitment of monocytes, leading to enhanced atherogenesis.
Detection and Quantification of Left Atrial Structural Remodeling With Delayed-Enhancement Magnetic Resonance Imaging in Patients With Atrial Fibrillation
Authors: Oakes Robert S. , Badger Troy J. , Kholmovski Eugene G. , Akoum Nazem , Burgon Nathan S. , Fish Eric N. , Blauer Joshua J.E. , Rao Swati N. , DiBella Edward V.R. , Segerson Nathan M. , Daccarett Marcos , Windfelder Jessiciah , McGann Christopher J. , Parker Dennis , MacLeod Rob S. , Marrouche Nassir F.
Published: March 2009

Background—

Atrial fibrillation (AF) is associated with diffuse left atrial fibrosis and a reduction in endocardial voltage. These changes are indicators of AF severity and appear to be predictors of treatment outcome. In this study, we report the utility of delayed-enhancement magnetic resonance imaging (DE-MRI) in detecting abnormal atrial tissue before radiofrequency ablation and in predicting procedural outcome.

Methods and Results—

Eighty-one patients presenting for pulmonary vein antrum isolation for treatment of AF underwent 3-dimensional DE-MRI of the left atrium before the ablation. Six healthy volunteers also were scanned. DE-MRI images were manually segmented to isolate the left atrium, and custom software was implemented to quantify the spatial extent of delayed enhancement, which was then compared with the regions of low voltage from electroanatomic maps from the pulmonary vein antrum isolation procedure. Patients were assessed for AF recurrence at least 6 months after pulmonary vein antrum isolation, with an average follow-up of 9.6±3.7 months (range, 6 to 19 months). On the basis of the extent of preablation enhancement, 43 patients were classified as having minimal enhancement (average enhancement, 8.0±4.2%), 30 as having moderate enhancement (21.3±5.8%), and 8 as having extensive enhancement (50.1±15.4%). The rate of AF recurrence was 6 patients (14.0%) with minimal enhancement, 13 (43.3%) with moderate enhancement, and 6 (75%) with extensive enhancement (
P
<0.001).

Conclusions—

DE-MRI provides a noninvasive means of assessing left atrial myocardial tissue in patients suffering from AF and might provide insight into the progress of the disease. Preablation DE-MRI holds promise for predicting responders to AF ablation and may provide a metric of overall disease progression.
Molecular Magnetic Resonance Imaging of Myocardial Perfusion With EP-3600, a Collagen-Specific Contrast Agent
Authors: Spuentrup Elmar , Ruhl Karl M. , Botnar Rene M. , Wiethoff Andrea J. , Buhl Alexandra , Jacques Vincent , Greenfield Matthew T. , Krombach Gabriele A. , Günther Rolf W. , Vangel Mark G. , Caravan Peter
Published: March 2009

Background—

Cardiac magnetic resonance (MR) perfusion imaging during the first pass after intravenous administration of extracellular contrast agents is hampered by the spatial and temporal resolution achievable and by the artifacts seen in ultrafast MR imaging. Furthermore, time-consuming quantitative data analysis is often added. The use of molecular MR imaging with a target-specific contrast agent with perfusion-dependent binding to myocardium may enable prolonged visualization of perfusion defects and thus may help to overcome limitations of currently used first-pass extracellular MR imaging. EP-3600 is a new gadolinium-containing molecular contrast agent that binds reversibly to myocardial collagen.

Methods and Results—

A significant but nonocclusive coronary artery stenosis was modeled in 7 domestic swine with an undersized MR-compatible balloon positioned in the left anterior descending artery as verified by x-ray angiography. Two animals died before contrast injection as a result of arrhythmias. In 5 swine, high-spatial-resolution gradient echo imaging (≈1×1 mm
2
in-plane resolution) was performed before and 5, 20, 40, and 60 minutes after intravenous administration of 12.3 μmol/kg EP-3600. Contrast was administered during stress induced by an infusion of 250 μmol · kg
−1
· min
−1
adenosine. Yb-DTPA was administered simultaneously for comparison of myocardium-to-plasma ratios. Images were assessed subjectively by 2 investigators, and signal-to-noise and contrast-to-noise ratios over time were calculated. Normal myocardium showed a significant signal-to-noise ratio increase during the entire examination time. In all animals (n=5), the perfusion defect in the left anterior descending artery territory could be visualized with a high contrast-to-noise ratio for at least 20 minutes after contrast injection. A significantly higher myocardium-to-plasma ratio was found for EP-3600 compared with the control agent Yb-DTPA (0.85±0.26 versus 0.22±0.08, respectively;
P
<0.01).

Conclusion—

EP-3600 is a new molecular MR imaging contrast agent that binds to the myocardium and enables prolonged, high-contrast, high-spatial-resolution visualization of myocardial perfusion defects.
Complement-Dependent Neutrophil Recruitment Is Critical for the Development of Elastase-Induced Abdominal Aortic Aneurysm
Authors: Pagano Monica B. , Zhou Hui-fang , Ennis Terri L. , Wu Xiaobo , Lambris John D. , Atkinson John P. , Thompson Robert W. , Hourcade Dennis E. , Pham Christine T.N.
Published: March 2009

Background—

We previously established that neutrophils play a critical role in the development of experimental abdominal aortic aneurysm (AAA). The signal that initiates the influx of neutrophils to the aortic wall, however, remains unknown. In this study, we tested the hypothesis that complement participates in the development of AAA by providing the necessary chemotactic signal that recruits neutrophils to the aortic wall.

Methods and Results—

Using an elastase-induced model of AAA, we showed that pretreatment of C57BL/6 mice with cobra venom factor, which depleted serum of complement activity, protected mice from AAA development. Whereas control mice exhibited a mean aortic diameter of 156±2% on day 14 after elastase perfusion, mice treated with cobra venom factor exhibited a mean aortic diameter of 90±4% (
P
<0.001). Examination of mice deficient in factor B further indicated that the alternative pathway of complement played a major role in this process (mean aortic diameter of 105±4% in factor B–deficient mice,
P
<0.001 compared with controls). Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, which recruited neutrophils to the aortic wall. Moreover, antagonism of both C3a and C5a activity was required to block AAA, which suggests that each can independently promote the aneurysmal phenotype. In addition, we demonstrated that complement alternative-pathway involvement was not restricted to this experimental model but was also evident in human AAAs.

Conclusions—

The identification of involvement of the complement system in the pathophysiology of AAA provides a new target for therapeutic intervention in this common disease.
The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL
Authors: Ci Weimin , Polo Jose M. , Cerchietti Leandro , Shaknovich Rita , Wang Ling , Yang Shao Ning , Ye Kenny , Farinha Pedro , Horsman Douglas E. , Gascoyne Randy D. , Elemento Olivier , Melnick Ari
Published: March 2009

The BCL6 transcriptional repressor is required for development of germinal center (GC) B cells and when expressed constitutively causes diffuse large B-cell lymphomas (DLBCLs). We examined genome-wide BCL6 promoter binding in GC B cells versus DLBCLs to better understand its function in these settings. BCL6 bound to both distinct and common sets of functionally related gene in normal GC cells versus DLBCL cells. Certain BCL6 target genes were preferentially repressed in GC B cells, but not DLBCL cells. Several such genes have prominent oncogenic functions, such as BCL2, MYC, BMI1, EIF4E, JUNB, and CCND1. BCL6 and BCL2 expression was negatively correlated in primary DLBCLs except in the presence of BCL2 translocations. The specific BCL6 inhibitor retro-inverso BCL6 peptidomimetic inhibitor-induced expression of BCL2 and other oncogenes, consistent with direct repression effects by BCL6. These data are consistent with a model whereby BCL6 can directly silence oncogenes in GC B cells and counterbalance its own tumorigenic potential. Finally, a BCL6 consensus sequence and binding sites for other physiologically relevant transcription factors were highly enriched among target genes and distributed in a pathway-dependent manner, suggesting that BCL6 forms specific regulatory circuits with other B-cell transcriptional factors.
Comparable survival between HIV+ and HIV− non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation
Authors: Díez-Martín José L. , Balsalobre Pascual , Re Alessandro , Michieli Mariagrazia , Ribera José M. , Canals Carmen , Conde Eulogio , Rosselet Anne , Gabriel Ian , Varela Rosario , Allione Bernardino , Cwynarski Kate , Genet Philippe , Espigado Ildefonso , Biron Pierre , Schmitz Norbert , Hunter Anne E. , Ferrant Augustin , Guillerm Gaelle , Hentrich Mark , Jurado Manuel , Fernández Pascual , Serrano David , Rossi Giuseppe , Sureda Anna
Published: March 2009

Autologous stem cell transplantation (ASCT) has been successfully used in HIV-related lymphoma (HIV-Ly) patients on highly active antiretroviral therapy. We report the first comparative analysis between HIV-Ly and a matched cohort of HIV− lymphoma patients. This retrospective European Group for Blood and Marrow Transplantation study included 53 patients (66% non-Hodgkin and 34% Hodgkin lymphoma) within each cohort. Both groups were comparable except for the higher proportion of males, mixed-cellularity Hodgkin lymphoma and patients receiving granulocyte colony-stimulating factor before engraftment and a smaller proportion receiving total body irradiation-based conditioning within the HIV-Ly cohort. Incidence of relapse, overall survival, and progression-free survival were similar in both cohorts. A higher nonrelapse mortality within the first year after ASCT was observed in the HIV-Ly group (8% vs 2%), predominantly because of early bacterial infections, although this was not statistically significant and did not influence survival. Thus, within the highly active antiretroviral therapy era, HIV patients should be considered for ASCT according to the same criteria adopted for HIV− lymphoma patients.
Migration of Chadic speaking pastoralists within Africa based on population structure of Chad Basin and phylogeography of mitochondrial L3f haplogroup
Authors: Černý Viktor , Fernandes Verónica , Costa Marta D , Hájek Martin , Mulligan Connie J , Pereira Luísa
Published: March 2009

Background

Chad Basin, lying within the bidirectional corridor of African Sahel, is one of the most populated places in Sub-Saharan Africa today. The origin of its settlement appears connected with Holocene climatic ameliorations (aquatic resources) that started ~10,000 years before present (YBP). Although both Nilo-Saharan and Niger-Congo language families are encountered here, the most diversified group is the Chadic branch belonging to the Afro-Asiatic language phylum. In this article, we investigate the proposed ancient migration of Chadic pastoralists from Eastern Africa based on linguistic data and test for genetic traces of this migration in extant Chadic speaking populations.

Results

We performed whole mitochondrial genome sequencing of 16 L3f haplotypes, focused on clade L3f3 that occurs almost exclusively in Chadic speaking people living in the Chad Basin. These data supported the reconstruction of a L3f phylogenetic tree and calculation of times to the most recent common ancestor for all internal clades. A date ~8,000 YBP was estimated for the L3f3 sub-haplogroup, which is in good agreement with the supposed migration of Chadic speaking pastoralists and their linguistic differentiation from other Afro-Asiatic groups of East Africa. As a whole, the Afro-Asiatic language family presents low population structure, as 92.4% of mtDNA variation is found within populations and only 3.4% of variation can be attributed to diversity among language branches. The Chadic speaking populations form a relatively homogenous cluster, exhibiting lower diversification than the other Afro-Asiatic branches (Berber, Semitic and Cushitic).

Conclusion

The results of our study support an East African origin of mitochondrial L3f3 clade that is present almost exclusively within Chadic speaking people living in Chad Basin. Whole genome sequence-based dates show that the ancestral haplogroup L3f must have emerged soon after the Out-of-Africa migration (around 57,100 ± 9,400 YBP), but the "Chadic" L3f3 clade has much less internal variation, suggesting an expansion during the Holocene period about 8,000 ± 2,500 YBP. This time period in the Chad Basin is known to have been particularly favourable for the expansion of pastoralists coming from northeastern Africa, as suggested by archaeological, linguistic and climatic data.
Suppression of RNA interference increases alphavirus replication and virus-associated mortality in Aedes aegypti mosquitoes
Authors: Cirimotich Chris M , Scott Jaclyn C , Phillips Aaron T , Geiss Brian J , Olson Ken E
Published: March 2009

Background

Arthropod-borne viruses (arboviruses) can persistently infect and cause limited damage to mosquito vectors. RNA interference (RNAi) is a mosquito antiviral response important in restricting RNA virus replication and has been shown to be active against some arboviruses. The goal of this study was to use a recombinant Sindbis virus (SINV; family Togaviridae; genus Alphavirus) that expresses B2 protein of Flock House virus (FHV; family Nodaviridae; genus Alphanodavirus), a protein that inhibits RNAi, to determine the effects of linking arbovirus infection with RNAi inhibition.

Results

B2 protein expression from SINV (TE/3'2J) inhibited the accumulation of non-specific small RNAs in Aedes aegypti mosquito cell culture and virus-specific small RNAs both in infected cell culture and Ae. aegypti mosquitoes. More viral genomic and subgenomic RNA accumulated in cells and mosquitoes infected with TE/3'2J virus expressing B2 (TE/3'2J/B2) compared to TE/3'2J and TE/3'2J virus expressing GFP. TE/3'2J/B2 exhibited increased infection rates, dissemination rates, and infectious virus titers in mosquitoes following oral bloodmeal. Following infectious oral bloodmeal, significantly more mosquitoes died when TE/3'2J/B2 was ingested. The virus was 100% lethal following intrathoracic inoculation of multiple mosquito species and lethality was dose-dependent in Ae. aegypti.

Conclusion

We show that RNAi is active in Ae. aegypti cell culture and that B2 protein inhibits RNAi in mosquito cells when expressed by a recombinant SINV. Also, SINV more efficiently replicates in mosquito cells when RNAi is inhibited. Finally, TE/3'2J/B2 kills mosquitoes in a dose-dependent manner independent of infection route and mosquito species.
A functional type I topoisomerase from Pseudomonas aeruginosa
Authors: Jain Teesta , Roper Benjamin J , Grove Anne
Published: March 2009

Background

Pseudomonas aeruginosa encodes a putative topoisomerase with sequence similarity to the eukaryotic type IB topoisomerase from Vaccinia virus. Residues in the active site are conserved, notably Tyr292 which would be predicted to form the transient covalent bond to DNA.

Results

The gene encoding the P. aeruginosa topoisomerase I was cloned and expressed in E. coli. The enzyme relaxes supercoiled DNA, while a mutant containing a Tyr292 to Phe substitution at the active site was found to be catalytically inert. This is consistent with the role of Tyr in forming the covalent intermediate. Like Vaccinia topoisomerase, the P. aeruginosa topoisomerase relaxes DNA in the absence of ATP, but unlike Vaccinia topoisomerase, P. aeruginosa topoisomerase does not relax supercoiled DNA without MgCl2 present. In addition, high concentration of NaCl is not able to substitute for MgCl2 as seen for Vaccinia topoisomerase. A truncated derivative of the topoisomerase lacking residues 1–98 relaxes DNA, with both full length and truncated enzyme exhibiting equivalent requirements for divalent cations and the ability to relax DNA to completion, suggesting a shared domain organization. DNA-binding assays suggest an only modest preference for the CCCTT pentameric sequence required for transesterification by Vaccinia topoisomerase IB.

Conclusion

P. aeruginosa encodes a functional topoisomerase with significant similarity to the type IB enzyme encoded by poxviruses. In contrast to the Vaccinia-encoded homolog, the P. aeruginosa-encoded enzyme requires divalent cations for catalytic activity, relaxes DNA to completion, and does not exhibit a strong preference for the pentameric sequence stringently required by the Vaccinia-encoded homolog. A comparison with the structure of poxviral topoisomerase in complex with DNA suggests that bacterial homologs of the eukaryotic type IB topoisomerase may exhibit a relaxed sequence preference due to the lack of conservation of certain residues involved in sequence-specific DNA contacts, and that interaction with an only modestly preferred sequence may result in suboptimal positioning of catalytic residues.
Interaction of Cupidin/Homer2 with two actin cytoskeletal regulators, Cdc42 small GTPase and Drebrin, in dendritic spines
Authors: Shiraishi-Yamaguchi Yoko , Sato Yumi , Sakai Rieko , Mizutani Akihiro , Knöpfel Thomas , Mori Nozomu , Mikoshiba Katsuhiko , Furuichi Teiichi
Published: March 2009

Background

Homer is a postsynaptic scaffold protein that links various synaptic signaling proteins, including the type I metabotropic glutamate receptor subunits 1α and 5, the inositol 1,4,5-trisphosphate receptor, Shank and Cdc42 small GTPase. Overexpression of Homer induces changes in dendritic spine morphology in cultured hippocampal neurons. However, the molecular basis underpinning Homer-mediated spine morphogenesis remains unclear. In this study, we aimed to elucidate the structural and functional properties of the interaction between Cupidin/Homer2 and two actin-cytoskeletal regulators, Cdc42 small GTPase and Drebrin.

Results

Cupidin/Homer2 interacted with activated Cdc42 small GTPase via the Cdc42-binding domain that resides around amino acid residues 191–283, within the C-terminal coiled-coil domain. We generated a Cupidin deletion mutant lacking amino acids 191–230 (CPDΔ191–230), which showed decrease Cdc42-binding ability but maintained self-multimerization ability. Cupidin suppressed Cdc42-induced filopodia-like protrusion formation in HeLa cells, whereas CPDΔ191–230 failed to do so. In cultured hippocampal neurons, Cupidin was targeted to dendritic spines, whereas CPDΔ191–230 was distributed in dendritic shafts as well as spines. Overexpression of CPDΔ191–230 decreased the number of synapses and reduced the amplitudes of miniature excitatory postsynaptic currents in hippocampal neurons. Cupidin interacted with a dendritic spine F-actin-binding protein, Drebrin, which possesses two Homer ligand motifs, via the N-terminal EVH-1 domain. CPDΔ191–230 overexpression decreased Drebrin clustering in the dendritic spines of hippocampal neurons.

Conclusion

These results indicate that Cupidin/Homer2 interacts with the dendritic spine actin regulators Cdc42 and Drebrin via its C-terminal and N-terminal domains, respectively, and that it may be involved in spine morphology and synaptic properties.
A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype
Authors: Park Hyung-Doo , Kim Yoon-Kyoung , Park Kyoung Un , Kim Jin Q , Song Young-Han , Song Junghan
Published: March 2009

Background

Many genetic variations ofGALK1have been identified in the patients with galactokinase (GALK1) deficiency. However, the molecular characteristics ofGALK1in individuals with elevated GALK1 activity are relatively unknown.

Methods

We investigated the relationship between elevated GALK1 activity and the molecularGALK1gene variations, and the molecular mechanism underlying elevated GALK1 activity. PCR products from 63 subjects, without any attenuation of galactose degradation enzymes, were sequenced to screen for nucleotide alterations in theGALK1promoter.

Results

Three nucleotide substitutions were identified: c.-179A>G, c.-27A>C, and c.-22T>C. With respect to the c.-22T>C mutation, GALK1 activity in 13 subjects with the T/C or C/C genotype was significantly higher than those in 50 subjects with the T/T genotype (p < 0.001). The dual luciferase reporter assay in Hep3B cells showed that the luciferase activity with theGALK1promoter with the c.-22C mutant allele increased approximately 2.5-fold, compared to that with the c.-22T. A specific DNA-protein complex was observed in an electrophoretic mobility shift assay, with slightly higher affinity to c.-22C than to c.-22T.

Conclusion

The c.-22T>C mutation, which was observed frequently in individuals with elevated GALK1 activity, increased the expression of a reporter gene through enhanced binding of a currently unidentified nuclear protein. These results suggest that the elevated GALK1 activity resulted from enhanced gene expression, due to nucleotide variation withinGALK1promoter.
Circulating cell death products predict clinical outcome of colorectal cancer patients
Authors: Koelink Pim J , Lamers Cornelis BHW , Hommes Daan W , Verspaget Hein W
Published: March 2009

Background

Tumor cell death generates products that can be measured in the circulation of cancer patients. CK18-Asp396 (M30 antigen) is a caspase-degraded product of cytokeratin 18 (CK18), produced by apoptotic epithelial cells, and is elevated in breast and lung cancer patients.

Methods

We determined the CK18-Asp396 and total CK18 levels in plasma of 49 colorectal cancer patients, before and after surgical resection of the tumor, by ELISA. Correlations with patient and tumor characteristics were determined by Kruskal-Wallis H and Mann-Whitney U tests. Disease-free survival was determined using Kaplan-Meier methodology with Log Rank tests, and univariate and multivariate Cox proportional hazard analysis.

Results

Plasma CK18-Asp396 and total CK18 levels in colorectal cancer patients were related to disease stage and tumor diameter, and were predictive of disease-free survival, independent of disease-stage, with hazard ratios (HR) of patients with high levels (> median) compared to those with low levels (≤ median) of 3.58 (95% CI: 1.17–11.02) and 3.58 (95% CI: 0.97–7.71), respectively. The CK18-Asp396/CK18 ratio, which decreased with tumor progression, was also predictive of disease-free survival, with a low ratio (≤ median) associated with worse disease-free survival: HR 2.78 (95% CI: 1.06–7.19). Remarkably, the plasma CK18-Asp396 and total CK18 levels after surgical removal of the tumor were also predictive of disease-free survival, with patients with high levels having a HR of 3.78 (95% CI: 0.77–18.50) and 4.12 (95% CI: 0.84–20.34), respectively, indicating that these parameters can be used also to monitor patients after surgery.

Conclusion

CK18-Asp396 and total CK18 levels in the circulation of colorectal cancer patients are predictive of tumor progression and prognosis and might be helpful for treatment selection and monitoring of these patients.
Population based prostate cancer screening in north Mexico reveals a high prevalence of aggressive tumors in detected cases
Authors: Gomez-Guerra Lauro S , Martinez-Fierro Margarita L , Alcantara-Aragon Valeria , Ortiz-Lopez Rocio , Martinez-Villarreal Rebeca T , Morales-Rodriguez Idelma B , Garza-Guajardo Raquel , Ponce-Camacho Marco A , Rojas-Martinez Augusto
Published: March 2009

Background

Prostate Cancer (PCa) is the second most frequent neoplasia in men worldwide. Previous reports suggest that the prevalence of PCa in Hispanic males is lower than in Africans (including communities with African ancestry) and Caucasians, but higher than in Asians. Despite these antecedents, there are few reports of open population screenings for PCa in Latin American communities. This article describes the results of three consecutive screenings in the urban population of Monterrey, Mexico.

Methods

After receiving approval from our University Hospital's Internal Review Board (IRB), the screening was announced by radio, television, and press, and it was addressed to male subjects over 40 years old in general. Subjects who consented to participate were evaluated at the primary care clinics of the University Health Program at UANL, in the Metropolitan area of Monterrey. Blood samples were taken from each subject for prostate specific antigen (PSA) determination; they underwent a digital rectal examination (DRE), and were subsequently interviewed to obtain demographic and urologic data. Based on the PSA (>4.0 ng/ml) and DRE results, subjects were appointed for transrectal biopsy (TRB).

Results

A total of 973 subjects were screened. Prostate biopsy was recommended to 125 men based on PSA values and DRE results, but it was performed in only 55 of them. 15 of these biopsied men were diagnosed with PCa, mostly with Gleason scores ≥ 7.

Conclusion

Our results reflect a low prevalence of PCa in general, but a high occurrence of high grade lesions (Gleason ≥ 7) among patients that resulted positive for PCa. This observation remarks the importance of the PCa screening programs in our Mexican community and the need for strict follow-up campaigns.
Toll-like receptor polymorphisms in malaria-endemic populations
Authors: Greene Jennifer A , Moormann Ann M , Vulule John , Bockarie Moses J , Zimmerman Peter A , Kazura James W
Published: March 2009

Background

Toll-like receptors (TLR) and related downstream signaling pathways of innate immunity have been implicated in the pathogenesis ofPlasmodium falciparummalaria. Because of their potential role in malaria pathogenesis, polymorphisms in these genes may be under selective pressure in populations where this infectious disease is endemic.

Methods

A post-PCR Ligation Detection Reaction-Fluorescent Microsphere Assay (LDR-FMA) was developed to determine the frequencies ofTLR2, TLR4, TLR9,MyD88-Adaptor Like Protein (MAL)single nucleotide polymorphisms (SNPs), andTLR2length polymorphisms in 170 residents of two regions of Kenya where malaria transmission is stable and high (holoendemic) or episodic and low, 346 residents of a malaria holoendemic region of Papua New Guinea, and 261 residents of North America of self-identified ethnicity.

Results

The difference in historical malaria exposure between the two Kenyan sites has significantly increased the frequency of malaria protective allelesglucose-6-phoshpate dehydrogenase(G6PD) andHemoglobin S (HbS)in the holoendemic site compared to the episodic transmission site. However, this study detected no such difference in theTLR2, TLR4, TLR9, andMALallele frequencies between the two study sites. All polymorphisms were in Hardy Weinberg Equilibrium in the Kenyan and Papua New Guinean populations.TLR9SNPs and length polymorphisms within theTLR25' untranslated region were the only mutant alleles present at a frequency greater than 10% in all populations.

Conclusion

Similar frequencies ofTLR2, TLR4, TLR9, andMALgenetic polymorphisms in populations with different histories of malaria exposure suggest that these innate immune pathways have not been under strong selective pressure by malaria. Genotype frequencies are consistent with Hardy-Weinberg Equilibrium and the Neutral Theory, suggesting that genetic drift has influenced allele frequencies to a greater extent than selective pressure from malaria or any other infectious agents in these populations.
Identification of a public CDR3 motif and a biased utilization of T-cell receptor V beta and J beta chains in HLA-A2/Melan-A-specific T-cell clonotypes of melanoma patients
Authors: Serana Federico , Sottini Alessandra , Caimi Luigi , Palermo Belinda , Natali Pier Giorgio , Nisticò Paola , Imberti Luisa
Published: March 2009

Background

Assessment of T-cell diversity, besides giving insights about the molecular basis of tumor antigen recognition, has clinical implications since it provides criteria for evaluating antigen-specific T cells clinically relevant for spontaneous and vaccine-induced anti-tumor activity. Melan-A is one of the melanoma antigens most frequently recognized by peripheral and tumor-infiltrating lymphocytes in HLA-A2+ melanoma patients. Many clinical trials involving anti-tumor vaccination have been conducted using modified versions of this peptide.

Methods

We conducted an in-depth characterization of 210 T-cell receptor beta chain (TRB) clonotypes derived from T cells of HLA-A2+ melanoma patients displaying cytotoxic activity against natural and A27L-modified Melan-A peptides. One hundred and thirteen Melan-A-specific clonotypes from melanoma-free subjects, 199 clonotypes from T-cell clones from melanoma patients specific for melanoma antigens other than Melan-A, and 305 clonotypes derived from T cells of HLA-A2+ individuals showing unrelated specificities, were used as control. After sequence analysis, performed according to the IMGT definitions, TRBV and TRBJ usage, CDR3 length and amino acid composition were compared in the four groups of clonotypes.

Results

TRB sequences of Melan-A-specific clonotypes obtained from melanoma patients were highly heterogeneous, but displayed a preferential usage of few TRBV and TRBJ segments. Furthermore, they included a recurrent "public" amino acid motif (Glycine-Leucine-Glycine at positions 110-112-113 of the CDR3) rearranged with dominant TRBV and TRBJ segments and, in one case, associated with a full conservation of the entire TRB sequence.

Conclusion

Contrary to what observed for public anti-Melan-A T-cell receptor alpha motifs, which had been identified in several clonotypes of both melanoma patients and healthy controls, the unexpectedly high contribution of a public TRB motif in the recognition of a dominant melanoma epitope in melanoma patients may provide important information about the biology of anti-tumor T-cell responses and improve monitoring strategies of anti-tumor vaccines.
Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors
Authors: Serrao Erik , Odde Srinivas , Ramkumar Kavya , Neamati Nouri
Published: March 2009

Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.