bluuebunny/crossref_metadata_2025 huggingface dataset:
PRESENT STATUS OF THE STUDY OF THE ANOMALOUS ACCELERATION OF THE PIONEER 10/11 SPACECRAFT
Authors: MBELEK J. P.
Published: June 2005

Results from an almost twenty years study of radiometric data from Pioneer 10/11, Galileo and Ulysses spacecraft indicate an anomalous time depending blueshift1, 2 which bares hardly prosaic explanations. Local manifestation of the expansion of the universe or new force terms are not favored either by the observational data. So, we explore the possibility that the reported anomaly, referred to as the "Pioneer anomaly", does not result from a real change in velocity. It turns out that the main Pioneer anomaly may be looked at as a new validation of general relativity (GR) in the weak field and low velocity limit on account of the "machian" behavior of quintessence like dark energy.
DISCRETE SYMMETRIES AND GENERAL RELATIVITY, THE DARK SIDE OF GRAVITY
Authors: HENRY-COUANNIER FREDERIC
Published: June 2005

The parity and time reversal invariant actions, equations and their conjugated metric solutions are obtained in the context of a general relativistic model modified in order to suitably take into account discrete symmetries. The equations are not covariant however the predictions of the model, in particular its Schwarzschild metric solution in vacuum, only start to differ from those of General Relativity at the Post-Post-Newtonian order. No coordinate singularity (black hole) arises in the privileged coordinate system where the energy of gravity is found to vanish. Vacuum energies have no gravitational effects. A flat universe accelerated expansion phase is obtained without resorting to inflation nor a cosmological constant. The context may be promising to help us elucidate several outstanding enigmas such as the Pioneer anomalous blue-shift, flat galactic rotation curves or the universe voids.
NON-SINGULAR GLOBAL COSMIC STRINGS
Authors: VERBIN Y. , LARSEN A. L.
Published: June 2005

Non-singular global cosmic strings are found in a non-linear sigma model with a potential term for a self-gravitating complex scalar field. Stationary solutions with angular momentum and possibly linear momentum are obtained by assuming an oscillatory dependence of the scalar field on t, φ and z. This dependence has an effect similar to gauging the global U(1) symmetry of the model, which is actually a Kaluza-Klein reduction from four to three spacetime dimensions. The method of analysis can be regarded as an extension of the gravito-electromagnetism formalism beyond the weak field limit.
QUANTUM COSMOLOGY WITH ROTATION
Authors: FIL'CHENKOV M. L.
Published: June 2005

The rotation of astronomical objects may be of a cosmological origin due to the Universe's specific angular momentum estimates proving to exceed those for spiral galaxies. The problem is expected to be solved in the framework of quantum geometrodynamics.
PROBLEMS OF COSMOLOGICAL CONSTANT, DARK ENERGY AND POSSIBLE ADJUSTMENT MECHANISM
Authors: DOLGOV A. D.
Published: June 2005

Vacuum and dark energy energy problems are reviewed. Cosmology with non-zero vacuum energy is discussed. The astronomical data which indicate that the universe is filled with an anti-gravitating state of matter are described. The mechanisms which may lead to cancellation of almost infinite vacuum energy down to the astronomically observed value are enumerated with an emphasis to dynamical adjustment.
TIME DEPENDENT COSMOLOGICAL TERM AND HOLOGRAPHY
Authors: CARNEIRO S. , LIMA J. A. S.
Published: June 2005

The physical space is believed to contain a kind of energy whose gravitational effect resembles the cosmological Λ-term introduced by Einstein. We discuss how the holographic conjecture, relating the universe entropy with the horizon area, may fix the late time variation of this effective Λ-term and the induced time dependence of the gravitational constant. The resulting cosmological solutions at late times present a constant ratio between the matter density and the vacuum energy density. It is then argued that, among the non-decelerating solutions, the coasting expansion is the only acceptable from a thermodynamic viewpoint. This solution is characterized by a universe age given by Ht = 1, and by density parameters Ωm= 1/3 and ΩΛ= 2/3, as required by the cosmic concordance model.
ASPECTS OF NEAR-HORIZON CONFORMAL SYMMETRY
Authors: GUPTA KUMAR S.
Published: June 2005

We analyze the features of the near-horizon conformal symmetry of black holes from an algebraic point of view. The implications of such a symmetry for black hole entropy and decay are also discussed.
HUMAN RIGHTS, BIOMEDICAL SCIENCE, AND INFECTIOUS DISEASES AMONG SOUTH AMERICAN INDIGENOUS GROUPS
Authors: Hurtado A. Magdalena , Lambourne Carol A. , James Paul , Hill Kim , Cheman Karen , Baca Keely
Published: June 2005

Despite the efforts of international health agencies to reduce global health inequalities, indigenous populations around the world remain largely unaffected by such initiatives. This chapter reviews the biomedical literature indexed by the PubMed database published between 1963 and 2003 on South American indigenous populations, a total of 1864 studies that include 63,563 study participants. Some language family groupings are better represented than are others, and lowland groups are better represented than are highland groups. Very few studies focus on major health threats (e.g., tuberculosis, influenza), public health interventions, or mestizo-indigenous epidemiological comparisons. The prevalence rates of three frequently studied infections—parasitism, human T-cell lymphotropic viral infection (HTLV), and hepatitis—are extraordinarily high, but these facts have been overlooked by national and international health agencies. This review underscores the urgent need for interventions based on known disease prevalence rates to reduce the burden of infectious diseases in indigenous communities.
SURFACING THE BODY INTERIOR
Authors: Taylor Janelle S.
Published: June 2005

In the wake of critiques that have rendered problematic such familiar objects of study as culture and social structure, anthropologists seeking ways to engage ethnographically with the complexities of the contemporary world have fashioned new kinds of objects of study. These generally continue, however, to be framed as just that—as objects. Rather than pursue the “anthropology of” any particular object that preexists ethnography, anthropologists should find ways of bringing the openness and creativity of ethnographic work more boldly into the theoretical framing of what it is that they study. I propose here the notion of surfacing the body interior as one framing device that may help facilitate such ethnographic explorations into bodies, their interiors, and their surfaces as contingent configurations made and unmade through practices that are at once social, material, and representational.
THE ECOLOGIES OF HUMAN IMMUNE FUNCTION
Authors: McDade Thomas W.
Published: June 2005

Immune function is notoriously complex, and current biomedical research elaborates this complexity by focusing on the cellular and molecular mechanisms that characterize immune defenses. However, the human immune system is a product of natural selection that develops and functions in whole organisms that are integral parts of their surrounding environments. A population-level, cross-cultural, adaptationist perspective is therefore a necessary complement to the micro levels of analysis currently favored by biomedical immunology. Prior field-based research on human immunity is reviewed to demonstrate the relevance of cultural ecological factors, with an emphasis on the ecologies of nutrition, infectious disease, reproduction, and psychosocial stress. Common themes and anthropological contributions are identified in an attempt to promote future research in human ecological immunology that integrates theory and method for a more contextualized understanding of this important physiological system.
QUORUM SENSING: Cell-to-Cell Communication in Bacteria
Authors: Waters Christopher M. , Bassler Bonnie L.
Published: June 2005

Bacteria communicate with one another using chemical signal molecules. As in higher organisms, the information supplied by these molecules is critical for synchronizing the activities of large groups of cells. In bacteria, chemical communication involves producing, releasing, detecting, and responding to small hormone-like molecules termed autoinducers . This process, termed quorum sensing, allows bacteria to monitor the environment for other bacteria and to alter behavior on a population-wide scale in response to changes in the number and/or species present in a community. Most quorum-sensing-controlled processes are unproductive when undertaken by an individual bacterium acting alone but become beneficial when carried out simultaneously by a large number of cells. Thus, quorum sensing confuses the distinction between prokaryotes and eukaryotes because it enables bacteria to act as multicellular organisms. This review focuses on the architectures of bacterial chemical communication networks; how chemical information is integrated, processed, and transduced to control gene expression; how intra- and interspecies cell-cell communication is accomplished; and the intriguing possibility of prokaryote-eukaryote cross-communication.
RHO GTPASES: Biochemistry and Biology
Authors: Jaffe Aron B. , Hall Alan
Published: June 2005

Approximately one percent of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho family of small GTPases. Through a series of complex biochemical networks, these highly conserved molecular switches control some of the most fundamental processes of cell biology common to all eukaryotes, including morphogenesis, polarity, movement, and cell division. In the first part of this review, we present the best characterized of these biochemical pathways; in the second part, we attempt to integrate these molecular details into a biological context.
EXPERT EVIDENCE AFTERDAUBERT
Authors: Saks Michael J. , Faigman David L.
Published: June 2005

▪ Abstract  Daubert stands for a trilogy of Supreme Court cases as well as revisions of the Federal Rules of Evidence. Together they represent American law's most recent effort to filter expert evidence offered at trial. This review begins by placing the Daubert trilogy in the context of earlier judicial efforts to solve the screening problem, which began well before the twentieth century, and then provides a brief explication of evidence law under Daubert. Next, we discuss several aspects of the jurisprudence of expert evidence: its connection to debates in the philosophy of science, the practical legal problems courts are trying to solve, and procedural implications. Then we review and discuss varied impacts of Daubert: changes in law, marked increases in cases and scholarship relating to expert evidence, and research examining judicial gatekeeping under Daubert (civil defendants appear to benefit greatly and criminal defendants hardly at all). We conclude by offering several predictions and prescriptions for the future of expert evidence.
PLEA BARGAINING AND THE ECLIPSE OF THE JURY
Authors: Smith Bruce P.
Published: June 2005

▪ Abstract  The right to criminal jury trial is protected by the U.S. Constitution and the constitutions of all 50 states. In practice, however, roughly 95% of persons convicted of felonies in America waive their right to trial by jury by entering guilty pleas. Most such pleas derive from plea bargaining, whereby defendants plead guilty in exchange for prosecutorial and judicial concessions. Although plea bargaining has generated an extensive scholarly literature, its history, until recently, has remained obscure. This review examines existing legal-historical scholarship on the origins and expansion of plea bargaining in the nineteenth century and explores the range of factors cited by legal historians for plea bargaining's rise. It reveals that plea bargaining was one of several methods employed by Anglo-American criminal justice administrators to dispose of criminal cases without juries. When compared with these other modes of bypassing trial by jury, plea bargaining appears less distinctive—and less distinctively American—than often considered.
Sex Hormones as Potential Modulators of Vascular Function in Hypertension
Authors: Khalil Raouf A.
Published: June 2005

The greater incidence of hypertension in men and postmenopausal women compared with premenopausal women has suggested gender differences in vascular function. Vascular effects of the female sex hormones estrogen and progesterone and the male hormone testosterone have been described. Sex steroid receptors have been identified in vascular endothelium and smooth muscle. Interaction of sex hormones with cytosolic/nuclear receptors initiates long-term genomic effects that stimulate endothelial cell growth but inhibit smooth muscle proliferation. Activation of sex hormone receptors on the plasma membrane triggers nongenomic effects that stimulate endothelium-dependent vascular relaxation via NO–cGMP, prostacyclin–cAMP, and hyperpolarization pathways. Sex hormones also cause endothelium-independent inhibition of vascular smooth muscle contraction, [Ca
2+
]
i
, and protein kinase C. These vasorelaxant/vasodilator effects suggested vascular benefits of hormone replacement therapy (HRT) during natural and surgically induced deficiencies of gonadal hormones. Although some clinical trials showed minimal benefits of HRT in postmenopausal hypertension, the lack of effect should not be generalized because it could be related to the type/dose of sex hormone, subjects’ age, and other cardiovascular conditions. The prospect of HRT relies on continued investigation of the molecular mechanisms underlying the vascular effects of sex hormones and identification of compounds that specifically target the vascular sex hormone receptors. Naturally occurring hormones and phytoestrogens may be more beneficial HRT than synthesized compounds. Also, the type/dose, time of initiation, and duration of HRT should be customized depending on the subject’s age and preexisting cardiovascular condition, and thereby enhance the outlook of sex hormones as potential modulators of vascular function in hypertension.
Parental Longevity and 7-Year Changes in Blood Pressures in Adult Offspring
Authors: Zureik Mahmoud , Galan Pilar , Bertrais Sandrine , Courbon Dominique , Czernichow Sébastien , Blacher Jacques , Ducimetière Pierre , Safar Michel E. , Hercberg Serge
Published: June 2005

In this report, we examined the cross-sectional and the 7-year longitudinal changes in blood pressures in adult offspring according to parental longevity. A population of volunteers free of symptomatic cardiovascular diseases who participated to the Supplementation en Vitamines et en Minéraux Antioxydants (SUVIMAX) Vascular Study (mean age 52.3 years; 48.3% women) were examined at baseline and 7 years later. Paternal (n=994) and maternal (n=896) longevity were analyzed separately. The prevalence of hypertension at baseline in subjects whose father died at <65 years of age, in those whose fathers were alive by age 65 but died by 80 years of age, and in those whose fathers were alive by age 80 was respectively 34.9%, 28.5%, and 20.2% (
P
<0.001). The means of systolic blood pressure in the 3 groups of paternal longevity were respectively 128.4 (±16.0), 125.3 (±14.2), and 123.6 (±14.4) mm Hg (
P
<0.001). During the follow-up, the mean systolic blood pressure increases in the 3 groups of paternal longevity were respectively 5.3 (±17.0), 4.2 (±14.0), and 1.6 (±13.2) mm Hg (
P
<0.001). In subjects without hypertension at baseline, hypertension occurred during the follow-up in 26.6%, 17.7%, and 15.3% (
P
<0.009), respectively. Multivariate analyses adjusted for baseline or changes in cardiovascular risk factors did not modify these results. In contrast, there was no relationship between maternal longevity and blood pressure measurements in either cross-sectional or longitudinal analyses. This study suggests that paternal premature death was associated with accelerated progression of systolic blood pressure and higher occurrence of hypertension in offspring. These results indicate that there are dynamic and continuous processes linking paternal longevity to blood pressure in adults.
Obstructive Sleep Apnea–Dependent and –Independent Adrenergic Activation in Obesity
Authors: Grassi Guido , Facchini Anna , Trevano Fosca Quarti , Dell’Oro Raffaella , Arenare Francesca , Tana Francesco , Bolla GianBattista , Monzani Anna , Robuschi Maria , Mancia Giuseppe
Published: June 2005

No agreement exists as to the mechanisms responsible for the sympathetic hyperactivity characterizing human obesity, which has been ascribed recently to a chemoreflex stimulation brought about by obstructive sleep apnea rather than to an increase in body weight, per se. In 86 middle-age normotensive subjects classified according to body mass index, waist-to-hip ratio, and apnea/hypopnea index (overnight polysomnographic evaluation) as lean and obese subjects without or with obstructive sleep apnea, we assessed via microneurography muscle sympathetic nerve traffic. The 4 groups were matched for age, gender, and blood pressure values, the 2 obese groups with and without obstructive sleep apnea showing a similar increase in body mass index (32.4 versus 32.0 kg/m
2
, respectively) and waist-to-hip ratio (0.96 versus 0.95, respectively) compared with the 2 lean groups with or without obstructive sleep apnea (body mass index 24.3 versus 23.8 kg/m
2
and waist-to-hip ratio 0.77 versus 0.76, respectively;
P
<0.01). Compared with the nonobstructive sleep apnea lean group, muscle sympathetic nerve activity showed a similar increase in the obstructive sleep apnea lean group and in the nonobstructive sleep apnea obese group (60.4±2.3 and 59.3±2.0 versus 40.9±1.8 bs/100 hb, respectively;
P
<0.01), a further increase being detected in obstructive sleep apnea subjects (73.1±2.5 bursts/100 heart beats;
P
<0.01). Our data demonstrate that the sympathetic activation of obesity occurs independently in obstructive sleep apnea. They also show that this condition exerts sympathostimulating effects independent of body weight, and that the obstructive sleep apnea–dependent and –independent sympathostimulation contribute to the overall adrenergic activation of the obese state.
Early Structural and Functional Changes of the Vasculature in HIV-Infected Children
Authors: Charakida Marietta , Donald Ann E. , Green Hannah , Storry Clare , Clapson Margaret , Caslake Muriel , Dunn David T. , Halcox Julian P. , Gibb Diana M. , Klein Nigel J. , Deanfield John E.
Published: June 2005

Background—

Premature cardiovascular disease is increasingly recognized in HIV-infected patients, but the mechanisms involved are unclear. The purpose of this study was to determine the impact of HIV infection and antiretroviral therapy (ART) on markers of early vascular disease in children.

Methods and Results—

We studied 83 HIV-infected children (56 had taken ART, of whom 31 received a regimen containing protease inhibitors [PIs]; 27 were never treated) and a control group of 59 healthy children. Carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were measured. IMT was significantly greater in HIV-infected children compared with the control subjects (
P
<0.001). Among the HIV-infected children, age and treatment were significantly associated with increased IMT. Children exposed to PIs had greater IMT compared with both non-PI-treated children and untreated children (
P
=0.02). FMD was also significantly reduced in the HIV-infected children compared with control subjects (
P
=0.02). Pairwise comparisons of different treatment exposure groups revealed that FMD was impaired by a mean of 3.6% (95% CI, 1.8 to 5.3;
P
<0.001) for children exposed to PIs compared with untreated children and by a mean of 1.8% (95% CI, 0.01 to 3.5;
P
=0.05) compared with non-PI-treated children. HIV-infected children had lipid abnormalities, but they did not account for the observed differences in either FMD or IMT.

Conclusions—

HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy. Longitudinal studies are required to differentiate the relative impact of HIV disease and ART and to assess the potential for prevention.
The Relationship between the Interannual Variation of the North Indian Ocean SST Induced by Surface Wind and ENSO during Boreal Summer
Authors: Nagura Motoki , Konda Masanori
Published: June 2005

The relationship between the interannual variation of the surface wind in the north Indian Ocean (0°–30°N, 30°–100°E) and El Niño–Southern Oscillation (ENSO) during boreal summer is investigated. The association of the surface wind with the sea surface temperature (SST) in the north Indian Ocean is evaluated. The NCEP–NCAR reanalysis, NOAA outgoing longwave radiation (OLR), and Reynolds SST data are used. The June–August mean of the surface wind anomaly over the north Indian Ocean is decomposed by EOF analysis, and two dominant modes are extracted. The first (second) mode shows the corresponding variation with the ENSO events maturing in the subsequent (previous) winter. The first mode has a large amplitude during the 1990s, while the amplitude of the second mode is large mainly during the 1980s. Such contrast of the amplitude of the two modes results in the temporal change of the surface wind–ENSO relationships between the two decades. The temporal characteristics of the first and second modes are consistent with those of convective variability in the eastern Indian Ocean and the Philippine Sea, respectively.

The local thermal forcings associated with these two contrastive modes are compared with the time change of the SST anomaly. The thermal forcings are evaluated in terms of the latent heat flux and the Ekman heat transport. The thermal forcing of the first mode is consistent with a meridionally antisymmetric pattern of the SST anomaly during the 1990s, while that of the second mode is correlated with the basinwide SST anomaly during the 1980s. This result suggests that the temporal change is also found in the north Indian Ocean SST anomaly.
A Climatology of Springtime Dryline Position in the U.S. Great Plains Region
Authors: Hoch Joseph , Markowski Paul
Published: June 2005

A climatology of dryline frequency and location is presented based on 30 yr (1973–2002) of April, May, and June surface observations from the Great Plains region of the United States. Drylines having a horizontal specific humidity gradient greater than or equal to 3 × 10−8 m−1 [greater than or equal to 3 g kg−1 (100 km)−1] are found to be present on 32% of the days, with the peak frequency occurring in mid- to late May. The most favored longitude of the generally meridionally oriented drylines is near −101°W at 0000 UTC, although the favored longitude tends to shift westward as the April–June period elapses. There is no robust suggestion of a shift in the annual mean dryline position over the period studied.

Relationships between dryline position and wind and relative humidity data at mandatory levels (e.g., 850, 700, and 500 mb) also are investigated. Dryline longitude increases with increasing westerly momentum aloft. Dryline longitude also increases with decreasing relative humidity at 850 mb, primarily at stations in the western Great Plains region, west of the climatologically favored dryline position near −101°. Dryline position is not as closely associated with either 850-mb relative humidity east of the climatologically favored dryline position or relative humidity in the middle troposphere.
The Impact of ENSO on Atmospheric Intraseasonal Variability as Inferred from Observations and GCM Simulations
Authors: Tam Chi-Yung , Lau Ngar-Cheung
Published: June 2005

The impact of the El Niño–Southern Oscillation (ENSO) on the atmospheric intraseasonal variability in the North Pacific is assessed, with emphasis on how ENSO modulates midlatitude circulation anomalies associated with the Madden–Julian oscillation (MJO) in the Tropics and the westward-traveling patterns (WTP) in high latitudes. The database for this study consists of the output of a general circulation model (GCM) experiment subjected to temporally varying sea surface temperature (SST) forcing in the tropical Pacific, and observational reanalysis products.

Diagnosis of the GCM experiment indicates a key region in the North Pacific over which the year-to-year variation of intraseasonal activity is sensitive to the SST conditions in the Tropics. In both the simulated and observed atmospheres, the development phase of the dominant circulation anomaly in this region is characterized by incoming wave activity from northeast Asia and the subtropical western Pacific. Southeastward dispersion from the North Pacific to North America can be found in later phases of the life cycle of the anomaly. The spatial pattern of this recurrent extratropical anomaly contains regional features that are similar to those appearing in composite charts for prominent episodes of the MJO and the WTP.

Both the GCM and reanalysis data indicate that the amplitude of intraseasonal variability near the key region, as well as incoming wave activity in the western Pacific and dispersion to the western United States, are enhanced in cold ENSO events as compared to warm events. Similar modulations of the MJO-related circulation patterns in the extratropics by ENSO forcing are discernible in the model simulation. It is inferred from these findings that ENSO can influence the North Pacific intraseasonal activity through its effects on the evolution of convective anomalies in the tropical western Pacific. On the other hand, there is little modification by ENSO of the circulation features associated with the WTP.

The combined effect of the MJO and WTP on the intraseasonal circulation in the North Pacific is studied. Based on multiple regression analysis, it is found that the MJO and WTP make comparable contributions to the variability in the midlatitude North Pacific. These contributions may be treated as a linear combination of the anomalies attributed to the MJO and WTP separately.
A Bayesian Quantitative Precipitation Nowcast Scheme
Authors: Fox Neil I. , Wikle Christopher K.
Published: June 2005

Very short-period quantitative precipitation forecast (QPF) or nowcast schemes provide deterministic output that fails to convey explicit measures of the uncertainty in the forecast. Presented here is a forecast methodology based upon a Bayesian hierarchical model that produces a QPF product for a 1-h period along with an associated estimated forecast error field. The precipitation forecast quality is comparable to other nowcast schemes and the uncertainty measures increase the utility of the methodology by allowing forecasters to judge the trustworthiness of the products.
Primary Commodity Exports and Civil War
Authors: Fearon James D.
Published: June 2005

Collier and Hoeffler reported that countries with a higher percentage of national income from primary commodity exports have been more prone to civil war, an interesting finding that has received much attention from policy makers and the media. The author shows that this result is quite fragile, even using Collier and Hoeffler’s data. Minor changes in the sample framing and the recovery of missing data undermine it. To the extent that there is an association, it is likely because oil is a major component of primary commodity exports and substantial oil production does associate with civil war risk. The author argues that oil predicts civil war risk not because it provides an easy source of rebel start-up finance but probably because oil producers have relatively low state capabilities given their level of per capita income and because oil makes state or regional control a tempting “prize.” An analysis of data on government observance of contracts and investor-perceived expropriation risk is consistent with this hypothesis.
Developing a Practical Forecasting Screener for Domestic Violence Incidents
Authors: Berk Richard A. , He Yan , Sorenson Susan B.
Published: June 2005

In this article, the authors report on the development of a short screening tool that deputies in the Los Angeles Sheriff’s Department could use in the field to help forecast domestic violence incidents in particular households. The data come from more than 500 households to which sheriff’s deputies were dispatched in fall 2003. Information on potential predictors was collected at the scene. Outcomes were measured during a 3-month follow-up. Data were analyzed with modern data-mining procedures in which true forecasts were evaluated. A screening instrument was developed based on a small fraction of the information collected. Making the screening instrument more complicated did not improve forecasting skill. Taking the relative costs of false positives and false negatives into account, the instrument correctly forecasted future calls for service about 60% of the time. Future calls involving domestic violence misdemeanors and felonies were correctly forecast about 50% of the time. The 50% figure is important because such calls require a law enforcement response and yet are a relatively small fraction of all domestic violence calls for service.
Full cyclic coordinate descent: solving the protein loop closure problem in Cα space
Authors: Boomsma Wouter , Hamelryck Thomas
Published: June 2005

Background

Various forms of the so-called loop closure problem are crucial to protein structure prediction methods. Given an N- and a C-terminal end, the problem consists of finding a suitable segment of a certain length that bridges the ends seamlessly.

In homology modelling, the problem arises in predicting loop regions. In de novo protein structure prediction, the problem is encountered when implementing local moves for Markov Chain Monte Carlo simulations.

Most loop closure algorithms keep the bond angles fixed or semi-fixed, and only vary the dihedral angles. This is appropriate for a full-atom protein backbone, since the bond angles can be considered as fixed, while the (φ, ψ) dihedral angles are variable. However, many de novo structure prediction methods use protein models that only consist of Cα atoms, or otherwise do not make use of all backbone atoms. These methods require a method that alters both bond and dihedral angles, since the pseudo bond angle between three consecutive Cα atoms also varies considerably.

Results

Here we present a method that solves the loop closure problem for Cα only protein models. We developed a variant of Cyclic Coordinate Descent (CCD), an inverse kinematics method from the field of robotics, which was recently applied to the loop closure problem. Since the method alters both bond and dihedral angles, which is equivalent to applying a full rotation matrix, we call our method Full CCD (FCDD). FCCD replaces CCD's vector-based optimization of a rotation around an axis with a singular value decomposition-based optimization of a general rotation matrix. The method is easy to implement and numerically stable.

Conclusion

We tested the method's performance on sets of random protein Cα segments between 5 and 30 amino acids long, and a number of loops of length 4, 8 and 12. FCCD is fast, has a high success rate and readily generates conformations close to those of real loops. The presence of constraints on the angles only has a small effect on the performance. A reference implementation of FCCD in Python is available as supplementary information.
Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress
Authors: Paradisi Mauro , McClintock Dayle , Boguslavsky Revekka L , Pedicelli Christina , Worman Howard J , Djabali Karima
Published: June 2005

Background

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare sporadic disorder with an incidence of approximately 1 per 8 million live births. The phenotypic appearance consists of short stature, sculptured nose, alopecia, prominent scalp veins, small face, loss of subcutaneous fat, faint mid-facial cyanosis, and dystrophic nails. HGPS is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. The most common mutation in subjects with HGPS is a de novo single-base pair substitution, G608G (GGC>GGT), within exon 11 of LMNA. This creates an abnormal splice donor site, leading to expression of a truncated protein.

Results

We studied a new case of a 5 year-old girl with HGPS and found a heterozygous point mutation, G608G, in LMNA. Complementary DNA sequencing of RNA showed that this mutation resulted in the deletion of 50 amino acids in the carboxyl-terminal tail domain of prelamin A. We characterized a primary dermal fibroblast cell line derived from the subject's skin. These cells expressed the mutant protein and exhibited a normal growth rate at early passage in primary culture but showed alterations in nuclear morphology. Expression levels and overall distributions of nuclear lamins and emerin, an integral protein of the inner nuclear membrane, were not dramatically altered. Ultrastructural analysis of the nuclear envelope using electron microscopy showed that chromatin is in close association to the nuclear lamina, even in areas with abnormal nuclear envelope morphology. The fibroblasts were hypersensitive to heat shock, and demonstrated a delayed response to heat stress.

Conclusion

Dermal fibroblasts from a subject with HGPS expressing a mutant truncated lamin A have dysmorphic nuclei, hypersensitivity to heat shock, and delayed response to heat stress. This suggests that the mutant protein, even when expressed at low levels, causes defective cell stability, which may be responsible for phenotypic abnormalities in the disease.
Cloning and characterization of cDNAs encoding putative CTCFs in the mosquitoes, Aedes aegypti and Anopheles gambiae
Authors: Gray Christine E , Coates Craig J
Published: June 2005

Background

One of the many ascribed functions of CCCTC-binding factor (CTCF) in vertebrates is insulation of genes via enhancer-blocking. Insulation allows genes to be shielded from "cross-talk" with neighboring regulatory elements. As such, endogenous insulator sequences would be valuable elements to enable stable transgene expression. Recently, CTCF joined Su(Hw), Zw5, BEAF32 and GAGA factor as a protein associated with insulator activity in the fruitfly, Drosophila melanogaster. To date, no known insulators have been described in mosquitoes.

Results

We have identified and characterized putative CTCF homologs in the medically-important mosquitoes, Aedes aegypti and Anopheles gambiae. These genes encode polypeptides with eleven C2H2 zinc fingers that show significant similarity to those of vertebrate CTCFs, despite at least 500 million years of divergence. The mosquito CTCFs are constitutively expressed and are upregulated in early embryos and in the ovaries of blood-fed females. We have uncovered significant bioinformatics evidence that CTCF is widespread, at least among Drosophila species. Finally, we show that the An. gambiae CTCF binds two known insulator sequences.

Conclusion

Mosquito CTCFs are likely orthologous to the widely-characterized vertebrate CTCFs and potentially also serve an insulating function. As such, CTCF may provide a powerful tool for improving transgene expression in these mosquitoes through the identification of endogenous binding sites.
"Anxiebo", placebo, and postoperative pain
Authors: Svedman Paul , Ingvar Martin , Gordh Torsten
Published: June 2005

Background

Surgical treatment and its consequences expose patients to stress, and here we investigated the importance of the psychological component of postoperative pain based on reports in the clinical literature.

Discussion

Postoperative pain remains a significant clinical problem. Increased pain intensity with increased demand for opioid medication, and/or a relative unresponsiveness to pain treatment was reported both when the analgesia was administered by means of conventional nurse injection regimes and patient-controlled analgesia (PCA). Both the quality of the analgesia, and the sensitivity of postoperative models for assessing analgesic efficacy could be significantly influenced.

The findings could be explained by increased penetration of an algesic anxiety-related nocebo influence (which we chose to call "anxiebo") relative to its analgesic placebo counterpart. To counteract this influence, the importance of psychological effects must be acknowledged, and doctors and attending nurses should focus on maintaining trustful therapist-patient relationships throughout the treatment period. The physical mechanism of anxiebo should be further explored, and those at risk for anxiebo better characterized. In addition, future systemic analgesic therapies should be directed towards being prophylactic and continuous to eliminate surgical pain as it appears in order to prevent the anxiebo effect.

Addressing anxiebo is the key to developing reproducible models for measuring pain in the postoperative setting, and to improving the accuracy of measurements of the minimum effective analgesic concentration.

Anxiebo and placebo act as counterparts postoperatively. The anxiebo state may impair clinical analgesia and reduce the sensitivity of analgesic trials. Ways to minimize anxiebo are discussed.
The BpTRU automatic blood pressure monitor compared to 24 hour ambulatory blood pressure monitoring in the assessment of blood pressure in patients with hypertension
Authors: Beckett Linda , Godwin Marshall
Published: June 2005

Background

Increasing evidence suggests that ABPM more closely predicts target organ damage than does clinic measurement. Future guidelines may suggest ABPM as routine in the diagnosis and monitoring of hypertension. This would create difficulties as this test is expensive and often difficult to obtain. The purpose of this study is to determine the degree to which the BpTRU automatic blood pressure monitor predicts results on 24 hour ambulatory blood pressure monitoring (ABPM).

Methods

A quantitative analysis comparing blood pressure measured by the BpTRU device with the mean daytime blood pressure on 24 hour ABPM. The study was conducted by the Centre for Studies in Primary Care, Queen's University, Kingston, Ontario, Canada on adult primary care patients who are enrolled in two randomized controlled trials on hypertension. The main outcomes were the mean of the blood pressures measured at the three most recent office visits, the initial measurement on the BpTRU-100, the mean of the five measurements on the BpTRU monitor, and the daytime average on 24 hour ABPM.

Results

The group mean of the three charted clinic measured blood pressures (150.8 (SD10.26) / 82.9 (SD 8.44)) was not statistically different from the group mean of the initial reading on BpTRU (150.0 (SD21.33) / 83.3 (SD12.00)). The group mean of the average of five BpTRU readings (140.0 (SD17.71) / 79.8 (SD 10.46)) was not statistically different from the 24 hour daytime mean on ABPM (141.5 (SD 13.25) / 79.7 (SD 7.79)). Within patients, BpTRU average correlated significantly better with daytime ambulatory pressure than did clinic averages (BpTRU r = 0.571, clinic r = 0.145). Based on assessment of sensitivity and specificity at different cut-points, it is suggested that the initial treatment target using the BpTRU be set at <135/85 mmHG, but achievement of target should be confirmed using 24 hour ABPM.

Conclusion

The BpTRU average better predicts ABPM than does the average of the blood pressures recorded on the patient chart from the three most recent visits. The BpTRU automatic clinic blood pressure monitor should be used as an adjunct to ABPM to effectively diagnose and monitor hypertension.
Alterations of tumor suppressor gene p16

INK4a
in pancreatic ductal carcinoma
Authors: Attri Jyotika , Srinivasan Radhika , Majumdar Siddhartha , Radotra Bishan Dass , Wig Jaidev
Published: June 2005

Background

Cell cycle inhibitor and tumor suppressor gene p16 / MTS-1 has been reported to be altered in a variety of human tumors. The purpose of the study was to evaluate primary pancreatic ductal adenocarcinomas for potentially inactivating p16 alterations.

Methods

We investigated the status of p16 gene by polymerase chain reaction (PCR), nonradioisotopic single strand conformation polymorphism (SSCP), DNA sequencing and hypermethylation analysis in 25 primary resected ductal adenocarcinomas. In addition, we investigated p16 protein expression in these cases by immunohistochemistry (IHC) using a monoclonal antibody clone (MS-887-PO).

Results

Out of the 25 samples analyzed and compared to normal pancreatic control tissues, the overall frequency of p16 alterations was 80% (20/25). Aberrant promoter methylation was the most common mechanism of gene inactivation present in 52% (13/25) cases, followed by coding sequence mutations in 16% (4/25) cases and presumably homozygous deletion in 12% (3/25) cases. These genetic alterations correlated well with p16 protein expression as complete loss of p16 protein was found in 18 of 25 tumors (72%).

Conclusion

These findings confirm that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behaviour of this tumor type.
WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome
Authors: Nunez María I , Rosen Daniel G , Ludes-Meyers John H , Abba Martín C , Kil Hyunsuk , Page Robert , Klein-Szanto Andres JP , Godwin Andrew K , Liu Jinsong , Mills Gordon B , Aldaz C Marcelo
Published: June 2005

Background

The putative tumor suppressor WWOX gene spans the common chromosomal fragile site 16D (FRA16D) at chromosome area 16q23.3-24.1. This region is a frequent target for loss of heterozygosity and chromosomal rearrangement in ovarian, breast, hepatocellular, prostate carcinomas and other neoplasias. The goal of these studies was to evaluate WWOX protein expression levels in ovarian carcinomas to determine if they correlated with clinico-pathological parameters, thus providing additional support for WWOX functioning as a tumor suppressor.

Methods

We performed WWOX protein expression analyses by means of immunobloting and immunohistochemistry on normal ovaries and specific human ovarian carcinoma Tissue Microarrays (n = 444). Univariate analysis of clinical-pathological parameters based on WWOX staining was determined by χ2 test with Yates' correction. The basic significance level was fixed at p < 0.05.

Results

Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels. The immunohistochemistry of normal human ovarian tissue sections confirmed strong WWOX expression in ovarian surface epithelial cells and in epithelial inclusion cysts within the cortex. Out of 444 ovarian carcinoma samples analyzed 30% of tumors showed lack of or barely detectable WWOX expression. The remaining ovarian carcinomas (70%) stained moderately to strongly positive for this protein. The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types. Reduced WWOX expression demonstrated a significant association with clinical Stage IV (FIGO) (p = 0.007), negative Progesterone Receptor (PR) status (p = 0.008) and shorter overall survival (p = 0.03).

Conclusion

These data indicate that WWOX protein expression is highly variable among ovarian carcinoma histotypes. It was also observed that subsets of ovarian tumors demonstrated loss of WWOX expression and is potentially associated with patient outcome.
Serum nucleosomes during neoadjuvant chemotherapy in patients with cervical cancer. Predictive and prognostic significance
Authors: Trejo-Becerril Catalina , Oñate-Ocaña Luis F , Taja-Chayeb Lucía , Vanoye-Carlo América , Cetina Lucely , Duenas-Gonzalez Alfonso
Published: June 2005

Background

It has been shown that free DNA circulates in serum plasma of patients with cancer and that at least part is present in the form of oligo- and monucleosomes, a marker of cell death. Preliminary data has shown a good correlation between decrease of nucleosomes with response and prognosis. Here, we performed pre- and post-chemotherapy determinations of serum nucleosomes with an enzyme-linked immunosorbent assay (ELISA) method in a group of patients with cervical cancer receiving neoadjuvant chemotherapy.

Methods

From December 2000 to June 2001, 41 patients with cervical cancer staged as FIGO stages IB2-IIIB received three 21-day courses of carboplatin and paclitaxel, both administered at day 1; then, patients underwent radical hysterectomy. Nucleosomes were measured the day before (baseline), at day seven of the first course and day seven of the third course of chemotherapy. Values of nucleosomes were analyzed with regard to pathologic response and to time to progression-free and overall survival.

Results

All patients completed chemotherapy, were evaluable for pathologic response, and had nucleosome levels determined. At a mean follow-up of 23 months (range, 7–26 months), projected progression time and overall survival were 80.3 and 80.4%, respectively. Mean differential values of nucleosomes were lower in the third course as compared with the first course (p >0.001). The decrease in the third course correlated with pathologic response (p = 0.041). Survival analysis showed a statistically significant, better progression-free and survival time in patients who showed lower levels at the third course (p = 0.0243 and p = 0.0260, respectively). Cox regression analysis demonstrated that nucleosome increase in the third course increased risk of death to 6.86 (95% confidence interval [CI 95%], 0.84–56.0).

Conclusion

Serum nucleosomes may have a predictive role for response and prognostic significance in patients with cervical cancer patients treated with neoadjuvant chemotherapy.
Differential gene expression profile reveals deregulation of pregnancy specific β1 glycoprotein 9 early during colorectal carcinogenesis
Authors: Salahshor Sima , Goncalves Jason , Chetty Runjan , Gallinger Steven , Woodgett James R
Published: June 2005

Background

APC (Adenomatous polyposis coli) plays an important role in the pathogenesis of both familial and sporadic colorectal cancer. Patients carrying germline APC mutations develop multiple colonic adenomas at younger age and higher frequency than non-carrier cases which indicates that silencing of one APC allele may be sufficient to initiate the transformation process.

Methods

To elucidate the biological dysregulation underlying adenoma formation we examined global gene expression profiles of adenomas and corresponding normal mucosa from an FAP patient. Differential expression of the most significant gene identified in this study was further validated by mRNA in situ hybridization, reverse transcriptase PCR and Northern blotting in different sets of adenomas, tumours and cancer cell lines.

Results

Eighty four genes were differentially expressed between all adenomas and corresponding normal mucosa, while only seven genes showed differential expression within the adenomas. The first group included pregnancy specific β-1 glycoprotein 9 (PSG9) (p < 0.006). PSG9 is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy, mainly by syncytiotrophoblasts. Further analysis of sporadic and familial colorectal cancer confirmed that PSG9 is ectopically upregulated in vivo by cancer cells. In total, deregulation of PSG9 mRNA was detected in 78% (14/18) of FAP adenomas and 75% (45/60) of sporadic colorectal cancer cases tested.

Conclusion

Detection of PSG9 expression in adenomas, and at higher levels in FAP cases, indicates that germline APC mutations and defects in Wnt signalling modulate PSG9 expression. Since PSG9 is not found in the non-pregnant adult except in association with cancer, and it appears to be an early molecular event associated with colorectal cancer monitoring of its expression may be useful as a biomarker for the early detection of this disease.