bluuebunny/crossref_metadata_2025 huggingface dataset:
Metaphysics or Theology? A Comment on Michael Gillespie's Theological Origins of Modernity
Authors: Merrill Thomas W.
Published: November 2010

Michael Gillespie's Theological Origins of Modernity provides a historically grounded and philosophically ambitious, at times even provocative, account of the deep unity of the modern tradition. The book is more historical than most works of political theory, and exhibits a healthy freedom from received wisdom about who the important thinkers are and about what they might have to say. Yet it would be quite wrong to read this book as a simple history: it is also—perhaps even primarily—a philosophical diagnosis of the present. Gillespie's thesis, stated far too crudely, is that the familiar Enlightenment story of an age of reason preceded by an age of darkness, superstition, and religion is far too simplistic. We late moderns, too, have thoughts about first things and divinity; but we hide the enduring presence of those thoughts and questions from ourselves by the pride we take in having overcome the atavisms of theology. Gillespie argues that, so far from being wholly novel, those thoughts are in fact the descendants of the theology of late medieval nominalism. Where others speak of the secularization of Christianity, Gillespie prefers to speak of the transference of divine attributes from God to man or nature.
CONTRACT, COVENANT, CONSTITUTION
Authors: Lomasky Loren E.
Published: November 2010

Contract is the dominant model for political philosophy's understanding of government grounded on the consent of the governed. However, there are at least five disabilities attached to classical social contract theory: (1) the grounding contract never actually occurred; (2) its provisions are vague and contestable; (3) the stringency of the obligation thereby established is dubious; (4) trans-generational consent is questionable; (5) interpretive methods for giving effect to the contract are ill-specified. By contrast, the biblical story of the covenant Israel embraces at Sinai is shown to be more adequately attentive to each of these five desiderata. The essay then focuses on the U.S. Constitution, arguing that in many ways it is more reflective of covenantal legitimating themes than those of social contract. The result is a promisingly different mode of understanding government by the consent of the governed.
CONSTITUTIONALISM IN THE AGE OF TERROR
Authors: Zuckert Michael , Valenzuela Felix
Published: November 2010

The threat of terrorism once again raises some of the classic questions about constitutionalism: is it possible for constitutions to do what they aim to do—channel and control political power in such a way as to make it safe and beneficent for those under its rule but also competent to govern? Does not terrorism reraise the Schmittian problem of “the exception”, i.e., the situation of emergency that necessarily escapes all constitutional limitations? Although they did not face the problem of terrorism as we know it, the American founders developed three different models of constitutionalism, embodying three different ways of responding to emergent circumstances and yet remaining bound to the constitutionalist aspiration. We develop the main outlines of the three models both conceptually and historically and show how they continue to be relevant to current discussions of constitutionalism in the age of terror. Finally, we make a tentative effort to judge which of the three models is most able to do what constitutions should do in difficult times.
DELIBERATIVE DEMOCRACY AND CONSTITUTIONS
Authors: Fishkin James S.
Published: November 2010

This paper examines the potential role of deliberative democracy in constitutional processes of higher law-making, either for the founding of constitutions or for constitutional change. It defines deliberative democracy as the combination of political equality and deliberation and situates this form of democracy in contrast to a range of alternatives. It then considers two contrasting processes—elite deliberation and plebiscitary mass democracy (embodied in referenda) as approaches to higher law-making that employ deliberation without political equality or political equality without deliberation. It finally turns to some institutional designs that might achieve both fundamental values at the same time, or in the process of realizing a sequence of choices.
THE CONSTITUTION OF NONDOMINATION
Authors: Pincione Guido
Published: November 2010

Pincione argues that procedural constitutional guarantees of market freedoms best protect individuals from domination. If he is right, Philip Pettit's claim that various forms of state interference with private markets are needed to forestall domination will prove to be unwarranted. Pincione further contends that market freedoms are best protected by procedural rules for political decision-making, as opposed to constitutional guarantees of private property and other substantive rules.

Central to his position are claims that the dispersion of economic power precludes domination, and that free entry into markets furthers such dispersion. As against the idea that the state is in a better position to disperse economic power, Pincione argues that the constitutional provisions needed to implement that idea are contestable, and to that extent require interpretive powers that themselves involve domination. Only a constitution that, as a side effect of its procedures for political decision making, generates full private property rights holds out hope of shielding citizens from domination. This is so, because a plurality of suppliers of goods and services is a structural feature of the free market, in a sense of “structural” that matters for measurements of domination based on fairly uncontroversial claims about persons and resources.
Germination characteristics of Syngonanthusseeds (Eriocaulaceae) incampos rupestresvegetation in south-eastern Brazil
Authors: Oliveira Patrícia G. , Garcia Queila S.
Published: November 2010

The present study evaluated the size and germination characteristics of seeds of seven species ofSyngonanthus(distributed among four sections) that occur in different microhabitats incampos rupestresvegetation in Minas Gerais State, to determine if (1) the germination responses of the various species characterize a single germination pattern for the genus; and (2) there is a correlation between the germination characteristics and the geographic distribution as well as the microhabitat of the different species. The experiments were undertaken with recently collected seeds exposed to a 12-h photoperiod and continuous darkness, at constant temperatures of 10–40°C (at intervals of 5°C) in germination chambers. The results indicated the existence of a pattern of reduced seed size and light requirements for germination within the genus. The geographic distribution of different species of the genus cannot be explained by the responses of seed germination to different temperatures, but suggests some relationship to their edaphic microhabitats. Therefore, germination characteristics of the populations studied may have been selected to colonize specific environments at different soil water conditions.
Dealing with Feelings: The Effectiveness of Cognitive Behavioural Group Treatment for Women in Secure Settings
Authors: Long Clive G. , Fulton Barbara , Dolley Olga , Hollin Clive R.
Published: November 2010

Background: Women in secure psychiatric settings have gender specific treatment needs. The current study examined the feasibility of a Dealing with Feelings Skills Group training for dual diagnosis women admitted to a medium secure setting. Method: A pre-test – post-test design was used to evaluate a group programme adapted from dialectical behaviour therapy skills training. Results: Most patients had a primary diagnosis of personality disorder. Treatment completers (n = 29) were compared with non-completers (n = 15). Clinically significant changes in treatment completers were apparent on coping response measures of positive reappraisal, problem solving and alternative rewards; on measures of anxiety and suicidality; on self-reported ability to engage in activities to reduce negative mood and to recognize mood changes. Self-harming and aggressive behaviours also reduced in the 3 months following group treatment. Conclusion: An adapted coping skills component of DBT benefit many dual diagnosis patients: issues related to treatment drop-out and failure to benefit are discussed.
Extra-cranial Stereotactic Radiation Therapy (ESRT) in the treatment of inoperable stage 1 & 2 non-small-cell lung cancer patients with highly mobile tumours: a literature review
Authors: Tooke Emily W. , Roe Benjamin
Published: November 2010

Objective: Extra-cranial Stereotactic Radiation Therapy (ESRT) techniques and equipment utilised in the treatment of Stage 1 or 2 inoperable non-small-cell lung cancer (NSCLC); accounting for Respiratory Induced Tumour Motion (RITM).

Methods: A narrative review of current world literature.

Results: Four main strategies are employed to address RITM: (1) tumour movement minimisation/immobilisation; (2) integration of respiratory movements into planning; (3) respiratory-gating techniques; and (iv) tumour-tracking techniques.

Discussion: Analysis of data gathered suggests that due to inherent difficulties with respiratory function, combined with co-morbidities and the level of dose escalation facilitated by ESRT: techniques that do not require patient ability to comply are more likely to be effective with a wider range of patients. Similarly, treatment planning must incorporate accurate four-dimensional (4D) data to ensure target coverage, although setup and verification should be controlled to smaller margins for error.

Conclusion: The disparate nature of reporting methods restricts statistical comparison. However, this paper suggests that the ESRT technique using abdominal compression (AC), free-breathing respiratory-gating (FBRG), 4D computed tomography (4DCT) planning, combined with daily on board kV cone beam computed tomography (CBCT) imaging for setup and target verification, is a possible candidate for further treatment regime assessments in large multi-centre trials.
Identification of gaps in pearl millet germplasm from Asia conserved at the ICRISAT genebank
Authors: Upadhyaya H. D. , Reddy K. N. , Irshad Ahmed M. , Gowda C. L. L.
Published: November 2010

The International Crops Research Institute for the Semi-Arid Tropics (1CRISAT) genebank in India holds the world's largest collection of 21,594 pearl millet germplasm accessions from 50 countries including 6529 landraces from ten Asian countries. Gap analysis using passport and characterization data and geographical information system tools revealed 134 distinct districts of 14 provinces in India and 12 districts of Punjab province in Pakistan as the major geographical gaps. Different methods of identifying geographical gaps used in the study indicated Chittoor, Karimnagar, Nizamabad, Prakasam and Warangal in Andhra Pradesh; Raigarh in Chattisgarh; Dewas and Rewa in Madhya Pradesh; Buldana and Hingoli in Maharashtra; Malkangiri, Nabarangapur, Naupada and Sundergarh in Orissa; Bhilwara, Chittaurgarh and Kota in Rajasthan; Thiruvallur and Vellore in Tamil Nadu; and Auraiya, Chandauli, Chitrakoot, Gonda, Gorakhpur, Hamirpur, Kushinagar, Mau, Shrawasti and Sonbhadra in Uttar Pradesh as common geographical gaps in India. A total of 208 distinct districts in 12 provinces were identified as gaps in diversity for one or more traits. Among all districts, Beed, Latur and Osmanabad in Maharashtra, India, for all traits; Rajanpur, Muzaffargarh, Multan and Lodhran for panicle length and Chakwal and Sargodha for panicle width in Pakistan; and southern parts of North Yemen and Lahiz provinces in Yemen were identified as gaps in the diversity. In India, Warangal in Andhra Pradesh; Rewa in Madhya Pradesh; Hingoli in Maharashtra; Vellore in Tamil Nadu; and Auraiya, Chandauli, Chitrakut, Gorakhpur and Mau in Uttar Pradesh were identified as gaps in diversity for one or more traits and found common to geographical gaps identified. In Pakistan, Lodhran, Multan and Muzaffargarh were identified as gaps common to probability and diversity methods. Area for exploration should be decided prior to launch of the collection mission in consultation with local government officials and extension officers, who are known to have knowledge in pearl millet cultivation in the identified districts. It is suggested to collect the complete passport data including georeference information while collecting the germplasm.
Schnelle Augenbewegungen und visuelle Fixation bei Kindern mit ADHS
Authors: Folta Kristian , Mähler Claudia
Published: November 2010

Die Aufmerksamkeitsdefizit/Hyperaktivitätsstörung (ADHS) gehört zu den bedeutendsten psychiatrischen Störungen des Kindes- und Jugendalters. Der Beitrag zeigt auf, wie moderne Blickbewegungs-Systeme helfen, die neurokognitiven Grundlagen der ADHS weitergehend zu erforschen. Exemplarisch wird eine Studie vorgestellt, die kompensatorische Effekte einer Stimulanzien-Medikation auf Fähigkeiten der exekutiven Kontrolle von ADHS-Kindern untersucht. Dazu wurden medikamentös behandelte ADHS-Kinder und gesunde Kontrollkinder in einer Zeitreproduktions- und einer Augenbewegungsaufgabe getestet, die entweder eine aktive Inhibition oder Ausführung von Prosakkaden erforderte. Beide Gruppen zeigten vergleichbar präzise und interferenzstabile Zeitreproduktionen sowie eine vergleichbare Anzahl, Latenz, Amplitude und Dauer von Prosakkaden. Die Ergebnisse lassen eine weitgehende pharmakologische Kompensation von Auffälligkeiten der exekutiven Kontrolle vermuten. Jedoch konnte für ADHS-Kinder unter Medikamenteneinfluss (im Vergleich zu gesunden Kindern) eine signifikant erhöhte Spitzengeschwindigkeit von Prosakkaden beobachtet werden, die einen diagnostisch relevanten Augenbewegungs-Parameter darstellen könnte.
An Antarctic Circumpolar Current driven by surface buoyancy forcing
Authors: Hogg Andrew McC.
Published: November 2010

Simulations of an idealised, but eddy‐resolving, channel model of the Antarctic Circumpolar Current (ACC) are used to investigate the sensitivity of ACC transport to wind and surface buoyancy forcing. The results are consistent with theoretical predictions of the eddy‐saturated limit, where transport is independent of wind stress. In this parameter regime, buoyancy forcing provides the primary control over ACC transport.
IRI‐2007 model overestimates electron density during the 23/24 solar minimum
Authors: Lühr H. , Xiong C.
Published: November 2010

We compare electron density predictions of the International Reference Ionosphere (IRI‐2007) model with in‐situ measurements of the satellites CHAMP and GRACE for the years 2000–2009. Orbital‐averages of the electron density are considered. During the first half of the period (2000–2004) measurements and collocated model predictions track each other reasonably well at both sampling heights. From 2005 onward the overestimation of the electron density by the model is progressively increasing. Annual averages show that IRI‐2007 values are too high by 50% for 2008 and by more than 60% by 2009. An inspection of the latitudinal and local time distributions reveals that the too high predictions primarily occur at low latitudes during daytime hours. From comparison with observations it becomes obvious that IRI‐2007 is strongly overestimating the equatorial ion fountain effect during the last deep solar minimum.
Dynamics of Ganymede's magnetopause: Intermittent reconnection under steady external conditions
Authors: Jia Xianzhe , Walker Raymond J. , Kivelson Margaret G. , Khurana Krishan K. , Linker Jon A.
Published: December 2010

Magnetic reconnection at the terrestrial magnetopause is frequently intermittent, leading to the formation of localized reconnected flux bundles referred to as flux transfer events (FTEs). It remains unclear whether the intermittency of the process is intrinsic or arises because of fluctuations of solar wind properties. Here we use Ganymede's magnetosphere, which is embedded in a background of field and plasma whose properties vary imperceptibly over time scales pertinent to plasma flow across the moon's magnetosphere, to demonstrate that reconnection is intrinsically intermittent. We run time‐dependent global magnetohydrodynamic (MHD) simulations that describe Ganymede's magnetospheric environment realistically and reproduce plasma and field measurements made on multiple Galileo passes by the moon with considerable fidelity. The simulations reveal that even under steady external conditions, dynamic variations associated with magnetic reconnection on time scales of the order of tens of seconds occur over a large region near the upstream magnetopause. The MHD simulations give direct evidence of magnetic reconnection at the magnetopause and reproduce the amplitude and spatial distribution of observed fluctuations of the magnetic field near boundary crossings. The consistency of data and simulations leads us to conclude that even under steady upstream conditions, upstream reconnection is intermittent. The bursty magnetopause structures at Ganymede and the FTEs identified at planetary magnetospheres (Mercury, Earth, and Jupiter) extend the parameter regime for analysis of intermittent magnetopause reconnection. We find that FTE recurrence times decrease with the scale length of the system.
Decomposing observations of high‐frequency radar‐derived surface currents by their forcing mechanisms: Decomposition techniques and spatial structures of decomposed surface currents
Authors: Kim Sung Yong , Cornuelle Bruce D. , Terrill Eric J.
Published: December 2010

Surface current observations from a high‐frequency radar network deployed in southern San Diego are decomposed according to their driving forces: pure tides and their neighboring off‐band energy, local winds, and low frequency. Several superposed ocean responses are present as a result of the complicated bottom topography and relatively weak winds off southern San Diego, as opposed to coastal regions where circulation can be explained by a dominant forcing mechanism. This necessitates an application of a statistical decomposition approach. Surface currents coherent with pure tides are calculated using harmonic analysis. Locally wind‐driven surface currents are estimated by regression of observed winds on observed surface currents. The dewinded and detided surface currents are filtered by weighted least‐squares fitting assuming white noise and three colored signal bands: low‐frequency band (less than 0.4 cycles per day) and near‐tidal peaks at the diurnal (K1) and semidiurnal (M2) frequencies. The spatial and temporal variability of each part of the decomposed surface currents is investigated in terms of ocean response to the driving forces. In addition, the spatial correlations of individual components exhibit Gaussian and exponential shapes with varying decorrelation length scales.
Laboratory experiment on rip current circulations over a moveable bed: Drifter measurements
Authors: Castelle B. , Michallet H. , Marieu V. , Leckler F. , Dubardier B. , Lambert A. , Berni C. , Bonneton P. , Barthélemy E. , Bouchette F.
Published: December 2010

This study describes a laboratory experiment on rip current circulations over a moveable bed. Rip current characteristics over eight contrasting nature‐like beach morphologies are investigated. The seabed varied from reasonably alongshore uniform to strongly alongshore nonuniform with crescentic patterns and bar‐rip morphologies, representative of a full morphological down‐state sequence. The same offshore shore‐normal waves were generated by the wavemaker for the eight situations with the same mean water level to study the sensitivity of rip current characteristics as a function of the beach morphology only. In each case, a 30 to 60 min video run was used to track a large number of drifters released within the surf zone. Results show the presence of classic rip current patterns with counterrotating cells and a relatively narrow offshore‐directed jet varying from shore‐normal to strongly skewed. Wave‐driven circulations were strongly unstable. Computed standard deviations of flow intensity and direction provide high‐resolution information on the spatial variability of rip current instabilities. Highly pulsating and weakly directionally variable offshore‐directed flow is observed in the rip neck for well‐developed bar‐rip morphologies that turns into a weakly pulsating and highly directional variable rip current flow with decreasing beach alongshore nonuniformity. Proposing a definition of rip current intensity based on the rip current circulation geometry, rip current intensity was found to linearly increase with increasing measure of beach alongshore nonuniformity within both the low‐energy and moderate‐energy rip current regimes. To date, our laboratory experiment provides the first extensive quantitative rip current information during a full down‐state sequence for a given wave condition.
Insights into rock‐ice avalanche dynamics by combined analysis of seismic recordings and a numerical avalanche model
Authors: Schneider Demian , Bartelt Perry , Caplan‐Auerbach Jacqueline , Christen Marc , Huggel Christian , McArdell Brian W.
Published: December 2010

Rock‐ice avalanches larger than 1 × 106 m3 are high‐magnitude, low‐frequency events that may occur in all ice‐covered, high mountain areas around the world and can cause extensive damage if they reach populated regions. The temporal and spatial evolution of the seismic signature from two events was analyzed, and recordings at selected stations were compared to numerical model results of avalanche propagation. The first event is a rock‐ice avalanche from Iliamna volcano in Alaska which serves as a “natural laboratory” with simple geometric conditions. The second one originated on Aoraki/Mt. Cook, New Zealand Southern Alps, and is characterized by a much more complex topography. A dynamic numerical model was used to calculate total avalanche momentum, total kinetic energy, and total frictional work rate, among other parameters. These three parameters correlate with characteristics of the seismic signature such as duration and signal envelopes, while other parameters such as flow depths, flow path and deposition geometry are well in agreement with observations. The total frictional work rate shows the best correlation with the absolute seismic amplitude, suggesting that it may be used as an independent model evaluation criterion and in certain cases as model calibration parameter. The good fit is likely because the total frictional work rate represents the avalanche's energy loss rate, part of which is captured by the seismometer. Deviations between corresponding calculated and measured parameters result from site and path effects which affect the recorded seismic signal or indicate deficiencies of the numerical model. The seismic recordings contain additional information about when an avalanche reaches changes in topography along the runout path and enable more accurate velocity calculations. The new concept of direct comparison of seismic and avalanche modeling data helps to constrain the numerical model input parameters and to improve the understanding of (rock‐ice) avalanche dynamics.
Immune responses to heat shock protein in Porphyromonas gingivalis‐infected periodontitis and atherosclerosis patients
Authors: Chung Sung‐Woon , Kang Ho‐Sung , Park Hae‐Ryoun , Kim Sung‐Jo , Kim Soo‐Jin , Choi Jeom‐Il
Published: November 2010

Background:  It has been widely thought that heat shock protein might be involved in autoimmune disease mechanisms in humans.

Objectives:  The present study was performed to evaluate the recognition of Porphyromonas gingivalis heat shock protein 60 (hsp60) and human hsp60 by immune sera in P. gingivalis‐infected periodontitis and atherosclerosis patients.

Materials and methods:  Mononuclear cells from atheroma lesions were stimulated with P. gingivalis hsp and sera from periodontitis or atherosclerosis patients were subjected to Western immunoblotting to P. gingivalis hsp or human hsp, respectively.

Results:  Western immunoblot analysis demonstrated the dual reactivity of anti‐P. gingivalis antisera with P. gingivalis hsp and human hsp. We could also establish P. gingivalis hsp‐specific T cell lines from the atheroma lesions, a mixture of CD4+ and CD8+ cells producing the cytokines characteristic of both Th1 and Th2 subsets.

Conclusion:  These observations suggest the modulating effect of P. gingivalis hsp60 in the immunopathogenesis of periodontitis and atherosclerosis.
Expression of endothelin‐1 in gingival epithelial cells
Authors: Yamamoto Eri , Awano Shuji , Koseki Takeyoshi , Ansai Toshihiro , Takehara Tadamichi
Published: November 2010

Objectives and background:  Endothelin‐1 (ET‐1) is a 21‐amino acid peptide with multifunctional regulation. ET‐1 expresses in various cells during inflammation. The present study aimed to examine the ET‐1 expression in oral epithelial cells after infection with the periodontal pathogen and to investigate the presence of ET‐1 in human inflamed and uninflamed gingival tissues.

Materials and methods:  The KB cells were infected with Porphyromonas gingivalis and the expression level of ET‐1 was examined using reverse transcription‐polymerase chain reaction (RT‐PCR) and enzyme‐linked immunosorbent assay (ELISA). The immunohistochemical analysis of ET‐1 was performed in gingival tissues obtained from patients. In addition, the ET‐1 mRNA expression in each tissue was also investigated by RT‐PCR.

Results:  The expression of ET‐1 in KB cells was strongly induced by the P. gingivalis infection. On the other hand, the strong immunoreactivity for ET‐1 was observed in the epithelium and vascular endothelial cells of the inflamed gingival tissue. Furthermore, the level of ET‐1 mRNA was greater in the inflamed tissues.

Conclusion:  These results suggested that the expression level of ET‐1 in gingival epithelial cells might be enhanced during the periodontal inflammation.
Invariant chain increases the half‐life of MHC II by delaying endosomal maturation
Authors: Landsverk Ole J B , Barois Nicolas , Gregers Tone F , Bakke Oddmund
Published: November 2010

Mounting adaptive immune responses requires the cell surface expression of major histocompatibility class II molecules (MHC II) loaded with antigenic peptide. However, in the absence of antigenic stimuli, the surface population of MHC II is highly dynamic and exhibits a high turnover. Several studies have focused on the regulation of MHC II, and it is now recognized that ubiquitination is one key mechanism operating in the turnover of MHC II in B cells and dendritic cells. Here, we describe how the invariant chain (Ii) can prolong the half‐life of MHC II through its action on the endocytic pathway. We find that in cells expressing intermediate‐to‐high levels of Ii, the half‐life of MHC II is increased, with MHC II accumulating in slowly‐maturing endosomes. The accumulation in endosomes is not due to retention of new MHC II directed from the endoplasmatic reticulum, as also mature, not Ii associated, MHC II is preserved. We suggest that this alternative endocytic pathway induced by Ii would serve to enhance the rate, quantity and diversity of MHC II antigen presentation by concentrating MHC II into specialized compartments and reducing the need for new MHC II synthesis upon antigen encounter.
Molecular analysis of promoter region of the SMN2 gene in the patients of spinal musculatr atrophy.
Authors: Baig Atif , Shamsudin Watihayati , Marzuki Marini , Hayati Fatemeh , Suriano Teguh , Yean Chan , Manicam Ravichandran , Alwi Zilfalil
Published: November 2010

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by the absence of the full length SMN protein (FL-SMN) as a result of mutation or deletion of SMN1 gene. The isoform to this gene, SMN2 gene, with mutation in 1 base pair, encodes for 10% of FL-SMN protein and is reported to decrease the severity of the disease when there is an increase gene dosage. There are 3 clinical types of SMA; type I, type II and type III. Type I SMA is the most severe type and only a small amount of FL-SMN protein is present in these individuals. We postulated that the difference in the promoter region of SMN2 gene produces the different level of FL-SMN protein. To verify this hypothesis, the DNA samples of 69 SMA patients who were referred to the Human Genome Center, USM were extracted from their blood. The SMN1 deletion analysis was performed, followed by the SMN2 copy no. analysis and NAIP deletion analysis to remove any clinical bias as NAIP gene deletion and SMN2 copy number have been reported to be associated with SMA disease severity. Only 10 SMA patients from different clinical types (type I=2, type II=3, type III=5) with homozygous deletion of the SMN1 and 2 copies of the SMN2 and deletion in NAIP were finally recruited. Primers were designed for the amplification of the SMN2 promoter region. Bioinformatics analysis was performed to identify the crucial transcription factor binding sites within the reported ~4.6 kb promoter region. As the core promoter region is still unknown (unreported), we analyzed 15 ORFs and 24 nested ORFs with 15 TATA boxes reflecting the diverse functional integrity of this region. The promoter prediction and core promoter prediction was also performed. Based on the bioinformatics analysis and the designed primers, PCR amplification was done for different regions in the promoter and the PCR products were subjected to direct DNA sequencing. The results were analyzed by Vector NTI suite 9, ClustalX and Gene Doc softwares. The molecular analysis confirmed the absence of any mutation in the promoter region of the SMN2 gene between normal healthy individuals (total 2) and SMA patients. In 4 patients and 1 normal healthy individual the CA repeats were found to be increased which we think cause no effect in disease progression and severity. In conclusion, there was no mutation found in the promoter region of the SMN2 gene among the SMA patients of different clinical types and normal controls. Further analysis involving the cloning of the promoter regions with highest probability of involvement in expression of the SMN2 gene using luciferase assay is ongoing. The results will be useful for the subsequent phase of the study involving the transcription initiation of the SMN2 gene.
New Lewis Structures through the application of the Hypertorus Electron Model
Authors: Yepez Omar
Published: November 2010

The hypertorus electron model is applied to the chemical bond. As a consequence, the bond topology can be determined. A linear correlation is found between the normalized bond area and the bond energy. The normalization number is a whole number. This number is interpreted as the Lewis's electron pair. A new electron distribution in the molecule follows. This discovery prompts to review the chemical bond, as it is understood in chemistry and physics.
The Effect of Urbanization on Bumble Bee Communities in Greater Philadelphia
Authors: Malfi Rosemary , Williams Neal
Published: November 2010

Bumble bees (Bombus spp.) are among the most important wild pollinators in temperate ecosystems in North America and Europe, and are believed to be vital to the functioning of the pollination networks in which they occur. Accordingly, evidence of their overall decline in Europe and more selective decline in the U.S. has raised concern about the long term persistence of many species. Human-induced changes in land use, including the loss of natural and semi-natural habitat and associated floral resources, are purported causes in several cases. Declines prompted an investigation of this potential trend in the urbanized landscape in and surrounding Philadelphia, PA. We surveyed the species richness and abundance of bumble bee communities in ten half-ha plots located in restored, managed meadows along a gradient of urban and suburban development in the Philadelphia metropolitan area from June 1 to August 15, 2006. In conjunction with collections, we measured floral density within each plot. We calculated the proportion of developed land at differing spatial scales ranging from 500 to 4000 m from survey sites. General linear models were used to test the effect of developed land, local meadow size, and floral resource density on overall bumble bee species richness and abundance.Development did not have any detectable effect on species richness at any tested spatial scale. Bee abundance was best explained by a model that included the proportion of developed land at the 2500 m scale. In contrast to our expectations, total bumble bee abundance was significantly higher in plots with a higher proportion of developed land surrounding the site (F1,5 = 8.13, P = 0.04). Local floral density did not significantly affect richness or abundance (F 1,5 = 0.93, P = 0.34), nor was local resource quality associated with development (r = 0.52, P = 0.12) . We hypothesize that gardens maintained in urban and suburban landscapes may provide an important and consistent food supply to bumble bees throughout the duration of their colony cycle. Forested habitats, which were the other dominate habitat type, may actually be relatively poor in bumble bee resources following closure of the canopy in late spring. This research indicates that restored meadows are excellent habitat for bumble bees and may promote pollination services in urbanized settings.
In silico Genetic Network Models for *Pre-clinical Drug Prioritization
Authors: Xiong Jianghui , Liu Juan , Rayner Simon , Tian Ze , Li Yinghui , Chen Shanguang
Published: November 2010

The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies.
Synthesis, Activation and Decomposition of N-Heterocyclic Carbene-containing Complexes
Authors: Praetorius Jeremy M. , Crudden Cathleen M.
Published: November 2010

NHC–transition metal complexes are described in terms of their synthesis, stability and utility as catalytic precursors. After a review of the more common methods of synthesis, the known decomposition reactions are described. These include displacement of the NHC from the metal coordination sphere, reductive elimination of the NHC and adjacent ligands, C–H/C–C or C–N activation of the NHC ligand in addition to other pathways such as migratory insertion reactions. With these decomposition routes in mind, the approaches required to prepare NHC–metal complexes that are resistant to degradation are depicted. Finally, useful methods for generating active catalysts from NHC metal complexes are described, including, in some cases, results gleaned during studies of decomposition pathways. Taken together, these sections will provide the reader with a detailed knowledge of the expected stability of typical NHC complexes, in addition to methods of generating active catalysts from them.
Biologically Active N-Heterocyclic Carbene–Metal Complexes
Authors: Deblock Michael C. , Panzner Matthew J. , Tessier Claire A. , Cannon Carolyn L. , Youngs Wiley J.
Published: November 2010

The increasing popularity of N-heterocyclic carbenes (NHCs) has yield in the past few years numerous new and exciting applications of these species, particularly as ligands in metal complexes. Complementarily, these ligands could have a prominent role in the development of new metallopharmaceuticals. Thanks to the number of different NHC–metal compounds that can be synthesized a wide variety of applications have emerged as bio-inorganic pharmaceuticals. Medicinal uses studied so far include powerful broad spectrum antibiotics and targeted antitumor agents.
Non-classical N-Heterocyclic Carbene Complexes
Authors: Krüger Anneke , Albrecht Martin
Published: November 2010

The expansion of N-heterocyclic carbenes as ligands for transition metals to mesoionic ligand systems has led to the discovery of a wide range of non-classical carbene-type ligands. These non-classical carbene-type ligands are characterised by a significantly lower heteroatom stabilisation of the (putative) free carbene, a situation that also affects the ligand donor properties and hence the reactivity of the coordinated metal centre. In consequence, a number of attractive transition metal-catalysed processes have been disclosed in recent years, predominantly in the areas of cross-coupling, hydrogenations, and olefin metathesis reactions.
The Chemical Genetic Approach: The Interrogation of Biological Mechanisms with Small Molecule Probes
Authors: Fisher Martin , Nelson Adam
Published: November 2010

The Chapter reviews the scope of the chemical genetic approach in the investigation of biological mechanisms. Particular emphasis is placed on the impact of chemistry in the synthesis of libraries of diverse small molecules; the screening of small molecule libraries for biological function; and the identification of the proteins that specific ligands target. The features of the chemical genetics are placed in the context of other approaches that may be used to modulate the functions of proteins (such as classical genetics and RNAi). Insights into specific fundamental biological mechanisms that have been gleaned from a chemical genetic approach are described. In addition, some of the major challenges in the future that will need to be addressed are outlined.
Targeted Intracellular Protein Degradation as a Potential Therapeutic Strategy
Authors: Schneekloth A.R. , Crews C.M.
Published: November 2010

Here we describe the development of a broadly applicable method for small molecule-mediated post-translational protein degradation known as PROteolysis TArgeting Chimeric molecules (PROTACs). This technique utilizes the Ubiquitin Proteasome System (UPS) that controls protein half-life through targeted degradation. The UPS functions by tagging proteins with a polyubiquitin chain, which facilitates their recognition and subsequent degradation in the 26S proteasome. PROTACs are heterobifunctional molecules that will target a specific protein for degradation via the UPS, by forming a complex between the target protein and an E3 ubiquitin ligase. The PROTAC is comprised of a recognition element for the target, a linker, and a recognition element for an E3 ligase. Following addition to cells, a PROTAC brings the targeted protein and E3 ligase into close physical proximity, facilitating the polyubiquitination of the target, and its subsequent recognition and degradation by the proteasome.

A number of different PROTACs, described herein, have been designed and successfully implemented, with considerable diversity in both the target protein and the E3 ligase component. This method has the potential to be useful as both a tool for understanding the role of specific proteins in cellular pathways, and also as a therapeutic designed to specifically eliminate disease-causing proteins from the cell.
Chemologics
Authors: Jones Lyn H.
Published: November 2010

The successful application of synthetic organic chemistry to the biotherapeutic arena has created an exciting paradigm for drug discovery and new opportunities for medicinal chemistry design. Chemistry is no longer restricted to the discovery of small molecule organic drugs since the workable opportunity space is arguably the entire spectrum of chemical space, inclusive of inorganics and biomolecules. Moreover, the emphasis for biotherapeutics is increasingly becoming the alignment of structure with function, and therefore methods that enable the delineation of structure-function relationships will become powerful tools in the design of improved therapeutics, thus avoiding traditionally empirical approaches. Chemistry can significantly modify the structure of a biological, improving its therapeutic effectiveness or imparting totally new properties to the designed molecule, thereby increasing the functionality of the construct. Here, the recent advances made in the area of chemistry-enabled biotherapeutics, or chemologics, are reviewed with a focus on the opportunities being unearthed through close partnerships between biology and chemistry.
Comparison of two- and three-dimensional activity landscape representations for different compound data sets
Authors: Iyer Preeti , Wawer Mathias , Bajorath Jürgen
Published: November 2010

A network-like similarity graph is mapped onto the surface of a 3D landscape model illustrating similarities and differences between these two approaches for graphical SAR analysis.
Endosome–lysosome fusion
Authors: Luzio J. Paul , Gray Sally R. , Bright Nicholas A.
Published: December 2010

The delivery of endocytosed cargo to lysosomes occurs through kissing and direct fusion of late endosomes/MVBs (multivesicular bodies) and lysosomes. Live-cell and electron microscopy experiments together with cell-free assays have allowed us to describe the characteristics of the delivery process and determine the core protein machinery required for fusion. The ESCRT (endosomal sorting complex required for transport) machinery is required for MVB biogenesis. The HOPS (homotypic fusion and vacuole protein sorting) complex is required for endosome–lysosome tethering and a trans-SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) complex including the R-SNARE VAMP7 (vesicle-associated membrane protein 7) mediates endosome–lysosome membrane fusion. Protein-binding partners of VAMP7 including the clathrin adaptors AP-3 (adaptor protein 3) and Hrb (HIV Rev-binding protein) are required for its correct intracellular localization and function. Overall, co-ordination of the activities of ESCRT, HOPS and SNARE complexes are required for efficient delivery of endocytosed macromolecules to lysosomes. Endosome–lysosome fusion results in a hybrid organelle from which lysosomes are re-formed. Defects in fusion and/or lysosome reformation occur in a number of lysosome storage diseases.
The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes
Authors: Metcalf Daniel , Isaacs Adrian M.
Published: December 2010

ESCRT (endosomal sorting complex required for transport) proteins were originally identified for their role in delivering endocytosed proteins to the intraluminal vesicles of late-endosomal structures termed multivesicular bodies. Multivesicular bodies then fuse with lysosomes, leading to degradation of the internalized proteins. Four ESCRT complexes interact to concentrate cargo on the endosomal membrane, induce membrane curvature to form an intraluminal bud and finally pinch off the bud through a membrane-scission event to produce the intraluminal vesicle. Recent work suggests that ESCRT proteins are also required downstream of these events to enable fusion of multivesicular bodies with lysosomes. Autophagy is a related pathway required for the degradation of organelles, long-lived proteins and protein aggregates which also converges on lysosomes. The proteins or organelle to be degraded are encapsulated by an autophagosome that fuses either directly with a lysosome or with an endosome to form an amphisome, which then fuses with a lysosome. A common machinery is beginning to emerge that regulates fusion events in the multivesicular body and autophagy pathways, and we focus in the present paper on the role of ESCRT proteins. These fusion events have been implicated in diseases including frontotemporal dementia, Alzheimer's disease, lysosomal storage disorders, myopathies and bacterial pathogen invasion, and therefore further examination of the mechanisms involved may lead to new insight into disease pathogenesis and treatments.
Cytoplasmic mRNA: move it, use it or lose it!
Authors: Coldwell Mark J. , Gray Nicola K. , Brook Matthew
Published: December 2010

Once an mRNA is synthesized and processed, the immediate translation and later destruction of the transcript is not as inevitable as the central molecular biology dogma suggests. Interest in the field of post-transcriptional control continues to grow rapidly, as regulation of these multiple steps in gene expression is implicated in diverse aspects of biology such as metabolism, neurology, reproduction and viral lifecycle regulation. Researchers who utilize various combinations of human studies, animal models, cellular, genetic, biochemical and molecular techniques were brought together at the University of Edinburgh to discuss their latest findings. In this article, we introduce the content of the related reviews presented in this issue of Biochemical Society Transactions which together illustrate a major theme of the meeting content: namely the need to understand how dynamic changes in mRNP (messenger ribonucleoprotein) complexes modulate the multifunctionality of regulatory proteins which link different post-transcriptional regulatory events.
Regulated and quality-control mRNA turnover pathways in eukaryotes
Authors: Reznik Boris , Lykke-Andersen Jens
Published: December 2010

Gene expression can be regulated at multiple levels, including transcription, RNA processing, RNA localization, translation and, finally, RNA turnover. RNA degradation may occur at points along the processing pathway or during translation as it undergoes quality control by RNA surveillance systems. Alternatively, mRNAs may be subject to regulated degradation, often mediated by cis-encoded determinants in the mRNA sequence that, through the recruitment of trans factors, determine the fate of the mRNA. The aim of the present review is to highlight mechanisms of regulated and quality-control RNA degradation in eukaryotic cells, with an emphasis on mammals.
Translational termination–reinitiation in RNA viruses
Authors: Powell Michael L.
Published: December 2010

Viruses utilize a number of translational control mechanisms to regulate the relative expression levels of viral proteins on polycistronic mRNAs. One such mechanism, that of termination-dependent reinitiation, has been described in a number of both negative- and positive-strand RNA viruses. Dicistronic RNAs which exhibit termination–reinitiation typically have a start codon of the 3′-ORF (open reading frame) proximal to the stop codon of the upstream ORF. For example, the segment 7 RNA of influenza B is dicistronic, and the stop codon of the M1 ORF and the start codon of the BM2 ORF overlap in the pentanucleotide UAAUG (the stop codon of M1 is shown in bold and the start codon of BM2 is underlined). Recent evidence has highlighted the potential importance of mRNA–rRNA interactions in reinitiation on caliciviral and influenza B viral RNAs, probably used to tether 40S ribosomal subunits to the RNA after termination in time for initiation factors to be recruited to the AUG of the downstream ORF. The present review summarizes how such interactions regulate reinitiation in an array of RNA viruses, and discusses what is known about reinitiation in viruses that do not rely on apparent mRNA–rRNA interactions.