bluuebunny/crossref_metadata_2025 huggingface dataset:
First-principles characterization of ferromagnetism in N-doped SrTiO3 and BaTiO3
Authors: Yang Kesong , Dai Ying , Huang Baibiao
Published: February 2012

The spin-polarization and magnetic coupling character of N-doped SrTiO3 (STO) and BaTiO3 (BTO) are studied through first-principles calculations. The substitutional N doping at O sites leads to a half-metallic property and produces a magnetic moment of 1.0 μB. The magnetic interaction between the nearest and next-nearest N dopants results in a strong ferromagnetic (FM) coupling. When the distance between the N dopants is larger than 7 Å, the ground state of the system tends to be paramagnetic. A nitrogen-concentration threshold to produce the ferromagnetism is estimated. The calculated results give a good explanation for the experimentally observed ferromagnetism in N-doped STO and BTO.
Energy harvesting in semiconductor-insulator-semiconductor junctions through excitation of surface plasmon polaritons
Authors: Pradhan A. K. , Holloway Terence , Mundle Rajeh , Dondapati Hareesh , Bahoura M.
Published: February 2012

We have demonstrated a simple approach for developing a photovoltaic device consisting of semiconductor-insulator-semiconductor (SIS) heterojunction using surface plasmon polaritons (SPPs) generated in one of the semiconductors (Al:ZnO) and propagated through the dielectric barrier (SiO2) to other (Si). This robust architecture based on surface plasmon excitation within an SIS device that produces power based on spatial confinement of electron excitation through plasmon absorption in Al:ZnO in a broad spectrum of visible to infrared wavelengths enhancing the photovoltaic activities. This finding suggests a range of applications for photovoltaics, sensing, waveguides, and others using SPPs enhancement on semiconductors without using noble metals.
Non-radiative complete surface acoustic wave bandgap for finite-depth holey phononic crystal in lithium niobate
Authors: Yudistira Didit , Pennec Yan , Djafari Rouhani Bahram , Dupont Samuel , Laude Vincent
Published: February 2012

We demonstrate the existence of non-radiative complete surface acoustic wave (SAW) bandgaps for two-dimensional piezoelectric phononic crystals of holes. Holes of finite depth in a semi-infinite LiNbO3 substrate are specifically considered. SAW bandgaps are determined from the band structure calculated with a three-dimensional finite element method taking into account material anisotropy and piezoelectricity. The effect of hole geometry on the bandgaps has been investigated. It is further found that the complete band gap does not close for moderately conical holes.
Alternative pathway of cell death in
Drosophila
mediated by NF-κB transcription factor Relish
Authors: Chinchore Yashodhan , Gerber Gloria F. , Dolph Patrick J.
Published: February 2012

Photoreceptor cell death accompanying many retinal degenerative disorders results in irreversible loss of vision in humans. However, the precise molecular pathway that executes cell death is not known. Our results from a
Drosophila
model of retinal degeneration corroborate previously reported findings that the developmental apoptotic pathway is not involved in photoreceptor cell demise. By undertaking a candidate gene approach, we find that players involved in the immune response against Gram-negative bacteria are involved in retinal degeneration. Here, we report that the NF-κB transcription factor Relish regulates neuronal cell death. Retinal degeneration is prevented in genetic backgrounds that block Relish activation. We also report that the N-terminal domain of Relish encodes unique toxic functions. These data uncover a unique molecular pathway of retinal degeneration in
Drosophila
and identify a previously unknown function of NF-κB signaling in cell death.
Crucial role of copper in detection of metal-coordinating odorants
Authors: Duan Xufang , Block Eric , Li Zhen , Connelly Timothy , Zhang Jian , Huang Zhimin , Su Xubo , Pan Yi , Wu Lifang , Chi Qiuyi , Thomas Siji , Zhang Shaozhong , Ma Minghong , Matsunami Hiroaki , Chen Guo-Qiang , Zhuang Hanyi
Published: February 2012

Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH2SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol–OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smellingtrans-cyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMT–copper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMT-responding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs.
Quantifying the hurricane risk to offshore wind turbines
Authors: Rose Stephen , Jaramillo Paulina , Small Mitchell J. , Grossmann Iris , Apt Jay
Published: February 2012

The U.S. Department of Energy has estimated that if the United States is to generate 20% of its electricity from wind, over 50 GW will be required from shallow offshore turbines. Hurricanes are a potential risk to these turbines. Turbine tower buckling has been observed in typhoons, but no offshore wind turbines have yet been built in the United States. We present a probabilistic model to estimate the number of turbines that would be destroyed by hurricanes in an offshore wind farm. We apply this model to estimate the risk to offshore wind farms in four representative locations in the Atlantic and Gulf Coastal waters of the United States. In the most vulnerable areas now being actively considered by developers, nearly half the turbines in a farm are likely to be destroyed in a 20-y period. Reasonable mitigation measures—increasing the design reference wind load, ensuring that the nacelle can be turned into rapidly changing winds, and building most wind plants in the areas with lower risk—can greatly enhance the probability that offshore wind can help to meet the United States’ electricity needs.
TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes
Authors: Kawahara Yukio , Mieda-Sato Ai
Published: February 2012

Although aberrant microRNA (miRNA) expression is linked to human diseases including cancer, the mechanisms that regulate the expression of each individual miRNA remain largely unknown. TAR DNA-binding protein-43 (TDP-43) is homologous to the heterogeneous nuclear ribonucleoproteins (hnRNPs), which are involved in RNA processing, and its abnormal cellular distribution is a key feature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases. Here, we show that TDP-43 facilitates the production of a subset of precursor miRNAs (pre-miRNAs) by both interacting with the nuclear Drosha complex and binding directly to the relevant primary miRNAs (pri-miRNAs). Furthermore, cytoplasmic TDP-43, which interacts with the Dicer complex, promotes the processing of some of these pre-miRNAs via binding to their terminal loops. Finally, we show that involvement of TDP-43 in miRNA biogenesis is indispensable for neuronal outgrowth. These results support a previously uncharacterized role for TDP-43 in posttranscriptional regulation of miRNA expression in both the nucleus and the cytoplasm.
Interdomain dynamics and coactivation of the mRNA decapping enzyme Dcp2 are mediated by a gatekeeper tryptophan
Authors: Floor Stephen N. , Borja Mark S. , Gross John D.
Published: February 2012

Conformational dynamics in bilobed enzymes can be used to regulate their activity. One such enzyme, the eukaryotic decapping enzyme Dcp2, controls the half-life of mRNA by cleaving the 5′ cap structure, which exposes a monophosphate that is efficiently degraded by exonucleases. Decapping by Dcp2 is thought to be controlled by an open-to-closed transition involving formation of a composite active site with two domains sandwiching substrate, but many details of this process are not understood. Here, using NMR spectroscopy and enzyme kinetics, we show that Trp43 of
Schizosaccharomyces pombe
Dcp2 is a conserved gatekeeper of this open-to-closed transition. We find that Dcp2 samples multiple conformations in solution on the millisecond-microsecond timescale. Mutation of the gatekeeper tryptophan abolishes the dynamic behavior of Dcp2 and attenuates coactivation by a yeast enhancer of decapping (Edc1). Our results determine the dynamics of the open-to-closed transition in Dcp2, suggest a structural pathway for coactivation, predict that Dcp1 directly contacts the catalytic domain of Dcp2, and show that coactivation of decapping by Dcp2 is linked to formation of the composite active site.
Two-dimensional IR spectroscopy and segmental
13
C labeling reveals the domain structure of human γD-crystallin amyloid fibrils
Authors: Moran Sean D. , Woys Ann Marie , Buchanan Lauren E. , Bixby Eli , Decatur Sean M. , Zanni Martin T.
Published: February 2012

The structural eye lens protein γD-crystallin is a major component of cataracts, but its conformation when aggregated is unknown. Using expressed protein ligation, we uniformly
13
C labeled one of the two Greek key domains so that they are individually resolved in two-dimensional (2D) IR spectra for structural and kinetic analysis. Upon acid-induced amyloid fibril formation, the 2D IR spectra reveal that the C-terminal domain forms amyloid β-sheets, whereas the N-terminal domain becomes extremely disordered but lies in close proximity to the β-sheets. Two-dimensional IR kinetics experiments show that fibril nucleation and extension occur exclusively in the C-terminal domain. These results are unexpected because the N-terminal domain is less stable in the monomer form. Isotope dilution experiments reveal that each C-terminal domain contributes two or fewer adjacent β-strands to each β-sheet. From these observations, we propose an initial structural model for γD-crystallin amyloid fibrils. Because only 1 μg of protein is required for a 2D IR spectrum, even poorly expressing proteins can be studied under many conditions using this approach. Thus, we believe that 2D IR and protein ligation will be useful for structural and kinetic studies of many protein systems for which IR spectroscopy can be straightforwardly applied, such as membrane and amyloidogenic proteins.
Signatures of electronic correlations in iron silicide
Authors: Tomczak Jan M. , Haule Kristjan , Kotliar Gabriel
Published: February 2012

The intermetallic FeSi exhibits an unusual temperature dependence in its electronic and magnetic degrees of freedom, epitomized by the cross-over from a low-temperature nonmagnetic semiconductor to a high-temperature paramagnetic metal with a Curie–Weiss-like susceptibility. Many proposals for this unconventional behavior have been advanced, yet a consensus remains elusive. Using realistic many-body calculations, we here reproduce the signatures of the metal-insulator cross-over in various observables: the spectral function, the optical conductivity, the spin susceptibility, and the Seebeck coefficient. Validated by quantitative agreement with experiment, we then address the underlying microscopic picture. We propose a new scenario in which FeSi is a band insulator at low temperatures and is metalized with increasing temperature through correlation induced incoherence. We explain that the emergent incoherence is linked to the unlocking of iron fluctuating moments, which are almost temperature independent at short timescales. Finally, we make explicit suggestions for improving the thermoelectric performance of FeSi based systems.
Active maintenance of nuclear actin by importin 9 supports transcription
Authors: Dopie Joseph , Skarp Kari-Pekka , Kaisa Rajakylä Eeva , Tanhuanpää Kimmo , Vartiainen Maria K.
Published: February 2012

Besides its essential and well established role as a component of the cytoskeleton, actin is also present in the cell nucleus, where it has been linked to many processes that control gene expression. For example, nuclear actin regulates the activity of specific transcription factors, associates with all three RNA polymerases, and is a component of many chromatin remodelling complexes. Despite the fact that two export receptors, Crm1 and exportin 6, have been linked to nuclear export of actin, the mechanism by which actin enters the nucleus to elicit these essential functions has not been determined. It is also unclear whether actin is actively exchanged between the nucleus and the cytoplasm, and whether this connection has any functional significance for the cell. By applying a variety of live-cell imaging techniques we revealed that actin constantly shuttles in and out of the nucleus. The fast transport rates, which depend on the availability of actin monomers, suggest an active transport mechanism in both directions. Importantly, we identified importin 9 as the nuclear import factor for actin. Furthermore, our RNAi experiments showed that the active maintenance of nuclear actin levels by importin 9 is required for maximal transcriptional activity. Measurements of nuclear export rates and depletion studies also clarified that nuclear export of actin is mediated by exportin 6, and not by Crm1. These results demonstrate that cytoplasmic and nuclear actin pools are dynamically connected and identify the nuclear import and export mechanisms of actin.
Metabolomic analysis reveals that carnitines are key regulatory metabolites in phase transition of the locusts
Authors: Wu Rui , Wu Zeming , Wang Xianhui , Yang Pengcheng , Yu Dan , Zhao Chunxia , Xu Guowang , Kang Le
Published: February 2012

Phenotypic plasticity occurs prevalently and plays a vital role in adaptive evolution. However, the underlying molecular mechanisms responsible for the expression of alternate phenotypes remain unknown. Here, a density-dependent phase polyphenism ofLocusta migratoriawas used as the study model to identify key signaling molecules regulating the expression of phenotypic plasticity. Metabolomic analysis, using high-performance liquid chromatography and gas chromatography–mass spectrometry, showed that solitarious and gregarious locusts have distinct metabolic profiles in hemolymph. A total of 319 metabolites, many of which are involved in lipid metabolism, differed significantly in concentration between the phases. In addition, the time course of changes in the metabolic profiles of locust hemolymph that accompany phase transition was analyzed. Carnitine and its acyl derivatives, which are involved in the lipid β-oxidation process, were identified as key differential metabolites that display robust correlation with the time courses of phase transition. RNAi silencing of two key enzymes from the carnitine system, carnitine acetyltransferase and palmitoyltransferase, resulted in a behavioral transition from the gregarious to solitarious phase and the corresponding changes of metabolic profiles. In contrast, the injection of exogenous acetylcarnitine promoted the acquisition of gregarious behavior in solitarious locusts. These results suggest that carnitines mediate locust phase transition possibly through modulating lipid metabolism and influencing the nervous system of the locusts.
STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability
Authors: Luo Tuoping , Masson Kristina , Jaffe Jacob D. , Silkworth Whitney , Ross Nathan T. , Scherer Christina A. , Scholl Claudia , Fröhling Stefan , Carr Steven A. , Stern Andrew M. , Schreiber Stuart L. , Golub Todd R.
Published: February 2012

Approximately 30% of human cancers harbor oncogenic gain-of-function mutations in KRAS. Despite interest in KRAS as a therapeutic target, direct blockade of KRAS function with small molecules has yet to be demonstrated. Based on experiments that lower mRNA levels of protein kinases, KRAS-dependent cancer cells were proposed to have a unique requirement for the serine/threonine kinase STK33. Thus, it was suggested that small-molecule inhibitors of STK33 might have therapeutic benefit in these cancers. Here, we describe the development of selective, low nanomolar inhibitors of STK33’s kinase activity. The most potent and selective of these, BRD8899, failed to kill KRAS-dependent cells. While several explanations for this result exist, our data are most consistent with the view that inhibition of STK33’s kinase activity does not represent a promising anti-KRAS therapeutic strategy.
Trans Chromosomal Methylation in
Arabidopsis
hybrids
Authors: Greaves Ian K. , Groszmann Michael , Ying Hua , Taylor Jennifer M. , Peacock W. James , Dennis Elizabeth S.
Published: February 2012

The heterotic hybrid offspring of
Arabidopsis
accessions C24 and Landsberg erecta have altered methylomes. Changes occur most frequently at loci where parental methylation levels are different. There are context-specific biases in the nonadditive methylation patterns with
m
CG generally increased and
m
CHH decreased relative to the parents. These changes are a result of two main mechanisms, Trans Chromosomal Methylation and Trans Chromosomal deMethylation, where the methylation level of one parental allele alters to resemble that of the other parent. Regions of altered methylation are enriched around genic regions and are often correlated with changes in siRNA levels. We identified examples of genes with altered expression likely to be due to methylation changes and suggest that in crosses between the C24 and Ler accessions, epigenetic controls can be important in the generation of altered transcription levels that may contribute to the increased biomass of the hybrids.
The marginalized positions of Thai professional writers on the global hegemony of English
Authors: Buripakdi Adcharawan
Published: February 2012

This qualitative study investigated the positions of the Thai professional writers towards Thai English. Data was collected from in-depth interviews of 20 Thai bilingual writers. The findings revealed that most of the writers had different ways to distant themselves from Thai English. The majority of the participants expressed a marginalized view toward their English. Their attitudes were greatly influenced by the hegemonic Standard English. Evidently, Thai perceptions of the English language conformed to a colonial, hierarchical standpoint which privileged the types of English spoken and written within the U.S. and Great Britain and denigrated spoken and written Thai English. The study not only reflected the reality of World Englishes but also addressed political aspect of language use related with identity, power, and hierarchical discourse. It clearly indicated the political nature of teaching English and called for a reconsideration of teaching practices in countries where English is not the native language.
Applying the extended parallel process model to examine posters in the 2008 Chinese Annual Anti-Drug Campaign
Authors: Shi Rui , Hazen Michael David
Published: February 2012

The present study sought to examine the content structure of the contemporary anti-drug campaign posters in China through the lens of the Extended Parallel Process Model. Four major factors of the EPPM (severity, susceptibility, response efficacy, and self-efficacy) served as the main coding categories of the content analysis to assess anti-drug posters’ potential persuasiveness. The findings revealed that the severity of drug abuse (n = 130, 87.2%) was communicated significantly more frequently than the other three factors, and response efficacy (n = 10, 6.7%) was significantly less prominent than the other three factors. “Legal punishment” is the most popular severity theme for both verbal (n = 71, 47.7%) and visual (n = 55, 36.9%) threats.
Same path, different experience
Authors: Liu Meina
Published: February 2012

This study examines cultural variations in negotiators’ attribution and emotion as a viable means to understand culture’s multiplex influence on goal pursuit when it interacts with situational factors. 277 US Americans and 239 mainland Chinese responded to a hypothetical employment negotiation scenario in two experimental conditions. Findings indicate that given the same set of persuasive messages by a counterpart, American participants judged the counterpart as more personally responsible for perceived negative behavior, felt more anger and less compassion toward the counterpart, and placed greater importance on competitive goals than Chinese participants. Although the paths whereby emotions arise and influence interaction goals are largely similar across cultures, mainland Chinese demonstrated a stronger tendency to compete when they felt angry, whereas US Americans were more likely to pursue cooperative goals across both conditions. Theoretical and practical implications of these seemingly contradictory findings are discussed in this article.
Imagined community, identity, and Chinese Language Teaching in Hong Kong
Authors: Gao Fang
Published: February 2012

Second language (L2) teaching and learning is mediated by imagined community involving positioning learners themselves or being positioned by others in possible worlds. This research explores how Chinese language subject teachers in Hong Kong imagine the possible memberships of the communities in which South Asian learners will participate, and how the imagination makes a difference to their pedagogies and classroom practice. Through classroom observations and interviews with 14 secondary school teachers, research findings illustrate that the teachers treat South Asian learners as legitimate ethnic minorities in Hong Kong, while labeling them as illegitimate Chinese language users and second-class citizens in the host society. This imagination, while reflecting the subordinate position South Asians occupy, has an impact upon the teachers’ pedagogies and classroom practice, which are oriented to the instruction of basic language knowledge, albeit being sensible of South Asian culture and customs. The research results suggest that imagining L2 learners as multilingual individuals and legitimate L2 users is a necessary condition to break the structural constraints on L2 acquisition.
Knl1 shows another face
Authors: Leslie Mitch
Published: February 2012

Kinetochore protein might not recruit key parts of spindle assembly checkpoint and instead might help silence the checkpoint.
Properties of Ca2+ sparks revealed by four-dimensional confocal imaging of cardiac muscle
Authors: Shkryl Vyacheslav M. , Blatter Lothar A. , Ríos Eduardo
Published: February 2012

Parameters (amplitude, width, kinetics) of Ca2+ sparks imaged confocally are affected by errors when the spark source is not in focus. To identify sparks that were in focus, we used fast scanning (LSM 5 LIVE; Carl Zeiss) combined with fast piezoelectric focusing to acquire x–y images in three planes at 1-µm separation (x-y-z-t mode). In 3,000 x–y scans in each of 34 membrane-permeabilized cat atrial cardiomyocytes, 6,906 sparks were detected. 767 sparks were in focus. They had greater amplitude, but their spatial width and rise time were similar compared with all sparks recorded. Their distribution of amplitudes had a mode at ΔF/F0 = 0.7. The Ca2+ release current underlying in-focus sparks was 11 pA, requiring 20 to 30 open channels, a number at the high end of earlier estimates. Spark frequency was greater than in earlier imaging studies of permeabilized ventricular cells, suggesting a greater susceptibility to excitation, which could have functional relevance for atrial cells. Ca2+ release flux peaked earlier than the time of peak fluorescence and then decayed, consistent with significant sarcoplasmic reticulum (SR) depletion. The evolution of fluorescence and release flux were strikingly similar for in-focus sparks of different rise time (T). Spark termination involves both depletion of Ca2+ in the SR and channel closure, which may be synchronized by depletion. The observation of similar flux in sparks of different T requires either that channel closure and other termination processes be independent of the determinants of flux (including [Ca2+]SR) or that different channel clusters respond to [Ca2+]SR with different sensitivity.
Some lessons about models from Michaelis and Menten
Authors: Gunawardena Jeremy
Published: February 2012

Michaelis and Menten's classic 1913 paper on enzyme kinetics is used to draw some lessons about the relationship between mathematical models and biological reality.
The identification of short linear motif-mediated interfaces within the human interactome
Authors: Weatheritt R. J. , Luck K. , Petsalaki E. , Davey N. E. , Gibson T. J.
Published: February 2012

Motivation: Eukaryotic proteins are highly modular, containing multiple interaction interfaces that mediate binding to a network of regulators and effectors. Recent advances in high-throughput proteomics have rapidly expanded the number of known protein–protein interactions (PPIs); however, the molecular basis for the majority of these interactions remains to be elucidated. There has been a growing appreciation of the importance of a subset of these PPIs, namely those mediated by short linear motifs (SLiMs), particularly the canonical and ubiquitous SH2, SH3 and PDZ domain-binding motifs. However, these motif classes represent only a small fraction of known SLiMs and outside these examples little effort has been made, either bioinformatically or experimentally, to discover the full complement of motif instances.

Results: In this article, interaction data are analysed to identify and characterize an important subset of PPIs, those involving SLiMs binding to globular domains. To do this, we introduce iELM, a method to identify interactions mediated by SLiMs and add molecular details of the interaction interfaces to both interacting proteins. The method identifies SLiM-mediated interfaces from PPI data by searching for known SLiM–domain pairs. This approach was applied to the human interactome to identify a set of high-confidence putative SLiM-mediated PPIs.

Availability: iELM is freely available at http://elmint.embl.de

Contact:  toby.gibson@embl.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Spliceman—a computational web server that predicts sequence variations in pre-mRNA splicing
Authors: Lim Kian Huat , Fairbrother William Guy
Published: February 2012

Summary: It was previously demonstrated that splicing elements are positional dependent. We exploited this relationship between location and function by comparing positional distributions between all possible 4096 hexamers around a database of human splice sites. The distance measure used in this study found point mutations that produced higher distances disrupted splicing, whereas point mutations with smaller distances generally had no effect on splicing. Reasoning the idea that functional splicing elements have signature positional distributions around constitutively spliced exons, we introduce Spliceman—an online tool that predicts how likely distant mutations around annotated splice sites were to disrupt splicing. Spliceman takes a set of DNA sequences with point mutations and returns a ranked list to predict the effects of point mutations on pre-mRNA splicing. The current implementation included the analyses of 11 genomes: human, chimp, rhesus, mouse, rat, dog, cat, chicken, guinea pig, frog and zebrafish.

Availability: Freely available on the web at http://fairbrother.biomed.brown.edu/spliceman/

Contact:  fairbrother@brown.edu
Susceptibility of the human pathways graphs to fragmentation by small sets of microRNAs
Authors: Naamati Guy , Friedman Yitzhak , Balaga Ohad , Linial Michal
Published: February 2012

Motivation: MicroRNAs (miRNAs) are short sequences that negatively regulate gene expression. The current understanding of miRNA and their corresponding mRNA targets is primarily based on prediction programs. This study addresses the potential of a coordinated action of miRNAs to manipulate the human pathways. Specifically, we investigate the effectiveness of disrupting the topology of human pathway graphs through a regulation by miRNAs.

Results: From a set of miRNA candidates that is associated with a pathway, an exhaustive search for all possible doubles and triplets (coined miR-Duo, miR-Trios) is performed. The impact of each miR-combination on the connectivity of the pathway graph was quantified. About 170 human pathways were tested, and the miR-Duos and miR-Trios were scored for their ability to disrupt these pathway graphs. We show that 75% of all pathways are effectively disconnected by a small number of pathway-specific miR-Trios. Only 15% of the human pathways are resistant to fragmentation by miR-Duos or miR-Trios. Significantly, the combination of the most effective miR-Trios is unique. Thus, a specific regulation of a pathway within the cell is guaranteed. The impact of the selected miR-Duo/Trios on various diseases is discussed.

Conclusions: The methodology presented shows that the synthesis of the topology of a network with a detailed understanding of the miRNAs' regulation is useful in exposing critical nodes of the network. We propose the miR-Trio approach as a basis for rationally designed perturbation experiments.

Contact:  michall@cc.huji.ac.il

Supplementary information:  Supplementary data are available at Bioinformatics online.
Biogem: an effective tool-based approach for scaling up open source software development in bioinformatics
Authors: Bonnal Raoul J.P. , Aerts Jan , Githinji George , Goto Naohisa , MacLean Dan , Miller Chase A. , Mishima Hiroyuki , Pagani Massimiliano , Ramirez-Gonzalez Ricardo , Smant Geert , Strozzi Francesco , Syme Rob , Vos Rutger , Wennblom Trevor J. , Woodcroft Ben J. , Katayama Toshiaki , Prins Pjotr
Published: February 2012

Summary: Biogem provides a software development environment for the Ruby programming language, which encourages community-based software development for bioinformatics while lowering the barrier to entry and encouraging best practices.

Biogem, with its targeted modular and decentralized approach, software generator, tools and tight web integration, is an improved general model for scaling up collaborative open source software development in bioinformatics.

Availability: Biogem and modules are free and are OSS. Biogem runs on all systems that support recent versions of Ruby, including Linux, Mac OS X and Windows. Further information at http://www.biogems.info. A tutorial is available at http://www.biogems.info/howto.html

Contact:  bonnal@ingm.org
Kingship
Authors: Hamilton Mark W.
Published: February 2012

Kingship is an ancient institution, originating in the 4th millennium bce (or perhaps even slightly earlier) as small-scale societies developed into states capable of monopolizing violence and resource collection for the purpose of building large-scale public works (canals, temples, palaces, tombs) that united peoples in unprecedented ways. Kings in many ancient cultures bore superhuman (and occasionally divine) reputations. Although the institution of monarchy exists today in a much reduced (and primarily ritualized) form, one should not underestimate its importance as the locus of reflection on the meaning and purpose of society. Political thinking began at least as early as the 3rd millennium bce as a reflection on the rights and duties of kings, and religious and literary texts about kings have been among the most influential in human history. This article focuses on ancient kingship in the Near East and western Mediterranean, though other areas of the world have also contributed to the ongoing reflection on monarchy. Israelite kingship began in approximately 1000 bce (just when is debated), likely as a mechanism for defending the previously loose collection of tribes from foreign (especially Philistine) incursions. The Bible reports a 10th-century United Monarchy, though the stories about that period (the reigns of Saul and especially David and Solomon) contain significant embellishments. By the 9th century, Israel consisted of two kingdoms, a northern one called Israel and a smaller and less developed southern one called Judah. The first lasted until annexed by Assyria in 722 bce, while the second was conquered by the Babylonians in 586 bce. The texts about these kingdoms and their rulers have been among the most influential in human history and have formed the basis for political reflection among Jews, Christians, and Muslims for more than twenty-five centuries.
Biblical Criticism
Authors: Harrington Daniel J.
Published: February 2012

The term “biblical criticism” refers to the process of establishing the plain meaning of biblical texts and of assessing their historical accuracy. Biblical criticism is also known as higher criticism (as opposed to “lower” textual criticism), historical criticism, and the historical-critical method. The word “criticism” need not be interpreted negatively, as if the task were mainly criticizing the Bible or pointing out its errors. Rather, “criticism” indicates the effort at using scientific criteria (historical and literary) and human reason to understand and explain as objectively as possible the meaning intended by the biblical writers. While the modern versions of biblical criticism have roots in patristic, medieval, Reformation, and Renaissance biblical interpretation, the earliest full statement of the approach came from the philosopher Baruch/Benedict Spinoza in his Tractatus Theologico-Politicus. Spinoza urged that the Bible should be treated like any other book, that it should be read in the light of the rules of philology and history, that one must attend to the context of a passage within Scripture and establish the circumstances in which the book was written, that the Bible’s truth (or untruth) can be recognized by the light of natural reason (without need of tradition or ecclesiastical interference), and that its miracle stories should be interpreted in terms of the physical laws of nature. Much in Spinoza’s declaration can be explained by its author’s historical circumstances (excommunicated by the local synagogue) and philosophy (his idea of nature as a substitute for God). However, it has been possible for biblical scholars and churches to ignore Spinoza’s philosophy and to develop a historical-critical methodology that does not deny the basic tenets of Judaism and/or Christianity—so much so that the historical-critical method shorn of Spinoza’s dubious philosophical assumptions has been repeatedly described in recent, official Roman Catholic documents as “indispensable” (though not completely adequate in itself) in interpreting biblical texts.
Miracle Stories
Authors: Cotter Wendy , Twelftree Graham H.
Published: February 2012

A miracle story is a narrative involving a report of supposed special divine action. This article notes key literature that interprets the miracle stories associated with Jesus of Nazareth through historical, socioreligious, and literary contextualization. It does not take into account miracle stories in which Jesus is portrayed as directly involved, such as the transfiguration or resurrection. The importance of contextualization of miracle stories cannot be overemphasized. Understanding the historical era, the cultural climate, the political realities, the Jewish and Hellenistic religious background of Jesus and his early followers, the social signals in the literature that were understood by that culture, and the literary context provided by the larger works in which the stories appear, contribute to interpreting the intentions of those responsible for the stories. This article is intended to provide an authoritative set of texts that addresses these various aspects of interpreting the miracle stories of Jesus as they stand in the New Testament canon, that is, in the Gospel sources, the Gospels themselves, the Acts of the Apostles, and the letters of Paul.
Buddhist Art and Architecture in Nepal
Authors: Lo Bue Erberto
Published: February 2012

The earliest evidence of the presence of Buddhism in the Nepal Valley belongs to the 5th century. According to inscriptions of the Licchavi dynasty, the Buddhist ruler Vrsadeva (fl. c. 400 ce) founded a monastery at Svayambhu. Most Licchavi foundations have disappeared, but a few, such as the Gum monastery near Sankhu, have survived. The Buddhist pantheon in Nepal is obviously related to the Indian tradition, in which Buddhism and Hinduism coexisted and influenced each other through many centuries. Although the sophisticated artistic production in the Nepal Valley represents to some extent the continuation of the aesthetics prevailing in India under the Gupta, Pâla, and Sena dynasties, the art and architecture of its original inhabitants, the Newars, developed in a unique way. Even after their Buddhist tradition was cut off from its sources following the destruction of all Indian monastic universities by the 13th century, Newar artists continued to produce images for Buddhists not only in Nepal, but also in other countries, particularly Tibet. At least two Buddhist traditions and related styles may be distinguished in Nepal: the Newar ones of the Nepal Valley, where Buddhism followed its own local development; and the Tibetan ones, in areas inhabited by people of Tibetan stock and language, such as Lo (Mustang) and Dölpo, and in the Nepal Valley itself, where the number of Tibetan monasteries has increased significantly since the 1960s. That accounts for iconographic and stylistic differences in images produced even by the same artist, who traditionally can adapt easily to the requests of his client. The traditional style of architecture characterizing most of the 363 monasteries in the Nepal Valley, the earliest ones dating to the Licchavi dynasty, may be traced to Buddhist monastic structures such as those found at Sanchi, Ajanta, and Ellora, representing stone versions of now-lost Indian wooden architecture, but at the same time prototypes of the brick and wood monasteries of the Nepal Valley. Newar monasteries are characterized by three essential elements: the main shrine, a small stupa in the middle of the courtyard, and a tantric temple above the shrine. Their courtyards are surrounded by rooms that do not necessarily conform in their function to their Indian models, since, following the decline of Buddhism in the Nepal Valley, they have sometimes turned into residential buildings. Another feature deriving from Indian architecture is the tòrana, originally a decorated arch leading to a shrine, which in the Nepal Valley turned into a semicircular panel placed above the doors of shrines or gates.
Classical Japanese Buddhist Philosophy
Authors: Ishida Masato
Published: February 2012

The word philosophy, or tetsugaku in modern Japanese, can be perceived as problematic when applied to Japanese Buddhism. There was no explicit term or concept in the Japanese mind corresponding to philosophy in the Western sense up to the late 19th century, while various conceptual and doctrinal formations of Japanese Buddhism mostly took place in the Middle Ages. Furthermore, the language and logic employed in Japanese Buddhist philosophy operate very differently from how they work, for example, in Indian Buddhist philosophy. There is rarely a logical argument that purports to convince the audience rationally, nor can there be found any clear division of philosophy into the common branches of epistemology, metaphysics, ethics, and aesthetics. Japanese Buddhist philosophy is more or less practice-oriented, and the distinction between philosophy and religion is often blurred, accordingly. On the other hand, scholastic approaches to canonical Buddhist texts have been valued in the literate sphere, which resulted in numerous commentaries on works by past masters. Classical Buddhist texts, brought to the country through China and the Korean Peninsula, were read and studied mostly in Chinese translations. A greater number of domestic Buddhist theories and texts appear in and after the Heian period, reflecting the complete naturalization process of Buddhism in Japan. The growth of honji suijaku (true nature manifestation) theory, according to which indigenous Japanese gods are transformed manifestations of the Buddhist pantheon, and the development of hongaku (original enlightenment) theory, which asserts the strict non-duality of the phenomenal and the real, offer fine examples of Japanese creativity. Syncretism is found across both theory and ritual practice in all sects of Japanese Buddhism, integrating Buddhist views with Shintoism, Confucianism, and Daoism. Buddhist philosophy has remained influential throughout the intellectual and cultural history of Japan since its introduction to the country in the mid-sixth century. Modern Japanese philosophy, initiated by Nishida Kitarō, the founder of the so-called Kyoto school philosophy, can be seen as a synthesis of Buddhist traditions and Western philosophical views encountered by Japanese intellectuals in the late 19th and early 20th century. Postwar Japanese Buddhist philosophers have involved themselves in comparative philosophy in order to enrich East-West dialogue in the modern world.
History of Skepticism
Authors: Reed Baron
Published: February 2012

The skeptical tradition originated in the Hellenistic period of ancient philosophy. After mostly lying dormant through much of the medieval era, it was revived and—to some extent—transformed in early modern philosophy. Determining to what extent there is a single view shared across the different periods is complicated by the fact that at least some of the main figures in the tradition said quite explicitly that they did not have any view at all. But if there are no theoretical commitments binding all of the different skeptics together, then what allows us to say that there is in fact a single tradition? There are at least two relevant considerations. The first is that the later figures in the tradition make use of many of the arguments originally formulated by the ancient skeptics—and, indeed, given their centrality to epistemology, those arguments are likely to be an enduring legacy of the skeptical tradition. The second consideration is that many of the later skeptics—Hume is a good example—arrived at their philosophical outlook through profound reflection on the earlier figures in the tradition. It is a matter of controversy whether key aspects of ancient skepticism have been retained or lost—for example, some scholars of ancient philosophy have argued that modern skepticism is in certain ways a watered down version of its ancient predecessor, given that the ancient skeptics focused on what we ought to believe and the modern skeptics focus, supposedly, only on whether we have knowledge. But, whether or not this is true, it has become increasingly clear that there is much to be learned about skepticism through study of the tradition as a whole. Given that so much of philosophy has been shaped by both skepticism and anti-skeptical responses to it, the importance of the history of skepticism cannot be overstated.
Canon Law
Authors: Peters Edward , Eichbauer Melodie H.
Published: February 2012

Canon law began as sets of norms for the regulation of Christian conduct in the world and the relations of Christians with each other. These were based on principles derived from scripture, the influence of respected teachers such as St. Paul, the decisions of ecclesiastical assemblies called synods or councils, and papal decretals. These norms were called canons, rather than laws. The term canon translates the Greek κανών, meaning a carpenter’s straight-edge and, by extension, a guide or rule. Decretals, or letters, were responses of the pope to questions posed to him regarding Church doctrine. While relevant only to that particular circumstance, papal decretals, over time, came to be regarded as binding for all of Christendom. Church councils sought to standardize doctrine, liturgy, and legal norms by the collective decisions of assembled bishops, but regional ecclesiastical identities endured, particularly in the person of the independent local bishop governing his own church with its own customs, in the increasing distinction between clergy and laity, and in the development of a clerical hierarchy. Regional and local councils, presided over by bishops, could either adapt or repeat canons issued at ecumenical councils depending upon the needs. Collections of canons, always privately compiled—until the Liber Extra Decretalium of Pope Gregory IX (r. 1227–1241) in 1234—and adopted for use by regional churches, were arranged either chronologically according to the assumed dates of their texts or systematically according to topics treated. The Greek Christian church adopted the term nomocanon to designate its canons that were approved by the Byzantine emperor and thereby became νομοι, laws. The Latin Christian church called its laws ius canonicum as a parallel, but not dependent, legal system to the study of Roman law. The shift from collections of texts to a legal science—whereby one went to Bologna or Paris, for example, for the specific purpose of studying law—occurred during the classical period, from shortly before 1140 to 1375, beginning with the almost universal adoption of the work of the canonist Gratian, the Decretum. During this period—frequently referred to as the classical period—the doctrine of papal judicial supremacy emerged, and papal legal decisions became the primary source of canon law. In the law books produced during the classical period, canon law acquired a form and structured that remained in effect in the Roman Catholic Church until 1917–1918. Parts of it were adopted in other Christian confessions from the 16th century.