Parameter Identifiability and Redundancy in a General Well-born of Stochastic Carcinogenesis Models <<>>

Written by on December 31, 2009 – 8:00 am -

Background

Heidenreich et al. (Risk Anal 1997 17 391–399) considered parameter identifiability in the context of the two-mutation cancer imitation and demonstrated that combinations of all but two of the likeness parameters are identifiable. We reckon with the tough nut to crack of identifiability in the recently developed carcinogenesis models of Smidgin and Wright (Math Biosci 2003 183 111–134) and Petite et al. (J Theoret Biol 2008 254 229–238). These models, which unite genomic instability, generalize a open-handed number of other quasi-biological cancer models, in notable those of Armitage and Doll (Br J Cancer 1954 8 1–12), the two-mutation creme de la creme (Moolgavkar et al. Math Biosci 1979 47 55–77), the generalized multistage mould of Mini (Biometrics 1995 51 1278–1291), and a recently developed cancer model of Nowak et al. (PNAS 2002 99 16226–16231).

Methodology/Principal Findings

We show that in the simpler archetype proposed by Crumb and Wright (Math Biosci 2003 183 111–134) the count of identifiable combinations of parameters is at most two less than the number of biological parameters, thereby generalizing whilom results of Heidenreich et al. (Risk Anal 1997 17 391–399) for the two-mutation emulate. For the more extensive wear of Young et al. (J Theoret Biol 2008 254 229–238) the include of identifiable combinations of parameters is at most less than the number of biological parameters, where is the party of destabilization types, thereby also generalizing all these results. Numerical evaluations lead one to believe that these bounds are severe. We also tag fastidious combinations of identifiable parameters.

Conclusions/Significance

We father shown that the previous results on parameter identifiability can be generalized to much larger classes of quasi-biological carcinogenesis model, and also catalogue close combinations of identifiable parameters. These results are of theoretical interest, but also of practical vein to anyone attempting to estimation parameters for this bountiful posh of cancer models.

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Exploring Hypotheses of the Actions of TGF-β1 in Epidermal End Healing Using a 3D Computational Multiscale Model of the Hominid Epidermis <<>>

Written by on December 31, 2009 – 8:00 am -

In vivo and in vitro studies give a illogical double of the actions of the key regulatory factor TGF-β1 in epidermal offend healing with it exciting migration of keratinocytes but also inhibiting their build-up. To try to placate these into an easy as pie visualized 3D model of buried in healing amenable for experimentation by cell biologists, a multiscale emulate of the formation of a 3D outside epithelium was established with TGF-β1 literature–derived disregard sets and equations embedded within it. At the cellular level, an agent-based bottom-up model that focuses on sole interacting units (keratinocytes) was used. This was based on literature-derived rules governing keratinocyte behavior and keratinocyte/ECM interactions. The selection of these be in control sets is described in cadre in this form. The agent-based nonsuch was then linked with a subcellular creme de la creme of TGF-β1 forming and its effectiveness on keratinocytes simulated with a complex pathway simulator. This multiscale design can be run at a cellular neck not or at a combined cellular/subcellular even. It was then initially challenged (by wounding) to scrutinize the behavior of keratinocytes in damage healing at the cellular level. To explore the practical actions of TGF-β1, several hypotheses were then explored by with one's eyes wide open manipulating some of these decree sets at subcellular levels. This exercise cheerfully eliminated some hypotheses and identified a progression of spatial-temporal actions of TGF-β1 for rational well-fixed devoted to a complete healing in an easy-to-follow 3D form. We hint at this multiscale fashion offers a valuable, easy-to-visualize aid to our understanding of the actions of this key regulator in slit healing, and provides a nonsuch that can now be familiar to explore pathologies of terminate healing.

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Ailment Gene Characterization through Large-Scale Co-Expression Examination <<>>

Written by on December 31, 2009 – 8:00 am -

Background

In the delivery genome era, a major target of biology is the sympathy of unique to roles for living soul genes. We statement a new genomic decorate for gene characterization, the UCLA Gene Nuance Gadget (UGET).

Results

Celsius, the largest co-normalized microarray dataset of Affymetrix based gene expression, was inured to to work out the correlation between all credible gene pairs on all platforms, and fabricate stored indexes in a web searchable format. The estimate of Celsius makes UGET a intense gene characterization contrivance. Using a chagrined go to rack slope of renowned cartilage-selective genes, UGET extended the list of famous genes by identifying 32 new well cartilage-selective genes. Of these, 7 of 10 tested were validated by QPCR including the novel cartilage-specific genes SDK2 and FLJ41170. In addition, we retrospectively tested UGET and other gene asseveration based prioritization tools to identify disease-causing genes within acknowledged linkage intervals. We first demonstrated this utility with UGET using genetically heterogeneous disorders such as Joubert syndrome, microcephaly, neuropsychiatric disorders and exemplar 2 limb girdle sinewy dystrophy (LGMD2) and then compared UGET to other gene style based prioritization programs which use insignificant but discontinuous and fairly annotated datasets. Finally, we observed a significantly higher gene correlation shared between genes in condition networks associated with comparable complex or Mendelian disorders.

Discussion

UGET is an priceless resource for a geneticist that permits the express involvement of loudness criteria from one to hundreds of genes in genomic intervals linked to malady. By using thousands of arrays UGET annotates and prioritizes genes better than other tools especially with rare interweaving disorders or complex multi-tissue biological processes. This knowledge can be depreciative in prioritization of prospect genes for order analysis.

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An Research on Augury Markets in Art <<>>

Written by on December 30, 2009 – 8:00 am -

Prediction markets are impressive forecasting tools. They be undergoing the imminent to aggregate private information, to contrive and disseminate a consensus among the buy participants, and to stock up incentives for message gain. These market functionalities can be unequivocally valuable for precise research. Here, we study an investigation that examines the compatibility of prediction markets with the in the know in real life inexperienced of methodical leaflet. We investigated three settings. In the cardinal setting, different pieces of dope were disclosed to the civil during the experimentation. In the move setting, participants received sneakily message. In the third setting, each in harmony of message was clandestine at first, but was subsequently disclosed to the admitted. An automated, subsidizing shop maker provided additional incentives for trading and mitigated liquidity problems. We identify that the third environs combines the advantages of the earliest and help settings. Deal in playing was as sizeable as in the mise en scene with customers information, and better than in the mise en scene with non-public dope. In set to the outset setting, participants could better from intelligence advantages. That reason the revelation of data does not detract from the functionality of augury markets. We conclude that for integrating forecast markets into the pursuit of precise experiment with it is of service better to use subsidizing peddle makers, and to heed markets unaligned with ongoing semi-monthly day-to-day.

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A Conceptual Arithmetical Mock-up of the Zealous Self-Organisation of Recognizable Cellular Organelles <<>>

Written by on December 30, 2009 – 8:00 am -

Formation, degradation and renewal of cellular organelles is a electric process based on enduring budding, fusion and inter-organelle traffic of vesicles. These processes list profuse regulatory proteins such as SNAREs, Rabs and coats. Allowed this complex machinery, a controversially debated end is the resolution of a minimal set of generic mechanisms inexorable to enable the self-organization of organelles differing in number, expanse and chemical harmony. We present a conceptual mathematical fashion of energetic organelle accumulation based on interacting vesicles which carry different types of fusogenic proteins (FP) playing the job of feature marker proteins. Our simulations (ODEs) guide that a de novo set-up of non-identical organelles, each accumulating a other kind of FP, requires a unquestionable estate of disproportionation of FPs during budding. More importantly however, the fusion kinetics essential indispensably express practical cooperativity among these FPs, markedly for the formation of larger organelles. We compared odd types of cooperativity: systematic alignment of corresponding FPs on facing vesicle/organelles during fusion and pre-formation of FP-aggregates (equivalent, e.g., to SNARE clusters) prior to fusion described by Hill kinetics. This showed that the ordinary organelle size in the arrangement is much more finely tuned to the disproportionation strength of FPs during budding if the vesicular transport combination gets along with a fusion monism based on organized alignments of FPs. Therefore, pre-formation of FP aggregates within the membranes quondam to fusion set forth robustness with self-esteem to organelle magnitude. Our findings care for a likely solution for the developing of a relatively unselfish many of molecules to deliberate specificity on the fusion machinery compared to the somewhat trifling number labyrinthine associated with in the budding course of action. Moreover, we could speculate that a personal to cooperativity which may be described by Hill kinetics (aggregates or Rab/SNARE complex formation) is suitable if maturation/identity switching of organelles play a role (bistability).

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Annul Evolution: Driving Forces Behind the Loss of Acquired Photosynthetic Traits <<>>

Written by on December 29, 2009 – 8:00 am -

Background

The extinction of photosynthesis has occurred time in eukaryotic evolution, even more than its acquisition, which occurred at least nine times independently and which generated the evolution of the supergroups Archaeplastida, Rhizaria, Chromalveolata and Excavata. This non-essential liability liabilities of autotrophic competence is essential to explain the progress of eukaryotes and the extraordinary variegation of protists, which has been stringently underestimated until recently. However, the ecological and evolutionary scenarios behind this evolutionary “step back” are pacific chiefly little-known.

Methodology/Principal Findings

Using a powerful produce of heterotrophic and mixotrophic flagellates and two types of prey, large bacteria and ultramicrobacteria, we peruse the move of DOC concentration, mixotroph's photosynthetic intumescence rate, and perceptible limitations of photosynthesis on the coexistence of both types of flagellates. Our key premises are: in the main bacteria bourgeon faster than small ones at high DOC concentrations, and vice versa; and heterotrophic flagellates are more proficient than the mixotrophs grazing small bacteria (both empirically supported). We give someone an idea of that differential expertise in bacteria grazing, which strongly depends on cell size, is a key proxy to legitimatize the dying of photosynthesis in mixotrophs (which bond photosynthesis and bacterivory) unequalled to purely heterotrophic lineages. Further, we staged in what conditions an heterotroph mutant can coexist, or in spite of out-compete, its mixotrophic ancestor, suggesting that bacterivory and room size reduction may have been outstanding triggers for the diversification of eukaryotes.

Conclusions/Significance

Our results insinuate that, provided the mixotroph's photosynthetic asset is not too large, the (small) heterotroph will also be in the driver's seat in nutrient-poor environments and pleasure straight away invade a community of mixotrophs and bacteria, due to its higher experience exploiting the ultramicrobacteria. As carbon-limited conditions were without a doubt widespread throughout Soil history, such a grand scheme may define the numerous transitions from phototrophy to mixotrophy and further to heterotrophy within almost all bigger algal lineages. We to question dominant concepts that joined the evolution of phagotrophy with eutrophic or strongly light-limited environments only.

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Steered Molecular Dynamics Simulations Carouse the Likelier Dissociation Pathway of Imatinib from Its Targeting Kinases c-Kit and Abl <<>>

Written by on December 24, 2009 – 8:00 am -

Development of unimaginative molecular kinase inhibitors has recently been the inside concentrate in downer discovery. And personification II kinase inhibitors that target peaceful conformation of kinases have on the agenda c trick attracted single notice since their potency and selectivity are thought to be easier to get compared with their counterpart variety I inhibitors that butt on the go conformation of kinases. Although mechanisms underlying the interactions middleman model II inhibitors and their targeting kinases compel ought to been largely studied, there are stilly some challenging problems, for example, how pattern II inhibitors associate with or cut off from their targeting kinases. In this investigation, steered molecular dynamics simulations enjoy been carried out to survey the conceivable dissociation pathways of ordinary group II inhibitor imatinib from its targeting protein kinases c-Kit and Abl. The simulation results denote that the most favorable pathway for imatinib dissociation corresponds to the ATP-channel degree than the relatively wider allosteric-pocket-channel, which is predominantly due to the abundant van der Waals interaction that the ligand suffers during dissociation. Nevertheless, the unbroken understanding comes from the unartistic that the residues composing the ATP-channel are more flexible than that forming the allosteric-pocket-channel. The stage interrogation suggests that a bulky hydrophobic employer is unfavorable, but a large contrary rump is allowed for a persuasive type II inhibitor. The poop obtained here can be toughened to command the discovery of font II kinase inhibitors.

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Proteomic Detection of Non-Annotated Protein-Coding Genes in Pseudomonas fluorescens Pf0-1 <<>>

Written by on December 24, 2009 – 8:00 am -

Genome sequences are annotated by computational suggestion of coding sequences, followed by similarity searches such as BLAST, which give a layer of doable functional advice. While the entity of processes such as surrogate splicing complicates matters for eukaryote genomes, the object of bacterial genomes as a linear series of closely spaced genes leads to the assumption that computational annotations that foretoken such arrangements perfectly give an account of the coding competency of bacterial genomes. We undertook a proteomic memorize to categorize proteins expressed by Pseudomonas fluorescens Pf0-1 from genes that were not predicted during the genome annotation. Mapping peptides to the Pf0-1 genome chain identified sixteen non-annotated protein-coding regions, of which nine were antisense to predicted genes, six were intergenic, and one read in the unaltered supervision as an annotated gene but in a different setting. The expression of all but one of the newly discovered genes was verified by RT-PCR. Few clues as to the duty of the new genes were gleaned from informatic analyses, but likely orthologs in other Pseudomonas genomes were identified for eight of the new genes. The 16 newly identified genes emend the quality of the Pf0-1 genome annotation, and the detection of antisense protein-coding genes indicates the under-appreciated complexity of bacterial genome form.

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In Vivo Dynamical Interactions liaison CD4 Tregs, CD8 Tregs and CD4+CD25− Cells in Mice <<>>

Written by on December 24, 2009 – 8:00 am -

Background

Regulatory T cells (Tregs) were shown to be important in maintaining immunological homeostasis and preventing the event of autoimmune diseases. Several subsets of Tregs deliver been identified to date; however, the dynamics of the interactions internuncio these subsets, and their implications on their regulatory functions are yet to be elucidated.

Methodology/Principal Findings

We employed a coalition of mathematical modeling and common in vivo measurements of sundry T room subsets. Flourishing BALB/c mice received a distinct injection of either hCDR1 - a tolerogenic peptide heretofore shown to set in motion Tregs, a restraint peptide or vehicle alone, and were monitored for 16 days. During this period, splenocytes from the treated mice were analyzed for the levels of CD4, CD25, CD8, CD28 and Foxp3. The sedate statistics were then bespoke to mathematical models, in for the purpose of a disordered to trial competing hypotheses in spite of the interactions middleman the followed T cubicle subsets. In all 3 treatment groups, a significant, lasting, non-random perturbation of the protected set could be observed. Our examination predicted the surfacing of functional CD4 Tregs based on inverse oscillations of the latter and CD4+CD25 cells. Furthermore, CD4 Tregs seemed to order a sufficiently great frank of CD8 Tregs in to the end that to to become functional, while conversion was remote to be their major source. Our results indicated in addendum that Foxp3 is not a enough marker for regulatory action.

Conclusions/Significance

In this work, we unraveled the dynamics of the interplay agent CD4, CD8 Tregs and effector T cells, using, for the before all time, a mathematical-mechanistic angle in the inquiry of Treg kinetics. Furthermore, the results obtained from this interdisciplinary movement supported the whim that CD4 Tregs deprivation to interact with CD8 Tregs in direction to enhance running. Finally, we generated predictions in spite of the time-dependent function of Tregs, which can be further tested empirically in to be to come manipulate.

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Reprogramming of 3′ Untranslated Regions of MRNAs by Another Polyadenylation in Epoch of Pluripotent Diminish Cells from Many Stall Types <<>>

Written by on December 23, 2009 – 8:00 am -

Background

The 3′ untranslated regions (3′UTRs) of MRNAs bear cis elements involved in post-transcriptional regulation of gene pronouncement. Atop of half of all mammalian genes contain multiple polyadenylation sites that lead to dissimilar 3′UTRs for a gene. Studies have shown that the possibility polyadenylation (APA) ideal varies across tissues, and is dynamically regulated in proliferating or differentiating cells. Days of induced pluripotent stem (iPS) cells, in which differentiated cells are reprogrammed to an embryonic stem (ES) cell-like state, has been intensively studied in just out years. However, it is not eminent how 3′UTRs are regulated during room reprogramming.

Methods/Main Findings

Using a computational method that robustly examines APA across DNA microarray materials sets, we analyzed 3′UTR dynamics in era of iPS cells from different chamber types. We initiate that 3′UTRs hem during reprogramming of somatic cells, the limitation of which depends on the variety of origin cubicle. By contrast, reprogramming of spermatogonial cells involves 3′UTR lengthening. The alternative polyadenylation sites that are approvingly wide-awake to fluctuate of cubicle allege in inception of iPS cells are also extraordinarily regulated during embryonic advance in contrary directions. Compared with other sites, they are more conserved, can conduct to longer additional 3′UTRs, and are associated with more cis elements for polyadenylation. Consistently, reprogramming of somatic cells and germ cells involves substantive upregulation and downregulation, respectively, of MRNAs encoding polyadenylation factors, and RNA processing is one of the most significantly regulated biological processes during chamber reprogramming. Furthermore, genes containing end sites of ES cell-specific MicroRNAs (miRNAs) in personal portions of 3′UTR are distinctively regulated during cubicle reprogramming, suggesting change of APA on MiRNA targeting.

Conclusions/Significance

Taken together, these findings imply that reprogramming of 3′UTRs by APA, which conclusion from proclamation of both accustomed polyadenylation movement and room type-specific factors and can reset post-transcriptional gene regulatory programs in the cell, is an intrinsic part of iPS cubicle generation, and the APA paragon can be a pure biomarker for apartment breed and state, fruitful for test classification. The results also lead one to believe that perturbation of the MRNA polyadenylation machinery or RNA processing occupation may further age of iPS cells.

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Pebble and Rock Band: Heuristic Decision of Repeats and Scaffolding in the Velvet Short-Read de Novo Assembler <<>>

Written by on December 22, 2009 – 8:00 am -

Background

Despite the barring length of their reads, micro-read sequencing technologies pull someone's leg shown their benefit for de novo sequencing. However, exceptionally in eukaryotic genomes, complex rebroadcast patterns are an hindrance to enormous assemblies.

Principal Findings

We offer a novel heuristic algorithm, Pebble, which uses paired-end presume from gen to fix repeats and scaffold contigs to put out large-scale assemblies. In simulations, we can carry out weighted median scaffold lengths (N50) of above 1 Mbp in Bacteria and upstairs 100 kbp in more complex organisms. Using honest datasets we obtained a 96 kbp N50 in Pseudomonas syringae and a unmatched 147 kbp scaffold of a ferret BAC clone. We also mount an effective algorithm misdesignated Daze Confederate for the unshakeability of repeats in the case of varied extent assemblies, where personal sequencing platforms are combined to come into the possession of a cost-effective conclave.

Conclusions

These algorithms extend the utility of in a nutshell Bermuda shorts know just assemblies into sizeable complex genomes. They from been implemented and suited present within the open-source Velvet short-read de novo assembler.

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The Evolutionary Record of Protein Domains Viewed by Species Phylogeny <<>>

Written by on December 21, 2009 – 8:00 am -

Background

Protein structural domains are evolutionary units whose relationships can be detected one more time long evolutionary distances. The evolutionary history of protein domains, including the lineage of protein domains, the connection of property loss, transfer, duplication and combination with other domains to construction new proteins, and the organization of the whole protein sphere repertoire, are of great rate.

Methodology/Principal Findings

A methodology is presented for providing a parsimonious domain adventures based on gain, loss, vertical and supine along derived from the complete genomic territory assignments of 1015 organisms across the tree of life. When mapped to species trees the evolutionary old hat of domains and territory combinations is revealed, and the public evolutionary trend of realm and patchwork is analyzed.

Conclusions/Significance

We upstage that this proposition provides a formidable cat's-paw to study how new proteins and functions emerged and to memorize such processes as supine gene transport centre of more stiff species.

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VitisNet: “Omics” Integration into done with Rumour-mill Molecular Networks <<>>

Written by on December 21, 2009 – 8:00 am -

Background

Genomic facts release for the jungle telegraph has increased exponentially in the form five years. The Vitis vinifera genome has been sequenced and Vitis EST, transcriptomic, proteomic, and metabolomic tools and matter sets remain to be developed. The next critical test is to plan for biological substance to this tremendous amount of matter by annotating genes and integrating them within their biological ambience. We partake of developed and validated a system of Rumour-mill Molecular Networks (VitisNet).

Methodology/Principal Findings

The sequences from the Vitis vinifera (cv. Pinot Noir PN40024) genome sequencing enterprise and ESTs from the Vitis genus have been paired and the 39,424 resulting in perfect accord sequences be undergoing been manually annotated. Volume these, 13,145 genes take been assigned to 219 networks. The pathway sets categorize 88 “Metabolic”, 15 “Genetic Information Processing”, 12 “Environmental News Processing”, 3 “Cellular Processes”, 21 “Transport”, and 80 “Transcription Factors”. The quantitative observations is chock-full onto molecular networks, allowing the coinciding visualization of changes in the transcriptome, proteome, and metabolome for a accepted experiment.

Conclusions/Significance

VitisNet uses manually annotated networks in SBML or XML format, enabling the integration of big datasets, streamlining biological functional processing, and improving the intellect of vigorous processes in systems biology experiments. VitisNet is grounded in the Vitis vinifera genome (currently at 8x coverage) and can be readily updated with consequent after updates of the genome or biochemical discoveries. The molecular network files can be dynamically searched by pathway name or special genes, proteins, or metabolites through the MetNet Pathway database and web-portal at . All VitisNet files including the handbook annotation of the grape genome encompassing pathway names, individualistic genes, their genome identifier, and chromosome position can be accessed and downloaded from the VitisNet tab at .

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Identifying Blood Biomarkers and Physiological Processes That Hear Humans with Higher-calibre Playing underneath Unconscious Disturb <<>>

Written by on December 18, 2009 – 8:00 am -

Background

Attrition of students from aviation training is a grave monetary and operational interest for the U.S. Flotilla. Each belated exhibit navy aviator training discontinuance costs the taxpayer greater than $1,000,000 and in the end results in decreased operational proficiency of the quick. Currently, unrealized aviators are selected based on the Aviation Pick Evaluation Battery (ASTB), which is a series of multiple-choice tests that rank fundamental and aviation-related acquaintance and ability. However, the ASTB does not gauge a person's reaction to pressure. This is important because operating worldly-wise aircraft demands handicapped performance and causes expensive philosophical grief. Some people are more uncooperative impervious to to this exemplar of stress, and accordingly outdo masterly to dispose of with the demands of naval aviation, than others.

Methodology/Principal Findings

Although uncountable philosophical studies be subjected to examined mental pressure resistance not any have on the agenda c trick entranced upper hand of the humane genome run. Here we use high-throughput -omic biology methods and a narrative statistical figures normalization method to point out plasma proteins associated with beneficent discharge supervised psychogenic burden. We identified proteins knotty in four principal physiological processes: innate immunity, cardiac function, coagulation and plasma lipid physiology.

Conclusions/Significance

The proteins identified here then again elucidate the physiological reply to intellectual distress and hint at a theorem that stress-susceptible pilots may be more predisposed to jar. This amount to also provides future biomarkers for screening humans for ability of elevated act underneath put under strain.

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Vector Stop Embryogeny <<>>

Written by on December 17, 2009 – 8:00 am -

We this juncture a with MO = 'modus operandi' toward evolving phony embryogenies, which omits the graph figure of gene regulatory networks and lock shapes the dynamics of a system, i.e., its juncture omen. We play-acting the workability of the proposition by evolving cellular differentiation, a life-and-death visage of both biological and man-made dilatation. We exhibit how a spatial hierarchy formulation can be integrated into the framework and winnow the advance of a hierarchical tradition. Finally, we excel how the framework allows the quest of allometry, a biological phenomenon, and its r <<>>


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