Almost all biomedical research to date has relied upon mean measurements from cell populations, however it is well established that what it is observed at this macroscopic level can be the result of many interactions of several different single cells. Thus, the observable macroscopic ‘average’ cannot outright be used as representative of the ‘average cell’. Rather, it is the resulting emerging behaviour of the actions and interactions of many different cells. Single‐cell RNA sequencing (scRNA‐Seq) enables the comparison of the (...) transcriptomes of individual cells. This provides high‐resolution maps of the dynamic cellular programmes allowing us to answer fundamental biological questions on their function and evolution. It also allows to address medical questions such as the role of rare cell populations contributing to disease progression and therapeutic resistance. Furthermore, it provides an understanding of context‐specific dependencies, namely the behaviour and function that a cell has in a specific context, which can be crucial to understand some complex diseases, such as diabetes, cardiovascular disease and cancer. Here, we provide an overview of scRNA‐Seq, including a comparative review of emerging technologies and computational pipelines. We discuss the current and emerging applications and focus on tumour heterogeneity a clear example of how scRNA‐Seq can provide new understanding of a complex disease. Additionally, we review the limitations and highlight the need of powerful computational pipelines and reproducible protocols for the broader acceptance of this technique in basic and clinical research. (shrink)

Mapping the paths that stem and progenitor cells take en route to differentiate and elucidating the underlying molecular controls are key goals in developmental and stem cell biology. However, with population level analyses it is difficult − if not impossible − to define the transition states and lineage trajectory branch points within complex developmental lineages. Single‐cell RNA‐sequencing analysis can discriminate heterogeneity in a population of cells and even identify rare or transient intermediates. In this review, we propose that using these (...) data, one can infer the lineage trajectories of individual stem cells and identify putative branch points. Clonal lineage tracing of stem cells allows one to define the outcome of differentiation. Integrating these single cell‐based approaches provides a robust strategy for establishing and testing models of how an individual stem cell changes through time to differentiate and self‐renew. (shrink)

Articles contained in fifteen volumes describe issues relating to and affecting the Catholic Church, in areas such as history, ethics, spirituality, and social sciences. Annual supplements update the original volumes and also include new entries.

Juan A. Nicolás, Department of Philosophy II, Universidad de Granada, Granada, Spain © 2010 Juan A. Nicolás Sociedad Española Leibniz has started the project ‘Leibniz en español’Leibniz in Spanish...

Juan A. Nicolás, Department of Philosophy II, Universidad de Granada, Granada, Spain © 2010 Juan A. Nicolás Sociedad Española Leibniz has started the project ‘Leibniz en español’Leibniz in Spanish...

Gene discovery reveals new biology, expands the utility of marker‐assisted selection, and enables targeted mutagenesis. Still, such discoveries can take over a decade. We present a general strategy, “Agile Genetics,” that uses nested, structured populations to overcome common limits on gene resolution. Extensive simulation work on realistic genetic architectures shows that, at population sizes of >5000 samples, single gene‐resolution can be achieved using bulk segregant pools. At this scale, read depth and technical replication become major drivers of resolution. Emerging enrichment (...) methods to address coverage are on the horizon; we describe one possibility – iterative depth sequencing (ID‐seq). In addition, graph‐based pangenomics in experimental populations will continue to maximize accuracy and improve interpretation. Based on this merger of agronomic scale with molecular and bioinformatic innovation, we predict a new age of rapid gene discovery. (shrink)

Transcriptional silencing may not necessarily depend on the continuous residence of a sequence‐specific repressor at a control element and may act via a “hit and run” mechanism. Due to limitations in assays that detect transcription factor (TF) binding, such as chromatin immunoprecipitation followed by high‐throughput sequencing (ChIP‐seq), this phenomenon may be challenging to detect and therefore its prevalence may be underappreciated. To explore this possibility, erythroid gene promoters that are regulated directly by GATA1 in an inducible system are analyzed. It (...) is found that many regulated genes are bound immediately after induction of GATA1 but the residency of GATA1 decreases over time, particularly at repressed genes. Furthermore, it is shown that the repressive mark H3K27me3 is seldom associated with bound repressors, whereas, in contrast, the active (H3K4me3) histone mark is overwhelmingly associated with TF binding. It is hypothesized that during cellular differentiation and development, certain genes are silenced by repressive TFs that subsequently vacate the region. Catching such repressor TFs in the act of silencing via assays such as ChIP‐seq is thus a temporally challenging prospect. The use of inducible systems, epitope tags, and alternative techniques may provide opportunities for detecting elusive “hit and run” transcriptional silencing. Also see the video abstract here https://youtu.be/vgrsoP_HF3g. (shrink)

The last decade has seen an explosion of research on the gut microbiota—the trillions of microorganisms that colonize the human gut. It is now clear that interindividual diversity in microbiota composition plays an important role in determining susceptibility to a wide variety of diseases. However, identifying the precise changes in microbiota composition that play causal roles has remained a largely unrealized goal. Here, we propose that functional classifications of microbes based on their interactions with and effects on the host—particularly the (...) host immune system—will illuminate the role of the microbiota in shaping human physiology. We outline the benefits of “functional” classification compared to phylogenetic classifications, and review current efforts at functional classification of the microbiota. Finally, we outline a theoretical framework for classifying host-microbiota interactions. Future advances enabling broader functional classifications of the microbiota promise to revolutionize our understanding of the role of gut microbes in health and disease. Functional classifications of the human microbiota reveal previously hidden patterns and will be key to cracking the microbiota composition code. This figure shows a theoretical comparison between phylogenetic classification and functional classification of a host-associated microbial community. (shrink)

Cofactor squelching is the term used to describe competition between transcription factors (TFs) for a limited amount of cofactors in a cell with the functional consequence that TFs in a given cell interfere with the activity of each other. Since cofactor squelching was proposed based primarily on reporter assays some 30 years ago, it has remained controversial, and the idea that it could be a physiologically relevant mechanism for transcriptional repression has not received much support. However, recent genome‐wide studies have (...) demonstrated that signal‐dependent TFs are very often absent from the enhancers that are acutely repressed by those signals, which is consistent with an indirect mechanism of repression such as squelching. Here we review these recent studies in the light of the classical studies of cofactor squelching, and we discuss how TF cooperativity in so‐called hotspots and super‐enhancers may sensitize these to cofactor squelching. (shrink)

During the last few months, several pioneer genome‐wide transcriptomic, proteomic and metabolomic studies have revolutionised the understanding of bacterial biological processes, leading to a picture that resembles eukaryotic complexity. Technological advances such as next‐generation high‐throughput sequencing and high‐density oligonucleotide microarrays have allowed the determination, in several bacteria, of the entire boundaries of all expressed transcripts. Consequently, novel RNA‐mediated regulatory mechanisms have been discovered including multifunctional RNAs. Moreover, resolution of bacterial proteome organisation (interactome) and global protein localisation (localizome) have unveiled an (...) unanticipated complexity that highlights the significance of protein multifunctionality and localisation in the cell. Also, analysis of a complete bacterial metabolic network has again revealed a high fraction of multifunctional enzymes and an unexpectedly high level of metabolic responses and adaptation. Altogether, these novel approaches have permitted the deciphering of the entire physiological landscape of one of the smallest bacteria, Mycoplasma pneumoniae. Here, we summarise and discuss recent findings aimed at defining the blueprint of any prokaryote. (shrink)

The brain is an ever‐changing organ that encodes memories and directs behavior. Neuroanatomical studies have revealed structural plasticity of neural architecture, and advances in gene expression technology and epigenetics have demonstrated new mechanisms underlying the brain's dynamic nature. Stressful experiences challenge the plasticity of the brain, and prolonged exposure to environmental stress redefines the normative transcriptional profile of both neurons and glia, and can lead to the onset of mental illness. A more thorough understanding of normal and abnormal gene expression (...) is needed to define the diseased brain and improve current treatments for psychiatric disorders. The efforts to describe gene expression networks have been bolstered by microarray and RNA‐sequencing technologies. The heterogeneity of neural cell populations and their unique microenvironments, coupled with broad ranging interconnectivity, makes resolving this complexity exceedingly challenging and requires the combined efforts of single cell and systems level expression profiling to identify targets for therapeutic intervention. (shrink)

Measurements of open chromatin in specific cell types are widely used to infer the spatiotemporal activity of transcriptional enhancers. How reliable are these predictions? In this review, it is argued that the relationship between the accessibility and activity of an enhancer is insufficiently described by simply considering open versus closed chromatin, or active versus inactive enhancers. Instead, recent studies focusing on the quantitative nature of accessibility signal reveal subtle differences between active enhancers and their different inactive counterparts: the closed silenced (...) state and the accessible primed and repressed states. While the open structure as such is not a specific indicator of enhancer activity, active enhancers display a higher degree of accessibility than the primed and repressed states. Molecular mechanisms that may account for these quantitative differences are discussed. A model that relates molecular events at an enhancer to changes in its activity and accessibility in a developing tissue is also proposed. (shrink)

In this review we highlight the importance of defining the untranslated parts of transcripts, and present a number of computational approaches for the discovery and quantification of alternative transcription start and poly-adenylation events in high-throughput transcriptomic data. The fate of eukaryotic transcripts is closely linked to their untranslated regions, which are determined by the position at which transcription starts and ends at a genomic locus. Although the extent of alternative transcription starts and alternative poly-adenylation sites has been revealed by sequencing (...) methods focused on the ends of transcripts, the application of these methods is not yet widely adopted by the community. We suggest that computational methods applied to standard high-throughput technologies are a useful, albeit less accurate, alternative to the expertise-demanding 5′ and 3′ sequencing and they are the only option for analysing legacy transcriptomic data. We review these methods here, focusing on technical challenges and arguing for the need to include better normalization of the data and more appropriate statistical models of the expected variation in the signal. We highlight the importance of defining the untranslated parts of transcripts, and present a number of computational approaches for the discovery and quantification of alternative transcription start site and alternative poly-adenylation events from standard high-throughput transcriptomic data. We discuss the challenges faced by these methods and argue for the use of better statistical models for dealing with biases in the data and variation in the signal. (shrink)

In humans over 15% of X‐linked genes have been shown to ‘escape’ from X‐chromosome inactivation (XCI): they continue to be expressed to some extent from the inactive X chromosome. Mono‐allelic expression is anticipated within a cell for genes subject to XCI, but random XCI usually results in expression of both alleles in a cell population. Using a study of allelic expression from cultured lymphoblasts and fibroblasts, many of which showed substantial skewing of XCI, we recently reported that the expression of (...) genes lies on a contiunuum between those that are subject to inactivation, and those that escape. We now review allelic expression studies from mouse, and discuss the variability in escape seen in both humans and mice in genic expression levels, between X chromosomes and between tissues. We also discuss current knowledge of the heterochromatic features, DNA elements and three‐dimensional topology of the inactive X that contribute to the balance of expression from the otherwise inactive X chromosome. (shrink)

During brain development, neural precursor cells (NPCs) in different brain regions produce different types of neurons, and each of these regions plays a different role in the adult brain. Therefore, precise regionalization is essential in the early stages of brain development, and irregular regionalization has been proposed as the cause of neurodevelopmental disorders. The mechanisms underlying brain regionalization have been well studied in terms of morphogen‐induced expression of critical transcription factors for regionalization. NPC potential in different brain regions is defined (...) by chromatin structures that regulate the plasticity of gene expression. Herein, we present recent findings on the importance of chromatin structure in brain regionalization, particularly with respect to its regulation by Polycomb‐group proteins and chromatin accessibility. (shrink)

Potts et seq. presents an analysis of gap-containing supplements where the gap is modelled as a variable over the semantic type of the constituent that the as-clause adjoins to. This much allows the meaning of the gap to be resolved purely compositionally, by defining as as a function that allows the anchor to bind the gap variable. This article presents a class of as-clauses where Potts’s analysis seems to break down, in that the gap cannot be modelled as a variable (...) over the semantic type of the anchor. I propose that these cases can be unified with those in Potts’s work, as well as a larger class of ellipsis phenomena, by assuming that, under certain conditions, surface gaps are composite entities, containing a bound variable and a free variable that are resolved independently of each other. The bound variable is bound by the anchor, and the free variable is resolved by anaphora to a salient discourse object. (shrink)

The fast advancing RNA‐seq technology has unveiled an unexpected diversity and expression specificity of 3′ untranslated regions (3′UTRs) of mRNAs. In particular, neural mRNAs seem to express significantly longer 3′UTRs, some of which are over 10 kb in length. The extensive elongation of 3′UTRs in neural tissues provides intriguing possibilities for cell type‐specific regulations that are governed by miRNAs, RNA‐binding proteins and ribonucleoprotein aggregates. In this article, we review recent progress in the characterization of mRNA 3′UTRs and discuss their implications (...) in the understanding of 3′UTR‐mediated gene regulation. (shrink)

A key challenge for understanding transcriptional regulation is being able to measure transcription factor (TF)‐DNA binding events with sufficient spatial and temporal resolution; that is, when and where TFs occupy their cognate sites. A recent study by Para et al. has highlighted the dynamics underlying the activation of gene expression by a master regulator TF. This study provides concrete evidence for a long‐standing hypothesis in biology, the “hit‐and‐run” mechanism, which was first proposed decades ago. That is, gene expression is dynamically (...) controlled by a TF that transiently binds and activates a target gene, which might stay in a transcriptionally active state after the initial binding event has ended. Importantly, the experimental procedure introduced, TARGET, provides a useful way for identifying multiple target genes transiently bound by their regulators, which can be used in conjunction with other well‐established methods to improve our understanding of transcriptional regulatory dynamics. (shrink)

In this paper, we consider certain cardinals in ZF (set theory without AC, the axiom of choice). In ZFC (set theory with AC), given any cardinals C and D, either C ≤ D or D ≤ C. However, in ZF this is no longer so. For a given infinite set A consider $\operatorname{seq}^{1 - 1}(A)$ , the set of all sequences of A without repetition. We compare $|\operatorname{seq}^{1 - 1}(A)|$ , the cardinality of this set, to |P(A)|, the cardinality of (...) the power set of A. What is provable about these two cardinals in ZF? The main result of this paper is that $ZF \vdash \forall A(|\operatorname{seq}^{1 - 1}(A)| \neq|\mathscr{P}(\mathscr{A})|)$ , and we show that this is the best possible result. Furthermore, it is provable in ZF that if B is an infinite set, then $|\operatorname{fin}(B)| <|\mathscr{P}(B)|$ even though the existence for some infinite set B* of a function f from $\operatorname{fin}(B^\ast)$ onto P(B*) is consistent with ZF. (shrink)

We write$\mathcal {S}_n(A)$for the set of permutations of a setAwithnnon-fixed points and$\mathrm {{seq}}^{1-1}_n(A)$for the set of one-to-one sequences of elements ofAwith lengthnwherenis a natural number greater than$1$. With the Axiom of Choice,$|\mathcal {S}_n(A)|$and$|\mathrm {{seq}}^{1-1}_n(A)|$are equal for all infinite setsA. Among our results, we show, in ZF, that$|\mathcal {S}_n(A)|\leq |\mathrm {{seq}}^{1-1}_n(A)|$for any infinite setAif${\mathrm {AC}}_{\leq n}$is assumed and this assumption cannot be removed. In the other direction, we show that$|\mathrm {{seq}}^{1-1}_n(A)|\leq |\mathcal {S}_{n+1}(A)|$for any infinite setAand the subscript$n+1$cannot be reduced ton. Moreover, (...) we also show that “$|\mathcal {S}_n(A)|\leq |\mathcal {S}_{n+1}(A)|$for any infinite setA” is not provable in ZF. (shrink)

The live streaming e-commerce market continues to grow with the rapid increase in contactless communication due to COVID-19. Live streaming e-commerce goes beyond the confines of traditional e-commerce of simply selling goods or services. It supplies information and allows synchronous information exchange between the online viewer and the Internet celebrity, who influences the consumers information behavior and ultimately contributes to the long-term profit generation of the company. From online commerce to new retail and live streaming, China has been at the (...) forefront of innovation in online commerce worldwide. Therefore, this study focuses on investigating the influences of live streaming e-commerce quality, such as service quality, information quality, and system quality, on consumer purchase intention in China by applying the extended model of technology acceptance. Furthermore, this study analyzes the paths through which the live streaming e-commerce quality affects the consumer purchase intention, based on paths of perceived usefulness, perceived ease of use, perceived trust, and perceived value. To analyze this study, the data were collected from 231 customers who had used live streaming e-commerce apps in China and empirical analysis was applied. The results were summarized as follows: SQ is positively related to PU and PT. Similarly, IQ is positively related to PEU and PT. In addition, SEQ is also positively related to PU and PEU. Moreover, SQ affected the PV through PU and PT significantly and ultimately influenced consumer PI. Also, the path in which SEQ affects PU, which in turn affects PV, and ultimately PI, was found. This study found out the paths of how the live streaming E-commerce quality affects the consumer purchasing intention and contributes to the research field of e-commerce and consumer behaviors. Additionally, the results of this study give useful marketing suggestions for relevant financial institutions and enterprises. (shrink)

For a set x, let ${\cal S}\left$ be the set of all permutations of x. We prove in ZF several results concerning this notion, among which are the following: For all sets x such that ${\cal S}\left$ is Dedekind infinite, $\left| {{{\cal S}_{{\rm{fin}}}}\left} \right| < \left| {{\cal S}\left} \right|$ and there are no finite-to-one functions from ${\cal S}\left$ into ${{\cal S}_{{\rm{fin}}}}\left$, where ${{\cal S}_{{\rm{fin}}}}\left$ denotes the set of all permutations of x which move only finitely many elements. For all sets (...) x such that ${\cal S}\left$ is Dedekind infinite, $\left| {{\rm{seq}}\left} \right| < \left| {{\cal S}\left} \right|$ and there are no finite-to-one functions from ${\cal S}\left$ into seq, where seq denotes the set of all finite sequences of elements of x. For all infinite sets x such that there exists a permutation of x without fixed points, there are no finite-to-one functions from ${\cal S}\left$ into x. For all sets x, $|{[x]^2}| < \left| {{\cal S}\left} \right|$. (shrink)

For a set x, let S(x) be the set of all permutations of x. We prove by the method of permutation models that the following statements are consistent with ZF: (1) There is an infinite set x such that |p(x)|<|S(x)|<|seq^1-1(x)|<|seq(x)|, where p(x) is the powerset of x, seq(x) is the set of all finite sequences of elements of x, and seq^1-1(x) is the set of all finite sequences of elements of x without repetition. (2) There is a Dedekind infinite set (...) x such that |S(x)|<|[x]^3| and such that there exists a surjection from x onto S(x). (3) There is an infinite set x such that there is a finite-to-one function from S(x) into x. (shrink)

Despite the emphasis placed by most curricula in the development of social and emotional competencies in education, there seems to be a general lack of knowledge of methods that integrate strategies for assessing these competencies into existing educational practices. Previous research has shown that the development of social and emotional competencies in children has multiple benefits, as they seem to contribute to better physical and mental health, an increase in academic motivation, and the well-being and healthy social progress of children. (...) This study aims at assessing the possible changes in children’s self-esteem, socio-emotional competencies, and school-related variables after participating in the Learning to Be project (L2B) project.Methods:This quasi-experimental study included an intervention group (L2B) and a control group. The participants were 221 students in primary education (55.2% girls) between the ages of eight and 11 (M= 9.31; SD = 0.89). The L2B intervention program took place over a period of 5 months. The assessment was carried out twice, before and after the intervention through three main evaluation instruments: the Rosenberg’s Self-Esteem questionnaire, the Socio-Emotional competence questionnaire (SEQ), and self-report scales for measuring school difficulties, school engagement, opinions about school, and school absence. Ten schools from different Spanish provinces participated.Results:The results indicate that those participants in the experimental group show higher self-esteem, better responsible decisions, and higher self-awareness than those in the control group. There were no other statistical differences between groups.Conclusions:The results of this work suggest that the implementation of the L2B program did not improve social and emotional competencies in primary school students. Further research related to how include formative assessment in SEL programs is needed. (shrink)

Long noncoding RNAs have been described in cell lines and various whole tissues, but lncRNA analysis of development in vivo is limited. Here, we comprehensively analyze lncRNA expression for the adult mouse subventricular zone neural stem cell lineage. We utilize complementary genome-wide techniques including RNA-seq, RNA CaptureSeq, and ChIP-seq to associate specific lncRNAs with neural cell types, developmental processes, and human disease states. By integrating data from chromatin state maps, custom microarrays, and FACS purification of the subventricular zone lineage, we (...) stringently identify lncRNAs with potential roles in adult neurogenesis. shRNA-mediated knockdown of two such lncRNAs, Six3os and Dlx1as, indicate roles for lncRNAs in the glial-neuronal lineage specification of multipotent adult stem cells. Our data and workflow thus provide a uniquely coherent in vivo lncRNA analysis and form the foundation of a user-friendly online resource for the study of lncRNAs in development and disease. © 2013 Elsevier Inc. (shrink)

The nomination of candidate genes underlying complex traits is often focused on genetic variations that alter mRNA abundance or result in non‐conservative changes in amino acids. Although inconspicuous in complex trait analysis, genetic variants that affect splicing or RNA editing can also generate proteomic diversity and impact genetic traits. Indeed, it is known that splicing and RNA editing modulate several traits in humans and model organisms. Using high‐throughput RNA sequencing (RNA‐seq) analysis, it is now possible to integrate the genetics of (...) transcript abundance, alternative splicing (AS) and editing with the analysis of complex traits. We recently demonstrated that both AS and mRNA editing are modulated by genetic and environmental factors, and potentially engender phenotypic diversity in a genetically segregating mouse population. Therefore, the analysis of splicing and RNA editing can expand not only the regulatory landscape of transcriptome and proteome complexity, but also the repertoire of candidate genes for complex traits. (shrink)

Embora algumas posições filosóficas de Gödel sejam bem conhecidas, como o platonismo, a sua teoria do conhecimento é, em comparação, menos divulgada. A partir do «Problema da Evidência» de Hilbert-Bernays, I, pg. 20 seq., apresento a seguir os traços essenciais da posição de Gödel sobre a caracterização epistemológica da evidência finitista, com especial relevo para a história dos conceitos utilizados.

Discusssion of passages 243 et. seq. of Wittgenstein's Philosophical lnvestigations tends to concentrate on the argument supporting the thesis that a logically private language is impossible. When the discussion becomes broader, the presumption is generally that this thesis is one premifs of an argument against solipsism. I believe that the passages will support a valid argument that might, at first glance, give comfort to someone in the egocentric predicament, but that this comfort would quickly grow cold on closer examination. I (...) do not mean to suggest that Wittgenstein offers no escape from the predicament, only that the escape will not be a consequence of the pluralism necessary to the existence of language, but rather a byproduct of his discussion of the logic of mental discourse. In this paper, I state an alternative to the contra-solipsist reading of the passages, taking Wittgenstein there to be reflecting a three part dispute, the other participants of which are a skeptic and a philosopher I'll call ‘the Realist'. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:53. AN INDEX OF HUME'S REFERENCES IN A TREATISE OF HUMAN NATURE The index below of Hume's references in the Treatise te the works of other authors excludes those which are accurate and full in his text (of which there are few) and those which are so general, e.g., to Spinoza's atheism, that no passage is specifiable. Hume mentions other writings, for which this index is compiled, in several (...) different ways. Occasionally he mentions the author's name, the title of his book and gives a reference which is less specific than it could be. These have been identified. Often he mentions an author's name only, e.g., de Retz, and in such cases the fullest possible reference has been given. One of Hume's notable intellectual gifts was his ability to distil several pages of a book into one or two sentences of crisp and accurate synthesis. (This skill is most apparent in his summaries of articles in Bayle' s Dictionary in his "Notes on Philosophy", of which the manuscript is in the Royal Society of Edinburgh Library.) In these instances, page references are impossible and the closest indication one can give is a section or chapter. Some of his references are anonymous, e.g., as an 'elegant writer' says, and so are some quotations. These have been identified with one exception. One anonymous reference (number 24 below) requires explanation because it is both anachronistic and interesting. Hume refers to an observation by "a late eminent philosopher". It is anachronistic because the book to which he refers was published after the Treatise; it is interesting because it provides further evidence of Hutcheson's influence on Hume and the latter' s regard for him. The explanation, for Hutcheson was still alive when Vol.11 of the Treatise appeared in 1739, is that 'late' is here being used in the sense of 'recent' - Hutcheson himself uses the word in the same way in referring to Mandeville when the latter was 54. alive. (An enquiry concerning moral good and evil. Section 1, VI.) Further, the System circulated widely among Hutcheson's friends in Scotland and over so many years that it finally appeared posthumously. That Hume could not cite a published work also accounts for the anonymity of the reference to someone he admired. It is often impossible to determine in which language or in which edition Hume read a particular author. Where there is evidence as to which language he used, the title has been given in that language. There are now so many extant editions of the Treatise that Volume, Part, Chapter and Section references are given, as well as the pagination of Selby-Bigge' s edition, so that readers of other editions may be able to use the index. 1.Vol. 1. Title-page. Tacitus, The Histories, Bk. I. 1. 2.Part 1, Sect. 1, p. 2, n. John Locke, An Essay concerning Human Understanding, Bk. I, Chap. I, 8. 3.Sect. VII, p. 17, n. George Berkeley, A Treatise concerning the Principles of Human Knowledge, Introductixi, Sect. 7, e_t seq. 4.Part II, Sect. II, p. 30, n. Nicolas de Malezieu, Elementa Geometrica. 5.Sect. Ill, p. 35, n. John Locke, Essay, Bk. II, Chap. XIV. 6.Sect. IV, p. 43, n. Antoine Arnauld, La logique ou l'art de penser. Part I, Chap. 5. (In some editions Pierre Nicole is named as co-author. The book is also known as the Port Royal Logic). 7.Sect. IV, p. 46, n. Isaac Barrow, Mathematical Lectures. 8.Part III, Sect. Ill, p. 80, n. Thomas Hobbes, Elements of Philosophy, Part Second, Chap. 9. And Tripos : in Three Discourse. Ill, of Liberty and Necessity. 55. Sect. Ill, p. 80, n. e.g., Samuel Clarke, A Demonstration of the Being and Attributes of God, Props. I-III, et. seq. 10.Sect. Ill, p. 81, n. John Locke, Essay, Bk. IV, Chap. X. 11.Sect. VIII, p. 100 and appendix Vol. Ill, p. 630. Cicero, De Finibus Bonorum et Malorum, Bk. V. 1.2. 12.Sect. XIII, p. 153. Jean Francois Paul de Gondi, Cardinal de Retz, Mémoires, Bk. III. The second 'observation' is from Book... (shrink)

Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co‐activators, co‐repressors, multiple TFs, histone‐modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a pioneering (...) role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP‐Seq, digital genomic footprinting, DHS‐Seq, live cell protein dynamics, and biochemical studies of ATP‐dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy‐dependent, non‐equilibrium steady states. (shrink)

. In this paper we address the question of recovering a logic system by combining two or more fragments of it. We show that, in general, by fibring two or more fragments of a given logic the resulting logic is weaker than the original one, because some meta-properties of the connectives are lost after the combination process. In order to overcome this problem, the categories Mcon and Seq of multiple-conclusion consequence relations and sequent calculi, respectively, are introduced. The main feature (...) of these categories is the preservation, by morphisms, of meta-properties of the consequence relations, which allows, in several cases, to recover a logic by fibring of its fragments. The fibring in this categories is called meta−fibring. Several examples of well-known logics which can be recovered by meta-fibring its fragments (in opposition to fibring in the usual categories) are given. Finally, a general semantics for objects in Seq (and, in particular, for objects in Mcon) is proposed, obtaining a category of logic systems called Log. A general theorem of preservation of completeness by fibring in Log is also obtained. (shrink)

Ἠλ. ὑμᾶς δὲ κωκυτοῖς ἐπανθίζειν νόμος, 150παιᾶνα τοῦ θανόντος ἐξαυδωμένας.Χο. ἵετε δάκρυ καναχὲς ὀλόμενονὀλομένωι δεσπόταιπρὸς ῥεῦμα τόδε κεδνῶν κακῶν τ’ἀπότροπον, ἄγος ἀπεύχετον 155κεχυμένων χοᾶν.κλύε δέ μοι σέβας, κλύ’, ὦ δέσποτ’, ἐξἀμαυρᾶς φρενός.ὀτοτοτοτοτοτοῖ⋅ἴτω τις δορυσθενὴς ἀνὴρ 160ἀναλυτὴρ δόμων †Σκυθιτά τ’ ἐν χεροῖνπαλίντον’ ἐν ἔργωι† βέλη ’πιπάλλων Ἄρηςσχέδιά τ’ αὐτόκωπα νωμῶν ξίφη.152–63 lectio dubia 154 ῥεῦμα Weil: ἔρυμα Μ κεδνῶν κακῶν τ᾽ Schütz: κακῶν κεδνῶν τ᾽ Μ; locum interpr. DoddsCQ3, 13–15 155 ἄγος ΜΣ: ἄλγος Μ; ἄγος χοᾶν ad ῥεῦμα adpositum est 157 (...) μου Blaydes σέβας κλύ᾽ Bamberger: κλύε σέβας Μ 160 ἴτω Bothe: ἰὼ Μ 161 seq. Σκυθιτά, supra ιτ scr. ης, Μ; Σκύθης an Σκυθικά incertum; fort. Σκυθικά τ᾽ ἐν χεροῖν | ἐναργῶς βέλη κτλ., del. παλίντονα tamquam e schol. ad Σκυθικά illatum 163 ξίφη Pauw ex ΜΣ: βέλη Μ. (shrink)

This paper is a continuation of dag-like proof compression research initiated in [9]. We investigate proof compression phenomenon in a particular, most transparent case of propositional DNF Logic. We define and analyze a very efficient semi-analytic sequent calculus SEQ*0 for propositional DNF. The efficiency is achieved by adding two special rules CQ and CS; the latter rule is a variant of the weakened substitution rule WS from [9], while the former one being specially designed for DNF sequents. We show that (...) dag-like SEQ*0 has good deterministic proof search strategy. Furthermore, we expose six examples showing that dag-like deducibility in SEQ*0 admits exponential-size proof compression, as compared to familiar proof systems like cutfree sequent calculi, resolution and cutting plane proof systems. (shrink)

System image is an extension of multiplicative linear logic with the rules mix, nullary mix, and a self-dual, noncommutative logical operator, called seq. While the rules mix and nullary mix extend the deductive system, the operator seq extends the language of image. Due to the operator seq, system image extends the applications of image to those where the sequential composition is crucial, e.g., concurrency theory. System image is an extension of image with the rules mix and nullary mix. In this (...) paper, by relying on the fact that system image is a conservative extension of system image, I show that system image is NP-complete by encoding the 3-Partition problem in image. I provide a simple completeness proof of this encoding by resorting to a novel proof theoretical method for reducing nondeterminism in proof search, which is also of independent interest. (shrink)

The analysis of genetic and epigenetic mechanisms of the genotype–phenotypic connection has, so far, only been possible in a handful of genetic model systems. Recent technological advances, including next‐generation sequencing methods such as RNA‐seq, ChIP‐seq and RAD‐seq, and genome‐editing approaches including CRISPR‐Cas, now permit to address these fundamental questions of biology also in organisms that have been studied in their natural habitats. We provide an overview of the benefits and drawbacks of these novel techniques and experimental approaches that can now (...) be applied to ecological and evolutionary vertebrate models such as sticklebacks and cichlid fish. We can anticipate that these new methods will increase the understanding of the genetic and epigenetic factors influencing adaptations and phenotypic variation in ecological settings. These new arrows in the methodological quiver of ecologist will drastically increase the understanding of the genetic basis of adaptive traits – leading to a further closing of the genotype–phenotype gap. -/- . (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Gonzales v. Oregon and the Politics of MedicineRonald A. Lindsay (bio)Throughout 2005, the morbid joke on Capitol Hill was that the twin inevitabilities of "death and taxes" had been replaced by "death politics and taxes." There seemed to be some truth in this observation given the highly publicized intervention by some members of Congress in the Schiavo case and the continuing controversy over government regulation of end-of-life care. The (...) Supreme Court's recent decision in Gonzales v. Oregon (74 U.S.L.W. 4068 (17 January 2006)) has resolved one of the critical issues relating to this controversy by holding that a physician may prescribe controlled substances to provide assistance in dying if such a practice is authorized by state law and not expressly prohibited by federal law. However, other issues remain. In fact, the Court's decision has underscored some of the reasons why there is not only continuing controversy over end-of-life care, but also over other aspects of the practice of medicine. First, it is apparent there is no consensus among health care professionals about the precise boundaries of the legitimate practice of medicine. Second, the regulation of the practice of medicine traverses ill-defined legal territory. In particular, there is significant uncertainty concerning the implications of some regulations as well as the allocation of regulatory authority between and within state and federal governments. This uncertainty leaves substantial room for political maneuvers.Before discussing the politics of medicine, it is worth looking at the regulation of controlled substances in some detail both because this review will provide the necessary background for understanding the ruling in Gonzales v. Oregon and because it will illustrate the uncertainty resulting from multiple sources of regulatory authority.Federal and State Regulation of Controlled SubstancesSince the Pure Food and Drug Act of 1906, the federal government has regulated certain aspects of the distribution and administration of drugs deemed susceptible to abuse. The current primary vehicle for federal regulation is the Comprehensive Drug Abuse Prevention and Control Act, enacted in 1970, of which Title II is known as the Controlled Substances Act (CSA) (21 U.S.C. § 801 et seq.). A [End Page 99] "controlled" substance is just that, a substance that is regulated under the CSA. The CSA classifies controlled substances in five categories or schedules based on their potential for abuse, their accepted medical use, and the risks associated with their use under medical supervision. Schedule I substances have a high potential for abuse and have no currently accepted use in medical treatment. Schedule II-V substances are approved for medical use but are subject to a descending hierarchy of restrictions on their use. To give a lawful prescription for a controlled substance, a physician must be registered with the appropriate federal agency, currently the Drug Enforcement Administration (DEA). Moreover, to be valid, such a prescription must be issued for "a legitimate medical purpose" (21 U.S.C. § 830(b)(3)(A)(ii)).There is little dispute that the primary purposes of the CSA are to control drug abuse and to eliminate illicit trafficking in drugs. In accomplishing these objectives, there is a division of responsibility among various federal agencies, in particular the Department of Health and Human Services and the Department of Justice. Of particular relevance to the controversy in Gonzales v. Oregon is the Attorney General's authority to revoke a physician's registration for prescribing controlled substances if the physician's registration would be inconsistent with the public interest.All 50 states have their own statutes and regulations that address various aspects of the distribution and administration of controlled substances. Most states have adopted versions of the model Uniform Controlled Substances Act, which largely mimics federal law, but several states have placed additional restrictions on a physician's ability to prescribe controlled substances, including time limits on the validity of a prescription and limits on the quantity of a drug that can be prescribed. States are the primary, but by no means the exclusive, source of regulation of medical practice in general. States license physicians, establish boards and agencies to regulate the actions of physicians, and promulgate rules and guidelines to which physicians... (shrink)

A partition is finitary if all its members are finite. For a set A, $\mathscr {B}(A)$ denotes the set of all finitary partitions of A. It is shown consistent with $\mathsf {ZF}$ (without the axiom of choice) that there exist an infinite set A and a surjection from A onto $\mathscr {B}(A)$. On the other hand, we prove in $\mathsf {ZF}$ some theorems concerning $\mathscr {B}(A)$ for infinite sets A, among which are the following: (1) If there is a finitary (...) partition of A without singleton blocks, then there are no surjections from A onto $\mathscr {B}(A)$ and no finite-to-one functions from $\mathscr {B}(A)$ to A. (2) For all $n\in \omega $, $|A^n|<|\mathscr {B}(A)|$. (3) $|\mathscr {B}(A)|\neq |\mathrm {seq}(A)|$, where $\mathrm {seq}(A)$ is the set of all finite sequences of elements of A. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Colin Falck STRUCTURE AND INTUITION I KANT'S ANSWER, in his Critique ofPure Reason, to the Humean problem that there seemed to be no way of explaining the principle of our experiential unity, of what it is that holds us together as experiencing selves or consciousnesses, was to argue that it was language itselfwhich underlay the whole possibility of our self-consciousness and of our consciousness of a world of objects (...) around us. Experience would not be possible without a unified consciousness, and a unified consciousness is only possible for us because of the use which we make of certain concepts of"the objects of experience." ' Kant argues at some length that there can be no perceptual experience without conceptual language, and in particular without our use of what he calls the a priori "categories" or "pure concepts of understanding " (CPR, B. 102 et seq.). (A similar, but more sophisticated, argument about the necessary dependence of perceptual experience on conceptual language was developed later by Wittgenstein.) Saussure, in his Course in General Linguistics,2 though never it seems in a fully aware or explicit way, founds his entire argument on this Kantian conclusion when he remarks that the notion "that ready-made ideas exist before words" is "open to criticism at several points" (p. 65), and goes on to elaborate a view of linguistic meanings as based in the relationships which hold between linguistic terms or units themselves rather than in any kind of "namingprocess " or "correspondence" between individual words and the things that they name (pp. 65, 111-18). A difficulty which faces, and which (unless certain amendments are made) must ultimately invalidate, the account of experience and language which Kant sets out in the Critique of Pure Reason is that the Kantian experiencing self, even though it is a concept-using and therefore perhaps 184 Colin Falck185 logically plausible subject, is at the same time also a disembodied subject. To that extent it is open to some of the same objections that can be brought against Descartes's conception of the thinking subject, or ego, as the foundation of all our experiencing. The problem which Kant did not recognize is that there could be no way for us to know about the existence of other experiencing agents, or therefore to have any awareness of the distinction between ourselves and other selves, if we could not in fact see the putative other person as an experiencing and thinking consciousness. To see another person in this way it must be possible to see him as, and it must be essential to his identity that he should really be, an embodied consciousness, rather than merely a Cartesian disembodied ego or (since the same arguments must apply) a Kantian disembodied concept-using self. (Without being embodied or located, there is no way for the Kantian self to be a perceiving agent with an identity which endures through time: the mere "unity of self-consciousness" which Kant offers us does not in fact give us any solution to Hume's problem at all.) The body, we might say, is that realm in which, or through which, we have our contact with, and therefore our awareness of, other consciousnesses — and at the same time, by contrast, our awareness of our own selfhood or consciousness as well.3 We cannot see another person only as "external" behavior, but must necessarily see his behavior as already inhabited by mind or spirit. Were this not so, there would be no way, to use the Kantian or "transcendental" turn of argument, for us to have the kind of experience which we indisputably do have. Ultimately therefore, if we reflect on the deficiencies of the Kantian position in the "disembodied" form in which Kant himself sets it out, we shall be obliged to recognize that the only kind of concept which will make the required connections between the "inside" and the "outside" of human behavior — a logical gap which seems all too easily to open up beneath us in this area — will be some kind of concept oí sympathy, or of preconscious imitative identification, which, by bridging the divide between "internally experienced" consciousness and "externally observable" movement, makes it... (shrink)

Three recent genome‐wide studies in mice and humans have produced the most definitive map to date of genomic imprinting (gene expression that depends on parental origin) by incorporating multiple tissue types and developmental stages. Here, we explore the results of these studies in light of the kinship theory of genomic imprinting, which predicts that imprinting evolves due to differential genetic relatedness between maternal and paternal relatives. The studies produce a list of imprinted genes with around 120–180 in mice and ∼100 (...) in humans. The studies agree on broad patterns across mice and humans including the complex patterns of imprinted expression at loci like Igf2 and Grb10. We discuss how the kinship theory provides a powerful framework for hypotheses that can explain these patterns. Finally, since imprinting is rare in the genome despite predictions from the kinship theory that it might be common, we discuss evolutionary factors that could favor biallelic expression. (shrink)

The ontogeny of the vertebrate retina has been a topic of interest to developmental biologists and human geneticists for many decades. Understanding the unfolding of the genetic program that transforms a field of progenitors cells into a functionally complex and multi‐layered sensory organ is a formidable challenge. Although classical genetic studies succeeded in identifying the key regulators of retina specification, understanding the architecture of their gene network and predicting their behavior are still a distant hope. The emergence of next‐generation sequencing (...) platforms revolutionized the field unlocking the access to genome‐wide datasets. Emerging techniques such as RNA‐seq, ChIP‐seq, ATAC‐seq, or single cell RNA‐seq are used to characterize eye developmental programs. These studies provide valuable information on the transcriptional and cis‐regulatory profiles of precursors and differentiated cells, outlining the trajectories that connect each intermediate state. Here, recent systems biology efforts are reviewed to understand the genetic programs shaping the vertebrate retina. (shrink)

Matrices that cannot be handled using conventional clustering, regression or classification methods are often found in every big data research area. In particular, datasets with thousands or millions of rows and less than a hundred columns regularly appear in biological so-called omic problems. The effectiveness of conventional data analysis approaches is hampered by this matrix structure, which necessitates some means of reduction. An evolutionary method called PreCLAS is presented in this article. Its main objective is to find a submatrix with (...) fewer rows that exhibits some group structure. Three stages of experiments were performed. First, a benchmark dataset was used to assess the correct functionality of the method for clustering purposes. Then, a microarray gene expression data matrix was used to analyze the method’s performance in a simple classification scenario, where differential expression was carried out. Finally, several classification methods were compared in terms of classification accuracy using an RNA-seq gene expression dataset. Experiments showed that the new evolutionary technique significantly reduces the number of rows in the matrix and intelligently performs unsupervised row selection, improving classification and clustering methods. (shrink)

The U.S. Supreme Court held, in American Manufacturers Mutual Insurance Co. v. Sullivan, 119 S. Ct. 988, that state workers’ compensation system insurers cannot be sued for withholding health care benefits for work-related injuries while they decide whether the treatment is “reasonable” and “necessary.” The respondents, ten employees and two organizations representing employees who received medical benefits under the Workers’ Compensation Act, brought a 42 U.S.C. § 1983 action against state officials, the Pennsylvania State Workers’ Insurance Fund, private insurers, and (...) the school district, alleging that their due process rights were violated by provisions of the Pennsylvania Workers’ Compensation Act, 77 Pa. Cons. Stat. Ann. § 1 et seq.. The Act permits suspension of benefits without notice or opportunity to be heard pursuant to a “utilization review” process.To control costs, Pennsylvania amended its workers’ compensation system in 1993. Under the Act, an employer or its insurer must pay for all reasonable and necessary medical treatment. (shrink)

Richard Swinburne, in his The Existence of God (2004), presents a cosmological argument in defence of theism (Swinburne 1991: 119, 135). God, Swinburne argues, is more likely to bring about an ordered universe than other states (ibid.: 144, 299). To defend this view, Swinburne presents the following arguments: (1) That this ordered universe is a priori improbable (2004: 49, 150, 1991: 304 et seq.), given the stringent requirements for life (cf. also Leslie 2000: 12), and the Second Law of Thermodynamics (...) (Giancoli 1990: 396); (2) That it seems as if this ordered universe can be explained by theism; (3) A theistic explanation for the universe is more probable because it is a simple explanation. To this end, Swinburne makes use of Bayes’ Theorem. Symbolically, this claim can be represented as (e) for the evidence of the existence of a complex universe, and (h) for a hypothesis. Swinburne’s argument is that theism has a higher prior probability, P(htheism) > P(hmaterialism), since theism is simpler than materialism. He concludes that P(e|htheism) > P(e|hmaterialism). In this paper I will address only this argument (3) above, and defend the view that it is false: theism is not simpler than materialism, nor it is more probably true. I conclude that theism is less probable than materialism, expressed by P(htheism) < P(hmaterialism) : 2/N(2n+1) < 1/n, where N is the number of possible universes and n the number of entities in existence. (shrink)

Genome‐wide identification of transcription factor binding sites with the ChIP‐seq method is an extremely important scientific endeavor − one that should ideally be performed for every transcription factor in as many cell types as possible. A major hurdle on the way to this goal is the necessity for a specific, ChIP‐grade antibody for each transcription factor of interest, which is often not available. Here, we describe CETCh‐seq, a recently published method utilizing genome engineering with the CRISPR/Cas9 system to circumvent the (...) need for a specific antibody. Using the CETCh‐seq method, targeted genomic editing results in an epitope‐tagged transcription factor, which is recognized by a well‐characterized, standard antibody, efficacious for ChIP‐seq. We have used CETCh‐seq in human cancer cell lines as well as mouse embryonic stem cells. We find that roughly 60% of transcription factors tagged using CETCh‐seq produce a high quality ChIP‐seq map, a significant improvement over traditional antibody‐based methods. (shrink)

Para elaborar sua profetologia, Maimônides retoma conceitos relativos às teorias do intelecto de Al-Fārābī e de Avicena, que, por sua vez, se baseiam nas noções sobre a alma de Aristóteles. Dessa perspectiva, a Revelação divina deve ser considerada um fato natural inserido na totalidade da natureza criada por Deus. Compreender a Revelação significa, portanto, compreendê-la a partir do homem, uma vez que o profeta, apesar de se tratar de alguém que se destaca do conjunto da humanidade, é sempre um ser (...) humano, possuidor de uma natureza humana. Desse modo, a doutrina da profecia – central no "Guia dos Perplexos" ‒ é elaborada a partir da natureza humana à luz da filosofia racional greco-árabe. Os falāsifa – filósofos muçulmanos helenizantes – já ensinavam que a profecia é possível graças a certa perfeição da natureza humana . Esse ensinamento está fundamentado na teoria do intelecto apresentada por Aristóteles em "De Anima" III, 5, 430a 10 et seq. Contudo, para os filósofos de expressão árabe , a profecia é resultante de certas condições físicas e psíquicas determinadas pelo fluxo necessário das emanações, cuja teoria deriva da "Teologia Pseudo-Aristotélica", um tratado neoplatônico atribuído ao Estagirita que, durante a Idade Média, circulou amplamente nos ambientes filosóficos tanto dos judeus quanto dos muçulmanos. Na cosmovisão neoplatônica adotada por eles, o intelecto do profeta reflete a luz e o conhecimento divino derramado pelo fluxo emanatório do Ser primeiro no mundo celeste, composto pelas dez inteligências separadas, suas almas e esferas. No processo emanatório, a faculdade da imaginação do profeta recebe da última inteligência, o Intelecto Agente, as verdades dos preceitos positivos e culturais da religião, que a imaginação transforma em alegorias e símbolos a serem transmitidos para a humanidade. Maimônides faz da imaginação a pedra de toque de sua profetologia. To elaborate his prophetology, Maimonides uses concepts relating to Al-Fārābī and Avicenna's theories of the intellect which, in turn, are based on Aristotle's notions of the soul. Within this perspective, divine Revelation should be considered a natural fact within the totality of nature created by God. Understanding Revelation therefore means understanding it from a human standpoint, since the prophet ‒ despite being a figure who is set apart from the rest of humanity – is always a human being, with a human nature. Thus, the doctrine of prophecy ‒ central to "The Guide of the Perplexed" ‒ is elaborated based on human nature in light of the rational Greco-Arabic philosophy. The falāsifa – the Hellenizing Muslim philosophers – taught that prophecy is possible thanks to certain perfection of the human nature . This teaching is based on the theory of the intellect, as presented by Aristotle in "De Anima" III, 5, 430a 10 et seq. Therefore, for the philosophers of Arabic expression , prophecy is the result of certain physical and psychic conditions determined by the necessary flow of emanations, whose theory is derived from the "Pseudo-Aristotelian Theology", a Neoplatonic treatise attributed to the Stagyrite which, in the Middle Age, widely circulated in the philosophical milieu, among both Jewish and Muslim. In the Neoplatonic cosmic vision which they adopted, the prophet's intellect reflects the divine light and knowledge overflowing from the emanatory flow from the first Being in the celestial world, which is composed of the ten separate intelligences, their souls and their spheres. In the emanatory process, the prophet's faculty of imagination receives from the ultimate intelligence, the Active Intellect, the truths of the positive and cultural precepts of religion, which the imagination transforms into allegories and symbols to be transmitted to humanity. Maimonides makes the imagination the cornerstone of his prophetology. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Epistemologies and the Limitations of Philosophical Enquiry: Doctrine in Madhva VedantaChristopher BartleyEpistemologies and the Limitations of Philosophical Enquiry: Doctrine in Madhva Vedanta. By Deepak Sarma. London and New York: RoutledgeCurzon, 2005. Pp. xiii + 101.Epistemologies and the Limitations of Philosophical Enquiry: Doctrine in Madhva Vedanta, by Deepak Sarma, purports to discuss the possibility of philosophical evaluation of a tradition of thought and practice, in this case the Dvaita (...) school of Vedānta to which the author belongs, that upholds a "strict insider epistemology." (Although the work bears the subtitle "Doctrine in Madhva Vedanta," for information about beliefs and epistemology the reader would be better advised to consult Deepak Sarma's An Introduction to Madhva Vedanta [Ashgate, 2003].)The present reviewer is not privy to the "insider-outsider debate" apparently current in some centers of Religious Studies, and I state at the outset that I cannot see what all the fuss is about. If one is not a member of a private club, one probably doesn't care about what goes on within its walls. If a tradition is closed to nonmembers, successfully concealing its beliefs and practices (in the manner of some versions of Freemasonry), that's the end of the matter. If texts are really not accessible (p. 6), the activities that the philosopher can pursue are not just "severely restricted"! If what a tradition involves is public (even allowing for esoteric elements revealed only to initiates and for rituals of restricted participation), there are still "outsiders," but they are not debarred from appreciation, discussion, and critical philosophical [End Page 126] analysis of its truth claims. Albeit a middle-aged male member of the Church of England, I can understand (in the conventional sense of the term, which is the only one it has) the Dvaitin adoption of the unusual reading "atat tvam asi" (Chandogya Upanishad 6.8.7 et seq.).What is meant by "insider epistemology"? Sarma says:[T]here are two kinds of communities that uphold insider epistemologies. One is centred around experiential data and claims that outsiders can neither know nor understand what it is like to be an insider. The other simply does not permit outsiders to access root texts. Though actual communities are likely to lie somewhere between these two, or combine elements from each, this bivalent taxonomy is useful as a heuristic device [sic]. (p. 9)The Madhvas, insofar as they deny noninitiates access to some of their basic texts, belong to the second group. (Members of the first are what can politely be called eccentric.) Madhvāchārya, the founder, prohibited outsiders from reading certain texts and from learning from teachers. These restrictions on eligibility, it is claimed, "insulated his position from criticism and evaluation."Even if outsiders' views of core Madhva school doctrines are deemed irrelevant by insiders, Sarma's assertion that Madhvāchārya's views are immune to rational consideration by people who do not belong to the same tradition will astonish anyone familiar with medieval Vedāntic debates. The second chapter describes the historical context in which Madhvāchārya's "insider epistemology" was established. The problem here for the author's insistence on some particularly exigent sort of Dvaitin exclusivity is that there is nothing strikingly un-Vedāntic about that tradition's claims where eligibility for hearing and understanding Scripture (shruti) is concerned. As the author makes clear, Vedāntic theological enquiry, the systematic elucidation of the Upanishads and Brahma-sūtras in the context of dialectic between rival schools, was the preserve of males born into the higher three castes who could understand Sanskrit. This constraint is sometimes intensified by sectarianism, where cultic initiation is additional to caste-based qualification. In the latter respect, the Madhvas are comparable to Shrī Vaishnavas and sundry Shaiva cults. But none of this impeded a plethora of rational disputation! Had the Madhva school prohibited outsiders from "accessing its texts altogether," argument could never have gotten off the ground. But it certainly did. Moreover, the restrictions on eligibility or qualification (adhikara) to study Scripture amount to the claim that there are moral and intellectual preconditions for a proper understanding of some subject matter. At its most... (shrink)

Protein turnover (PT) has been formally defined only in equilibrium conditions, which is ill‐suited to quantify PT during dynamic processes that occur during embryogenesis or (extra) cellular signaling. In this Hypothesis, we propose a definition of PT in an out‐of‐equilibrium regime that allows the quantification of PT in virtually any biological context. We propose a simple mathematical and conceptual framework applicable to a broad range of available data, such as RNA sequencing coupled with pulsed‐SILAC datasets. We apply our framework to (...) a published dataset and show that stimulation of mouse dendritic cells with LPS leads to a proteome‐wide change in PT. This is the first quantification of PT out‐of‐equilibrium, paving the way for the analysis of biological systems in other contexts. (shrink)