ALBERT

Description: In logic and epistemology, the concept of autoimmunity refers to the partial incapability of the human agent to distinguish between her knowledge and her ignorance, due to an involuntary mechanism which underlies the fixation and revision of beliefs. The idea originated within the project initiated by Dov Gabbay and John Woods of a Naturalization of Logic , which aims at informing elaborated notions of logic and epistemology with well-established results of cognitive science. The term autoimmunity follows from the consideration that the cognitive states of belief, doubt, knowledge and ignorance affect the epistemic status of the agent who experiences them in ways she cannot anticipate nor control. Thus, we contend that the concept of autoimmunity could be usefully employed beyond the epistemological and logical fieldwork, in order to describe the cognitive mechanism supporting what the philosophical literature calls ‘epistemic feelings’, explaining some problematic occurrences of them related to the incorrect analysis of the agent’s own cognition (tip-of-the-tongue experience, misplaced feeling of knowing, etc).

Description: I will analyse some properties of abduction that are essential from a logical standpoint. When dealing with the so-called ‘inferential problem’, I will opt for the more general concepts of input and output instead of those of premisses and conclusions, and show that in this framework two consequences can be derived that help clarify basic logical aspects of abductive reasoning: (i) it is more natural to accept the ‘multimodal’ and ‘context-dependent’ character of the inferences involved, (ii) inferences are not merely conceived of in the terms of the process leading to the ‘generation of an output’ or to the proof of it, as in the traditional and standard view of deductive proofs, but rather, from this perspective abductive inferences can be seen as related to logical processes in which input and output fail to hold each other in an expected relation, with the solution involving the modification of inputs, not that of outputs. I will also describe that if we wish to naturalize the logic of the abductive processes and its special consequence relation, we should refer to the following main aspects: ‘optimization of situatedness’, ‘maximization of changeability’ of both input and output, and high ‘information-sensitiveness’.

Description: It is well known that the computational complexity of propositional knowledge base revision is at the second level of polynomial hierarchy. A way to solve this kind of problems is to introduce approximate algorithms. In this paper, an approximate approach is introduced for belief change. Operators, which satisfy the AGM rational postulates, are defined to change belief sets or belief bases. Furthermore, approximate algorithms to implement the revision of finite belief bases are presented. The time complexities of the approximate algorithms shown in this paper are at lower level than the time complexities of the existed approaches in literatures, although they may not generate the optimal solution, and this is meaningful from the theoretical point of view.

Description: Chromatin constitutes a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Nucleosomes prevent the binding of estrogen receptor α (ERα) in absence of ligand and thus represent an important level of transcriptional regulation. Here, we show that in breast cancer MCF-7 cells, TLE3, a co-repressor of the Groucho/Grg/TLE family, interacts with FoxA1 and is detected at regulatory elements of ERα target genes in absence of estrogen. As a result, the chromatin is maintained in a basal state of acetylation, thus preventing ligand-independent activation of transcription. In absence of TLE3, the basal expression of ERα target genes induced by E2 is increased. At the TFF1 gene, the recruitment of TLE3 to the chromatin is FoxA1-dependent and prevents ERα and RNA polymerase II recruitment to TFF1 gene regulatory elements. Moreover, the interaction of TLE3 with HDAC2 results in the maintenance of acetylation at a basal level. We also provide evidence that TLE3 is recruited at several other regulatory elements of ERα target genes and is probably an important co-regulator of the E2 signaling pathway. In sum, our results describe a mechanism by which TLE3 affects ligand dependency in ERα-regulated gene expression via its binding restricting function and its role in gene regulation by histone acetylation.

Description: Primary cilia are complex subcellular structures that play key roles during embryogenesis by controlling the cellular response to several signaling pathways. Defects in the function and/or structure of primary cilia underlie a large number of human syndromes collectively referred to as ciliopathies. Often, ciliopathies are associated with mental retardation (MR) and malformation of the corpus callosum. However, the possibility of defects in other forebrain axon tracts, which could contribute to the cognitive disorders of these patients, has not been explored. Here, we investigate the formation of the corticothalamic/thalamocortical tracts in mice mutant for Rfx3 , which regulates the expression of many genes involved in ciliogenesis and cilia function. Using DiI axon tracing and immunohistochemistry experiments, we show that some Rfx3 –/– corticothalamic axons abnormally migrate toward the pial surface of the ventral telencephalon (VT). Some thalamocortical axons (TCAs) also fail to leave the diencephalon or abnormally project toward the amygdala. Moreover, the Rfx3 –/– VT displays heterotopias containing attractive guidance cues and expressing the guidance molecules Slit1 and Netrin1. Finally, the abnormal projection of TCAs toward the amygdala is also present in mice carrying a mutation in the Inpp5e gene, which is mutated in Joubert Syndrome and which controls cilia signaling and stability. The presence of identical thalamocortical malformations in two independent ciliary mutants indicates a novel role for primary cilia in the formation of the corticothalamic/thalamocortical tracts by establishing the correct cellular environment necessary for its development.

Description: The C-type lectin E-selectin mediates the rolling of circulating leukocytes on vascular endothelial cells during the inflammatory process. In numerous studies, the S128R mutation of the E-selectin was associated with cardiovascular and autoimmune diseases. There is evidence that the S128R E-selectin mutation leads to a loss in ligand specificity, thus increasing leukocyte recruitment. Apart from the natural tetrasaccharide ligand sialyl Lewis x (sLe x ), it has previously been proposed that non-fucosylated carbohydrates also bind to S128R E-selectin. To evaluate the therapeutic potential of the antagonism of the E-selectin mutant, ligand specificity was reinvestigated on a molecular basis. We determined the ligand specificity of wild-type and S128R E-selectin in a target-based competitive assay, a glycan array screen and cell-based binding assays under static and flow conditions. Regarding ligand-specificity, the binding properties of S128R E-selectin were identical to those of wt E-selectin, i.e., no mutant-specific binding of 3'-sialyl- N -acetyllactosamine, heparin, fetuin and K562 cells was observed. Additionally, the binding affinities of glycomimetic E-selectin antagonists were identical for wt and S128R E-selectin. Overall, the previous reports on carbohydrate ligand promiscuity of S128R E-selectin could not be confirmed.

Description: Chromatin immunoprecipitation with massively parallel DNA sequencing (ChIP-seq) has greatly improved the reliability with which transcription factor binding sites (TFBSs) can be identified from genome-wide profiling studies. Many computational tools are developed to detect binding events or peaks, however the robust detection of weak binding events remains a challenge for current peak calling tools. We have developed a novel Bayesian approach (ChIP-BIT) to reliably detect TFBSs and their target genes by jointly modeling binding signal intensities and binding locations of TFBSs. Specifically, a Gaussian mixture model is used to capture both binding and background signals in sample data. As a unique feature of ChIP-BIT, background signals are modeled by a local Gaussian distribution that is accurately estimated from the input data. Extensive simulation studies showed a significantly improved performance of ChIP-BIT in target gene prediction, particularly for detecting weak binding signals at gene promoter regions. We applied ChIP-BIT to find target genes from NOTCH3 and PBX1 ChIP-seq data acquired from MCF-7 breast cancer cells. TF knockdown experiments have initially validated about 30% of co-regulated target genes identified by ChIP-BIT as being differentially expressed in MCF-7 cells. Functional analysis on these genes further revealed the existence of crosstalk between Notch and Wnt signaling pathways.

Description: We made CO(1–0) observations of 103 lines of sight in the core and envelope of the high-latitude cloud MBM 40 to determine how the CO-H 2 conversion factor ( X CO ) varies throughout the cloud. Calibrating X CO with CH data at similar resolution (1 arcmin for CO, 1.5 arcmin for CH) yields values of X CO ranging from 0.6 10 20 to 3.3 10 20  cm –2 (K km s –1 ) –1 with an average of 1.3 10 20  cm –2 (K km s –1 ) –1 . Given that the cloud has a peak reddening of 0.24 mag, it should be classed as a diffuse rather than a translucent molecular cloud. The mass obtained from the CO data and our values of X CO is 9.6 M for the core, 12 M for the envelope and 10 M for the periphery of the cloud. A third of the molecular mass of the cloud is found in a region with E ( B  – V ) 〈 0.12 mag. With these mass estimates, we determine that the cloud is not gravitationally bound.

Description: Abduction is a procedure in which something that lacks classical explanatory epistemic virtue can be accepted because it has virtue of another kind: Gabbay and Woods (2005, The Reach of Abduction ) contend (GW-model) that abduction presents an ignorance-preserving or (ignorance-mitigating) character. From this perspective abductive reasoning is a response to an ignorance-problem; through abduction the basic ignorance—that does not have to be considered a total ‘ignorance’—is neither solved nor left intact. Abductive reasoning is an ignorance-preserving accommodation of the problem at hand. Is abduction really ignorance-preserving? To better answer this question I will take advantage of my eco-cognitive model (EC-model) of abduction and of three examples taken from the areas of both philosophy and epistemology. It will be illustrated that through abduction, knowledge can be enhanced, even when abduction is not considered an inference to the best explanation (IBE) in the classical sense of the expression, i.e. an inference necessarily characterized by an empirical evaluation phase, or an inductive phase, as Peirce called it. (1) Peirce provides various justifications of the knowledge enhancing role of abduction, even when abduction is not considered an IBE in the classical sense of the expression, i.e. an inference necessarily characterized by an empirical evaluation phase, or inductive phase. These justifications basically resort to the conceptual exploitation of evolutionary and metaphysical ideas, which clearly show that abduction is constitutively akin to truth, even if certainly always ignorance-preserving or mitigating in the sense that the ‘absolute truth’ is never reached through abduction; (2) in empirical science abducing conventions favours and increases knowledge even if these hypotheses remain evidentially inert—at least in the sense that it is not possible to empirically falsify them. Consequently abduced conventions are evidentially inert but knowledge enhancing at the rational level of science; (3) in science we do not have to confuse the process of abducing models with the process of abducing fictions: the recent epistemological conundrum concerning fictionalism presents to us the epistemic situation in which the models abduced by scientists reveal themselves not to be ‘airy nothings’ at all, and certainly different in their gnoseological status from literary fictions. Scientific models instead play fundamental ‘rational’ knowledge enhancing roles: in a static perspective (e.g. when inserted in a textbook) scientific models can appear fictional to the epistemologist, but their fictional character disappears if a dynamic perspective is adopted. Abduction in scientific model-based reasoning is not a suspicious process of guessing fictions.