Text-Independent, Open-Set Speaker Recognition

Speaker recognition, like other biometric personal identification techniques, depends upon a person\u27s intrinsic characteristics. A realistically viable system must be capable of dealing with the open-set task. This effort attacks the open-set task, identifying the best features to use, and proposes the use of a fuzzy classifier followed by hypothesis testing as a model for text-independent, open-set speaker recognition. Using the TIMIT corpus and Rome Laboratory\u27s GREENFLAG tactical communications corpus, this thesis demonstrates that the proposed system succeeded in open-set speaker recognition. Considering the fact that extremely short utterances were used to train the system (compared to other closed-set speaker identification work), this system attained reasonable open-set classification error rates as low as 23% for TIMIT and 26% for GREENFLAG. Feature analysis identified the filtered linear prediction cepstral coefficients with or without the normalized log energy or pitch appended as a robust feature set (based on the 17 feature sets considered), well suited for clean speech and speech degraded by tactical communications channels

Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation.

The K+ channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:β-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/β-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by β-catenin:T-cell factor (TCF)-4. In welldifferentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with β-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of β-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped β-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of β-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/β-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis

The Astounding Assumption of Infinite Life

The multimillennial philosophical discussion about life after death has received a recent boost in the prospect of immortality attained via technologies. In this newer version, humans generally are considered mortal but may develop means of making themselves immortal. If “immortal” means not mortal, thus existing for infinity, and if the proposed infinite-existing entity is material, it must inhabit an infinite material universe. If the proposed entity is not material, there must be means by which it can shed its material substance and exist nonmaterially. The article examines arguments for how an infinite life would be possible given current physical understanding. The paper considers a Pascalian-style wager weighing the likelihood of adjusting to existence wholly within a finite universe versus betting on there being some way to construe the universe(s) as a viable medium for infinite beings. Conclusion: the case for a finite being to exist infinitely has little viable support

Pharmacological characterization of low molecular weight biased agonists at the follicle stimulating hormone receptor

International audienceFollicle-stimulating hormone receptor (FSHR) plays a key role in reproduction through the activation of multiple signaling pathways. Low molecular weight (LMW) ligands composed of biased agonist properties are highly valuable tools to decipher complex signaling mechanisms as they allow selective activation of discrete signaling cascades. However, available LMW FSHR ligands have not been fully characterized yet. In this context, we explored the pharmacological diversity of three benzamide and two thiazolidinone derivatives compared to FSH. Concentration/activity curves were generated for Gαs, Gαq, Gαi, β-arrestin 2 recruitment, and cAMP production, using BRET assays in living cells. ERK phosphorylation was analyzed by Western blotting, and CRE-dependent transcription was assessed using a luciferase reporter assay. All assays were done in either wild-type, Gαs or β-arrestin 1/2 CRISPR knockout HEK293 cells. Bias factors were calculated for each pair of read-outs by using the operational model. Our results show that each ligand presented a discrete pharmacological efficacy compared to FSH, ranging from super-agonist for β-arrestin 2 recruitment to pure Gαs bias. Interestingly, LMW ligands generated kinetic profiles distinct from FSH (i.e., faster, slower or transient, depending on the ligand) and correlated with CRE-dependent transcription. In addition, clear system biases were observed in cells depleted of either Gαs or β-arrestin genes. Such LMW properties are useful pharmacological tools to better dissect the multiple signaling pathways activated by FSHR and assess their relative contributions at the cellular and physio-pathological level

Doubly diastereoselective conjugate addition of homochiral lithium amides to homochiral alpha,beta-unsaturated esters containing cis- and trans-dioxolane units.

As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a range of homochiral alpha,beta-unsaturated esters containing cis- and trans-dioxolane units was investigated. These reactions resulted in "matching" and "mismatching" effects. In the "matched" cases a single diastereoisomer of the corresponding beta-amino ester (containing three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral alpha,beta-unsaturated ester containing a cis-dioxolane unit, in the "mismatched" case it is the stereocontrol of the substrate which is dominant over that of the lithium amide, whilst upon addition to homochiral alpha,beta-unsaturated esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant. Hydrogenolytic N-deprotection of the beta-amino ester products of conjugate addition gives access to polyoxygenated beta-amino acid derivatives