Wnt-beta-catenin signaling initiates taste papilla development

Fungiform taste papillae form a regular array on the dorsal tongue. Taste buds arise from papilla epithelium and, unusually for epithelial derivatives, synapse with neurons, release neurotransmitters and generate receptor and action potentials. Despite the importance of taste as one of our five senses, genetic analyses of taste papilla and bud development are lacking. We demonstrate that Wnt-beta-catenin signaling is activated in developing fungiform placodes and taste bud cells. A dominant stabilizing mutation of epithelial beta-catenin causes massive overproduction of enlarged fungiform papillae and taste buds. Likewise, genetic deletion of epithelial beta-catenin or inhibition of Wnt-beta-catenin signaling by ectopic dickkopf1 (Dkk1) blocks initiation of fungiform papilla morphogenesis. Ectopic papillae are innervated in the stabilizing beta-catenin mutant, whereas ectopic Dkk1 causes absence of lingual epithelial innervation. Thus, Wnt-beta-catenin signaling is critical for fungiform papilla and taste bud development. Altered regulation of this pathway may underlie evolutionary changes in taste papilla patterning.     

Three challenges to the complementarity of the logic and the pragmatics of science

The bipartite metatheory thesis attributes to Rudolf Carnap, Philipp Frank and Otto Neurath a conception of the nature of post-metaphysical philosophy of science that sees the purely formal-logical analyses of the logic of science as complemented by empirical inquiries into the psychology, sociology and history of science. Three challenges to this thesis are considered in this paper: that Carnap did not share this conception of the nature of philosophy of science even on a programmatic level, that Carnap's detailed analysis of the language of science is incompatible with one developed by Neurath for the pursuit of empirical studies of science, and, finally, that Neurath himself was confused about the programme of which the bipartite metatheory thesis makes him a representative. I argue that all three challenges can be met and refuted.     

Quantum Theory and the Nature of Consciousness

Our interest focusses on the idea, that consciousness is a powerful acting entity. Up to now there does not exist a scientific concept for this idea. This is not due to problems within the field of psychology or brain research, but rather in resisting theories of modern physics. That is, why we have to search for a solution in the field of physics. A solution can be found in a new understanding of the basics of physical theory. That could be given by abstract and absolute quantum bits of information (AQI bits). To avoid the popular misunderstanding of “information” as “meaningful” it was necessary to find a new word for the free-of-meaning AQI bits: the AQI bits establish a quantum pre-structure termed “Protyposis” (Greek: “pre-formation”), out of which real objects can be formed, starting from energetical and material elementary particles. The Protyposis AQI bits provide a pre-structure for all entities in natural sciences. They are the basic entities, whereof the physical nature of the brain, on the one hand, and the mental nature of consciousness, on the other hand, were formed during the cosmological and the following biological evolution. A deeper understanding of quantum structures may help to overcome the resistance against quantum theory in the field of brain research and consciousness. The key for an understanding is the concept of Protyposis, which means an abstract quantum information free of any definite meaning. With the AQI bits of the Protyposis, both, massless and massive quantum particles can be constructed. Even quantum information with special meanings, in example grammatically formulated thoughts, eventually could be explained. As long as the fundamental basis of quantum theory is misunderstood as being formed by a manifold of some small objects like atoms, quarks, or strings, the problem of understanding consciousness has no solution. If instead we understand quantum theory as based on truly simple quantum structures, there would be no longer fundamental problems for an understanding of consciousness.     

Parvalbumin alters mitochondrial dynamics and affects cell morphology

The Ca²⁺-binding protein parvalbumin (PV) and mitochondria play important roles in Ca²⁺ signaling, buffering and sequestration. Antagonistic regulation of PV and mitochondrial volume is observed in in vitro and in vivo model systems. Changes in mitochondrial morphology, mitochondrial volume and dynamics (fusion, fission, mitophagy) resulting from modulation of PV were investigated in MDCK epithelial cells with stable overexpression/downregulation of PV. Increased PV levels resulted in smaller, roundish cells and shorter mitochondria, the latter phenomenon related to reduced fusion rates and decreased expression of genes involved in mitochondrial fusion. PV-overexpressing cells displayed increased mitophagy, a likely cause for the decreased mitochondrial volumes and the smaller overall cell size. Cells showed lower mobility in vitro, paralleled by reduced protrusions. Constitutive PV down-regulation in PV-overexpressing cells reverted mitochondrial morphology and fractional volume to the state present in control MDCK cells, resulting from increased mitochondrial movement and augmented fusion rates. PV-modulated, bi-directional and reversible mitochondrial dynamics are key to regulation of mitochondrial volume.     

Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and xenografts via blockade of the cell cycle at G2/M

The protein kinase D (PKD) family of proteins are important regulators of tumor growth, development, and progression. CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer are not understood. In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro. We also demonstrate that CRT0066101 blocked tumor growth in a mouse flank xenograft model of bladder cancer. To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants. Furthermore, our cell cycle analysis by flow cytometry revealed that CRT0066101 treatment or PKD2 silencing arrested bladder cancer cells at the G2/M phase, the arrest being accompanied by decreases in the levels of cyclin B1, CDK1 and phospho-CDK1 (Thr161) and increases in the levels of p27^Kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating/inactivating Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which reduce the CDK1-cyclin B1 complex activity. These novel findings suggest that CRT0066101 suppresses bladder cancer growth by inhibiting PKD2 through induction of G2/M cell cycle arrest, leading to the blockade of cell cycle progression.     

Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency

An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.