The Quasi-Verbal Dispute Between Kripke and 'Frege-Russell'

Traditional descriptivism and Kripkean causalism are standardly interpreted as rival theories on a single topic. I argue that there is no such shared topic, i.e. that there is no question that they can be interpreted as giving rival answers to. The only way to make sense of the commitment to epistemic transparency that characterizes traditional descriptivism is to interpret Russell and Frege as proposing rival accounts of how to characterize a subject’s beliefs about what names refer to. My argument relies on a development of the distinction between speaker’s reference and semantic reference

The core clock gene, Bmal1, and its downstream target, the SNARE regulatory protein secretagogin, are necessary for circadian secretion of glucagon-like peptide-1.

OBJECTIVES:The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L-cells upon nutrient intake. While recent evidence has shown that GLP-1 is released in a circadian manner in rats, whether this occurs in mice and if this pattern is regulated by the circadian clock remain to be elucidated. Furthermore, although circadian GLP-1 secretion parallels expression of the core clock gene Bmal1, the link between the two remains largely unknown. Secretagogin (Scgn) is an exocytotic SNARE regulatory protein that demonstrates circadian expression and is essential for insulin secretion from β-cells. The objective of the current study was to establish the necessity of the core clock gene Bmal1 and the SNARE protein SCGN as essential regulators of circadian GLP-1 secretion. METHODS:Oral glucose tolerance tests were conducted at different times of the day on 4-hour fasted C57BL/6J, Bmal1 wild-type, and Bmal1 knockout mice. Mass spectrometry, RNA-seq, qRT-PCR and/or microarray analyses, and immunostaining were conducted on murine (m) and human (h) primary L-cells and mGLUTag and hNCI-H716 L-cell lines. At peak and trough GLP-1 secretory time points, the mGLUTag cells were co-stained for SCGN and a membrane-marker, ChIP was used to analyze BMAL1 binding sites in the Scgn promoter, protein interaction with SCGN was tested by co-immunoprecipitation, and siRNA was used to knockdown Scgn for GLP-1 secretion assay. RESULTS:C57BL/6J mice displayed a circadian rhythm in GLP-1 secretion that peaked at the onset of their feeding period. Rhythmic GLP-1 release was impaired in Bmal1 knockout (KO) mice as compared to wild-type controls at the peak (p < 0.05) but not at the trough secretory time point. Microarray identified SNARE and transport vesicle pathways as highly upregulated in mGLUTag L-cells at the peak time point of GLP-1 secretion (p < 0.001). Mass spectrometry revealed that SCGN was also increased at this time (p < 0.001), while RNA-seq, qRT-PCR, and immunostaining demonstrated Scgn expression in all human and murine primary L-cells and cell lines. The mGLUTag and hNCI-H716 L-cells exhibited circadian rhythms in Scgn expression (p < 0.001). The ChIP analysis demonstrated increased binding of BMAL1 only at the peak of Scgn expression (p < 0.01). Immunocytochemistry showed the translocation of SCGN to the cell membrane after stimulation at the peak time point only (p < 0.05), while CoIP showed that SCGN was pulled down with SNAP25 and β-actin, but only the latter interaction was time-dependent (p < 0.05). Finally, Scgn siRNA-treated cells demonstrated significantly blunted GLP-1 secretion (p < 0.01) in response to stimulation at the peak time point only. CONCLUSIONS:These data demonstrate, for the first time, that mice display a circadian pattern in GLP-1 secretion, which is impaired in Bmal1 knockout mice, and that Bmal1 regulation of Scgn expression plays an essential role in the circadian release of the incretin hormone GLP-1

Thermodynamic characterization of halide−π interactions in solution using “two-wall” aryl extended calix[4]pyrroles as model system

Herein, we report our latest experimental investigations of halide−π interactions in solution. We base this research on the thermodynamic characterization of a series of 1:1 complexes formed between halides (Cl–, Br–, and I–) and several α,α-isomers of “two-wall” calix[4]pyrrole receptors bearing two six-membered aromatic rings in opposed meso positions. The installed aromatic systems feature a broad range of electron density as indicated by the calculated values for their electrostatic surface potentials at the center of the rings. We show that a correlation exists between the electronic nature of the aromatic walls and the thermodynamic stability of the X–⊂receptor complexes. We give evidence for the existence of both repulsive and attractive interactions between π systems and halide anions in solution (between 1 and −1 kcal/mol). We dissect the measured free energies of binding for chloride and bromide with the receptor series into their enthalpic and entropic thermodynamic quantities. In acetonitrile solution, the binding enthalpy values remain almost constant throughout the receptor series, and the differences in free energies are provoked exclusively by changes in the entropic term of the binding processes. Most likely, this unexpected behavior is owed to strong solvation effects that make up important components of the measured magnitudes for the enthalpies and entropies of binding. The use of chloroform, a much less polar solvent, limits the impact of solvation effects revealing the expected existence of a parallel trend between free energies and enthalpies of binding. This result indicates that halide−π interactions in organic solvents are mainly driven by enthalpy. However, the typical paradigm of enthalpy–entropy compensation is still not observed in this less polar solvent

Zebrafish-based identification of apicularen A as an anticonvulsant compound from myxobacteria

Purpose: Given the need for new and improved anti-epileptic drugs, this study focused on the identification of new anticonvulsant compounds from myxobacterial origin, using zebrafish larvae as the primary screening model. Methods: A library of 242 myxobacterial compounds from the Helmholtz Centre for Infection Research was screened for neuroactivity by the zebrafish photomotor response (PMR) assay. Next, neuroactive hits were screened for anticonvulsant activity by the zebrafish pentylenetetrazole (PTZ) seizure assay. Anticonvulsant activity was further investigated by local field potential (LFP) recordings of the zebrafish midbrain to evaluate the effect of a compound on PTZ-induced epileptiform discharges. Finally, anticonvulsant activity was investigated in the mouse timed i.v. PTZ assay to investigate activity in the mouse model. Results: 56 myxobacterial compounds were identified as neuroactive by the PMR assay. 24 selected neuroactive hits were screened for anticonvulsant activity by the zebrafish PTZ assay. 8 compounds were identified as anticonvulsant hits and confirmed for their activity. Among them, apicularen A significantly reduced PTZ-induced seizure behavior with high efficacy in a concentration-dependent manner and significantly reduced PTZ-induced epileptiform discharges. Moreover, apicularen A significantly increased the PTZ dose needed to trigger forelimb clonus in the mouse timed i.v. PTZ assay. Conclusions: Myxobacteria are increasingly recognized as producers of bioactive secondary metabolites and can be considered as a rich source for drug discovery. In this study, we identified for the first time anticonvulsant myxobacterial compounds using a zebrafish-based screening approach. The anticonvulsant activity of apicularen A was verified by LFP recordings of the zebrafish midbrain and confirmed in the mouse timed i.v. PTZ model. Our results not only support the potential of myxobacterial compounds, but expand their utility as an interesting source for anti-epileptic drug discovery.status: publishe

Water-soluble aryl-extended calix[4]pyrroles with unperturbed aromatic cavities: synthesis and binding studies

We report the synthesis of a novel, water-soluble aryl-extended calix[4]pyrrole receptor. The water-solubilising groups are placed at the lower rim of the receptor, leaving the binding pocket unperturbed and open for modification. Binding studies were performed with a series of pyridine N-oxides. These studies revealed the ability of the receptor to bind neutral and charged N-oxides in basified water with stability constants higher than 104 M−

CCDC 1002696: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 1002695: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

The core clock gene, Bmal1, and its downstream target, the SNARE regulatory protein secretagogin, are necessary for circadian secretion of glucagon-like peptide-1.

OBJECTIVES:The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L-cells upon nutrient intake. While recent evidence has shown that GLP-1 is released in a circadian manner in rats, whether this occurs in mice and if this pattern is regulated by the circadian clock remain to be elucidated. Furthermore, although circadian GLP-1 secretion parallels expression of the core clock gene Bmal1, the link between the two remains largely unknown. Secretagogin (Scgn) is an exocytotic SNARE regulatory protein that demonstrates circadian expression and is essential for insulin secretion from β-cells. The objective of the current study was to establish the necessity of the core clock gene Bmal1 and the SNARE protein SCGN as essential regulators of circadian GLP-1 secretion. METHODS:Oral glucose tolerance tests were conducted at different times of the day on 4-hour fasted C57BL/6J, Bmal1 wild-type, and Bmal1 knockout mice. Mass spectrometry, RNA-seq, qRT-PCR and/or microarray analyses, and immunostaining were conducted on murine (m) and human (h) primary L-cells and mGLUTag and hNCI-H716 L-cell lines. At peak and trough GLP-1 secretory time points, the mGLUTag cells were co-stained for SCGN and a membrane-marker, ChIP was used to analyze BMAL1 binding sites in the Scgn promoter, protein interaction with SCGN was tested by co-immunoprecipitation, and siRNA was used to knockdown Scgn for GLP-1 secretion assay. RESULTS:C57BL/6J mice displayed a circadian rhythm in GLP-1 secretion that peaked at the onset of their feeding period. Rhythmic GLP-1 release was impaired in Bmal1 knockout (KO) mice as compared to wild-type controls at the peak (p < 0.05) but not at the trough secretory time point. Microarray identified SNARE and transport vesicle pathways as highly upregulated in mGLUTag L-cells at the peak time point of GLP-1 secretion (p < 0.001). Mass spectrometry revealed that SCGN was also increased at this time (p < 0.001), while RNA-seq, qRT-PCR, and immunostaining demonstrated Scgn expression in all human and murine primary L-cells and cell lines. The mGLUTag and hNCI-H716 L-cells exhibited circadian rhythms in Scgn expression (p < 0.001). The ChIP analysis demonstrated increased binding of BMAL1 only at the peak of Scgn expression (p < 0.01). Immunocytochemistry showed the translocation of SCGN to the cell membrane after stimulation at the peak time point only (p < 0.05), while CoIP showed that SCGN was pulled down with SNAP25 and β-actin, but only the latter interaction was time-dependent (p < 0.05). Finally, Scgn siRNA-treated cells demonstrated significantly blunted GLP-1 secretion (p < 0.01) in response to stimulation at the peak time point only. CONCLUSIONS:These data demonstrate, for the first time, that mice display a circadian pattern in GLP-1 secretion, which is impaired in Bmal1 knockout mice, and that Bmal1 regulation of Scgn expression plays an essential role in the circadian release of the incretin hormone GLP-1

Thermodynamic Characterization of Halide-pi Interactions in Solution using "Two-wall" Aryl extended Calix[4]pyrroles as Model System

[eng] Herein, we report our latest experimental investigations of halide−π interactions in solution. We base this research on the thermodynamic characterization of a series of 1:1 complexes formed between halides (Cl−, Br−, and I−) and several α,α-isomers of "two-wall" calix[4]pyrrole receptors bearing two six-membered aromatic rings in opposed meso positions. The installed aromatic systems feature a broad range of electron density as indicated by the calculated values for their electrostatic surface potentials at the center of the rings. We show that a correlation exists between the electronic nature of the aromatic walls and the thermodynamic stability of the X−⊂receptor complexes. We give evidence for the existence of both repulsive and attractive interactions between π systems and halide anions in solution (between 1 and −1 kcal/ mol). We dissect the measured free energies of binding for chloride and bromide with the receptor series into their enthalpic and entropic thermodynamic quantities. In acetonitrile solution, the binding enthalpy values remain almost constant throughout the receptor series, and the differences in free energies are provoked exclusively by changes in the entropic term of the binding processes. Most likely, this unexpected behavior is owed to strong solvation effects that make up important components of the measured magnitudes for the enthalpies and entropies of binding. The use of chloroform, a much less polar solvent, limits the impact of solvation effects revealing the expected existence of a parallel trend between free energies and enthalpies of binding. This result indicates that halide−π interactions in organic solvents are mainly driven by enthalpy. However, the typical paradigm of enthalpy−entropy compensation is still not observed in this less polar solvent