Complete suppression of Htt fibrillization and disaggregation of Htt fibrils by a trimeric chaperone complex

Carbohydrate recognition is biologically important but intrinsically challenging, for both nature and host-guest chemists. Saccharides are complex, subtly variable, and camouflaged by hydroxyl groups that hinder discrimination between substrate and water. We have developed a rational strategy for the biomimetic recognition of carbohydrates with all-equatorial stereochemistry (β-glucose, analogs, and homologs) and have now applied it to disaccharides such as cellobiose. Our synthetic receptor showed good affinities, not unlike those of some lectins (carbohydrate-binding proteins). Binding was demonstrated by nuclear magnetic resonance, induced circular dichroism, fluorescence spectroscopy, and calorimetry, all methods giving self-consistent results. Selectivity for the target substrates was exceptional; minor changes to disaccharide structure (for instance, cellobiose to lactose) caused almost complete suppression of complex formation.

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VTC4 Polyphosphate Polymerase Knockout Increases Stress Resistance of Saccharomyces cerevisiae Cells

Biology ◽

10.3390/biology10060487 ◽

2021 ◽

Vol 10 (6) ◽

pp. 487

Author(s):

Alexander Tomashevsky ◽

Ekaterina Kulakovskaya ◽

Ludmila Trilisenko ◽

Ivan V. Kulakovskiy ◽

Tatiana Kulakovskaya ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Heavy Metal ◽

Stress Response ◽

Stress Resistance ◽

Alkaline Stress ◽

Inorganic Polyphosphate ◽

Divalent Metal Transporter ◽

Metal Transporter ◽

Elevated Expression ◽

Chaperone Complex

Inorganic polyphosphate (polyP) is an important factor of alkaline, heavy metal, and oxidative stress resistance in microbial cells. In yeast, polyP is synthesized by Vtc4, a subunit of the vacuole transporter chaperone complex. Here, we report reduced but reliably detectable amounts of acid-soluble and acid-insoluble polyPs in the Δvtc4 strain of Saccharomyces cerevisiae, reaching 10% and 20% of the respective levels of the wild-type strain. The Δvtc4 strain has decreased resistance to alkaline stress but, unexpectedly, increased resistance to oxidation and heavy metal excess. We suggest that increased resistance is achieved through elevated expression of DDR2, which is implicated in stress response, and reduced expression of PHO84 encoding a phosphate and divalent metal transporter. The decreased Mg2+-dependent phosphate accumulation in Δvtc4 cells is consistent with reduced expression of PHO84. We discuss a possible role that polyP level plays in cellular signaling of stress response mobilization in yeast.

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Ectopic expression of the Stabilin2 gene triggered by an intracisternal A particle (IAP) element in DBA/2J strain of mice

Mammalian Genome ◽

10.1007/s00335-019-09824-1 ◽

2020 ◽

Vol 31 (1-2) ◽

pp. 2-16 ◽

Cited By ~ 4

Author(s):

Nobuyo Maeda-Smithies ◽

Sylvia Hiller ◽

Sharlene Dong ◽

Hyung-Suk Kim ◽

Brian J. Bennett ◽

...

Keyword(s):

Promoter Region ◽

Transmembrane Protein ◽

Scavenger Receptor ◽

Ectopic Expression ◽

Complete Suppression ◽

Liver Sinusoidal Endothelial Cells ◽

Normal Expression ◽

Number Of Genes ◽

Genes Encoding ◽

Intracisternal A Particle

AbstractStabilin2 (Stab2) encodes a large transmembrane protein which is predominantly expressed in the liver sinusoidal endothelial cells (LSECs) and functions as a scavenger receptor for various macromolecules including hyaluronans (HA). In DBA/2J mice, plasma HA concentration is ten times higher than in 129S6 or C57BL/6J mice, and this phenotype is genetically linked to the Stab2 locus. Stab2 mRNA in the LSECs was significantly lower in DBA/2J than in 129S6, leading to reduced STAB2 proteins in the DBA/2J LSECs. We found a retrovirus-derived transposable element, intracisternal A particle (IAP), in the promoter region of Stab2DBA which likely interferes with normal expression in the LSECs. In contrast, in other tissues of DBA/2J mice, the IAP drives high ectopic Stab2DBA transcription starting within the 5′ long terminal repeat of IAP in a reverse orientation and continuing through the downstream Stab2DBA. Ectopic transcription requires the Stab2-IAP element but is dominantly suppressed by the presence of loci on 59.7–73.0 Mb of chromosome (Chr) 13 from C57BL/6J, while the same region in 129S6 requires additional loci for complete suppression. Chr13:59.9–73 Mb contains a large number of genes encoding Krüppel-associated box-domain zinc-finger proteins that target transposable elements-derived sequences and repress their expression. Despite the high amount of ectopic Stab2DBA transcript in tissues other than liver, STAB2 protein was undetectable and unlikely to contribute to the plasma HA levels of DBA/2J mice. Nevertheless, the IAP insertion and its effects on the transcription of the downstream Stab2DBA exemplify that stochastic evolutional events could significantly influence susceptibility to complex but common diseases.

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Complete Suppression of Recurrent Herpes Labialis with Lithium Carbonate

Pharmacopsychiatry ◽

10.1055/s-2007-979224 ◽

1999 ◽

Vol 32 (04) ◽

pp. 158-158 ◽

Cited By ~ 6

Author(s):

T. Bschor

Keyword(s):

Lithium Carbonate ◽

Complete Suppression ◽

Herpes Labialis ◽

Recurrent Herpes

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The Hsp90 Chaperone Complex Regulates GDI-dependent Rab Recycling

Molecular Biology of the Cell ◽

10.1091/mbc.e05-12-1096 ◽

2006 ◽

Vol 17 (8) ◽

pp. 3494-3507 ◽

Cited By ~ 33

Author(s):

Christine Y. Chen ◽

William E. Balch

Keyword(s):

Rab Gtpase ◽

Rab Gtpases ◽

Coding System ◽

Golgi Transport ◽

Guanine Nucleotide Dissociation Inhibitor ◽

Hsp90 Activity ◽

Hsp90 Chaperone ◽

Chaperone Complex ◽

Hsp 90 ◽

Synaptic Vesicle Fusion

Rab GTPase regulated hubs provide a framework for an integrated coding system, the membrome network, that controls the dynamics of the specialized exocytic and endocytic membrane architectures found in eukaryotic cells. Herein, we report that Rab recycling in the early exocytic pathways involves the heat-shock protein (Hsp)90 chaperone system. We find that Hsp90 forms a complex with guanine nucleotide dissociation inhibitor (GDI) to direct recycling of the client substrate Rab1 required for endoplasmic reticulum (ER)-to-Golgi transport. ER-to-Golgi traffic is inhibited by the Hsp90-specific inhibitors geldanamycin (GA), 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), and radicicol. Hsp90 activity is required to form a functional GDI complex to retrieve Rab1 from the membrane. Moreover, we find that Hsp90 is essential for Rab1-dependent Golgi assembly. The observation that the highly divergent Rab GTPases Rab1 involved in ER-to-Golgi transport and Rab3A involved in synaptic vesicle fusion require Hsp90 for retrieval from membranes lead us to now propose that the Hsp90 chaperone system may function as a general regulator for Rab GTPase recycling in exocytic and endocytic trafficking pathways involved in cell signaling and proliferation.

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The Dependence of the Oxygen-Concentrating Mechanism of the Teleost Eye (Salmo gairdneri) on the Enzyme Carbonic Anhydrase

The Journal of General Physiology ◽

10.1085/jgp.54.2.203 ◽

1969 ◽

Vol 54 (2) ◽

pp. 203-211 ◽

Cited By ~ 51

Author(s):

Michael B. Fairbanks ◽

J. Russell Hoffert ◽

Paul O. Fromm

Keyword(s):

Carbonic Anhydrase ◽

Environmental Water ◽

Salmo Gairdneri ◽

Complete Suppression ◽

Oxygen Inhibition ◽

Rete Mirabile ◽

Arterial Blood ◽

Concentrating Mechanism ◽

The One ◽

Erythrocyte Carbonic Anhydrase

Microoxygen polarographic electrodes were constructed and used to measure oxygen tension (POO2) in the eyes of rainbow trout (Salmo gairdneri). The values obtained are compared with arterial blood and environmental water POO2 and indicate that there is an oxygen-concentrating mechanism in the eye supplying oxygen to the avascular retina. Anatomically similar retes suggest that the mechanism is similar to the one which exists in the swim bladder. Elimination of the arterial blood supply to the choroidal gland rete mirabile of the eye (through pseudobranchectomy) and the consequent lowering of ocular oxygen tensions implicate the choroidal gland as one of the major components of the oxygen-concentrating mechanism. After pseudobranchectomy the presence of ocular POO2 above that of arterial blood is indicative of a secondary structure in the eye capable of concentrating oxygen. Inhibition of carbonic anhydrase, using acetazolamide, is shown to result in complete suppression of the oxygen-concentrating mechanism. A hypothesis is advanced for the participation of retinal-choroidal and erythrocyte carbonic anhydrase in the oxygen-concentrating mechanism.

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The regulation of phosphate-activated glutaminase activity and glutamine metabolism in the streptozotocin-diabetic rat

Biochemical Journal ◽

10.1042/bj2240207 ◽

1984 ◽

Vol 224 (1) ◽

pp. 207-214 ◽

Cited By ~ 34

Author(s):

M Watford ◽

E M Smith ◽

E J Erbelding

Keyword(s):

Drinking Water ◽

Small Intestine ◽

Glutamine Metabolism ◽

Diabetic Rat ◽

Complete Suppression ◽

Chemically Induced ◽

Phosphate Activated Glutaminase ◽

Kidney Liver ◽

Nh4cl Solution ◽

Glutaminase Activity

The activity of phosphate-activated glutaminase was increased in the kidney, liver and small intestine of rats made diabetic for 6 days with injection of streptozotocin (75 mg/kg body wt.). Insulin prevented this increase in all three tissues. Treatment with NaHCO3, to correct the acidosis that accompanies diabetes, prevented the increase in renal glutaminase activity, but not that in liver or small intestine. Chemically induced acidosis (NH4Cl solution as drinking water) or alkalosis (NaHCO3 solution as drinking water) increased and decreased, respectively, glutaminase activity in the kidney, but were without significant effect on the activity in liver and small intestine. The increase in glutaminase activity in the small intestine during diabetes was due to an overall increase in the size of this organ, and was only detectable when activity was expressed in terms of whole organ, not mucosal scrapings or isolated enterocytes. Prolonged diabetes (40 days) resulted in an even greater increase in the size and glutaminase activity of the small intestine. Despite this marked increase in capacity for glutamine catabolism, arteriovenous-difference measurements showed a complete suppression of plasma glutamine utilization by the small intestine during diabetes, confirming the report by Brosnan, Man, Hall, Colbourne & Brosnan [(1983) Am. J. Physiol. 235, E261-E265].

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A Note on the Numerical Representation of Surface Dynamics in Quasigeostrophic Turbulence: Application to the Nonlinear Eady Model

Journal of the Atmospheric Sciences ◽

10.1175/2008jas2921.1 ◽

2009 ◽

Vol 66 (4) ◽

pp. 1063-1068 ◽

Cited By ~ 14

Author(s):

Ross Tulloch ◽

K. Shafer Smith

Keyword(s):

Numerical Models ◽

Buoyancy Frequency ◽

Complete Suppression ◽

Numerical Representation ◽

Vertical Resolution ◽

Surface Dynamics ◽

Coriolis Parameter ◽

Theoretical Predictions ◽

Vertical Grid ◽

Similar Restriction

Abstract The quasigeostrophic equations consist of the advection of linearized potential vorticity coupled with advection of temperature at the bounding upper and lower surfaces. Numerical models of quasigeostrophic flow often employ greater (scaled) resolution in the horizontal than in the vertical (the two-layer model is an extreme example). In the interior, this has the effect of suppressing interactions between layers at horizontal scales that are small compared to Nδz/f (where δz is the vertical resolution, N the buoyancy frequency, and f the Coriolis parameter). The nature of the turbulent cascade in the interior is, however, not fundamentally altered because the downscale cascade of potential enstrophy in quasigeostrophic turbulence and the downscale cascade of enstrophy in two-dimensional turbulence (occurring layerwise) both yield energy spectra with slopes of −3. It is shown here that a similar restriction on the vertical resolution applies to the representation of horizontal motions at the surfaces, but the penalty for underresolving in the vertical is complete suppression of the surface temperature cascade at small scales and a corresponding artificial steepening of the surface energy spectrum. This effect is demonstrated in the nonlinear Eady model, using a finite-difference representation in comparison with a model that explicitly advects temperature at the upper and lower surfaces. Theoretical predictions for the spectrum of turbulence in the nonlinear Eady model are reviewed and compared to the simulated flows, showing that the latter model yields an accurate representation of the cascade dynamics. To accurately represent dynamics at horizontal wavenumber K in the vertically finite-differenced model, it is found that the vertical grid spacing must satisfy δz ≲ 0.3f/(NK); at wavenumbers K > 0.3f/(Nδz), the spectrum of temperature variance rolls off rapidly.

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