Human saliva and model saliva at bulk to adsorbed phases – similarities and differences

Human saliva, a seemingly simple aqueous fluid, is, in fact, an extraordinarily complex biocolloid that is not fully understood, despite many decades of study. Salivary lubrication is widely believed to be a signature of good oral health and is also crucial for speech, food oral processing and swallowing. However, saliva has been often neglected in food colloid research, primarily due to its high intra- to inter-individual variability and altering material properties upon collection and storage, when used as an ex vivo research material. In the last decade, colloid scientists have attempted designing model (i.e. ‘saliva mimicking fluid’) saliva formulations to understand saliva-food colloid interactions in an in vitro set up and its contribution on microstructural aspects, lubrication properties and sensory perception. In this Review, we critically examine the current state of knowledge on bulk and interfacial properties of model saliva in comparison to real human saliva and highlight how far such model salivary formulations can match the properties of real human saliva. Many, if not most, of these model saliva formulations share similarities with real human saliva in terms of biochemical compositions, including electrolytes, pH and concentrations of salivary proteins, such as α-amylase and highly glycosylated mucins. This, together with similarities between model and real saliva in terms of surface charge, has led to significant advancement in decoding colloidal interactions (bridging, depletion) of charged emulsion droplets and associated sensory perception in the oral phase. However, model saliva represents significant dissimilarity to real saliva in the lubricating properties. Based on in-depth examination of properties of mucins from animal sources (e.g. pig gastric mucins (PGM) or bovine submaxillary mucin (BSM)), we can recommend that BSM is currently the most optimal mucin source when attempting to replicate saliva based on surface adsorption and lubrication properties. Even though purification via dialysis or chromatographic techniques may influence various physicochemical properties of BSM, such as structure and surface adsorption, the lubricating properties of model saliva formulations based on BSM are generally superior and more reliable than PGM counterpart at orally relevant pH. Comparison of mucin-containing model saliva with ex vivo human salivary conditioning films suggests that mucin alone cannot replicate the lubricity of real human salivary pellicle. Mucin-based multi-layers containing mucin and oppositely charged polyelectrolytes may offer promising avenues in the future for engineering biomimetic salivary pellicle, however, this has not been explored in oral tribology experiments to date. Hence, there is a strong need for systematic studies with employment of model saliva formulations containing mucins with and without polycationic additives before a consensus on a standardized model saliva formulation can be achieved. Overall, this review provides a comprehensive framework on simulating saliva for a particular bulk or surface property when doing food oral processing experiments

Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities

Interactions between wine phenolic compounds and human saliva in astringency perception

[EN] Astringency is a complex perceptual phenomenon involving several sensations that are perceived simultaneously. The mechanism leading to these sensations has been thoroughly and controversially discussed in the literature and it is still not well understood since there are many contributing factors. Although we are still far from elucidating the mechanisms whereby astringency develops, the interaction between phenolic compounds and proteins (from saliva, oral mucosa or cells) seems to be most important. This review summarizes the recent trends in the protein–phenol interaction, focusing on the effect of the structure of the phenolic compound on the interaction with salivary proteins and on methodologies based on these interactions to determine astringency

Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells

The probability of mitochondrial permeability transition (mPT) pore opening is inversely related to the magnitude of the proton electrochemical gradient. The module conferring sensitivity of the pore to this gradient has not been identified. We investigated mPT's voltage-sensing properties elicited by calcimycin or H2O2 in human fibroblasts exhibiting partial or complete lack of ANT1 and in C2C12 myotubes with knocked-down ANT1 expression. mPT onset was assessed by measuring in situ mitochondrial volume using the 'thinness ratio' and the 'cobalt-calcein' technique. De-energization hastened calcimycin-induced swelling in control and partially-expressing ANT1 fibroblasts, but not in cells lacking ANT1, despite greater losses of mitochondrial membrane potential. Matrix Ca(2+) levels measured by X-rhod-1 or mitochondrially-targeted ratiometric biosensor 4mtD3cpv, or ADP-ATP exchange rates did not differ among cell types. ANT1-null fibroblasts were also resistant to H2O2-induced mitochondrial swelling. Permeabilized C2C12 myotubes with knocked-down ANT1 exhibited higher calcium uptake capacity and voltage-thresholds of mPT opening inferred from cytochrome c release, but intact cells showed no differences in calcimycin-induced onset of mPT, irrespective of energization and ANT1 expression, albeit the number of cells undergoing mPT increased less significantly upon chemically-induced hypoxia than control cells. We conclude that ANT1 confers sensitivity of the pore to the electrochemical gradient

Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells

The probability of mitochondrial permeability transition (mPT) pore opening is inversely related to the magnitude of the proton electrochemical gradient. The module conferring sensitivity of the pore to this gradient has not been identified. We investigated mPT's voltage-sensing properties elicited by calcimycin or H2O2 in human fibroblasts exhibiting partial or complete lack of ANT1 and in C2C12 myotubes with knocked-down ANT1 expression. mPT onset was assessed by measuring in situ mitochondrial volume using the 'thinness ratio' and the 'cobalt-calcein' technique. De-energization hastened calcimycin-induced swelling in control and partially-expressing ANT1 fibroblasts, but not in cells lacking ANT1, despite greater losses of mitochondrial membrane potential. Matrix Ca(2+) levels measured by X-rhod-1 or mitochondrially-targeted ratiometric biosensor 4mtD3cpv, or ADP-ATP exchange rates did not differ among cell types. ANT1-null fibroblasts were also resistant to H2O2-induced mitochondrial swelling. Permeabilized C2C12 myotubes with knocked-down ANT1 exhibited higher calcium uptake capacity and voltage-thresholds of mPT opening inferred from cytochrome c release, but intact cells showed no differences in calcimycin-induced onset of mPT, irrespective of energization and ANT1 expression, albeit the number of cells undergoing mPT increased less significantly upon chemically-induced hypoxia than control cells. We conclude that ANT1 confers sensitivity of the pore to the electrochemical gradient

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes

An improved analysis of GW150914 using a fully spin-precessing waveform model

This paper presents updated estimates of source parameters for GW150914, a binary black-hole coalescence event detected by the Laser Interferometer Gravitational-wave Observatory (LIGO) on September 14, 2015 [1]. Reference presented parameter estimation [2] of the source using a 13-dimensional, phenomenological precessing-spin model (precessing IMRPhenom) and a 11-dimensional nonprecessing effective-one-body (EOB) model calibrated to numerical-relativity simulations, which forces spin alignment (nonprecessing EOBNR). Here we present new results that include a 15-dimensional precessing-spin waveform model (precessing EOBNR) developed within the EOB formalism. We find good agreement with the parameters estimated previously [2], and we quote updated component masses of $35^{+5}_{-3}\mathrm{M}_\odot$ and $30^{+3}_{-4}\mathrm{M}_\odot$ (where errors correspond to 90% symmetric credible intervals). We also present slightly tighter constraints on the dimensionless spin magnitudes of the two black holes, with a primary spin estimate $0.65$ and a secondary spin estimate $0.75$ at 90% probability. Reference [2] estimated the systematic parameter-extraction errors due to waveform-model uncertainty by combining the posterior probability densities of precessing IMRPhenom and nonprecessing EOBNR. Here we find that the two precessing-spin models are in closer agreement, suggesting that these systematic errors are smaller than previously quoted

Properties of the Binary Black Hole Merger GW150914

On September 14, 2015, the Laser Interferometer Gravitational-Wave Observatory (LIGO) detected a gravitational-wave transient (GW150914); we characterize the properties of the source and its parameters. The data around the time of the event were analyzed coherently across the LIGO network using a suite of accurate waveform models that describe gravitational waves from a compact binary system in general relativity. GW150914 was produced by a nearly equal mass binary black hole of masses 36+5−4M⊙ and 29+4−4M⊙; for each parameter we report the median value and the range of the 90% credible interval. The dimensionless spin magnitude of the more massive black hole is bound to be <0.7 (at 90% probability). The luminosity distance to the source is 410+160−180  Mpc, corresponding to a redshift 0.09+0.03−0.04 assuming standard cosmology. The source location is constrained to an annulus section of 610  deg2, primarily in the southern hemisphere. The binary merges into a black hole of mass 62+4−4M⊙ and spin 0.67+0.05−0.07. This black hole is significantly more massive than any other inferred from electromagnetic observations in the stellar-mass regime