Isolation and characterization of microsatellite markers in the spiny lobster, <Emphasis Type="Italic">Panulirus echinatus</Emphasis> Smith, 1869 (Decapoda: Palinuridae) by Illumina MiSeq sequencing

Okra’s (Abelmoschus esculentus (L.) Moench) commercial cultivation is threatened in the tropics due to high incidence of yellow vein mosaic virus (YVMV) disease. Okra geneticists across the world tried to understand the inheritance pattern of YVMV disease tolerance without much success. Therefore, the inheritance pattern of YVMV disease in okra was revisited by employing six generations (\(\hbox {P}_{1}\), \(\hbox {P}_{2}\), \(\hbox {F}_{1}\), \(\hbox {F}_{2}\), \(\hbox {BC}_{1}\) and \(\hbox {BC}_{2}\)) of four selected crosses (one tolerant \(\times \) tolerant, two tolerant \(\times \) susceptible and one susceptible \(\times \) susceptible) using two tolerant (BCO-1 and Lal Bhendi) and two susceptible (Japanese Jhar Bhendi and PAN 2127) genotypes. Qualitative genetic analysis was done on the basis of segregation pattern of tolerant and susceptible plants in \(\hbox {F}_{2}\) and backcross generations of all the four crosses. It revealed that a single dominant gene along with some minor factors governed the disease tolerant trait in both the tolerant parents used. However, it was observed that genes governing disease tolerance identified in both the tolerant variety used was different. It could be concluded that the gene governing YVMV disease tolerance in okra was genotype specific. Further, duplicate gene action as evident from an approximate ratio of 15 : 1 (tolerant : susceptible) in the \(\hbox {F}_{2}\) population in the cross of two tolerant varieties gave a scope of increasing the tolerance level of the hybrid plants when both the tolerant genes are brought together. However, generation mean analysis revealed involvement of both additive and nonadditive effects in the inheritance of disease tolerance. Thus, the present study confirms that a complicated genetic inheritance pattern is involved in the disease tolerance against YVMV trait. The major tolerance genes could be transferred to other okra varieties, but the tolerance breaking virus strains might not allow them to achieve tolerance in stable condition. Therefore, accumulation of additional genes may be needed for a sustainable tolerance phenotype in okra.     

Genomewide identification of PPR gene family and prediction analysis on restorer gene in <Emphasis Type="BoldItalic">Gossypium</Emphasis>

Pentatricopeptide repeat (PPR) gene family plays an essential role in the regulation of plant growth and organelle gene expression. Some PPR genes are related to fertility restoration in plant, but there is no detailed information in Gossypium. In the present study, we identified 482 and 433 PPR homologues in Gossypium raimondii (\(\hbox {D}_{5}\)) and G. arboreum (\(\hbox {A}_{2}\)) genomes, respectively. Most PPR homologues showed an even distribution on the whole chromosomes. Given an evolutionary analysis to PPR genes from G. raimondii (\(\hbox {D}_{5}\)), G. arboreum (\(\hbox {A}_{2}\)) and G. hirsutum genomes, eight PPR genes were clustered together with restoring genes of other species. Most cotton PPR genes were qualified with no intron, high proportion of \(\upalpha \)-helix and classical tertiary structure of PPR protein. Based on bioinformatics analyses, eight PPR genes were targeted in mitochondrion, encoding typical P subfamily protein with protein binding activity and organelle RNA metabolism in function. Further verified by RNA-seq and quantitative real-time PCR (qRT-PCR) analyses, two PPR candidate genes, Gorai.005G0470 (\(\hbox {D}_{5}\)) and Cotton_A_08373 (\(\hbox {A}_{2}\)), were upregulated in fertile line than sterile line. These results reveal new insights into PPR gene evolution in Gossypium.     

Assessment of genetic diversity and population genetic structure of <Emphasis Type="BoldItalic">Carthamus</Emphasis> species and Iranian cultivar collection using developed SSR markers

Genetic diversity during prebreeding or postbreeding programme, is the key pillar to characterize the valuable traits and gene of interest. Whereas, superior or inferior heterotic performance of \(\hbox {F}_{1}\) depend on the diverse nature of their pedigree. Therefore, the aim of this study was to see the diversity between the interspecific crosses and effect of heterosis, and inheritance for the morphological traits and ToLCV resistance. All the 24 \(\hbox {F}_{1}\) interspecific crosses were classified into four clusters on the basis of morphological traits as well as simple sequence repeat (SSR) markers. Among the \(\hbox {F}_{1}\) hybrids, 23 were grouped into clusters II, III and IV with different phylogeny, while \(\hbox {PBC} \times \) EC 521080 was individual with cluster I. On the basis of visual observation of fruit colour, deep red and green colours in the crosses of S. pimpinellifolium (EC 521080) and S. habrochaites (EC 520061) exhibited dominant effects. In context of heterosis breeding, the crosses which were made using Solanum pimpinellifolium (EC 521080), S. chmielewskii (EC 520049) and S. cerasiforme (EC 528372) were better for yield capacity and the crosses of S. habrochaites (EC 520061) exhibited low and negative heterosis for ToLCV resistance. The \(\hbox {F}_{2}\) progenies were segregated in various Mendelian ratio as follows 3:1, 1:2:1, 1:3, 13:3, 15:1, 12:3:1 and 9:6:1 for ToLCV disease reaction of incidence, plant growth habit and fruit colour appearance, respectively. Therefore, these interspecific crosses can be utilized for developing high yield, impressive fruit colour combiners and resistant hybrids/varieties of tomato.     

Prediction of heterosis in rice based on divergence of morphological and molecular markers

Identifying the best performing hybrid without a field test was essential to save resources and time. In this study, the genetic divergence was estimated using morphological and expressed sequence tag (EST)-derived simple sequence repeats (SSR) markers. Cluster analysis showed that APMS6A and RPHR 1005 belong to groups I and II, respectively, and the hybrid combination recorded the highest mean grain yield of 32.25 g among generated 40 \(\hbox {F}_{1}\hbox {s}\) with standard heterosis of 8.4% over hybrid check, KRH2. The coefficient of marker polymorphism (CMP) value was calculated based on EST-SSR markers; it ranged from 0.40 to 0.80, and a higher CMP value of 0.80 was obtained for the parental combination APMS6A \(\times \) RPHR1005. We predicted heterosis for 40 \(\hbox {F}_{1}\hbox {s}\) based on correlation between CMP and standard heterosis in different traits with standard varietal and hybrid checks indicating positive correlation and significant value for grain yield per plant (\(r=0.58\)**), productivity per day (\(r=0.54\)**), productive tillers (\(r=0.34\)*) and panicle weight (\(r=0.42\)**). This study revealed that the relationship of molecular marker heterozygosity, along with the combining ability, high mean value of different traits, grouping of parental lines based on morphological and molecular characterization is helpful to identify heterotic patterns in rice.     

Cellular mechanosensitivity to substrate stiffness decreases with increasing dissimilarity to cell stiffness

Computational modelling has received increasing attention to investigate multi-scale coupled problems in micro-heterogeneous biological structures such as cells. In the current study, we investigated for a single cell the effects of (1) different cell-substrate attachment (2) and different substrate modulus \(\textit{E}_\mathrm{s}\) on intracellular deformations. A fibroblast was geometrically reconstructed from confocal micrographs. Finite element models of the cell on a planar substrate were developed. Intracellular deformations due to substrate stretch of \(\lambda =1.1\), were assessed for: (1) cell-substrate attachment implemented as full basal contact (FC) and 124 focal adhesions (FA), respectively, and \(\textit{E}_\mathrm{s}\,=\,\)140 KPa and (2) \(\textit{E}_\mathrm{s}\,=\,10\), 140, 1000, and 10,000 KPa, respectively, and FA attachment. The largest strains in cytosol, nucleus and cell membrane were higher for FC (1.35\(\text {e}^{-2}\), 0.235\(\text {e}^{-2}\) and 0.6\(\text {e}^{-2}\)) than for FA attachment (0.0952\(\text {e}^{-2}\), 0.0472\(\text {e}^{-2}\) and 0.05\(\text {e}^{-2}\)). For increasing \(\textit{E}_\mathrm{s}\), the largest maximum principal strain was 4.4\(\text {e}^{-4}\), 5\(\text {e}^{-4}\), 5.3\(\text {e}^{-4}\) and 5.3\(\text {e}^{-4}\) in the membrane, 9.5\(\text {e}^{-4}\), 1.1\(\text {e}^{-4}\), 1.2\(\text {e}^{-3}\) and 1.2\(\text {e}^{-3}\) in the cytosol, and 4.5\(\text {e}^{-4}\), 5.3\(\text {e}^{-4}\), 5.7\(\text {e}^{-4}\) and 5.7\(\text {e}^{-4}\) in the nucleus. The results show (1) the importance of representing FA in cell models and (2) higher cellular mechanical sensitivity for substrate stiffness changes in the range of cell stiffness. The latter indicates that matching substrate stiffness to cell stiffness, and moderate variation of the former is very effective for controlled variation of cell deformation. The developed methodology is useful for parametric studies on cellular mechanics to obtain quantitative data of subcellular strains and stresses that cannot easily be measured experimentally.     

Resolving the viscoelasticity and anisotropy dependence of the mechanical properties of skin from a porcine model

The mechanical response of skin to external loads is influenced by anisotropy and viscoelasticity of the tissue, but the underlying mechanisms remain unclear. Here, we report a study of the main effects of tissue orientation (TO, which is linked to anisotropy) and strain rate (SR, a measure of viscoelasticity), as well as the interaction effects between the two factors, on the tensile properties of skin from a porcine model. Tensile testing to rupture of porcine skin tissue was conducted to evaluate the sensitivity of the tissue modulus of elasticity (E) and fracture-related properties, namely maximum stress \((\sigma _{U})\) and strain \((\varepsilon _{U})\) at \(\sigma _{U}\), to varying SR and TO. Specimens were excised from the abdominal skin in two orientations, namely parallel (P) and right angle (R) to the torso midline. Each TO was investigated at three SR levels, namely 0.007–0.015 \(\hbox {s}^{-1}\) (low), 0.040 \(\hbox {s}^{-1}\) (mid) and 0.065 \(\hbox {s}^{-1}\) (high). Two-factor analysis of variance revealed that the respective parameters responded differently to varying SR and TO. Significant changes in the \(\sigma _{U}\) were observed with different TOs but not with SR. The \(\varepsilon _{U}\) decreased significantly with increasing SR, but no significant variation was observed for different TOs. Significant changes in E were observed with different TOs; E increased significantly with increasing SR. More importantly, the respective mechanical parameters were not significantly influenced by interactions between SR and TO. These findings suggest that the trends associated with the changes in the skin mechanical properties may be attributed partly to differences in the anisotropy and viscoelasticity but not through any interaction between viscoelasticity and anisotropy.     

Cell Volume Regulation in the Proximal Tubule of Rat Kidney

We developed a dynamic model of a rat proximal convoluted tubule cell in order to investigate cell volume regulation mechanisms in this nephron segment. We examined whether regulatory volume decrease (RVD), which follows exposure to a hyposmotic peritubular solution, can be achieved solely via stimulation of basolateral K\(^+\) and \(\hbox {Cl}^-\) channels and \(\hbox {Na}^+\)–\(\hbox {HCO}_3^-\) cotransporters. We also determined whether regulatory volume increase (RVI), which follows exposure to a hyperosmotic peritubular solution under certain conditions, may be accomplished by activating basolateral \(\hbox {Na}^+\)/H\(^+\) exchangers. Model predictions were in good agreement with experimental observations in mouse proximal tubule cells assuming that a 10% increase in cell volume induces a fourfold increase in the expression of basolateral K\(^+\) and \(\hbox {Cl}^-\) channels and \(\hbox {Na}^+\)–\(\hbox {HCO}_3^-\) cotransporters. Our results also suggest that in response to a hyposmotic challenge and subsequent cell swelling, \(\hbox {Na}^+\)–\(\hbox {HCO}^-_3\) cotransporters are more efficient than basolateral K\(^+\) and \(\hbox {Cl}^-\) channels at lowering intracellular osmolality and reducing cell volume. Moreover, both RVD and RVI are predicted to stabilize net transcellular \(\hbox {Na}^+\) reabsorption, that is, to limit the net \(\hbox {Na}^+\) flux decrease during a hyposmotic challenge or the net \(\hbox {Na}^+\) flux increase during a hyperosmotic challenge.     

Backbone resonance assignments for the SET domain of the human methyltransferase NSD2

Aberrant NSD2 methyltransferase activity is implicated as the oncogenic driver in multiple myeloma, suggesting opportunities for novel therapeutic intervention. The methyltransferase activity of NSD2 resides in its catalytic SET domain, which is conserved among most lysine methyltransferases. Here we report the backbone \(\hbox {H}^{\mathrm{N}}\), N, C\(^{\prime }\), \(\hbox {C}^\alpha\) and side-chain \(\hbox {C}^\beta\) assignments of a 25 kDa NSD2 SET domain construct, spanning residues 991–1203. A chemical shift analysis of C\(^{\prime }\), \(\hbox {C}^\alpha\) and \(\hbox {C}^\beta\) resonances predicts a secondary structural pattern that is in agreement with homology models.     

Glutathione <Emphasis Type="BoldItalic">S</Emphasis>-transferase P1 gene polymorphisms and susceptibility to coronary artery disease in a subgroup of north Indian population

The present study aimed to investigate the association of \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) and \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) polymorphisms of GSTP1 with coronary artery disease (CAD) in a subgroup of north Indian population. In the present case–control study, CAD patients (\(n = 200\)) and age-matched, sex-matched and ethnicity-matched healthy controls (\(n = 200\)) were genotyped for polymorphisms in GSTP1 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotype distribution of \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) and \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) polymorphisms of GSTP1 gene was significantly different between cases and controls (\(P = 0.005\) and 0.024, respectively). Binary logistic regression analysis showed significant association of A/G (odds ratio (OR): 1.6, 95% CI: 1.08–2.49, \(P = 0.020\)) and G/G (OR: 3.1, 95% CI: 1.41–6.71, P \(=\) 0.005) genotypes of GSTP1 \(\hbox {g}.313\hbox {A}{\!>\!}\hbox {G}\), and C/T (OR: 5.8, 95% CI: 1.26–26.34, \(P = 0.024\)) genotype of GSTP1 \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) with CAD. The A/G and G/G genotypes of \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) and C/T genotype of \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) conferred 6.5-fold increased risk for CAD (OR: 6.5, 95% CI: 1.37–31.27, \(P = 0.018\)). Moreover, the recessive model of GSTP1 \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) is the best fit inheritance model to predict the susceptible gene effect (OR: 2.3, 95% CI: 1.11–4.92, \(P = 0.020\)). In conclusion, statistically significant associations of GSTP1 \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) (A/G, G/G) and \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) (C/T) genotypes with CAD were observed.     

A Mathematical Model for the Macrophage Response to Respiratory Viral Infection in Normal and Asthmatic Conditions

Respiratory viral infections are common in the general population and one of the most important causes of asthma aggravation and exacerbation. Despite many studies, it is not well understood how viral infections cause more severe symptoms and exacerbations in asthmatics. We develop a mathematical model of two types of macrophages that play complementary roles in fighting viral infection: classically \((\hbox {CA}\)-\(\hbox {M}\Phi )\) and alternatively activated macrophages \((\hbox {AA}\)-\(\hbox {M}\Phi )\). \(\hbox {CA}\)-\(\hbox {M}\Phi \) destroy infected cells and tissues to remove viruses, while \(\hbox {AA}\)-\(\hbox {M}\Phi \) repair damaged tissues. We show that a higher viral load or longer duration of infection provokes a stronger immune response from the macrophage system. By adjusting the parameters, we model the differences in response to respiratory viral infection in normal and asthmatic subjects and show how this skews the system toward a response that generates more severe symptoms in asthmatic patients.     

Genetic analysis and location of a resistance gene for <Emphasis Type="BoldItalic">Puccinia striiformis</Emphasis> f. sp. <Emphasis Type="BoldItalic">tritici</Emphasis> in wheat cultivar Zhengmai 7698

Wheat stripe (yellow) rust, caused by Puccinia striiformis West. f. sp. tritici (Pst), is one of the most destructive diseases in many wheat-growing countries, especially in China, the largest stripe rust epidemic area in the world. Growing the resistant cultivars is an effective, economic and environmentally friendly way to control this disease. Wheat cultivar Zhengmai 7698 has shown a high-level resistance to wheat stripe rust. To elucidate its genetic characteristics and location of the resistance gene, Zhengmai 7698 was crossed with susceptible variety Taichung 29 to produce \(\hbox {F}_{{1}}\), \(\hbox {F}_{{2}}\) and \(\hbox {BC}_{{1}}\) progeny generations. The genetic analysis showed that the stripe rust resistance in Zhengmai 7698 to Pst predominant race CYR32 was controlled by a single-dominant gene, namedYrZM. Bulked segregant analysis and simple sequence repeat (SSR) markers were used to map the gene. Four SSR markers, Xbarc198, Xwmc179, Xwmc786 and Xwmc398 on chromosome 6BL were polymorphic between the parents and resistance, and susceptible bulks. A linkage genetic map was constructed using 212 \(\hbox {F}_{{2}}\) plants in the sequential order of Xwmc398, Xwmc179, YrZM, Xbarc198, Xwmc786. As this gene is effective against predominant race CYR32, it is useful in combination with other resistance genes for developing new wheat cultivars with resistance to stripe rust.     

A viscoplastic model for the active component in cardiac muscle

The HMK model (Hunter et al. in Prog Biophys Mol Biol 69:289–331, 1998) proposes mechanobiological equations for the influence of intracellular calcium concentration \(\hbox {Ca}_\mathrm{i}\) on the evolution of bound calcium concentration \(\hbox {Ca}_\mathrm{b}\) and the tropomyosin kinetics parameter z, which model processes in the active component of the tension in cardiac muscle. The inelastic response due to actin-myosin crossbridge kinetics is modeled in the HMK model with a function Q that depends on the history of the rate of total stretch of the muscle fiber. Here, an alternative model is proposed which models the active component of the muscle fiber as a viscoplastic material. In particular, an evolution equation is proposed for the elastic stretch \(\lambda _\mathrm{a} \) in the active component. Specific forms of the constitutive equations are proposed and used to match experimental data. The proposed viscoplastic formulation allows for separate modeling of three processes: the high rate deactivation of crossbridges causing rapid reduction in active tension; the high but lower rate reactivation of crossbridges causing recovery of active tension; and the low rate relaxation effects characterizing the Hill model of muscles.     

Comparison of the Functional Activities of Xanthine Oxidases Isolated from Microorganisms and from Cow’s Milk

The characteristics of the formation of the superoxide radical anion (\(\rm{O}_2^{\bullet-}\)) and hydrogen peroxide by xanthine oxidases isolated from microorganisms and from cow’s milk were investigated. The increase in pH led to an increase in the rate of xanthine oxidation with oxygen by both xanthine oxidases. The functioning of xanthine oxidase from milk along with the two-electron reduction of O₂ to H₂O₂ carries through the one-electron reduction of O₂ to \(\rm{O}_2^{\bullet-}\), and the rate and the fraction of generation of \(\rm{O}_2^{\bullet-}\) increased with increasing pH. Under operation of the microbial xanthine oxidase, the \(\rm{O}_2^{\bullet-}\) radical was not detected in the medium. The results suggest a difference in the operation of active centers of enzyme from different sources.     

Failure properties of vena cava tissue due to deep penetration during filter insertion

In this work, we use an in-vitro mechanical test to explore the resistance of biaxially stretched vena cava tissue against deep perforation and a methodology which integrates experimental and numerical modeling to identify constitutive fracture properties of the vena cava. Six sheep vena cava were harvested just after killing, and cyclic uniaxial tension tests in longitudinal and circumferential directions and biaxial deep penetration tests were performed. After that, we use a nonlinear finite element model to simulate in vitro penetration of the cava tissue in order to fit the fracture properties under penetration of the vena cava by defining a cohesive fracture zone. An iterative process was developed in order to fit the fracture properties of the vena cava using the previously obtained experimental results. The proposed solutions were obtained with fracture energy of 0.22 or 0.33 N/mm. In comparison with the experimental data, the simulation using \(\delta _{0}=0.01\,\hbox {mm}\), \(\delta _{r}=0.35\,\hbox {mm}\), and \(K=220\, \hbox {N}/\hbox {mm}^{3}\) parameters (\(F_{\hbox {max}}=0.92\)) is in good agreement with results from penetration experiments of cava tissue. It is noticeable that the parameter estimation process of the fracture behavior is more accurate than the estimation process of the elastic behavior for the toe region of the curve.     

The effective elastic properties of human trabecular bone may be approximated using micro-finite element analyses of embedded volume elements

Boundary conditions (BCs) and sample size affect the measured elastic properties of cancellous bone. Samples too small to be representative appear stiffer under kinematic uniform BCs (KUBCs) than under periodicity-compatible mixed uniform BCs (PMUBCs). To avoid those effects, we propose to determine the effective properties of trabecular bone using an embedded configuration. Cubic samples of various sizes (2.63, 5.29, 7.96, 10.58 and 15.87 mm) were cropped from \(\mu \hbox {CT}\) scans of femoral heads and vertebral bodies. They were converted into \(\mu \hbox {FE}\) models and their stiffness tensor was established via six uniaxial and shear load cases. PMUBCs- and KUBCs-based tensors were determined for each sample. “In situ” stiffness tensors were also evaluated for the embedded configuration, i.e. when the loads were transmitted to the samples via a layer of trabecular bone. The Zysset–Curnier model accounting for bone volume fraction and fabric anisotropy was fitted to those stiffness tensors, and model parameters \(\nu _{0}\) (Poisson’s ratio) \(E_{0}\) and \(\mu _{0}\) (elastic and shear moduli) were compared between sizes. BCs and sample size had little impact on \(\nu _{0}\). However, KUBCs- and PMUBCs-based \(E_{0}\) and \(\mu _{0}\), respectively, decreased and increased with growing size, though convergence was not reached even for our largest samples. Both BCs produced upper and lower bounds for the in situ values that were almost constant across samples dimensions, thus appearing as an approximation of the effective properties. PMUBCs seem also appropriate for mimicking the trabecular core, but they still underestimate its elastic properties (especially in shear) even for nearly orthotropic samples.     

Calcium signaling as a novel method to optimize the biosynthetic response of chondrocytes to dynamic mechanical loading

Chondrocyte sensitization and desensitization to mechanical stimuli are complex phenomena that have not been fully described. In this study, we investigated the temporal response of chondrocytes to dynamic mechanical loading and whether changes in calcium signaling could be used a predictor of the biosynthetic response. Cell-seeded agarose gels pre-incubated with an intracellular \(\hbox {Ca}^{2+}\) dye (Fluo-4) were subjected to dynamic compressive loading under varying conditions (amplitude and duration). Induced changes in \(\hbox {Ca}^{2+}\) signaling were determined by confocal imaging and matrix biosynthesis by radioisotope incorporation. It was observed that chondrocytes required a minimum amount of stimulation in order to elicit an anabolic response and they quickly became insensitive to the imposed stimulus. The response appeared to be amplitude dependent and could be predicted by measuring resultant changes in \(\hbox {Ca}^{2+}\) signaling. A positive correlation between \(\hbox {Ca}^{2+}\) signaling and matrix synthesis was achieved when changes in \(\hbox {Ca}^{2+}\) signaling was expressed as a relative number of cells experiencing multiple transients. In addition, these changes in \(\hbox {Ca}^{2+}\) signaling were effective at determining optimal recovery period between successive applications of intermittent mechanical loading, in which full mechanosensitivity was achieved when \(\hbox {Ca}^{2+}\) signaling was allowed to return to baseline (control) levels. The use of \(\hbox {Ca}^{2+}\) signaling to predict the effectiveness of a particular mechanical stimulus as well as to determine optimal refractory periods appears to be advantageous over empirical-based approaches. Future work will investigate the process of \(\hbox {Ca}^{2+}\) ion sequestration into intracellular stores to elucidate potential desensitization mechanisms to dynamic mechanical loading.     

A Mathematical Model Supports a Key Role for Ae4 (Slc4a9) in Salivary Gland Secretion

We develop a mathematical model of a salivary gland acinar cell with the objective of investigating the role of two \(\mathrm{Cl}^-/\mathrm{HCO}_3^-\) exchangers from the solute carrier family 4 (Slc4), Ae2 (Slc4a2) and Ae4 (Slc4a9), in fluid secretion. Water transport in this type of cell is predominantly driven by \(\mathrm{Cl}^-\) movement. Here, a basolateral \(\mathrm{Na}^+/ \mathrm{K}^+\) adenosine triphosphatase pump (NaK-ATPase) and a \(\mathrm{Na}^+\)–\(\mathrm{K}^+\)–\(2 \mathrm{Cl}^-\) cotransporter (Nkcc1) are primarily responsible for concentrating the intracellular space with \(\mathrm{Cl}^-\) well above its equilibrium potential. Gustatory and olfactory stimuli induce the release of \(\mathrm{Ca}^{2+}\) ions from the internal stores of acinar cells, which triggers saliva secretion. \(\mathrm{Ca}^{2+}\)-dependent \(\mathrm{Cl}^-\) and \(\mathrm{K}^+\) channels promote ion secretion into the luminal space, thus creating an osmotic gradient that promotes water movement in the secretory direction. The current model for saliva secretion proposes that \(\mathrm{Cl}^-/ \mathrm{HCO}_3^-\) anion exchangers (Ae), coupled with a basolateral \(\mathrm{Na}^+/\hbox {proton}\) (\(\hbox {H}^+\)) (Nhe1) antiporter, regulate intracellular pH and act as a secondary \(\mathrm{Cl}^-\) uptake mechanism (Nauntofte in Am J Physiol Gastrointest Liver Physiol 263(6):G823–G837, 1992; Melvin et al. in Annu Rev Physiol 67:445–469, 2005.  https://doi.org/10.1146/annurev.physiol.67.041703.084745). Recent studies demonstrated that Ae4 deficient mice exhibit an approximate \(30\%\) decrease in gland salivation (Peña-Münzenmayer et al. in J Biol Chem 290(17):10677–10688, 2015). Surprisingly, the same study revealed that absence of Ae2 does not impair salivation, as previously suggested. These results seem to indicate that the Ae4 may be responsible for the majority of the secondary \(\mathrm{Cl}^-\) uptake and thus a key mechanism for saliva secretion. Here, by using ‘in-silico’ Ae2 and Ae4 knockout simulations, we produced mathematical support for such controversial findings. Our results suggest that the exchanger’s cotransport of monovalent cations is likely to be important in establishing the osmotic gradient necessary for optimal transepithelial fluid movement.