A finite-element model of mechanosensation by a Pacinian corpuscle cluster in human skin

The Pacinian corpuscle (PC) is the cutaneous mechanoreceptor responsible for sensation of high-frequency (20–1000 Hz) vibrations. PCs lie deep within the skin, often in multicorpuscle clusters with overlapping receptive fields. We developed a finite-element mechanical model of one or two PCs embedded within human skin, coupled to a multiphysics PC model to simulate action potentials elicited by each PC. A vibration was applied to the skin surface, and the resulting mechanical signal was analyzed using two metrics: the deformation amplitude ratio (\({\rho }_{\mathrm{1S}} \), \({\rho }_{\mathrm{2S}} )\) and the phase shift of the vibration (\({\delta }_{\mathrm{S}1}^{\mathrm{mech}} \), \({\delta }_{\mathrm{S}2}^{\mathrm{mech}} )\) between the stimulus and the PC. Our results showed that the amplitude attenuation and phase shift at a PC increased with distance from the stimulus to the PC. Differences in amplitude (\(\rho _{12} )\) and phase shift (\({\delta }_{12}^{\mathrm{mech}} )\) between the two PCs in simulated clusters directly affected the interspike interval between the action potentials elicited by each PC (\({\delta }_{12}^{\mathrm{spike}} )\). While \({\delta }_{12}^{\mathrm{mech}} \) had a linear relationship with \({\delta }_{12}^{\mathrm{spike}} \), \(\rho _{12} \)’s effect on \({\delta }_{12}^{\mathrm{spike}} \) was greater for lower values of \(\rho _{12} \). In our simulations, the separation between PCs and the distance of each PC from the stimulus location resulted in differences in amplitude and phase shift at each PC that caused \({\delta }_{12}^{\mathrm{spike}} \) to vary with PC location. Our results suggest that PCs within a cluster receive different mechanical stimuli which may enhance source localization of vibrotactile stimuli, drawing parallels to sound localization in binaural hearing.     

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.     

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.     

Performance and kinetics of ANAMMOX granular sludge with pH shock in a sequencing batch reactor

As an efficient and cost-effective nitrogen removal process, anaerobic ammonium oxidation (ANAMMOX) could be well operated at suitable pH condition. However, pH shock occurred in different kinds of wastewater and affected ANANNOX process greatly. The present research aimed at studying the performance and kinetics of ANAMMOX granular sludge with pH shock. When influent pH was below 7.5, effluent \({\text{NH}}_{4}^{ + }\)–N and \({\text{NO}}_{2}^{ - }\)–N increased with decreasing pH. At Ph 6.0, effluent \({\text{NO}}_{2}^{ - }\)–N approached 100 mg/L, and the ratios of \(\Delta {\text{NO}}_{2}^{ - } - {\text{N}}:\Delta {\text{NH}}_{4}^{ + } - {\text{N and }}\Delta {\text{NO}}_{3}^{ - } - {\text{N}}:\Delta {\text{NH}}_{4}^{ + } - {\text{N}}\) approached 2.2 and 1.3, respectively. Both greatly deviated from theoretical values. When influent pH was above 7.5, effluent \({\text{NH}}_{4}^{ + }\)–N and \({\text{NO}}_{2}^{ - }\)–N increased with increasing pH. At pH 9.0, ammonium removal rate (ARR) and nitrite removal rate (NRR) decreased to 0.011 ± 0.004 and 0.035 ± 0.004 kg/(m³·d), respectively. Besides, \(\Delta {\text{NO}}_{2}^{ - }\)–N:\(\Delta {\text{NH}}_{4}^{ + }\)–N deviated from theoretical value. Longer recovery time from pH 9.0 than from pH 6.0 indicated that alkaline surroundings inhibited anaerobic ammonium oxidizing bacteria (AAOB) greater. The sludge settling velocity was 2.15 cm/s at pH 7.5. However, it decreased to 2.02 cm/s when pH was 9.0. Acidic pH had little effect on sludge size, but disintegration of ANAMMOX granule was achieved with pH of 9.0. The Bell-shaped (A) model and the Ratkowsky model were more applicable to simulate the effect resulting from pH shock on ANAMMOX activity (R² > 0.95), and both could describe ANAMMOX activity well with pH shock. They indicated that q_max was 0.37 kg \(\Delta {\text{NH}}_{4}^{ + }\)–N/(kgMLSS·d) at the optimum pH value (7.47) in present study. The minimum pH during which ANAMMOX occurred was 5.68 while the maximum pH for ANAMMOX reaction was 9.26. Based on nitrogen removal performance with different pH, strongly acidic (pH ≤ 6.5) or alkaline (pH ≥ 8.5) inhibited ANAMMOX process. Besides, ANAMMOX appeared to be more susceptible to alkaline wastewater. Compared to extremely acidic condition (low pH), extremely alkaline condition (high pH) affected ANAMMOX granules much more.     

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.     

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.     

Similarity of decay-associated spectra for tryptophan fluorescence of proteins with different structures

Tryptophan fluorescence lifetimes were analyzed for three proteins: human serum albumin, bovine serum albumin, and bacterial luciferase, which contain one, two, and seven tryptophan residues, respectively. For all of the proteins, the fluorescence decays were fitted by three lifetimes: τ₁ = 6–7 ns, τ₂ = 2.0–2.3 ns, and τ₃ ≤ 0.1 ns (the native state), and τ₁ = 4.4–4.6 ns, τ₂ = 1.7–1.8 ns, and τ₃ ≤ 0.1 ns (the denatured state). Corresponding decay-associated spectra had similar peak wavelengths and spectrum half-widths both in the native state (\(\lambda _{\max }^{{\tau _1}} = 324nm\), \(\lambda _{\max }^{{\tau _2}} = 328nm\), and \(\lambda _{\max }^{{\tau _3}} = 315nm\)), and in the denatured state (\(\lambda _{\max }^{{\tau _1}} = 350nm\), \(\lambda _{\max }^{{\tau _2}} = 343nm\), and \(\lambda _{\max }^{{\tau _3}} = 317nm\)). The differences in the steady-state spectra of the studied proteins were accounted for the individual ratio of the lifetime component contributions. The lifetime components were compared with a classification of tryptophan residues in the structure of these proteins within the discrete states model.     

Can captive populations function as sources of genetic variation for reintroductions into the wild? A case study of the Arabian oryx from the Phoenix Zoo and the Shaumari Wildlife Reserve,Jordan

The Arabian oryx (Oryx leucoryx) historically ranged across the Arabian Peninsula and neighboring countries until its extirpation in 1972. In 1963–1964 a captive breeding program for this species was started at the Phoenix Zoo (PHX); it ultimately consisted of 11 animals that became known as the ‘World Herd’. In 1978–1979 a wild population was established at the Shaumari Wildlife Reserve (SWR), Jordan, with eight descendants from the World Herd and three individuals from Qatar. We described the mtDNA and nuclear genetic diversity and structure of PHX and SWR. We also determined the long-term demographic and genetic viability of these populations under different reciprocal translocation scenarios. PHX displayed a greater number of mtDNA haplotypes (n = 4) than SWR (n = 2). Additionally, PHX and SWR presented nuclear genetic diversities of \(\bar{N}_{\text{A}}\) = 2.88 vs. 2.75, \(\bar{H}_{\text{O}}\) = 0.469 vs. 0.387, and \(\bar{H}_{\text{E}}\) = 0.501 vs. 0.421, respectively. Although these populations showed no signs of inbreeding (\(\bar{F}_{\text{IS}}\) ≈ 0), they were highly differentiated (\(G^{\prime\prime}_{\text{ST}}\) = 0.580; P < 0.001). Migration between PHX and SWR (Nm = 1, 4, and 8 individuals/generation) increased their genetic diversity in the short-term and substantially reduced the probability of extinction in PHX during 25 generations. Under such scenarios, maximum genetic diversities were achieved in the first generations before the effects of genetic drift became predominant. Although captive populations can function as sources of genetic variation for reintroduction programs, we recommend promoting mutual and continuous gene flow with wild populations to ensure the long-term survival of this species.     

Towards the prediction of flow-induced shear stress distributions experienced by breast cancer cells in the lymphatics

Tumour metastasis in the lymphatics is a crucial step in the progression of breast cancer. The dynamics by which breast cancer cells (BCCs) travel in the lymphatics remains poorly understood. The goal of this work is to develop a model capable of predicting the shear stresses metastasising BCCs experience using numerical and experimental techniques. This paper models the fluidic transport of large particles (\(\eta =d_{\mathrm{p}}/W=0.1-0.4\) where \(d_{\mathrm{p}}\) is the particle diameter and W is the channel width) subjected to lymphatic flow conditions (\({ Re}=0.04\)), in a \(100\times 100\,\upmu \hbox {m}\) microchannel. The feasibility of using the dynamic fluid body interaction (DFBI) method to predict particle motion was assessed, and particle tracking experiments were performed. The experiments found that particle translational velocity decreased from the undisturbed fluid velocity with increasing particle size (5–14% velocity lag for \(\eta =0.1-0.3\)). DFBI simulations were found to better predict particle behaviour than theoretical predictions; however, mesh restrictions in the near-wall region (\(0.2\,\mathrm{W}>y>0.8\,\mathrm{W}\)) result in computationally expensive models. The simulations were in good agreement with the experiments (\(<12\%\) difference) across the channel (\(0.2\,\mathrm{W}\le y\le 0.8\,\mathrm{W}\)), with differences up to 25% in the near-wall region. Particles experience a range of shear stresses (0.002–0.12 Pa) and spatial shear gradients (\(0.004-0.137\,\hbox {Pa}/\upmu \hbox {m}\)) depending on their size and radial position. The predicted shear gradients are far in excess of values associated with BCC apoptosis (\(0.004-0.023\,\hbox {Pa}/\upmu \hbox {m}\)). Increasing our understanding of the shear stress magnitudes and gradients experienced by BCCs could be leveraged to elucidate whether a particular BCC size or location exists that encourages metastasis within the lymphatics.     

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.     

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.     

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.     

Minor stable carbon isotope fractionation between respired carbon dioxide and bulk soil organic matter during laboratory incubation of topsoil

A common assumption in paleoenvironmental reconstructions using soils is that the carbon isotope composition of soil-respired CO₂ is equivalent to the carbon isotope composition of bulk soil organic matter (SOM). However, the occurrence of a non-zero per mil carbon isotope enrichment factor between CO₂ and SOM (\(\varepsilon_{{{\text{CO}}_{ 2} - {\text{SOM}}}}\)) during soil respiration is the most widely accepted explanation for the down-profile increase in SOM δ¹³C values commonly observed in well-drained soils. In order to shed light on this apparent discrepancy, we incubated soil samples collected from the top 2 cm of soils with pure C₃ vegetation and compared the δ¹³C values of soil-respired CO₂ to the δ¹³C values of bulk SOM. Our results show near-zero \(\varepsilon_{{{\text{CO}}_{ 2} - {\text{SOM}}}}\) values (?0.3 to 0.4 ‰), supporting the use of paleosol organic matter as a proxy for paleo soil-respired CO₂. Significantly more negative \(\varepsilon_{{{\text{CO}}_{ 2} - {\text{SOM}}}}\) values are required to explain the typical δ¹³C profiles of SOM in well-drained soils. Therefore our results also suggest that typical SOM δ¹³C profiles result from either (1) a process other than carbon isotope fractionation between CO₂ and SOM during soil respiration or (2) \(\varepsilon_{{{\text{CO}}_{ 2} - {\text{SOM}}}}\) values that become increasingly negative as SOM matures.     

DFT study of nano zinc/copper voltaic cells

To facilitate the development of new materials for use in batteries, it is necessary to develop ab initio full-electron computational techniques for modeling potential new battery materials. Here, we tested density functional theory procedures that are accurate enough to obtain the energetics of a zinc/copper voltaic cell. We found the magnitude of the zero-point energy correction to be 0.01–0.2 kcal/mol per atom or molecule and the magnitude of the dispersion correction to be 0.1–0.6 kcal/mol per atom or molecule for Zn _n , (H₂O) _n , \( \mathrm{Zn}{\left({\mathrm{H}}_2\mathrm{O}\right)}_n^{2+} \), \( \mathrm{Cu}{\left({\mathrm{H}}_2\mathrm{O}\right)}_n^{2+} \), and Cu _n . Counterpoise correction significantly affected the values of ?\( {E}_n^{\mathrm{abs}} \), ?\( {E}_n^{\mathrm{coh}} \), and ?E^solv by 1.0–3.1 kcal/mol per atom or molecule at the B3PW91/6-31G(d) level of theory, but by only 0.04–0.4 kcal/mol per atom or molecule at the B3PW91/cc-pVTZ level of theory. The application of B3PW91/6-31G(d) yielded results that differed from macroscopic experimental values by 0.1–7.1 kcal/mol per atom or molecule, whereas applying B3PW91/cc-pVTZ produced results that differed from macroscopic experimental values by 0.1–4.8 kcal/mol per atom or molecule, with the smallest differences occurring for reactions with a small macroscopic experimental ?E and the largest differences occurring for reactions with a large macroscopic experimental ?E, implying size consistency.     

A new indicator-based many-objective ant colony optimizer for continuous search spaces

In this paper, we propose a novel multi-objective ant colony optimizer (called iMOACO\(_{\mathbb {R}}\)) for continuous search spaces, which is based on ACO\(_{\mathbb {R}}\) and the R2 performance indicator. iMOACO\(_{\mathbb {R}}\) is the first multi-objective ant colony optimizer (MOACO) specifically designed to tackle continuous many-objective optimization problems (i.e., multi-objective optimization problems having four or more objectives). Our proposed iMOACO\(_{\mathbb {R}}\) is compared to three state-of-the-art multi-objective evolutionary algorithms (NSGA-III, MOEA/D and SMS-EMOA) and a MOACO algorithm called MOACO\(_{\mathbb {R}}\) using standard test problems and performance indicators taken from the specialized literature. Our experimental results indicate that iMOACO\(_{\mathbb {R}}\) is very competitive with respect to NSGA-III and MOEA/D and it is able to outperform SMS-EMOA and MOACO\(_{\mathbb {R}}\) in most of the test problems adopted.     

Delay decomposition approach to $$\mathcal {H}_{\infty }$$ filtering analysis of genetic oscillator networks with time-varying delays

In this paper, the \(\mathcal {H}_{\infty }\) filtering problem is treated for N coupled genetic oscillator networks with time-varying delays and extrinsic molecular noises. Each individual genetic oscillator is a complex dynamical network that represents the genetic oscillations in terms of complicated biological functions with inner or outer couplings denote the biochemical interactions of mRNAs, proteins and other small molecules. Throughout the paper, first, by constructing appropriate delay decomposition dependent Lyapunov–Krasovskii functional combined with reciprocal convex approach, improved delay-dependent sufficient conditions are obtained to ensure the asymptotic stability of the filtering error system with a prescribed \(\mathcal {H}_{\infty }\) performance. Second, based on the above analysis, the existence of the designed \(\mathcal {H}_{\infty }\) filters are established in terms of linear matrix inequalities with Kronecker product. Finally, numerical examples including a coupled Goodwin oscillator model are inferred to illustrate the effectiveness and less conservatism of the proposed techniques.     

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.     

Transmission Fitness in Co-colonization and the Persistence of Bacterial Pathogens

Humans are often colonized by polymorphic bacteria such as Streptococcus pneumoniae, Bordetella pertussis, Staphylococcus Aureus, and Haemophilus influenzae. Two co-colonizing pathogen clones may interact with each other upon host entry and during within-host dynamics, ranging from competition to facilitation. Here we examine the significance of these exploitation strategies for bacterial spread and persistence in host populations. We model SIS epidemiological dynamics to capture the global behavior of such multi-strain systems, focusing on different parameters of single and dual colonization. We analyze the impact of heterogeneity in clearance and transmission rates of single and dual colonization and find the criteria under which these asymmetries enhance endemic persistence. We obtain a backward bifurcation near \(R_0 = 1\) if the reproductive value of the parasite in dually infected hosts is sufficiently higher than that in singly infected ones. In such cases, the parasite is able to persist even in sub-threshold conditions, and reducing the basic reproduction number below 1 would be insufficient for elimination. The fitness superiority in co-colonized hosts can be attained by lowering net parasite clearance rate (\(\gamma _\mathrm{{d}}\)), by increasing transmission rate (\(\beta _\mathrm{{d}}\)), or both, and coupling between these traits critically constrains opportunities of pathogen survival in the \(R_0<1\) regime. Finally, using an adaptive dynamics approach, we verify that despite their importance for sub-threshold endemicity, traits expressed exclusively in coinfection should generally evolve independently of single infection traits. In particular, for \(\beta _\mathrm{{d}}\) a saturating parabolic or hyperbolic function of \(\gamma _\mathrm{{d}}\), co-colonization traits evolve to an intermediate optimum (evolutionarily stable strategy, ESS), determined only by host lifespan and the trade-off parameters linking \(\beta _\mathrm{{d}}\) and \(\gamma _\mathrm{{d}}\). Our study invites more empirical attention to the dynamics and evolution of parasite life-history traits expressed exclusively in coinfection.     

Optimal Therapy Scheduling Based on a Pair of Collaterally Sensitive Drugs

Despite major strides in the treatment of cancer, the development of drug resistance remains a major hurdle. One strategy which has been proposed to address this is the sequential application of drug therapies where resistance to one drug induces sensitivity to another drug, a concept called collateral sensitivity. The optimal timing of drug switching in these situations, however, remains unknown. To study this, we developed a dynamical model of sequential therapy on heterogeneous tumors comprised of resistant and sensitive cells. A pair of drugs (DrugA, DrugB) are utilized and are periodically switched during therapy. Assuming resistant cells to one drug are collaterally sensitive to the opposing drug, we classified cancer cells into two groups, \(A_\mathrm{R}\) and \(B_\mathrm{R}\), each of which is a subpopulation of cells resistant to the indicated drug and concurrently sensitive to the other, and we subsequently explored the resulting population dynamics. Specifically, based on a system of ordinary differential equations for \(A_\mathrm{R}\) and \(B_\mathrm{R}\), we determined that the optimal treatment strategy consists of two stages: an initial stage in which a chosen effective drug is utilized until a specific time point, T, and a second stage in which drugs are switched repeatedly, during which each drug is used for a relative duration (i.e., \(f \Delta t\)-long for DrugA and \((1-f) \Delta t\)-long for DrugB with \(0 \le f \le 1\) and \(\Delta t \ge 0\)). We prove that the optimal duration of the initial stage, in which the first drug is administered, T, is shorter than the period in which it remains effective in decreasing the total population, contrary to current clinical intuition. We further analyzed the relationship between population makeup, \(\mathcal {A/B} = A_\mathrm{R}/B_\mathrm{R}\), and the effect of each drug. We determine a critical ratio, which we term \(\mathcal {(A/B)}^{*}\), at which the two drugs are equally effective. As the first stage of the optimal strategy is applied, \(\mathcal {A/B}\) changes monotonically to \(\mathcal {(A/B)}^{*}\) and then, during the second stage, remains at \(\mathcal {(A/B)}^{*}\) thereafter. Beyond our analytic results, we explored an individual-based stochastic model and presented the distribution of extinction times for the classes of solutions found. Taken together, our results suggest opportunities to improve therapy scheduling in clinical oncology.