Approximating subject-specific brain injury models via scaling based on head–brain morphological relationships

Biomechanics and Modeling in Mechanobiology - Most human head/brain models represent a generic adult male head/brain. They may suffer in accuracy when investigating traumatic brain injury (TBI) on...     

The Rosenzweig–MacArthur system via reduction of an individual based model

Journal of Mathematical Biology - The Rosenzweig–MacArthur system is a particular case of the Gause model, which is widely used to describe predator–prey systems. In the classical...     

A facile fluorescence turn-on biosensor customized for monitoring of protein kinase activity based on carboxylic carbon nanoparticle–peptide complexes

In this study, we present a facile and low-cost approach for detecting protein kinase A (PKA) by assembling a purpose-designed carboxyfluorescein (FAM)-labelled peptide with carboxylic carbon nanoparticles (CNPs). Fluorescence of the FAM-labelled peptide gradually decreases to a low background signal as a result of the electron transfer from CNPs to FAM-labelled peptide via the peptide, which acts as a bridge. The reaction in the sensor in the presence of adenosine 5′-triphosphate and PKA phosphorylates the substrate peptide and disrupts the electrostatic repulsive force between the CNPs and the peptide, therefore altering the spectroscopic signal of the system. The change in fluorescence signal was directly proportional to the PKA concentration in the range 0–1.8 U/ml with a detection limit of 0.04 U/ml. These results suggest that PKA activity can be effectively measured using the developed PKA biosensor. Moreover, the fluorescence biosensor was successfully used in the investigation of PKA in spiked human embryonic kidney (HEK) 293 cells lysates, indicating its potential applications in protein kinase-related biochemical fundamental research.     

New chemistry based on reduction of homobinuclear bis(μ-phosphido) metal complexes

Studies are reported on the chemical reduction of the homobinuclear bis(μ-phosphido) metal complexes ${(CO)}_3\stackrel{︹}{Fe{(\mu -P{R}_2)}_{2}F}e{(CO)}_3$ (R = Ph or Me), ${(NO)}_2-\stackrel{︹}{Fe{(\mu -PP{h}_2)}_{2}F}e{(NO)}_2$ and ${(CO)}_4\stackrel{︹}{M{(\mu -PP{h}_2)}_{2}M}{(CO)}_4$ (M = Mo or W). Two reduction pathways have been observed which result in different two-electron transformations: (1) with Na or LiAlH₄, electron transfer to yield the corresponding symmetric dianions of the type L_nM(μ-PR₂)₂ML_n^2? without metalmetal bond and (2) with M′BR′₃H(M′ = Li, Na, or K; R′ = Et or sec-Bu), hydride transfer to give monoanionic complexes of the type $L_n\stackrel{︹}{M(\mu -P{R}_2)(\mu -L)M}{L}_{n?1}{(P{R}_{2}H)}^{?}$ or $L_n\stackrel{︹}{M(\mu -P{R}_2)M}{L}_n{(P{R}_{2}H)}^{?}$ (M = Fe, Mo, or W; L = CO or NO; R = Ph or Me). The monoanionic complexes can be deprotonated with n-BuLi at ?78 °C to the corresponding unsymmetric dianions $L_n\stackrel{︹}{M(\mu -P{R}_2)(\mu -L)M}{L}_{n?1}{(P{R}_2)}^{2?}$ (M = Fe; L = CO or NO; R = Ph) or symmetric dianions L_nM(μ-PR₂)₂ML_n^2? (M = Mo or W; L = CO; R = Ph). The unsymmetric dianions isomerize on slight warming to the symmetric dianions, which undergo protonation by CF₃COOH to yield the aforementioned monoanions. Reactions of several members of these three classes of binuclear anions with CF₃COOH, alkylating reagents, 1,1-diiodohydrocarbons and metal diiodo complexes have resulted in the synthesis of new binuclear and trinuclear compounds. Examples include ${(CO)}_3(H)\stackrel{︹}{Fe(\mu -PP{h}_2)Fe}{(CO)}_3(PP{H}_{2}H)$, ${(CO)}_3\stackrel{︹}{Fe(\mu -PP{h}_2)(\mu -C(R)O)Fe}{(CO)}_2(PP{h}_{2}R)$ (R = Me, Et, n-Pr, or i-Pr), ${(CO)}_4\stackrel{︹}{M{(\mu -PP{h}_2)}_{2}M}{(CO)}_3(C(R)Ome)$ (M = Mo or W; R = Me or Ph), ${(CO)}_2({\eta }^3?C_3{H}_5)\stackrel{︹}{Fe(\mu ?PP{h}_2)?F}e{(CO)}_3(PP{h}_2{C}_3{H}_5)$, ${(CO)}_4\stackrel{︹}{M{(\mu ?PP{h}_2)}_{2}M}{(CO)}_3(C(R)Ome)$, ${(NO)}_2\stackrel{︹}{Fe(\mu ?C{H}_2)(\mu ?P{h}_{2}PPP{h}_2)Fe}{(NO)}_2$, and Fe₂Co(η⁵-C₅H₅)(CO)(NO)₄(μ-PPh₂)₂. Synthetic and mechanistic studies on these reactions are presented.     

In vitro hepatic steatosis model based on gut–liver-on-a-chip

Hepatic steatosis, also known as fatty liver disease, occurs due to abnormal lipid accumulation in the liver. It has been known that gut absorption also plays an important role in the mechanism underlying hepatic steatosis. Conventional in vitro cell culture models have limitations in recapitulating the mechanisms of hepatic steatosis because it does not include the gut absorption process. Previously, we reported development of a microfluidic gut–liver chip that can recapitulate the gut absorption of fatty acids and subsequent lipid accumulation in liver cells. In this study, we performed a series of experiments to verify that our gut–liver chip reproduces various aspects of hepatic steatosis. The absorption of fatty acids was evaluated under various culture conditions. The anti-steatotic effect of turofexorate isopropyl (XL-335) and metformin was tested, and both drugs showed different action mechanisms. In addition, the oxidative stress induced by lipid absorption was evaluated. Our results demonstrate the potential of the gut–liver chip for use as a novel, physiologically realistic in vitro model to study fatty liver disease.     

Finite element–based injury metrics for pulmonary contusion via concurrent model optimization

This study explores the relationship between impact severity and resulting pulmonary contusion (PC) for four impact conditions using a rat model of the injury. The force–deflection response from a Finite Element (FE) model of the lung was simultaneously matched to experimental data from distinct impacts via a genetic algorithm optimization. Sprague-Dawley rats underwent right-side thoracotomy prior to impact. Insults were applied directly to the lung via an instrumented piston. Five cohorts were tested: a sham group and four groups experiencing lung insults of varying degrees of severity. The values for impact velocity (V) and penetration depth (D) of the cohorts were Group 1, (V = 6.0 m · s⁻¹, D = 5.0 mm), Group 2, (V = 1.5 m · s⁻¹,D = 5.0 mm), Group 3, (V = 6 m · s⁻¹, D = 2.0 mm), and Group 4, (V = 1.5 m · s⁻¹, D = 2.0 mm). CT scans were acquired at 24 h, 48 h, and 1 week post-insult. Contusion volume was determined through segmentation. FE-based injury metrics for PC were determined at 24 h and 1 week post-impact, based on the observed volume of contusion and first principal strain. At 24 h post-impact, the volume of high radiopacity lung (HRL) was greatest for the severe impact group (mean HRL = 9.21 ± 4.89) and was significantly greater than all other cohorts but Group 3. The concurrent optimization matched simulated and observed impact energy within one standard deviation for Group 1 (energy = 3.88 ± 0.883 mJ, observed vs. 4.47 mJ, simulated) and Group 2 (energy = 1.46 ± 0.403 mJ, observed vs. 1.50 mJ, simulated) impacts. Statistically significant relationships between HRL and impact energy are presented. The FEA-based injury metrics at 24 h post-contusion are e_max·[(e)\dot]_max{\varepsilon_{\max}\cdot \dot {\varepsilon}_{\max}} exceeding 94.5 s⁻¹, ε _max exceeding 0.284 and [(e)\dot]_max{\dot{\varepsilon}_{\max}} exceeding 470 s⁻¹. Thresholds for injury to the lung still present at 1 week post-impact were also determined. They are e_max·[(e)\dot]_max{\varepsilon_{\max}\cdot \dot {\varepsilon}_{\max}} exceeding 149 s⁻¹, ε _max exceeding 0.343 and [(e)\dot]_max{\dot{\varepsilon}_{\max}} exceeding 573 s⁻¹. A mesh sensitivity study found that thresholds based on strain rate were more sensitive to changes to mesh density than the threshold based on strain only.     

Impact of Perinatal Systemic Hypoxic–Ischemic Injury on the Brain of Male Offspring Rats: An Improved Model of Neonatal Hypoxic–Ischemic Encephalopathy in Early Preterm Newborns

In this study, we attempted to design a model using Sprague-Dawley rats to better reproduce perinatal systemic hypoxic-ischemic encephalopathy (HIE) in early preterm newborns. On day 21 of gestation, the uterus of pregnant rats were exposed and the blood supply to the fetuses of neonatal HIE groups were thoroughly abscised by hemostatic clamp for 5, 10 or 15 min. Thereafter, fetuses were moved from the uterus and manually stimulated to initiate breathing in an incubator at 37 °C for 1 hr in air. We showed that survival rates of offspring rats were decreased with longer hypoxic time. TUNEL staining showed that apoptotic cells were significant increased in the brains of offspring rats from the 10 min and 15 min HIE groups as compared to the offspring rats in the control group at postnatal day (PND) 1, but there was no statistical difference between the offspring rats in the 5 min HIE and control groups. The perinatal hypoxic treatment resulted in decreased neurons and increased cleaved caspase-3 protein levels in the offspring rats from all HIE groups at PND 1. Platform crossing times and the percentage of the time spent in the target quadrant of Morris Water Maze test were significantly reduced in the offspring rats of all HIE groups at PND 30, which were associated with decreased brain-derived neurotrophic factor levels and neuronal cells in the hippocampus of offspring rats at PND 35. These data demonstrated that perinatal ischemic injury led to the death of neuronal cells and long-lasting impairment of memory. This model reproduced hypoxic ischemic encephalopathy in early preterm newborns and may be appropriate for investigating therapeutic interventions.     

Structural investigations on the lignin–carbohydrate complexes of Lolium perenne

1. Lignin-carbohydrate complexes isolated from leaf blade, leaf sheath and stem tissue of ryegrass by extraction with dimethyl sulphoxide were examined by fractionation procedures. Although the complexes are heterogeneous, heterogeneity is shown only in the ratio of the individual monosaccharide residues and not in the ratio of lignin to carbohydrate. 2. The molecular weight of the complexes is high (>/=150000), but chemical modification by alkaline hydrolysis, borohydride reduction or lead tetra-acetate oxidation does not drastically decrease it. Low-molecular-weight fragments released by alkaline treatment were shown to contain acetic acid, ferulic acid and p-coumaric acid. 3. On the basis of the chemical stability of the complexes, it is postulated that at least three types of bonding may be present between lignin and carbohydrate, namely one cleaved on borohydride reduction, another cleaved by alkali and a linkage resistant to alkali. 4. The carbohydrate portion of the complexes is composed of beta-(1-->4)-linked d-glucose residues (cellulose) and beta-(1-->4)-linked chains of xylose residues. Side chains involving arabinose and galactose residues are linked to C-3 of some of the xylose residues. 5. How the components of the complexes are held together is not certain, but it is suggested that the phenolic acids may act as cross-linking agents.     

Study on properties of liquid ammonia via molecular dynamics simulation based on ABEEMσπ polarisable force field

Abstract

The molecular dynamics simulation has been performed to investigate the charge distribution, structural and dynamical properties of liquid ammonia at 273 K using a polarisable force field of the atom-bond electronegativity equalisation method (ABEEMσπ). One ammonia molecule in this model has eight charge sites, one N atomic site, three H atomic sites, three N–H bond sites and one lone-pair electron site. ABEEMσπ model can present the quantitative site charges of molecular ammonias in liquid and their changing in response to their surroundings. The radial distribution functions and dynamical properties are in fair agreement with the available experimental data. The first peak of g_NN(r) appears at N–N distance of ~3.50 ± 0.05 Å where most hydrogen bonds are formed. The average coordination number of the first shell is 13.0 ± 0.1 among which a central ammonia molecule intimately connects 3 ~ 4 ammonia molecules by hydrogen bonds. The power spectrum shows the vibrations of hydrogen bonds. For a reference, a simple estimation of the average hydrogen bonding energy in liquid ammonia is 6.5 ± 0.1 kcal/mol larger than 3.8 ± 0.3 kcal/mol in dimer ammonia. Our simulation results provide more detailed information about liquid ammonia.     

Structures of inclusion complexes of halogenbenzoic acids and α-cyclodextrin based on AM1 calculations

Semi-empirical quantum mechanics calculations using AM1 (Austin Method 1) were carried out for various host-guest combinations of α-cyclodextrin and mono-halogen benzoic acids. The energetically favorable inclusion structures were identified. The AM1 results show that α-cyclodextrin complexes with mono-halogen benzoic acid acids (where the halogen is chlorine, bromide, iodine) as guest compounds are more stable in the “head first” position than in the “tail-first” position for meta and para isomers while ortho mono-halogen benzoic acids complexes with α-cyclodextrin are more stable in “tail-first” position. The calculated structures were found to be in good agreement with those obtained from crystalographic databases.      

Neuroprotection of Up-Regulated Carbon Monoxide by Electrical Acupuncture on Perinatal Hypoxic–Ischemic Brain Damage in Rats

This study investigated the neuroprotection and potential mechanism of carbon monoxide (CO) against perinatal hypoxic–ischemic brain damage in rats by electrical acupuncture (EA). Animal behavior, morphological changes, cystathionine beta-synthase (CBS), hypoxia-inducible factor-1α (HIF-1α), and heme oxygenase-1 (HO-1) expression levels, and CO content in rat cortex cells were determined. Results demonstrated that EA treatment decreased the slope behavior and increased the overhang behavior of perinatal rats. The treatment also decreased the number of positive cells. The activator and inhibitor of CBS aggravated and remitted the hypoxic damage in cortex cells, respectively. EA treatment decreased CBS expression level and increased HO-1 and HIF-1α expression levels in perinatal rat cortex cells. Compared with the control groups, the CO content of cortex cells in the EA treatment group significantly increased (**p < 0.01). We hypothesized that EA treatment increases cortical CO content to protect against hypoxic damage via the hydrogen sulfide/CBS–CO/HO-1–HIF-1α system. This study provided a significant reference for EA therapy and cued a novel protective mechanism for cerebral palsy.     

Effect of electrolytes and of distilled water on antigen–antibody complexes

Specific immune precipitates dissolve in concentrated solutions of alkali-metal halides, and of alkaline-earth-metal halides and thiocyanates. The quantity of protein dissolved depends on the nature of the antigen-antibody system, on the proportion of the antigen in the precipitate, and on the avidity of the antibody. The extent of solubilization is a function of the temperature, of the volume of solution used and of the concentration of the ions in the solution, and also depends on the nature of these ions. The dissolving power of bivalent cations is greater than that of monovalent ones, and is as follows: Mg(2+)[unk]Ba(2+)[unk]Ca(2+)[unk]Sr(2+). Antigen-antibody complexes and free antibodies, but no free antigen, are detected in supernatants of specific precipitates dissolved in solutions of electrolytes of low ionic strength. Antigen-antibody complexes, free antibodies and also free antigen are detected in supernatants of specific precipitates dissolved in solutions of electrolytes of high ionic strength. Comparable results are obtained when the electrolyte solutions are studied for their effect on the bonds formed between an antibody and its corresponding immunosorbent. Moreover, in the latter case, 50% of the fixed antibodies could be recovered by elution with distilled water.     

Herfindahl–Hirschman Index based performance analysis on the convergence development

The converging performance of culture industry and financial industry in Beijing is an essential method to transform the way of Beijing economic development and promote culture industry into an economic pillar industry of Beijing. Based on this, this paper starts from the convergence status quo of culture industry and finance industry in Beijing, adopts Herfindahl–Hirschman Index (HHI) and input–output analysis to respectively study the converging degree between them. The results are that the converging degree of them is not high, the financial contribution to the industry convergence is not enough and the converging performance is far from expectations for government. In conclusion, this paper puts forward some policy suggestions to improve the convergence of culture industry and finance industry in Beijing.     

Electron-paramagnetic-resonance studies on cobalt(II) carbonic anhydrase–sulphonamide complexes

Sulphonamide adducts of three Co(II) carbonic anhydrases were investigated by e.p.r. (electron paramagnetic resonance) at helium temperatures. The highly anisotropic 9 GHz spectra exhibited only three distinct features, with g values between 6.3 and 1.5. Such spectra arise from an electronic state with effective spin S'=(1/2), indicating that the high-spin (S=3/2) ground level is split into two spin doublets differing in energy by an amount large compared with the microwave quantum, but small in relation to thermal energies at ambient temperature. This situation would occur in a tetrahedral system suffering a large rhombic distortion. Calculations based on this model accounted for apparent discrepancies in integrated spectral intensities, and yielded magnetic moments in good agreement with independent measurements, especially in the case of certain small Co(II) complexes resembling the enzyme adducts in their e.p.r. signals. Precise sets of g values, reflecting a particular co-ordination geometry, were found to be representative of each enzyme variant and the type of sulphonamide inhibitor, whether benzocyclic or heterocyclic. A series of substituted benzene sulphonamides bound to the same enzyme gave rise to closely similar spectra despite a wide range of pK(i) values. Thus benzocyclic and heterocyclic sulphonamides were evidently held in the active-site cleft in characteristic orientations irrespective of side chains that might considerably influence the total binding strength. Visible absorption spectra of various sulphonamide adducts at room temperature showed a similar pattern of inhibitor dependence to the e.p.r. spectra, suggesting a correspondence between the co-ordination structures in liquid and frozen solution. E.p.r. spectra of the sulphonamide complexes were remarkable not only for their range of g values, but also for their variations in line-width and spin-lattice relaxation behaviour. Addition of glycerol to the medium produced marked enhancement in resolution, owing to the creation of a more homogeneous frozen matrix. The non-uniform spin relaxation was probably a consequence of the large anisotropy in effective g tensor.     

Protein complex prediction based on maximum matching with domain–domain interaction

With the development of high-throughput methods for identifying protein–protein interactions, large scale interaction networks are available. Computational methods to analyze the networks to detect functional modules as protein complexes are becoming more important. However, most of the existing methods only make use of the protein–protein interaction networks without considering the structural limitations of proteins to bind together. In this paper, we design a new protein complex prediction method by extending the idea of using domain–domain interaction information. Here we formulate the problem into a maximum matching problem (which can be solved in polynomial time) instead of the binary integer linear programming approach (which can be NP-hard in the worst case). We also add a step to predict domain–domain interactions which first searches the database Pfam using the hidden Markov model and then predicts the domain–domain interactions based on the database DOMINE and InterDom which contain confirmed DDIs. By adding the domain–domain interaction prediction step, we have more edges in the DDI graph and the recall value is increased significantly (at least doubled) comparing with the method of Ozawa et al. (2010) [1] while the average precision value is slightly better. We also combine our method with three other existing methods, such as COACH, MCL and MCODE. Experiments show that the precision of the combined method is improved. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction.     

Spatial velocity distributions in pulse-wave propagation based on fluid–structure interaction

In this paper, spatial velocity distributions in pulse-wave propagation based on a fluid–structure interaction model are presented. The investigation is performed using the assumption of laminar flow and a linear-elastic wall. The fluid–structure interaction scheme is constructed using the finite element method. The results show that velocity distributions embody an obvious time delay in an elastic tube model. Further, the fully developed flow is delayed and the velocity values are increased in comparison with a rigid tube model. The increase in the wall thickness makes the time delay between the velocity peaks of different sites smaller while the time delay between the velocity minima is unchanged. Similarly, the time delay between the velocity bottoms is more easily found when decreasing the internal radius. The model gives valid results for spatial velocity distributions, which provide important information for wave propagation.     

Structure–activity relationship exploration of Kv1.3 blockers based on diphenoxylate

Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC₅₀ values.     

Identification of lamin B–regulated chromatin regions based on chromatin landscapes

Lamins, the major structural components of the nuclear lamina (NL) found beneath the nuclear envelope, are known to interact with most of the nuclear peripheral chromatin in metazoan cells. Although NL–chromatin associations correlate with a repressive chromatin state, the role of lamins in tethering chromatin to NL and how such tether influences gene expression have remained challenging to decipher. Studies suggest that NL proteins regulate chromatin in a context-dependent manner. Therefore understanding the context of chromatin states based on genomic features, including chromatin–NL interactions, is important to the study of lamins and other NL proteins. By modeling genome organization based on combinatorial patterns of chromatin association with lamin B1, core histone modification, and core and linker histone occupancy, we report six distinct large chromatin landscapes, referred to as histone lamin landscapes (HiLands)-red (R), -orange (O), -yellow (Y), -green (G), -blue (B), and -purple (P), in mouse embryonic stem cells (mESCs). This HiLands model demarcates the previously mapped lamin-associated chromatin domains (LADs) into two HiLands, HiLands-B and HiLands-P, which are similar to facultative and constitutive heterochromatins, respectively. Deletion of B-type lamins in mESCs caused a reduced interaction between regions of HiLands-B and NL as measured by emerin–chromatin interaction. Our findings reveal the importance of analyzing specific chromatin types when studying the function of NL proteins in chromatin tether and regulation.