Digital smart internal fixation surgery for coronal process basal fracture with normal joint spaces or radius-shortening: Occult factor of radius-ulna load sharing.

BACKGROUND: Reasonable postoperative humeroradial and humeroulnar joint spaces maybe an important indicator in biomechanical stability of smart internal fixation surgery for coronoid process basal fractures (CPBF). The aim of this study is to compare elbow articular stresses and elbow-forearm stability under smart internal fixations for the CPBF between normal elbow joint spaces and radius-shortening, and to determine the occult factor of radius-ulna load sharing. METHODS: CT images of 70 volunteers with intact elbow joints were retrospectively collected for accurate three-dimensional reconstruction to measure the longitudinal and transverse joint spaces. Two groups of ten finite element (FE) models were established prospectively between normal joint space and radius-shortening with 2.0 mm, including intact elbow joint and forearm, elbow-forearm with CPBF trauma, anterior or posterior double screws-cancellous bone fixation, mini-plate-cancellous bone fixation. Three sets of physiological loads (compression, valgus, varus) were used for FE intelligent calculation, FE model verification, and biomechanical and motion analysis. RESULTS: The stress distribution between coronoid process and radial head, compression displacements and valgus angles of elbow-forearm in the three smart fixation models of the normal joint spaces were close to those of corresponding intact elbow model, but were significantly different from those of preoperative CPBF models and fixed radius-shortening models. The maximum stresses of three smart fixation instrument models of normal joint spaces were significantly smaller than those of the corresponding fixed radius-shortening models. CONCLUSIONS: On the basis of the existing trauma of the elbow-forearm system in clinical practice, which is a dominant factor affecting radius-ulna load sharing, the elbow joint longitudinal space has been found to be the occult factor affecting radius-ulna load sharing. The stability and load sharing of radius and ulna after three kinds of smart fixations of the CPBF is not only related to the anatomical and biomechanical stability principles of smart internal fixations, but also closely related to postoperative elbow joint longitudinal space.

Focal opening of the neuronal plasma membrane by shock-induced bubble collapse for drug delivery: a coarse-grained molecular dynamics simulation.

Cell permeabilization using shock-induced bubble collapse provides an attractive choice for drug delivery systems. In this work, based on a realistically human brain plasma membrane (PM) model, we investigated the focal opening of this complex model by the jet from cavitation, focusing on the effect of characteristic membrane components, particle velocity (up) and bubble diameters (D). Both high levels of cholesterol and specific cerebrosides in the PM model limit the pore opening of cavitation jets. Sphingomyelin is the opposite, but has little effect due to its low content. Two adjustable parameters of up and D can be coupled to control the opening size. The relationship between them and the maximum pore area was provided for the first time. The maximum pore area increases with the up (or the impulse that is positively related to up) in the low-speed range, which agrees with the experimentally observed impulse determinism. However, the maximum area drops in the high-speed range. Combined with D, we proposed that the jet size determines the pore size, not the impulse. Larger bubbles that can create a larger pore in the membrane have a larger jet size, but their impulse is relatively small. Finally, the recovery simulation shows that the membrane with a small pore can be quickly recovered within 300 ps, while that with a larger pore did not recover until 2 µs. These rules from this work may be helpful to optimize the choice of shock waves for the delivery of different drugs across membranes.

How Shockwaves Open Tight Junctions of Blood-Brain Barrier: Comparison of Three Biomechanical Effects.

Revealing how blast shockwaves open the tight junction of the blood-brain barrier (BBB) is very important for understanding blast-induced traumatic brain injury (bTBI) and shockwave-assisted drug delivery; however, the underlying mechanism remains unresolved. Here, we used multiscale molecular dynamics simulations to reveal the disruption mechanism of claudin-5 protein in a relatively complex BBB model by comparing three typical effects from blast loads. The results showed that the opening of claudin-5 did not result from the direct compressive loading of the single shockwave but from indirect cavitation and stretching effects induced by shockwaves. Importantly, stretch-mediated mechanical opening from the asymmetric distribution of overpressure in temporal and spatial dimensions is a novel damage mode. In detail, the nanojet from the cavitation pushed away two adjacent endothelial cell membranes and the embedded claudin-5 was rapidly stretched. Even α-helix showed a drastic conformational breakdown and its content was only 15.9%. Structural changes of this magnitude are difficult to repair in a short time, which may be related to chronic BBB dysfunction and persistent neurological deficits. This is a more common injury, since the tensile response of membranes to blast loads is relatively common. Taken together, we provided a biomechanical underpinning for acute disruption of tight junction proteins in BBB from exposure to blast shockwaves, and this may be helpful as a therapeutic strategy for bTBI.

Extreme Membrane Tensile Loads Induce Half-Activation of the Thermosensitive TRPV1 Channel.

Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels convert a wide range of physical and chemical stimuli into channel opening is essential to understanding their normal function. Here, half-activation of thermosensitive TRPV1 channel under extreme membrane stretching from blast loads was provided by molecular dynamics simulations. The results show that such extreme membrane stretch loading will only lead to half-activation of the TRPV1 channel: that is, the upper gate is open for high-speed stretching (>15m/s), but the lower gate is still closed. The corresponding activation threshold also depends on both the tensile speed and the area strain. This means that the direct mechanical gating of TRP channels in one step is unlikely to occur.

A Novel Gating Mechanism of Aquaporin-4 Water Channel Mediated by Blast Shockwaves for Brain Edema.

As the principal water channel in the brain, aquaporin-4 (AQP4) plays a vital role in brain edema, but its role in blast brain edema is unclear. On the basis of molecular simulations, we reveal the atomically detailed picture of AQP4 in response to blast shockwaves. The results show that the shockwave alone closes the AQP4 channel; however, shock-induced bubble collapse opens it. The jet from bubble collapse forcefully increases the distance between helices and the tilt angles of six helices relative to the membrane vertical direction in a very short time. The average channel size increases about 2.6 times, and the water flux rate is nearly 20 times higher than for normal states. It is responsible for abnormal water transport and a potential cause of acute blast brain edema. Additionally, the open AQP4 channel quickly returns to its normal state, which is in turn helpful for edema absorption. Thus, a novel gating mechanism for AQP4 related to the secondary structure change has been provided, which is different from the previous residue-mediated gating mechanism.

The effects of molecular weight and orientation on the membrane permeation and partitioning of polycyclic aromatic hydrocarbons: a computational study.

Membrane permeation and the partitioning of polycyclic aromatic hydrocarbons (PAHs) are crucial aspects affecting their carcinogenicity and mutagenicity. However, a clear understanding of these processes is still rare due to the difficulty of determining the details experimentally. Here, the interactions between PAHs and lipid bilayers were studied by molecular simulations, mainly to check the influence of molecular weight and orientation. The liposome-water partition coefficient (KLW), transmembrane time (τ), and permeability coefficient (P) of the PAHs were calculated by integrating free energy profiles from umbrella sampling. For selected PAHs, the membrane adsorption is a spontaneous process. The preferred location is near the CC bond and the orientation is related to the molecular structure. The P values of all the PAHs are basically the same order of magnitude, which means that the molecular weight contributes little to the process. As for KLW and τ, they show obvious increases with different molecular weights. Unconstrained simulations showed that a flat orientation on the membrane surface would prevent PAHs from being transported through the membrane. Highly hydrophobic driving forces are not always good for the absorption of PAHs, especially the formation of aggregates. In addition, the orientations and energetic barriers of PAHs near the midplane of the lipid bilayer explain the different transitions of high- and low-weight PAHs. This work provides molecular level details relating to the interactions of PAHs with lipid membranes, with significance for understanding the health effects of PAHs.

Impact of Lipid Peroxidation on the Response of Cell Membranes to High-Speed Equibiaxial Stretching: A Computational Study.

The difference between diseased and healthy cellular membranes in response to mechanical stresses is crucial for biology, as well as in the development of medical devices. However, the biomolecular mechanisms by which mechanical stresses interact with diseased cellular components remain largely unknown. In this work, we focus on the response of diseased cellular membranes with lipid peroxidation to high-speed tensile loadings. We find that the critical areal strain (ξc, when the pore forms) is highly sensitive to lipid peroxidation. For example, ξc of a fully oxidized bilayer is only 64 and 69% of the nonoxidized one at the stretching speed of 0.1 and 0.6 m/s, respectively. ξc decreases with the increase in the oxidized lipid ratio, regardless of the speeds. Also, the critical rupture tension of membranes exhibits a similar change. It is obvious that the oxidized membranes are more easily damaged than normal ones by high-speed stretching, which coincides with experimental findings. The reason is that peroxidation introduces a polar group to the tail of lipids, increases the hydrophilicity of tails, and warps the tails to the membrane-water interface, which causes loose accumulation and disorder of lipid tails. This can be deduced from the variation in the area per lipid and order parameter. In addition, the lowering stretching modulus and line tension of membranes (i.e., softening) after lipid peroxidation is also a significant factor. We reveal the difference between the peroxidized (diseased) and normal membrane in response to high-speed stretching, give the ξc value in the pore formation of membranes and analyze the influence of the stretching speed, peroxidation ratio, and molecular structure of phospholipids. We hope that the molecular-level information will be useful for the development of biological and medical devices in the future.

Impact of Shock-Induced Cavitation Bubble Collapse on the Damage of Cell Membranes with Different Lipid Peroxidation Levels.

Although the interaction mechanism between shock waves and cells is critical for advancing the medical applications of shock waves, we still have little understanding about it. This work aims to study the response of diseased cells subjected to lipid peroxidation to the nanojet from shock wave-induced bubble collapse by using the coarse-grained molecular dynamics simulation. Factors considered in the simulations include the shock velocity (up), movement time of piston (τp), bubble size (R), and peroxidation level of membranes. Here, we mainly focus on the role of peroxidation levels, that is, the degree (%) and the distribution of oxidized lipids in membranes. The results indicate that the shock damage threshold (up at which the pore in membranes is formed) of peroxidation membranes is less than that of normal membranes and decreases with the peroxidation degree. Importantly, the distribution of oxidized lipids has more effect on the damage threshold than the peroxidation degree. The threshold of membrane with 33% localized oxidized lipids is lower than that of membrane with 50% average oxidized lipids. The results can be explained by the stretching modulus (κs) and bending modulus (κb) of cell membranes. For example, the κb value (4.3 × 10-20 J) of 100% peroxidation membrane is about half of that (8.4 × 10-20 J) of a membrane without peroxidation. A lower modulus means high deformation under the same impact. Further analysis shows that peroxidation introduces a polar hydrophobic group to the tail of phospholipids that increases the hydrophilicity of tails and warps the tail of phospholipids toward the membrane-water interface, resulting in looser accumulation. This can be confirmed by the increased average phospholipid area with peroxidation levels. Indeed, most of the pores formed during the shock can heal. However, the permeation of water molecules across the healing membrane still increased. All these membrane-level information obtained from this study will be useful for improving the biomedical applications of shock waves.

A Density Functional Theory Study toward Ring-Opening Reaction Mechanisms of 2,4,6-Trinitrotoluene's Meisenheimer Complex for the Biodegradation of Old Yellow Enzyme Flavoprotein Reductase.

The subsequent degradation pathway of the dihydride-Meisenheimer complex (2H--TNT), which is the metabolite of 2,4,6-trinitrotoluene (TNT) by old yellow enzyme flavoprotein reductases of yeast and bacteria, was investigated computationally at the SMD/TPSSH/6-311+G(d,p) level of theory. Combining the experimentally detected products, a series of protonation, addition, substitution (dearomatization), and ring-opening reaction processes from 2H--TNT to alkanes were proposed. By analyzing reaction free energies, we determined that the protonation is more advantageous thermodynamically than the dimerization reaction. In the ring-opening reaction of naphthenic products, the water molecule-mediated proton transfer mechanism plays a key role. The corresponding activation energy barrier is 37.7 kcal·mol-1, which implies the difficulty of this reaction. Based on our calculations, we gave an optimum pathway for TNT mineralization. Our conclusions agree qualitatively with available experimental results. The details on transition states, intermediates, and free energy surfaces for all proposed reactions are given and make up for a lack of experimental knowledge.

iDHS-DSAMS: Identifying DNase I hypersensitive sites based on the dinucleotide property matrix and ensemble bagged tree.

DNase I hypersensitive site (DHS) is related to DNA regulatory elements, so the understanding of DHS sites is of great significance for biomedical research. However, traditional experiments are not very good at identifying recombinant sites of a large number of emerging DNA sequences by sequencing. Some machine learning methods have been proposed to identify DHS, but most methods ignore spatial autocorrelation of the DNA sequence. In this paper, we proposed a predictor called iDHS-DSAMS to identify DHS based on the benchmark datasets. We develop a feature extraction method called dinucleotide-based spatial autocorrelation (DSA). Then we use Min-Redundancy-Max-Relevance (mRMR) to remove irrelevant and redundant features and a 100-dimensional feature vector is selected. Finally, we utilize ensemble bagged tree as classifier, which is based on the oversampled datasets using SMOTE. Five-fold cross validation tests on two benchmark datasets indicate that the proposed method outperforms its existing counterparts on the individual accuracy (Acc), Matthews correlation coefficient (MCC), sensitivity (Sn) and specificity (Sp).