Effect of collagenase–gelatinase ratio on the mechanical properties of a collagen fibril: a combined Monte Carlo–molecular dynamics study

Loading in cartilage is supported primarily by fibrillar collagen, and damage will impair the function of the tissue, leading to pathologies such as osteoarthritis. Damage is initiated by two types of matrix metalloproteinases, collagenase and gelatinase, that cleave and denature the collagen fibrils in the tissue. Experimental and modeling studies have revealed insights into the individual contributions of these two types of MMPs, as well as the mechanical response of intact fibrils and fibrils that have experienced random surface degradation. However, no research has comprehensively examined the combined influences of collagenases and gelatinases on collagen degradation nor studied the mechanical consequences of biological degradation of collagen fibrils. Such preclinical examinations are required to gain insights into understanding, treating, and preventing degradation-related cartilage pathology. To develop these insights, we use sequential Monte Carlo and molecular dynamics simulations to probe the effect of enzymatic degradation on the structure and mechanics of a single collagen fibril. We find that the mechanical response depends on the ratio of collagenase to gelatinase—not just the amount of lost fibril mass—and we provide a possible mechanism underlying this phenomenon. Overall, by characterizing the combined influences of collagenases and gelatinases on fibril degradation and mechanics at the preclinical research stage, we gain insights that may facilitate the development of targeted interventions to prevent the damage and loss of mechanical integrity that can lead to cartilage pathology.

     

Using human brain lesions to infer function: a relic from a past era in the fMRI age?

Recent technological advances, such as functional imaging techniques, allow neuroscientists to measure and localize brain activity in healthy individuals. These techniques avoid many of the limitations of the traditional method for inferring brain function, which relies on examining patients with brain lesions. This has fueled the zeitgeist that the classical lesion method is an inferior and perhaps obsolescent technique. However, although the lesion method has important weaknesses, we argue that it complements the newer activation methods (and their weaknesses). Furthermore, recent developments can address many of the criticisms of the lesion method. Patients with brain lesions provide a unique window into brain function, and this approach will fill an important niche in future research.     

Is there a gender difference of somatostatin-receptor density in the human brain?

Animal experiments and observations in human brains have convincingly shown that sexual differentiation not only concerns the genitalia but also the brain. This has been investigated also in the light of a possible explanation of a presumed biological aetiology of transsexuality. The volume of the central subdivision of the bed nucleus of the stria terminalis, a brain area that is essential for sexual behaviour, has been reported to be larger in men than in women. Additionally, the number of somatostatin expressing neurons in this region was shown to be higher in men than in women. As neuronal production of somatostatin is involved the idea is striking whether somatostatin-receptor density in the cortex of cerebral hemispheres might be related to gender identity. We investigated in vivo the density of somatostatin-receptors in selected regions of the human brain in both sexes by means of receptor scintigraphy. Basal ganglia tracer uptake of 111-In-Pentreotide was equally low in both genders at 0,80% +/ 0,26 (related to tracer uptake of the whole brain layer). Temporal cortex accumulated at 2,9% +/ 1,1 in men and at 2,3% +/ 0,76 in women. Frontal brain region had an uptake of 3,0% +/ 1,4 in male and of 2,5% +/ 1,3 in female. This shows a tendency in males for relatively augmented uptake indicating higher somatostatin receptor density in temporal and frontal cerebral cortex.     

Effect of the A30P mutation on the structural dynamics of micelle-bound αSynuclein released in water: a molecular dynamics study

Atomistic molecular dynamics simulation has been used to probe the effect of the A30P mutation on the structural dynamics of micelle-bound, helical αSynuclein when released in an aqueous environment. On the timescales simulated, the effect of the mutation on the secondary structure is restricted to local changes close to the mutation site in the N-terminal helical domain. The changes are transient, and all residues except Lys23 recover their initial structure. The local behavior due to the mutation gives rise to a global difference in the A30P mutant in the form of a permanent kink in the N-terminal helical domain.     

IB–LBM simulation of the haemocyte dynamics in a stenotic capillary

To study the behaviour of a haemocyte when crossing a stenotic capillary, the immersed boundary–lattice Boltzmann method was used to establish a quantitative analysis model. The haemocyte was assumed to be spherical and to have an elastic cell membrane, which can be driven by blood flow to adopt a highly deformable character. In the stenotic capillary, the spherical blood cell was stressed both by the flow and the wall dimension, and the cell shape was forced to be stretched to cross the stenosis. Our simulation investigated the haemocyte crossing process in detail. The velocity and pressure were anatomised to obtain information on how blood flows through a capillary and to estimate the degree of cell damage caused by excessive pressure. Quantitative velocity analysis results demonstrated that a large haemocyte crossing a small stenosis would have a noticeable effect on blood flow, while quantitative pressure distribution analysis results indicated that the crossing process would produce a special pressure distribution in the cell interior and to some extent a sudden change between the cell interior and the surrounding plasma.     

Transient spatio-temporal dynamics of a diffusive plant–herbivore system with Neumann boundary conditions

In many existing predator–prey or plant–herbivore models, the numerical response is assumed to be proportional to the functional response. In this paper, without such an assumption, we consider a diffusive plant–herbivore system with Neumann boundary conditions. Besides stability of spatially homogeneous steady states, we also derive conditions for the occurrence of Hopf bifurcation and steady-state bifurcation and provide geometrical methods to locate the bifurcation values. We numerically explore the complex transient spatio-temporal behaviours induced by these bifurcations. A large variety of different types of transient behaviours including oscillations in one or both of space and time are observed.     

The combined impact of mechanical factors on the wall stress of the human ascending aorta – a finite elements study

Background

Biomechanical factors influence stress in the aortic wall. The aim of this study was to assess how the diameter and shape of the vessel, blood pressure and longitudinal systolic aortic stretching (SAS) caused by the contraction of the myocardium influence stress in the aortic wall.

Methods

Three computational models of the non-dilated aorta and aneurysms of the ascending aorta and aortic root were created. Then, finite elements analyses were carried out. The models were subjected to blood pressure (120 mmHg and 160 mmHg) and longitudinal systolic aortic stretching (0 mm, 5 mm, 10 mm and 15 mm). The influence of wall elasticity was examined too.

Results

Blood pressure had a smaller impact on the stress than the SAS. An increase in blood pressure from 120 mmHg to 160 mmHg increased the peak wall stress (PWS) on average by 0.1 MPa in all models. A 5 mm SAS caused a 0.1–0.2 MPa increase in PWS in all the models. The increase in PWS caused by a 10 mm and 15 mm SAS was 0.2 MPa and 0.4 MPa in the non-dilated aorta, 0.2–0.3 MPa and 0.3–0.5 MPa in the aneurysm of the ascending aorta, and 0.1–0.2 MPa and 0.2–0.3 MPa in the aortic root aneurysm model, respectively. The loss of elasticity of the aneurysmal wall resulted in an increase of PWS by 0.1–0.2 MPa.

Conclusions

Aortic geometry, wall stiffness, blood pressure and SAS have an impact on PWS. However, SAS had the biggest impact on wall stress. The results of this study may be useful in future patient-specific computational models used to assess the risk of aortic complications.

     

The role of the acidic domain of α-synuclein in amyloid fibril formation: a molecular dynamics study

The detailed mechanism of the pathology of α-synuclein in the Parkinson’s disease has not been clearly elucidated. Recent studies suggested a possible chaperone-like role of the acidic C-terminal region of α-synuclein in the formation of amyloid fibrils. It was also previously demonstrated that the α-synuclein amyloid fibril formation is accelerated by mutations of proline residues to alanine in the acidic region. We performed replica exchange molecular dynamics simulations of the acidic and nonamyloid component (NAC) domains of the wild type and proline-to-alanine mutants of α-synuclein under various conditions. Our results showed that structural changes induced by a change in pH or an introduction of mutations lead to a reduction in mutual contacts between the NAC and acidic regions. Our data suggest that the highly charged acidic region of α-synuclein may act as an intramolecular chaperone by protecting the hydrophobic domain from aggregation. Understanding the function of such chaperone-like parts of fibril-forming proteins may provide novel insights into the mechanism of amyloid formation.     

Metapopulation dynamics of a persisting predator–prey system in the laboratory: time series analysis

The scarcity of experimental evidence for the persistence of predator–prey systems at the metapopulation level inspired us to develop a simple predator–prey experiment that could be used for testing several theoretical predictions concerning persistence and its causes. The experimental system used consisted of one or several islands with small bean plants, the phytophagous mite Tetranychus urticae and the predatory mite Phytoseiulus persimilis. In the first experiment, one large system was used consisting of 90 small bean plants, prey and predators. The system persisted for only 120 days. Second, a system was used consisting of eight islands with ten plants each where the islands were connected by bridges. Two replicate experiments showed persistence for at least 393 days. The difference between the first and the second experiments suggests that the longer persistence is caused by a limited migration between the eight islands. Despite efforts to start both replicates of the second experiment with similar initial conditions, the dynamics of both replicates varied substantially. In one replicate the prey and predator numbers showed a trend through time, whereas the numbers fluctuated around a fixed value in the other replicate. A time series analysis of the data of the prey and predators showed the presence of periodicity with a lag of 8.5 weeks in one replicate, whereas such cyclic behaviour was not found in the other replicate. The differences between the two replicates suggest that it is difficult to perform experiments where one replicate is perturbed and the other serves as an undisturbed control. We suggest using a longer time series, where a system is disturbed only during the second half of the experiment. The data from the first and second halves can subsequently be used to estimate the effect of the perturbation. The advantages and disadvantages of this method are discussed. This revised version was published online in November 2006 with corrections to the Cover Date.     

Population study of a sequence polymorphism in intron 2 of the human β-globin gene

The distribution of a nucleotide polymorphism in intron 2 of the -globin gene (IVS-2 nt 666 C > T was examined in populations in southern Germany and Cameroon. The allelic frequencies were 0.86 for T and 0.14 for C in southern Germany and 0.87 for T and 0.13 for C in Cameroon, respectively.     

Structure of the UreD–UreF–UreG–UreE complex in Helicobacter pylori: a model study

The molecular details of the protein complex formed by UreD, UreF, UreG, and UreE, accessory proteins for urease activation in the carcinogenic bacterium Helicobacter pylori, have been elucidated using computational modeling. The calculated structure of the complex supports the hypothesis of UreF acting as a GTPase activation protein that facilitates GTP hydrolysis by UreG during urease maturation, and provides a rationale for the design of new drugs against infections by ureolytic bacterial pathogens.     

Critical test of bead–spring model to resolve the scaling laws of polymer melts: a molecular dynamics study

Abstract

To examine the intrinsic nature of the bead–spring Kremer–Grest (KG) model, long-time molecular dynamics simulations are performed. Certain scaling laws for representative polymer properties are compared with theoretical predictions. The results for static properties satisfy the expected static Gaussian nature, irrespective of the chain length. In contrast, the results for the dynamic properties of short chains show a clear discrepancy from theoretical predictions that assume ideal chain motion. This is clear evidence that the Gaussian nature of the dynamics of short chains is not necessarily established for the actual KG model, despite it being designed to have Gaussian characteristics by virtue of its stochastic equations of motion. This intrinsic nature of the KG model should be considered carefully when using this model for applications that involve relatively short chains.     

An immunohistochemical analysis of SERT in the blood–brain barrier of the male rat brain

5-Hydroxytryptamine (5-HT) was originally discovered as a vasoconstrictor. 5-HT lowers blood pressure when administered peripherally to both normotensive and hypertensive male rats. Because the serotonin transporter (SERT) can function bidirectionally, we must consider whether 5-HT can be transported from the bloodstream to the central nervous system (CNS) in facilitating the fall in blood pressure. The blood–brain barrier (BBB) is a highly selective barrier that restricts movement of substances from the bloodstream to the CNS and vice versa, but the rat BBB has not been investigated in terms of SERT expression. This requires us to determine whether the BBB of the rat, the species in which we first observed a fall in blood pressure to infused 5-HT, expresses SERT. We hypothesized that SERT is present in the BBB of the male rat. To test this hypothesis, over 500 blood vessels were sampled from coronal slices of six male rat brains. Immunofluorescence of these coronal slices was used to determine whether SERT and RecA-1 (an endothelial cell marker) colocalized to the BBB. Blood vessels were considered to be capillaries if they were between 1.5 and 23 µm (intraluminal diameter). SERT was identified in the largest pial vessels of the BBB (mean ± SEM = 228.70 ± 18.71 µm, N = 9) and the smallest capillaries (mean ± SEM = 2.75 ± 0.12 µm, N = 369). SERT was not identified in the endothelium of blood vessels ranging from 20 to 135 µm (N = 45). The expression of SERT in the rat BBB means that 5-HT entry into the CNS must be considered a potential mechanism when investigating 5-HT-induced fall in blood pressure.     

Recovery of the motor function of the arm with the aid of a hand exoskeleton controlled by a brain–computer interface in a patient with an extensive brain lesion

The dynamics of motor function recovery in a patient with an extensive brain lesion has been investigated during a course of neurorehabilitation assisted by a hand exoskeleton controlled by a brain–computer interface. Biomechanical analysis of the movements of the paretic arm recorded during the rehabilitation course was used for an unbiased assessment of motor function. Fifteen procedures involving hand exoskeleton control (one procedure per week) yielded the following results: (a) the velocity profile for targeted movements of the paretic hand became nearly bell-shaped; (b) the patient began to extend and abduct the hand, which was flexed and adducted at the beginning of the course; and (c) the patient started supinating the forearm, which was pronated at the beginning of the rehabilitation course. The first result is interpreted as improvement of the general level of control over the paretic hand, and the two other results are interpreted as a decrease in spasticity of the paretic hand.