Exploring the Free Energy Landscape: From Dynamics to Networks and Back

The knowledge of the Free Energy Landscape topology is the essential key to understand many biochemical processes. The determination of the conformers of a protein and their basins of attraction takes a central role for studying molecular isomerization reactions. In this work, we present a novel framework to unveil the features of a Free Energy Landscape answering questions such as how many meta-stable conformers are, how the hierarchical relationship among them is, or what the structure and kinetics of the transition paths are. Exploring the landscape by molecular dynamics simulations, the microscopic data of the trajectory are encoded into a Conformational Markov Network. The structure of this graph reveals the regions of the conformational space corresponding to the basins of attraction. In addition, handling the Conformational Markov Network, relevant kinetic magnitudes as dwell times or rate constants, and the hierarchical relationship among basins, complete the global picture of the landscape. We show the power of the analysis studying a toy model of a funnel-like potential and computing efficiently the conformers of a short peptide, the dialanine, paving the way to a systematic study of the Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press

Conversion of patellofemoral arthroplasty to total knee arthroplasty: A matched case-control study of 13 patients

Background and purpose The long-term outcome of patellofemoral arthroplasty is related to progression of femorotibial osteoarthritis with need for conversion to total knee arthroplasty. We investigated whether prior patellofemoral arthroplasty compromises the results of total knee arthroplasty

Evaluation of subsidence, chondrocyte survival and graft incorporation following autologous osteochondral transplantation

Contains fulltext : 95878.pdf (publisher's version ) (Open Access)PURPOSE: The aim of this study was to evaluate subsidence tendency, surface congruency, chondrocyte survival and plug incorporation after osteochondral transplantation in an animal model. The potential benefit of precise seating of the transplanted osteochondral plug on the recipient subchondral host bone ('bottoming') on these parameters was assessed in particular. METHODS: In 18 goats, two osteochondral autografts were harvested from the trochlea of the ipsilateral knee joint and inserted press-fit in a standardized articular cartilage defect in the medial femoral condyle. In half of the goats, the transplanted plugs were matched exactly to the depth of the recipient hole (bottomed plugs; n = 9), whereas in the other half of the goats, a gap of 2 mm was left between the plugs and the recipient bottom (unbottomed plugs; n = 9). After 6 weeks, all transplants were evaluated on gross morphology, subsidence, histology, and chondrocyte vitality. RESULTS: The macroscopic morphology scored significantly higher for surface congruency in bottomed plugs as compared to unbottomed reconstructions (P = 0.04). However, no differences in histological subsidence scoring between bottomed and unbottomed plugs were found. The transplanted articular cartilage of both bottomed and unbottomed plugs was vital. Only at the edges some matrix destaining, chondrocyte death and cluster formation was observed. At the subchondral bone level, active remodeling occurred, whereas integration at the cartilaginous surface of the osteochondral plugs failed to occur. Subchondral cysts were found in both groups. CONCLUSIONS: In this animal model, subsidence tendency was significantly lower after 'bottomed' versus 'unbottomed' osteochondral transplants on gross appearance, whereas for histological scoring no significant differences were encountered. Since the clinical outcome may be negatively influenced by subsidence, the use of 'bottomed' grafts is recommended for osteochondral transplantation in patients

Neuronal Plasticity and Multisensory Integration in Filial Imprinting

Many organisms sample their environment through multiple sensory systems and the integration of multisensory information enhances learning. However, the mechanisms underlying multisensory memory formation and their similarity to unisensory mechanisms remain unclear. Filial imprinting is one example in which experience is multisensory, and the mechanisms of unisensory neuronal plasticity are well established. We investigated the storage of audiovisual information through experience by comparing the activity of neurons in the intermediate and medial mesopallium of imprinted and naïve domestic chicks (Gallus gallus domesticus) in response to an audiovisual imprinting stimulus and novel object and their auditory and visual components. We find that imprinting enhanced the mean response magnitude of neurons to unisensory but not multisensory stimuli. Furthermore, imprinting enhanced responses to incongruent audiovisual stimuli comprised of mismatched auditory and visual components. Our results suggest that the effects of imprinting on the unisensory and multisensory responsiveness of IMM neurons differ and that IMM neurons may function to detect unexpected deviations from the audiovisual imprinting stimulus

Isolated patellofemoral osteoarthritis: A systematic review of treatment options using the GRADE approach

Background and purpose The optimal treatment for isolated patellofemoral osteoarthritis is unclear at present. We systematically reviewed the highest level of available evidence on the nonoperative and operative treatment of isolated patellofemoral osteoarthritis to develop an evidenced-based discussion of treatment options

Internally coupled ears in living mammals.

It is generally held that the right and left middle ears of mammals are acoustically isolated from each other, such that mammals must rely on neural computation to derive sound localisation cues. There are, however, some unusual species in which the middle ear cavities intercommunicate, in which case each ear might be able to act as a pressure-difference receiver. This could improve sound localisation at lower frequencies. The platypus Ornithorhynchus is apparently unique among mammals in that its tympanic cavities are widely open to the pharynx, a morphology resembling that of some non-mammalian tetrapods. The right and left middle ear cavities of certain talpid and golden moles are connected through air passages within the basicranium; one experimental study on Talpa has shown that the middle ears are indeed acoustically coupled by these means. Having a basisphenoid component to the middle ear cavity walls could be an important prerequisite for the development of this form of interaural communication. Little is known about the hearing abilities of platypus, talpid and golden moles, but their audition may well be limited to relatively low frequencies. If so, these mammals could, in principle, benefit from the sound localisation cues available to them through internally coupled ears. Whether or not they actually do remains to be established experimentally.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00422-015-0675-

Effects of Primary Imprinting on the Subsequent Development of Secondary Filial Attachments in the Chick

This study reinvestigates the effects of primary imprinting of chicks with either a naturalistic stimulus or an artificial object on subsequent imprinting with artificial objects. Initial experience with a live chick (group C) or a yellow cylinder (group Y) had differential effects on the development of a secondary filial attachment in chicks. In chicks of both groups, growth of attachment to the novel imprinting object manifested itself rather abruptly, but the change in response to the novel object occurred later in C- than in Y-chicks. There was no difference between the groups in the outcome of secondary imprinting: chicks in groups C and Y eventually became equally strongly attached to their novel imprinting stimulus, and when exposed to a third object, chicks in both groups imprinted equally well on this object. Thus, (1) initial imprinting on a naturalistic stimulus postponed, but did not block secondary imprinting on an artificial object, and (2) within the lengths of exposure used, the capacity to form new filial attachments was not limited, contrary to the prediction of the competitive exclusion model for imprinting. Secondary imprinting was delayed for a longer time when chicks were exposed to the novel imprinting stimulus in an unfamiliar environment. This indicates that induction of fear in chicks interfered with the occurrence of secondary imprinting. This effect may have contributed to the difference between groups C and Y in the length of delay of secondary imprinting. Possibly, separation from the first stimulus and exposure to the second stimulus was more fearful to C-chicks than to Y-chicks