Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury.

A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection

Leukemia Inhibitory Factor Augments Neurotrophin Expression and Corticospinal Axon Growth after Adult CNS Injury

The cytokine leukemia inhibitory factor (LIF) modulates glial and neuronal function in development and after peripheral nerve injury, but little is known regarding its role in the injured adult CNS. To further understand the biological role of LIF and its potential mechanisms of action after CNS injury, effects of cellularly delivered LIF on axonal growth, glial activation, and expression of trophic factors were examined after adult mammalian spinal cord injury. Fibroblasts genetically modified to produce high amounts of LIF were grafted to the injured spinal cords of adult Fischer 344 rats. Two weeks after injury, animals with LIF-secreting cells showed a specific and significant increase in corticospinal axon growth compared with control animals. Furthermore, expression of neurotrophin-3, but not nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor, or ciliary neurotrophic factor, was increased at the lesion site in LIF-grafted but not in control subjects. No differences in astroglial and microglial/macrophage activation were observed. Thus, LIF can directly or indirectly modulate molecular and cellular responses of the adult CNS to injury. These findings also demonstrate that neurotrophic molecules can augment expression of other trophic factors in vivo after traumatic injury in the adult CNS

Modeling transcription factor binding events to DNA using a random walker/jumper representation on a 1D/2D lattice with different affinity sites

Surviving in a diverse environment requires corresponding organism responses. At the cellular level, such adjustment relies on the transcription factors (TFs) which must rapidly find their target sequences amidst a vast amount of non-relevant sequences on DNA molecules. Whether these transcription factors locate their target sites through a 1D or 3D pathway is still a matter of speculation. It has been suggested that the optimum search time is when the protein equally shares its search time between 1D and 3D diffusions. In this paper, we study the above problem using a Monte Carlo simulation by considering a very simple physical model. A 1D strip, representing a DNA, with a number of low affinity sites, corresponding to non-target sites, and high affinity sites, corresponding to target sites, is considered and later extended to a 2D strip. We study the 1D and 3D exploration pathways, and combinations of the two modes by considering three different types of molecules: a walker that randomly walks along the strip with no dissociation; a jumper that represents dissociation and then re-association of a TF with the strip at later time at a distant site; and a hopper that is similar to the jumper but it dissociates and then re-associates at a faster rate than the jumper. We analyze the final probability distribution of molecules for each case and find that TFs can locate their targets fast enough even if they spend 15% of their search time diffusing freely in the solution. This indeed agrees with recent experimental results obtained by Elf et al. 2007 and is in contrast with theoretical expectation.Comment: 24 pages, 9 figure

Using the gibbs function as a measure of human brain development trends from fetal stage to advanced age

We propose to use a Gibbs free energy function as a measure of the human brain development. We adopt this approach to the development of the human brain over the human lifespan: from a prenatal stage to advanced age. We used proteomic expression data with the Gibbs free energy to quantify human brain’s protein–protein interaction networks. The data, obtained from BioGRID, comprised tissue samples from the 16 main brain areas, at different ages, of 57 post-mortem human brains. We found a consistent functional dependence of the Gibbs free energies on age for most of the areas and both sexes. A significant upward trend in the Gibbs function was found during the fetal stages, which is followed by a sharp drop at birth with a subsequent period of relative stability and a final upward trend toward advanced age. We interpret these data in terms of structure formation followed by its stabilization and eventual deterioration. Furthermore, gender data analysis has uncovered the existence of functional differences, showing male Gibbs function values lower than female at prenatal and neonatal ages, which become higher at ages 8 to 40 and finally converging at late adulthood with the corresponding female Gibbs functions

Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury.

Although axonal regeneration after CNS injury is limited, partial injury is frequently accompanied by extensive functional recovery. To investigate mechanisms underlying spontaneous recovery after incomplete spinal cord injury, we administered C7 spinal cord hemisections to adult rhesus monkeys and analyzed behavioral, electrophysiological and anatomical adaptations. We found marked spontaneous plasticity of corticospinal projections, with reconstitution of fully 60% of pre-lesion axon density arising from sprouting of spinal cord midline-crossing axons. This extensive anatomical recovery was associated with improvement in coordinated muscle recruitment, hand function and locomotion. These findings identify what may be the most extensive natural recovery of mammalian axonal projections after nervous system injury observed to date, highlighting an important role for primate models in translational disease research

Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair

Purpose: The ERCC1–XPF 5′–3′ DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs. Methods: We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein–protein interaction in cancer cells using proximity ligation assay. Results: Compound B9 showed the best activity being synergistic with cisplatin and mitomycin C in both colon and lung cancer cells. Also, B9 abolished the interaction between ERCC1 and XPF in cancer cells as shown by proximity ligation assay. Results of different compounds correlated with values from our previously obtained in silico predictions. Conclusion: Our results confirm the feasibility of the approach of targeting the protein–protein interaction between ERCC1 and XPF to sensitize cancer cells to alkylating agents, thanks to the improved binding affinity of the newly synthesized compounds

Generalized thermodynamics of q-deformed bosons and fermions

We study the thermostatistics of q-deformed bosons and fermions obeying the symmetric algebra and show that it can be built on the formalism of q-calculus. The entire structure of thermodynamics is preserved if ordinary derivatives are replaced by an appropriate Jackson derivative. In this framework, we derive the most important thermodynamic functions describing the q-boson and q-fermion ideal gases in the thermodynamic limit. We also investigate the semi-classical limit and the low temperature regime and demonstrate that the nature of the q-deformation gives rise to pure quantum statistical effects stronger than undeformed boson and fermion particles.Comment: 8 pages, Physical Review E in pres

Charge-density-wave instability in the Holstein model with quartic anharmonic phonons

The molecular-crystal model, that describes a one-dimensional electron gas interacting with quartic anharmonic lattice vibrations, offers great potentials in the mapping of a relatively wide range of low-dimensional fermion systems coupled to optical phonons onto quantum liquids with retarded interactions. Following a non-perturbative approach involving non-Gaussian partial functional integrations of lattice degrees of freedom, the exact expression of the phonon-mediated two-electron action for this model is derived. With the help of Hubbard-Stratonovich transformation the charge-density-wave instability is examined in the sequel, with particular emphasis on the effect of the quartic anharmonic phonons on the charge-density-wave transition temperature.Comment: 12 pages, 3 figure

Peripheral nerve growth within a hydrogel microchannel scaffold supported by a kink‐resistant conduit

Nerve repair in several mm‐long nerve gaps often requires an interventional technology. Microchannel scaffolds have proven effective for bridging nerve gaps and guiding axons in the peripheral nervous system (PNS). Nonetheless, fabricating microchannel scaffolds at this length scale remains a challenge and/or is time consuming and cumbersome. In this work, a simple computer‐aided microdrilling technique was used to fabricate 10 mm‐long agarose scaffolds consisting of 300 µm‐microchannels and 85 µm‐thick walls in less than an hour. The agarose scaffolds alone, however, did not exhibit adequate stiffness and integrity to withstand the mechanical stresses during implantation and suturing. To provide mechanical support and enable suturing, poly caprolactone (PCL) conduits were fabricated and agarose scaffolds were placed inside. A modified salt‐leaching technique was developed to introduce interconnected porosity in PCL conduits to allow for tuning of the mechanical properties such as elastic modulus and strain to failure. It was shown that the PCL conduits were effective in stabilizing the agarose scaffolds in 10 mm‐long sciatic nerve gaps of rats for at least 8 weeks. Robust axon ingress and Schwann cell penetration were observed within the microchannel scaffolds without using growth factors. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3392–3399, 2017.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139110/1/jbma36186_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139110/2/jbma36186.pd