Txn1 mutation causes epilepsy associated with vacuolar degeneration in the midbrain

Thioredoxin (TXN), encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of TXN in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with running seizures at around five-week of age revealed the relevance of Txn1 mutations to CNS disorders. Genetic mapping identified Txn1-F54L in epileptic rats. The insulin-reducing activity of Txn1-F54L rats was approximately one-third that of the wild-type. Vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocyte cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration began at three weeks of age, and spontaneous repair began at seven weeks; a dramatic change from cell death to repair occurred in the midbrain during a restricted period. In conclusion, Txn1 is essential for the development of the midbrain in juvenile rats.

Self-Healing in Titanium Alloys: A Materials Science Perspective

Self-healing materials (SHM’s) is an emerging class of smart materials, which are capable of autonomous or spontaneous repair of their damage under external stimuli, such as heat, light, and solvent, to the original or near original functionalities much like the biological organisms. The emergence of self-healing in metallic materials presents an exciting paradigm for an ideal combination of metallic and biological properties. The driving force behind this effort is to decrease the consequences of accidents, reduction of cost and extending the service life of metallic components. While previous reviews have focused on self-healing in polymers, composite, concrete and cementous materials, and ceramic, discussions about self-healing in metallic materials remains scarce and the survey of literatures suggests Ti-based self-healing materials known to be biocompatible in human body is rare. The present chapter examines the art of self-healing in titanium-based alloys with the scope to provide an overview of recent advancements and to highlight current problems and perspectives with respect to potential application.

Adult chondrogenesis and spontaneous cartilage repair in the skate, Leucoraja erinacea

Mammalian articular cartilage is an avascular tissue with poor capacity for spontaneous repair. Here, we show that embryonic development of cartilage in the skate (Leucoraja erinacea) mirrors that of mammals, with developing chondrocytes co-expressing genes encoding the transcription factors Sox5, Sox6 and Sox9. However, in skate, transcriptional features of developing cartilage persist into adulthood, both in peripheral chondrocytes and in cells of the fibrous perichondrium that ensheaths the skeleton. Using pulse-chase label retention experiments and multiplexed in situ hybridization, we identify a population of cycling Sox5/6/9+ perichondral progenitor cells that generate new cartilage during adult growth, and we show that persistence of chondrogenesis in adult skates correlates with ability to spontaneously repair cartilage injuries. Skates therefore offer a unique model for adult chondrogenesis and cartilage repair and may serve as inspiration for novel cell-based therapies for skeletal pathologies, such as osteoarthritis.

Adult chondrogenesis and spontaneous cartilage repair in the skate, Leucoraja erinacea

Mammalian articular cartilage is an avascular tissue with poor capacity for spontaneous repair. Here, we show that embryonic development of cartilage in the skate (Leucoraja erinacea) mirrors that of mammals, with developing chondrocytes co-expressing genes encoding the transcription factors Sox5, Sox6 and Sox9. However, in skate, transcriptional features of developing cartilage persist into adulthood, both in peripheral chondrocytes and in cells of the fibrous perichondrium that ensheaths the skeleton. Using pulse-chase label retention experiments and multiplexed in situ hybridization, we identify a population of cycling Sox5/6/9+ perichondral progenitor cells that generate new cartilage during adult growth, and we show that persistence of chondrogenesis in adult skates correlates with ability to spontaneously repair cartilage injuries. Skates therefore offer a unique model for adult chondrogenesis and cartilage repair and may serve as inspiration for novel cell-based therapies for skeletal pathologies, such as osteoarthritis.

Spatiotemporal Expression of 3-B-3(−) and 7-D-4 Chondroitin Sulfation, Tissue Remodeling, and Attempted Repair in an Ovine Model of Intervertebral Disc Degeneration

Objective Examination of intervertebral disc (IVD) regeneration in an ovine annular lesion model. Hypothesis Sulfation motifs are important functional determinants in glycosaminoglycans (GAGs). Previous studies have correlated 3-B-3(−) and 7-D-4 chondroitin sulfate (CS) motifs in tissues undergoing morphogenetic transition in development. We hypothesize that these motifs may also be expressed in degenerate IVDs and may represent a reparative response. Design Induction of disc degeneration by 5 mm or 6 × 20 mm lesions in the annulus fibrosus (AF) over 6 or 3 to 6 months postoperation (PO). Tissue sections were stained with toluidine blue–fast green, 3-B-3(−) and 7-D-4 CS-sulfation motifs were immunolocalized in 3-month PO 6 × 20 mm lesion IVDs. Sulfated glycosaminoglycan (GAG), 3-B-3(−), and 7-D-4 epitopes were quantitated by ELISIA (enzyme-linked immunosorbent inhibition assay) in extracts of AF (lesion site and contralateral half) and nucleus pulposus (NP) 0, 3, and 6 months PO. Results Collagenous overgrowth of lesions occurred in the outer AF. Chondroid metaplasia in ~20% of the 6 × 20 mm affected discs resulted in integration of an outgrowth of NP tissue with the inner AF lamellae preventing propagation of the lesion. 3-B-3(−) and 7-D-4 CS sulfation motifs were immunolocalized in this chondroid tissue. ELISIA quantified CS sulfation motifs demonstrating an increase 3 to 6 months PO in the AF lesion and a reduction in sulfated GAG not evident in the contralateral AF. Conclusions (1) Outer annular lesions underwent spontaneous repair. (2) Chondroid metaplasia of the inner 6 × 20 mm defect prevented its propagation suggesting an apparent reparative response.

Effects of Ultra-Purified Alginate Gel Implantation on Meniscal Defects in Rabbits

Background: Many tissue-engineered methods for meniscal repair have been studied, but their utility remains unclear. Hypothesis: Implantation of low-endotoxin, ultra-purified alginate (UPAL) gel without cells could induce fibrocartilage regeneration on meniscal defects in rabbits. Study Design: Controlled laboratory study. Methods: Forty-two mature Japanese White rabbits were divided into 2 groups of 21 animals each. In each animal, a cylindrical defect measuring 2 mm in diameter was created with a biopsy punch on the anterior horn of the medial meniscus. In the control group, no treatment was applied on the left medial meniscal defect. In the UPAL gel group, the right medial meniscal defect was injected with the UPAL gel and gelated by a CaCl2 solution. Samples were evaluated at 3, 6, and 12 weeks postoperatively. For biomechanical evaluation, 6 additional samples from intact animals were used for comparison. Results: The macroscopic score was significantly greater in the UPAL gel group than in the control group at 3 weeks (mean ± SE: 5.6 ± 0.82 vs 3.4 ± 0.83, P = .010), 6 weeks (5.9 ± 0.72 vs 2.5 ± 0.75, P = .026), and 12 weeks (5.2 ± 1.21 vs 1.0 ± 0.63, P = .020). The histological score was significantly greater in the UPAL group than in the control group at 3 weeks (2.1 ± 0.31 vs 1.2 ± 0.25, P = .029) and 12 weeks (2.2 ± 0.55 vs 0.3 ± 0.21, P = .016). The mean stiffness of the reparative tissue in the UPAL gel group was significantly greater than that in the control group at 6 weeks (24.325 ± 3.920 N/mm vs 8.723 ± 1.190 N/mm, P = .006) and at 12 weeks (27.804 ± 6.169 N/mm vs not applicable [because of rupture]). Conclusion: The UPAL gel enhanced the spontaneous repair of fibrocartilage tissues in a cylindrical meniscal defect in rabbits. Clinical Relevance: These results imply that the acellular UPAL gel may improve the repair of traumatic meniscal injuries.

RAB-5 regulates regenerative axonal fusion by controlling EFF-1 endocytosis

ABSTRACTFollowing a transection injury to the axon, neurons from a number of species have the ability to undergo spontaneous repair via fusion of the two separated axonal fragments. In the nematode C. elegans, this highly efficient regenerative axonal fusion is mediated by Epithelial Fusion Failure-1 (EFF-1), a fusogenic protein that functions at the membrane to merge the two axonal fragments. Identifying modulators of axonal fusion and EFF-1 is the next step towards harnessing this process for clinical applications. Here, we present evidence that the small GTPase RAB-5 acts to inhibit axonal fusion, a function achieved via endocytosis of EFF-1 within the injured neuron. Consequently, we find that perturbing RAB-5 activity increases the capacity of the neuron to undergo axonal fusion, through enhanced membranous localization of EFF-1 and the production of extracellular EFF-1-containing vesicles. These findings identify RAB-5 as a novel regulator of axonal fusion and the first regulator of EFF-1 in neurons.