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Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly l -lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.

Non-thermal atmospheric-pressure plasma (NTAPP) is attracting widespread interest for use in medical applications. The tissue repair capacity of NTAPP has been reported in various fields; however, little is known about its effect on fracture healing. Non-union or delayed union after a fracture is a clinical challenge. In this study, we aimed to investigate how NTAPP irradiation promotes fracture healing in a non-union fracture model and its underlying mechanism, in vitro and in vivo. For the in vivo study, we created normal and non-union fracture models in LEW/SsNSlc rats to investigate the effects of NTAPP. To create a fracture, a transverse osteotomy was performed in the middle of the femoral shaft. To induce the non-union fracture model, the periosteum surrounding the fracture site was cauterized after a normal fracture model was created. The normal fracture model showed no significant difference in bone healing between the control and NTAPP-treated groups. The non-union fracture model demonstrated that the NTAPP-treated group showed consistent improvement in fracture healing. Histological and biomechanical assessments confirmed the fracture healing. The in vitro study using pre-osteoblastic MC3T3-E1 cells demonstrated that NTAPP irradiation under specific conditions did not reduce cell proliferation but did enhance osteoblastic differentiation. Overall, these results suggest that NTAPP is a novel approach to the treatment of bone fractures.

During development, the retinal vasculature grows toward hypoxic areas in an organized fashion. By contrast, in ischemic retinopathies, new blood vessels grow out of the retinal surfaces without ameliorating retinal hypoxia. Restoration of proper angiogenic directionality would be of great benefit to reoxygenize the ischemic retina and resolve disease pathogenesis. Here, we show that binding of the semaphorin 3E (Sema3E) ligand to the transmembrane PlexinD1 receptor initiates a signaling pathway that normalizes angiogenic directionality in both developing retinas and ischemic retinopathy. In developing mouse retinas, inhibition of VEGF signaling resulted in downregulation of endothelial PlexinD1 expression, suggesting that astrocyte-derived VEGF normally promotes PlexinD1 expression in growing blood vessels. Neuron-derived Sema3E signaled to PlexinD1 and activated the small GTPase RhoJ in ECs, thereby counteracting VEGF-induced filopodia projections and defining the retinal vascular pathfinding. In a mouse model of ischemic retinopathy, enhanced expression of PlexinD1 and RhoJ in extraretinal vessels prevented VEGF-induced disoriented projections of the endothelial filopodia. Remarkably, intravitreal administration of Sema3E protein selectively suppressed extraretinal vascular outgrowth without affecting the desired regeneration of the retinal vasculature. Our study suggests a new paradigm for vascular regeneration therapy that guides angiogenesis precisely toward the ischemic retina.

Monolayer transition metal dichalcogenides (TMDCs) including WS 2 , MoS 2 , WSe 2 and WS 2 , are two-dimensional semiconductors with direct bandgap, providing an excellent field for exploration of many-body effects in 2-dimensions (2D) through optical measurements. To fully explore the physics of TMDCs, the prerequisite is preparation of high-quality samples to observe their intrinsic properties. For this purpose, we have focused on high-quality samples, WS 2 grown by chemical vapor deposition method with hexagonal boron nitride as substrates. We observed sharp exciton emissions, whose linewidth is typically 22~23 meV, in photoluminescence spectra at room temperature, which result clearly demonstrates the high-quality of the current samples. We found that biexcitons formed with extremely low-excitation power (240 W/cm 2 ) at 80 K, and this should originate from the minimal amount of localization centers in the present high-quality samples. The results clearly demonstrate that the present samples can provide an excellent field, where one can observe various excitonic states, offering possibility of exploring optical physics in 2D and finding new condensates.

Pathologies associated with neural blood disturbance have been reported in patients with chronic nerve compression (CNC) neuropathy. Fluorescein angiography (FAG) and laser Doppler flowmetry (LDF) are effective for real-time peripheral nerve blood flow assessment. However, their reliability in severe neuropathy models in large animals or clinical conditions remains unclear. Initially, we aim to apply FAG to two different CNC animal models and evaluate their characteristics in comparison with those of LDF. In FAG, we quantified the peak luminance at the compression site following fluorescein injection. Then, we positioned the LDF probe at the center of the compression site and recorded the blood flow. Subsequently, we analyzed whether the FAG characteristics obtained in this animal experiment were consistent with those of clinical studies in patients with severe carpal tunnel syndrome (CTS). In the CNC rat model, FAG and LDF effectively monitored reduced neural blood flow over time. We observed significant blood flow reduction using both techniques in a newly developed severe CNC rabbit model. Notably, FAG correlated strongly with the compound muscle action potential (CMAP) amplitude in electrodiagnostic findings, unlike LDF. As a next step, we performed FAG after open carpal tunnel release in clinical cases of CTS. FAG correlated significantly with preoperative CMAP amplitude. This indicates FAG’s importance for assessing nerve blood flow during surgery, potentially improving diagnostic accuracy and surgical outcomes.

Preparation of specific lineages at high purities from embryonic stem (ES) cells requires both selective culture conditions and markers to guide and monitor the differentiation. In this study, we distinguished definitive and visceral endoderm by using a mouse ES cell line that bears the gfp and human IL2Rα (also known as CD25 ) marker genes in the goosecoid ( Gsc ) and Sox17 loci, respectively. This cell line allowed us to monitor the generation of Gsc + Sox17 + definitive endoderm and Gsc − Sox17 + visceral endoderm and to define culture conditions that differentially induce definitive and visceral endoderm. By comparing the gene expression profiles of definitive and visceral endoderm, we identified seven surface molecules that are expressed differentially in the two populations. One of the seven markers, Cxcr4, to which a monoclonal antibody is available allowed us to monitor and purify the Gsc + population from genetically unmanipulated ES cells under the condition that selects definitive endoderm.

Background While some traumatic closed index extensor tendon ruptures at the musclotendinous junction have been previously reported, closed index extensor tendon pseudorupture due to intertendinous attenuation is exceedingly rare with only one case report of a gymnastics-related sports injury in the English literature. Herein, we report two non-sports injury related cases of traumatic index extensor tendon attenuation mimicking closed tendon rupture, including the pathological findings and intraoperative video of the attenuated extensor indicis proprius tendon. Case presentation A 28-year-old man and a 30-year-old man caught their hands in a high-speed drill and lathe, respectively, which caused a sudden forced flexion of their wrists. They could not actively extend the metacarpophalangeal joints of their index fingers. Intraoperatively, although the extensor indicis proprius and index extensor digitorum communes tendons were in continuity without ruptures, both tendons were attenuated and stretched. The attenuated index extensor tendons were reconstructed either with shortening by plication or step-cut when the tendon damage was less severe or, in severely attenuated tendons, with tendon grafting (ipsilateral palmaris longus) or tendon transfer. Six months after the operation, the active extension of the index metacarpophalangeal joints had recovered well. Conclusions Two cases of traumatic index extensor tendon attenuation were treated successfully by shortening the attenuated tendon in combination with tendon graft or transfer. We recommend WALANT (wide-awake local anesthesia and no tourniquet) in the reconstruction surgery of index extensor tendon attenuation to determine the appropriate amount of tendon shortening or optimal tension for tendon grafting or transfer. Intraoperative voluntary finger movement is essential, as it is otherwise difficult to judge the stretch length of intratendinous elongation and extent of traumatic intramuscular damage affecting tendon excursion.

The paper traces the development and the role of syntactic reduction in Edmund Husserl's (1856–1938) early writings on mathematics and logic, especially on arithmetic. The notion has its origin in Hermann Hankel's (1839–1873) principle of permanence that Husserl set out to clarify. In Husserl's early texts the emphasis of the reductions was meant to guarantee the consistency of the extended algorithm. Around the turn of the century Husserl uses the same idea in his conception of definiteness of what he calls \"mathematical manifolds.\" The paper argues that the notion anticipates the notion of reduction in term rewrite theory in computer science. The role of the reduction for Husserl is, however, primarily epistemological: its purpose is to impart clarity to (at least parts of) formal mathematics.

Drugs inhibiting vascular endothelial growth factor (VEGF) signaling are globally administered to suppress deregulated angiogenesis in a variety of eye diseases. However, anti-VEGF therapy potentially affects the normal functions of retinal neurons and glias which constitutively express VEGF receptor 2. Thus, it is desirable to identify novel drug targets which are exclusively expressed in endothelial cells (ECs). Here we attempted to identify an EC-specific Rho guanine nucleotide exchange factor (GEF) and evaluate its role in retinal angiogenesis. By exploiting fluorescence-activated cell sorting and microarray analyses in conjunction with in silico bioinformatics analyses, we comprehensively identified endothelial genes in angiogenic retinal vessels of postnatal mice. Of 9 RhoGEFs which were highly expressed in retinal ECs, we show that Arhgef15 acted as an EC-specific GEF to mediate VEGF-induced Cdc42 activation and potentiated RhoJ inactivation, thereby promoting actin polymerization and cell motility. Disruption of the Arhgef15 gene led to delayed extension of vascular networks and subsequent reduction of total vessel areas in postnatal mouse retinas. Our study provides information useful to the development of new means of selectively manipulating angiogenesis without affecting homeostasis in un-targeted tissues; not only in eyes but also in various disease settings such as cancer.

Ulnar shortening osteotomy is widely performed as the standard surgical treatment for ulnar impaction syndrome and has a high percentage of success for pain relief. However, delayed union and nonunion of the osteotomy site remain the most concerning complications. In particular, smokers have a higher incidence of nonunion, which amounts to 30% of cases. For the treatment of nonunion, secondary surgical interventions such as bone grafting will be necessary but are extremely challenging. Recently, teriparatide (recombinant human parathyroid hormone [PTH 1–34]) administration has been reported in several clinical studies as a noninvasive pharmacological systemic treatment for fracture healing or nonunion. The authors present 2 cases of smokers, a 62-year-old man and a 42-year-old woman, with nonunion after ulnar shortening osteotomy and fixation with 6-hole non-locking plate for ulnar impaction syndrome. For treatment of nonunion, noninvasive therapy with teriparatide (20-µg, subcutaneous injection) in addition to low-intensity pulsed ultrasound was underwent. In both cases, partial bone union began to be observed on radiographs after the first 4 weeks of teriparatide administration and successful bone healing without additional surgical interventions was achieved after 10 and 6 months of treatment with teriparatide, respectively. The current case reports showed that non-invasive combination therapy of teriparatide and low-intensity pulsed ultrasound were a possible alternative to surgical intervention. In the future, teriparatide therapy might be applied actively to patients who have risk factors for delayed union, such a heavy smoking habit, and are expected to experience nonunion after ulnar shortening osteotomy. [Ulnar shortening osteotomy is widely performed as the standard surgical treatment for ulnar impaction syndrome and has a high percentage of success for pain relief. However, delayed union and nonunion of the osteotomy site remain the most concerning complications. In particular, smokers have a higher incidence of nonunion, which amounts to 30% of cases. For the treatment of nonunion, secondary surgical interventions such as bone grafting will be necessary but are extremely challenging. Recently, teriparatide (recombinant human parathyroid hormone [PTH 1–34]) administration has been reported in several clinical studies as a noninvasive pharmacological systemic treatment for fracture healing or nonunion. The authors present 2 cases of smokers, a 62-year-old man and a 42-year-old woman, with nonunion after ulnar shortening osteotomy and fixation with 6-hole non-locking plate for ulnar impaction syndrome. For treatment of nonunion, noninvasive therapy with teriparatide (20-µg, subcutaneous injection) in addition to low-intensity pulsed ultrasound was underwent. In both cases, partial bone union began to be observed on radiographs after the first 4 weeks of teriparatide administration and successful bone healing without additional surgical interventions was achieved after 10 and 6 months of treatment with teriparatide, respectively. The current case reports showed that non-invasive combination therapy of teriparatide and low-intensity pulsed ultrasound were a possible alternative to surgical intervention. In the future, teriparatide therapy might be applied actively to patients who have risk factors for delayed union, such a heavy smoking habit, and are expected to experience nonunion after ulnar shortening osteotomy. [ Orthopedics. 2015; 38(8):e733–e737.]