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Extramedullary myelopoiesis occurs commonly in tumor-bearing animals and is known to lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which play an important role in immune escape. However, the cellular and molecular mechanisms by which tumors induce extramedullary myelopoiesis are poorly understood. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2–MAPK pathway. Osteopontin-mediated extramedullary myelopoiesis was directly associated with increased MDSCs in tumor-bearing hosts. More importantly, osteopontin silencing in tumor cells delayed both tumor growth and extramedullary myelopoiesis, while the same treatment did not affect tumor growth in vitro. Finally, treatment with an antibody against osteopontin inhibited tumor growth and synergized with cell-based immunotherapeutic vaccines in mediating antitumor immunity. Our findings unveil a novel immunosuppressive role for tumor-derived osteopontin and offer a rationale for its therapeutic targeting in cancer treatment. Cancer Res; 74(22); 6705–16. ©2014 AACR.

Supplemental data. Supplementary method, Supplementary figure legends and Supplementary figures 1-9. Supplementary figure 1. Gating strategies for the flow cytometric analysis. Supplementary figure 2. Changes of MDSCs, lymphoid cells and lymphoid progenitor cells in the CT26 TBM. Supplementary figure 3. Accumulated MDSCs in MC38 TBM. Supplementary figure 4. Increased osteopontin in MC38 TBM. Supplementary figure 5. In vivo proliferation and apoptosis of tumors. Supplementary figure 6. Changes of sub-populations of LK cells. Supplementary figure 7. Induction of extramedullary myelopoiesis by osteopontin from malignant tumor cells in the tumor microenvironment. Supplementary figure 8. The role of osteopontin in LK cell migration and MDSC survival. Supplementary figure 9. Osteopontin-induced LK cell proliferation was mediated by the CD44-ERK/MAPK signaling pathway.

Inertial sensors are devices that can monitor inertial movements, such as linear acceleration and angular motions, in industrial and human systems. For portable and wearable applications, inertial sensors must be self-powered and miniaturized. In this article, we report a self-powered inertial sensor with high accuracy based on carbon nanotube (CNT) yarn. By harvesting the mechanical energy of a coiled CNT yarn, our inertial sensor can detect inertial movements without the need for external power. For practical applications, the sensor can monitor various inertial movements, such as vibrations, external impacts, tilting, and body motions (squatting, walking, running, and jumping motions). These findings suggest that the self-powered inertial sensor exhibits the advantages of portability and wearability in industrial and human system applications.

Accelerometers are indispensable for detecting accelerating forces in automotive electronic systems. Although several accelerometers have been developed, they are still unstable for vehicle dynamics’ applications in the low-frequency range (0–20 Hz). Here, we report a novel type of accelerometer based on a coiled carbon nanotube (CNT) yarn as a self-powered and low-frequency range-covered acceleration sensor. The proposed sensor is designed in a compact fiber-like structure for practical applications. Open-circuit voltage (OCV) signals are consistently generated during the stretch-and-release process of the coiled CNT yarn by the applied sinusoidal accelerations, and the OCV changes increase linearly with increasing acceleration from 4.84 to 48.37 m/s2. Our accelerometer exhibits excellent dynamic sensing performance in the low-frequency range compared with commercial accelerometers. In an application as a CNT yarn device configured with a mass load, the OCV change is linearly proportional to the applied acceleration. When our accelerometer is attached to a seatbelt in a vehicle, it generates OCV changes from the movement of the body mass underlying a certain acceleration change. Given its excellent sensing performance, the CNT yarn acceleration sensor could further be developed for practical applications, such as seatbelts and car seats with fabric and textile.

Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases., Neuropharmacology: a potential treatment strategy for dopamine-related brain disorders Compounds that activate a gene-regulating protein called Nurr1 could help treat Parkinson’s disease and other brain disorders related to abnormal dopamine signaling. A team led by Kwang-Soo Kim from Harvard Medical School, Belmont, USA, reviews the various compounds, both synthetic and natural, known to enhance the activity of Nurr1. This protein binds DNA to regulate the expression of target genes and was long thought not to have such triggering molecules or ligands, which have recently been identified by the team. These activating compounds seem to protect dopamine-producing neurons from cell injury in various Parkinson’s-related cell and animal models. Given Nurr1’s role in the development, differentiation, and survival of dopaminergic neurons in the midbrain, these compounds could help boost the capacity of malfunctioning dopaminergic neurons in patients with Parkinson’s disease, schizophrenia, bipolar disorder, and other neuropsychiatric conditions.

Crotamiton is an anti-scabies drug, but it was recently found that crotamiton also suppresses non-scabietic itching in mice. However, the underlying mechanism is largely unclear. Therefore, aim of the study is to investigate mechanisms of the anti-pruritic effect of crotamiton for non-scabietic itching. Histamine and chloroquine are used as non-scabietic pruritogens. The effect of crotamiton was identified using fluorometric intracellular calcium assays in HEK293T cells and primary cultured dorsal root ganglion (DRG) neurons. Further in vivo effect was evaluated by scratching behavior tests. Crotamiton strongly inhibited histamine-induced calcium influx in HEK293T cells, expressing both histamine receptor 1 (H1R) and transient receptor potential vanilloid 1 (TRPV1), as a model of histamine-induced itching. Similarly, it also blocked chloroquine-induced calcium influx in HEK293T cells, expressing both Mas-related G-protein-coupled receptor A3 (MRGPRA3) and transient receptor potential A1 (TRPA1), as a model of histamine-independent itching. Furthermore, crotamiton also suppressed both histamine- and chloroquine-induced calcium influx in primary cultures of mouse DRG. Additionally, crotamiton strongly suppressed histamine- and chloroquine-induced scratching in mice. Overall, it was found that crotamiton has an anti-pruritic effect against non-scabietic itching by histamine and chloroquine. Therefore, crotamiton may be used as a general anti-pruritic agent, irrespective of the presence of scabies.

Flexible and stretchable fiber supercapacitors have been progressively improved for wearable electronic devices. However, they should be further improved with respect to stretchable range and stable electrochemical performance during dynamic movement when considering the tensile range for wearable applications. Here, we report a quasi-solid-state circular knitted MnO2@CNT supercapacitor with high tensile range. To fabricate this, CNT fibers were knitted into a circular shape using a knitting machine then subsequently electrochemically deposited by a pseudocapacitive material, MnO2. Consequently, the knitted MnO2@CNT fiber supercapacitors were structurally 100% stretchable, and their energy storage performance remained stable during knitted capacitor stretching of up to 100%. Maximum linear capacitance and area capacitance are considerably large (321.08 mF cm−1, 511.28 mF cm−2). In addition, the supercapacitor showed negligible loss of capacitance after 10 000 repeated charge/discharge cycles and dynamic stretching cycle testing. Furthermore, we also provided double-walled knitted MnO2@CNT supercapacitors by symmetrically inserting one knitted supercapacitor into another. The double-walled supercapacitor also exhibited a stable stretchability of up to 100% without loss of capacitance. Therefore, this highly stretchable fiber-type supercapacitor could be utilized for energy storage in wearable devices.

Anoctamin1 (ANO1) also known as TMEM16A is a transmembrane protein that functions as a Ca2+ activated chloride channel. Recently, the structure determination of a fungal Nectria haematococca TMEM16 (nhTMEM16) scramblase by X-ray crystallography and a mouse ANO1 by cryo-electron microscopy has provided the insight in molecular architecture underlying phospholipid scrambling and Ca2+ binding. Because the Ca2+ binding motif is embedded inside channel protein according to defined structure, it is still unclear how intracellular Ca2+ moves to its deep binding pocket effectively. Here we show that EF-hand like region containing multiple acidic amino acids at the N-terminus of ANO1 is a putative site regulating the activity of ANO1 by Ca2+ and voltage. The EF-hand like region of ANO1 is highly homologous to the canonical EF hand loop in calmodulin that contains acidic residues in key Ca2+-coordinating positions in the canonical EF hand. Indeed, deletion and Ala-substituted mutation of this region resulted in a significant reduction in the response to Ca2+ and changes in its key biophysical properties evoked by voltage pulses. Furthermore, only ANO1 and ANO2, and not the other TMEM16 isoforms, contain the EF-hand like region and are activated by Ca2+. Moreover, the molecular modeling analysis supports that EF-hand like region could play a key role during Ca2+ transfer. Therefore, these findings suggest that EF-hand like region in ANO1 coordinates with Ca2+ and modulate the activation by Ca2+ and voltage.

Significance Radial glial cells (RGCs), a type of neural stem cell in the developing brain, not only generate progenitors, newly born neurons and glial cells, but also deliver neurons through its process to the appropriate cortical target layers. Thus, the function of RGCs is crucial for cortex development, in which Cl− channels are thought to play a role. Here we highlight that Anoctamin 1 (ANO1)/TMEM16A, a Ca2+-activated Cl− channel, mediates the process extension in RGCs. ANO1-null mice show a decrease in cortical thickness with disorganized cortical layers. Thus, as a Cl− channel, ANO1 is involved in the process maturation of RGCs and contributes to cortex development., Neural stem cells (NSCs) are primary progenitor cells in the early developmental stage in the brain that initiate a diverse lineage of differentiated neurons and glia. Radial glial cells (RGCs), a type of neural stem cell in the ventricular zone, are essential for nurturing and delivering new immature neurons to the appropriate cortical target layers. Here we report that Anoctamin 1 (ANO1)/TMEM16A, a Ca2+-activated chloride channel, mediates the Ca2+-dependent process extension of RGCs. ANO1 is highly expressed and functionally active in RGCs of the mouse embryonic ventricular zone. Knockdown of ANO1 suppresses RGC process extension and protrusions, whereas ANO1 overexpression stimulates process extension. Among various trophic factors, brain-derived neurotrophic factor (BDNF) activates ANO1, which is required for BDNF-induced process extension in RGCs. More importantly, Ano1-deficient mice exhibited disrupted cortical layers and reduced cortical thickness. We thus conclude that the regulation of RGC process extension by ANO1 contributes to the normal formation of mouse embryonic brain.

The transdermal delivery system of nutrients, cosmetics, and drugs is particularly attractive for painless, noninvasive delivery and sustainable release. Recently, atmospheric pressure plasma techniques have been of great interest to improve the drug absorption rate in transdermal delivery. Currently, plasma-mediated changes in the lipid composition of the stratum corneum are considered a possible mechanism to increase transdermal permeability. Nevertheless, its molecular and cellular mechanisms in transdermal delivery have been largely confined and still veiled. Herein, we present the effects of cold plasma on transdermal transmission on porcine skin and the cellular permeability of keratinocytes and further demonstrate the production of nitric oxide from keratinocytes. Consequently, argon plasma irradiation for 60 s resulted in 2.5-fold higher transdermal absorption of aniline blue dye on porcine skin compared to the nontreated control. In addition, the plasma-treated keratinocytes showed an increased transmission of high-molecular-weight molecules (70 and 150 kDa) with the production of nitric oxide. Therefore, these findings suggest a promoting effect of low-temperature plasma on transdermal absorption, even for high-molecular-weight molecules. Moreover, plasma-induced nitric oxide from keratinocytes is likely to regulate transdermal permeability in the epidermal layer.

Biohybrid artificial muscle produced by integrating living muscle cells and their scaffolds with free movement in vivo is promising for advanced biomedical applications, including cell-based microrobotic systems and therapeutic drug delivery systems. Herein, we provide a biohybrid artificial muscle constructed by integrating living muscle cells and their scaffolds, inspired by bundled myofilaments in skeletal muscle. First, a bundled biohybrid artificial muscle was fabricated by the integration of skeletal muscle cells and hydrophilic polyurethane (HPU)/carbon nanotube (CNT) nanofibers into a fiber shape similar to that of natural skeletal muscle. The HPU/CNT nanofibers provided a stretchable basic backbone of the 3-dimensional fiber structure, which is similar to actin-myosin scaffolds. The incorporated skeletal muscle fibers contribute to the actuation of biohybrid artificial muscle. In fact, electrical field stimulation reversibly leads to the contraction of biohybrid artificial muscle. Therefore, the current development of cell-actuated artificial muscle provides great potential for energy delivery systems as actuators for implantable medibot movement and drug delivery systems. Moreover, the innervation of the biohybrid artificial muscle with motor neurons is of great interest for human-machine interfaces.

Bacterial vaginosis is a common female disease caused by a vaginal infection due to an overgrowth of bacteria that naturally live in the vaginal tract. Bacterial vaginosis has frequently been treated with the oral or vaginal administration of antibiotics and topical disinfectants. However, hygienic application of topical treatment deep in the vagina remains difficult. Herein, we introduce a novel vaginal cleaning device using plasma-activated water generated from supplied water. Remarkably, plasma source generation at atmospheric pressure is well known to eradicate bacterial infection through the generation of free radicals and/or chlorine chemicals with antimicrobial activity. The device was designed to alleviate a bacterial infection by spraying plasma-activated water generated from a cleaning solution container with plasma modules. The spray nozzle contains both a clean outlet and a suction outlet to spray and recover the plasma water, respectively, and is connected to a disposable silicone tube. The other nozzle, which has a laser light and air pump, can perform a second sterilization and dry the vagina after washing. Free chlorine chemicals with antibacterial activity were detected in the plasma-activated water by the device. Clinical application in patients with bacterial vaginosis confirmed the stability and effectiveness of our device. Therefore, these results show a novel clinical application of atmospheric pressure plasma to medical field as a plasma medicine.

Burn-related injuries are devastating injuries with a high mortality rate that affect people of all ages worldwide. We assessed the effectiveness of plasma jet treatment in altering the expression of genes involved in wound healing in a prospective longitudinal observational animal study. Six male Sprague–Dawley rats weighing 350 g were used, and burn wounds were made by applying a preheated brass comb (100°C) to the back of the rats, resulting in four full-thickness burn wounds separated by three interspaces. A total of 18 burn wounds were induced on three rats. One side of the burn, on each rat received plasma treatment (plasma group), while the other side did not (control group). The interspaces were subjected to the plasma jet for 2 minutes per day until 7 days post-wounding. Plasma treatment significantly decreased the expression of proinflammatory cytokines. Furthermore, an increase in the expression of anti-inflammatory cytokines was observed in the plasma group. We showed that plasma jet treatment could improve burn wound healing by altering the expression of genes involved in the development of wound healing.

Flexible and stretchable fiber supercapacitors have been progressively improved for wearable electronic devices. However, they should be further improved with respect to stretchable range and stable electrochemical performance during dynamic movement when considering the tensile range for wearable applications. Here, we report a quasi-solid-state circular knitted MnO

The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function. Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) This work was supported by NIH grant nos. NS070577 and NS084869 (to K.-S.K.), NRF-2018M3A9B5023055 grant (to C.-H.K.), Ministry of Education Singapore AcRF Tier 2 Grant (no. ARC55/16) and Tang Tieng See Advancement Fund (to H.S.Y.), and National Medical Research Council, Singapore (grant no. TCR/013-NNI/2014; to K.L.L. and H.S.Y.).

TRPM2 a cation channel is also known to work as an enzyme that hydrolyzes highly reactive, neurotoxic ADP-ribose (ADPR). Although ADPR is hydrolyzed by NUT9 pyrophosphatase in major organs, the enzyme is defective in the brain. The present study questions the role of TRPM2 in the catabolism of ADPR in the brain. Genetic ablation of Trpm2 results in the disruption of ADPR catabolism that leads to the accumulation of ADPR and reduction in AMP. Trpm2−/− mice elicit the reduction in autophagosome formation in the hippocampus. Trpm2−/− mice also show aggregations of proteins in the hippocampus, aberrant structural changes and neuronal connections in synapses, and neuronal degeneration. Trpm2−/− mice exhibit learning and memory impairment, enhanced neuronal intrinsic excitability, and imbalanced synaptic transmission. These results respond to long-unanswered questions regarding the potential role of the enzymatic function of TRPM2 in the brain, whose dysfunction evokes protein aggregation. In addition, the present finding answers to the conflicting reports such as neuroprotective or neurodegenerative phenotypes observed in Trpm2−/− mice. Electronic supplementary material The online version of this article (10.1007/s12035-018-1309-0) contains supplementary material, which is available to authorized users.

Anoctamin 1 (ANO1) is an anion channel that is activated by changes in cytosolic Ca2＋ concentration and noxious heat. Although the critical roles of ANO1 have been elucidated in various cell types, the control of its gating mechanisms by Ca2＋ and heat remain more elusive. To investigate critical amino acid residues for modulation of Ca2＋ and heat sensing, we constructed a randomized mutant library for ANO1. Among 695 random mutants, reduced Ca2＋ sensitivity was observed in two mutants (mutant 84 and 87). Consequently, the E143A mutant showed reduced sensitivity to Ca2＋ but not to high temperatures, whereas the E705V mutant exhibited reduced sensitivity to both Ca2＋ and noxious heat. These results suggest that the glutamic acids (E) at 143 and 705 residues in ANO1 are critical for modulation of Ca2＋ and/or heat responses. Furthermore, these findings help to provide a better understanding of the Ca2＋-mediated activation and heat-sensing mechanism of ANO1. [BMB Reports 2018; 51(5): 236-241].

A self-healing electrode is an electrical conductor that can repair internal damage by itself, similar to human skin. Since self-healing electrodes are based on polymers and hydrogels, these components are still limited by low electrical conductivity and mechanical strength. In this study, we designed an electrically conductive, mechanically strong, and printable self-healing electrode using liquid crystal graphene oxide (LCGO) and silver nanowires (AgNWs). The conductive ink was easily prepared by simply mixing LCGO and AgNWs solutions. The ultrathin (3 μm thick) electrode can be printed in various shapes, such as a butterfly, in a freestanding state. The maximum conductivity and strength of the LCGO/AgNW composite were 17 800 S/cm and 4.2 MPa, respectively; these values are 24 and 4 times higher, respectively, than those of a previously developed self-healing electrode. The LCGO/AgNW composite self-healed internal damage in ambient conditions with moisture and consequently recovered 96.8% electrical conductivity and 95% mechanical toughness compared with the undamaged state. The electrical properties of the composite exhibited metallic tendencies. Therefore, these results suggest that the composite can be used as an artificial electronic skin that detects environmental conditions, such as compression and temperature. This self-healing artificial electronic skin could be applied to human condition monitoring and robotic sensing systems.

For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates TREG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1’s ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic TH17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of TREG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.

Spider silks represent stretchable and contractible fibers with high toughness. Those tough fibers with stretchability and contractibility are attractive as energy absorption materials, and they are needed for wearable applications, artificial muscles, and soft robotics. Although carbon-based materials and poly(vinyl alcohol) (PVA) composite fibers exhibit high toughness, they are still limited in low extensibility and an inability to operate in the wet-state condition. Herein, we report stretchable and contractible fiber with toughness that is inspired by the structure of spider silk. The bioinspired tough fiber provides 495 J/g of gravimetric toughness, which exceeds 165 J/g of spider silk. Besides, the tough fiber was reversibly stretched to ∼80% strain without damage. This toughness and stretchability are realized by hybridization of aligned graphene oxide/multiwalled carbon nanotubes in a polyurethane matrix as elastic amorphous regions and β-sheet segments of spider silk. Interestingly, the bioinspired tough fiber contracted up to 60% in response to water and humidity similar to supercontraction of the spider silk. It exhibited 610 kJ/m3 of contractile energy density, which is higher than previously reported moisture driven actuators. Therefore, this stretchable and contractible tough fiber could be utilized as an artificial muscle in soft robotics and wearable devices.

Controllable and miniaturised mechanical actuation is one of the main challenges facing various emerging technologies, such as soft robotics, drug delivery systems, and microfluidics. Here we introduce a simple method for constructing actuating devices with programmable complex motions. Thermally responsive hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) and its functionalized derivatives (f-PNIPAM) were used to control the lower critical solution temperature (LCST) or the temperature at which the gel volume changes. Techniques for ultra-violet crosslinking the monomer solutions were developed to generate gel sheets with controllable crosslink density gradients that allowed bending actuation to specified curvatures by heating through the LCST. Simple molding processes were then used to construct multi-transform devices with complex shape changes, including a bioinspired artificial flower that shows blossoming and reverse blossoming with a change in temperature.

Smart systems are those that display autonomous or collaborative functionalities, and include the ability to sense multiple inputs, to respond with appropriate operations, and to control a given situation. In certain circumstances, it is also of great interest to retain flexible, stretchable, portable, wearable, and/or implantable attributes in smart electronic systems. Among the promising candidate smart materials, carbon nanotubes (CNTs) exhibit excellent electrical and mechanical properties, and structurally fabricated CNT-based fibers and yarns with coil and twist further introduce flexible and stretchable properties. A number of notable studies have demonstrated various functions of CNT yarns, including sensors, actuators, and energy storage. In particular, CNT yarns can operate as flexible electronic sensors and electrodes to monitor strain, temperature, ionic concentration, and the concentration of target biomolecules. Moreover, a twisted CNT yarn enables strong torsional actuation, and coiled CNT yarns generate large tensile strokes as an artificial muscle. Furthermore, the reversible actuation of CNT yarns can be used as an energy harvester and, when combined with a CNT supercapacitor, has promoted the next-generation of energy storage systems. Here, progressive advances of CNT yarns in electrical sensing, actuation, and energy storage are reported, and the future challenges in smart electronic systems considered.

The strong peristaltic contraction of the stomach facilitates mixing and emptying of ingested food, which occurs rhythmically at approximately 3 cycles/min (cpm) in humans. Generally, most patients with gastroparesis show gastric electrical dysrhythmia that is disrupted electrical signals controlling gastric contractions. For treatment of gastric electrical dysrhythmia, in vivo electrical impulses to the stomach via an implanted gastric stimulator have been known to restore these gastric deformations. Nevertheless, improved sensors to monitor gastric contractions are still needed in current gastric stimulators. Recently, we have developed a new technology converting mechanical motion to electrical energy by using stretch-induced capacitance changes of a coiled carbon-nanotube (CNT) yarn. For its potential use as a gastric deformation sensor, the performance of a coiled CNT yarn was evaluated in several biological fluids. For a sinusoidal stretch to 30%, the peak-to-peak open-circuit voltage (OCV) was consistently generated at frequencies below 0.1 Hz. This sinusoidal variation in OCV augmented as the strain increased from 10 to 30%. In an in vitro artificial gastric system, the OCV was approximately linearly proportional to the balloon volume, which can monitor periodic deformations of the balloon at 2, 3, and 4 cpm as shown for human gastric deformations. Moreover, stretchy coiled yarns generate the peak electrical voltage and power when deformed. The present study shows that a self-powered CNT yarn sensor can not only monitor the changes in frequency and amplitude of volumetric change but also generate electrical power by periodic deformations of the balloon. Therefore, it seems possible to automatically deliver accurate electrical impulses according to real-time evaluation of a patient's gastric deformation based on information on the frequency, amplitude, and rate of the OCV from CNT yarn.

Although guest-filled carbon nanotube yarns provide record performance as torsional and tensile artificial muscles, they are expensive, and only part of the muscle effectively contributes to actuation. We describe a muscle type that provides higher performance, in which the guest that drives actuation is a sheath on a twisted or coiled core that can be an inexpensive yarn. This change from guest-filled to sheath-run artificial muscles increases the maximum work capacity by factors of 1.70 to 2.15 for tensile muscles driven electrothermally or by vapor absorption. A sheath-run electrochemical muscle generates 1.98 watts per gram of average contractile power-40 times that for human muscle and 9.0 times that of the highest power alternative electrochemical muscle. Theory predicts the observed performance advantages of sheath-run muscles.

Underwater robots and vehicles have received great attention due to their potential applications in remote sensing and search and rescue. A challenge for micro aquatic robots is the lack of small motors needed for three-dimensional locomotion in water. Here, we show a simple diving and surfacing device fabricated from thermo-sensitive poly(N-isopropylacrylamide) or a poly(N-isopropylacrylamide)-containing hydrogel. The poly(N-isopropylacrylamide)-containing device exhibited fast and reversible diving/surfacing cycles in response to changing temperature. Modulation of the interaction between poly(N-isopropylacrylamide) chains and water molecules at temperatures above or below the lower critical solution temperature regulates the gel density through the swelling and de-swelling. The gel surfaced in water when heated and sank when cooled. We further showed reversible diving/surfacing cycles of the device when exposed to electrical and ultrasonic stimuli. Finally, a small electrically heated gel was incorporated into a miniature submarine and used to control the diving depth. These results suggest that the poly(N-isopropylacrylamide)-containing device has good potential for underwater remote-controlled micro aquatic robots.

SUMMARY During somatic reprogramming, cellular energy metabolism fundamentally switches from predominantly mitochondrial oxidative phosphorylation toward glycolysis. This metabolic reprogramming, also called the Warburg effect, is critical for the induction of pluripotency, but its molecular mechanisms remain poorly defined. Notably, SIRT2 is consistently downregulated during the reprogramming process and regulates glycolytic switch. Here, we report that downregulation of SIRT2 increases acetylation of mitogen-activated protein kinase (MAPK) kinase-1 (MEK1) at Lys175, resulting in activation of extracellular signal-regulated kinases (ERKs) and subsequent activation of the pro-fission factor dynamin-related protein 1 (DRP1). In parallel, downregulation of SIRT2 hyperacetylates the serine/threonine protein kinase AKT1 at Lys20 in a non-canonical way, activating DRP1 and metabolic reprogramming. Together, our study identified two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that critically link mitochondrial dynamics and oxidative phosphorylation to the somatic reprogramming process. These upstream signals, together with SIRT2’s role in glycolytic switching, may underlie the Warburg effect observed in human somatic cell reprogramming., In brief Mitochondrial remodeling has critical roles for the somatic cell reprogramming process. Cha et al. report the functional role of SIRT2 in mitochondrial dynamics and remodeling during the human somatic cell reprogramming process. They identify two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that link SIRT2 downregulation to mitochondrial remodeling and somatic cell reprogramming., Graphical Abstract

Various studies about harvesting energy for future energy production have been conducted. In particular, replacing batteries in implantable medical devices with electrical harvesting is a great challenge. Here, we have improved the electrical harvesting performance of twisted carbon nanotube yarn, which was previously reported to be an electrical energy harvester, by biscrolling positively charged ferritin protein in a biofluid environment. The harvester electrodes are made by biscrolling ferritin (40 wt%) in carbon nanotube yarn and twisting it into a coiled structure, which provides stretchability. The coiled ferritin/carbon nanotube yarn generated a 2.8-fold higher peak-to-peak open circuit voltage (OCV) and a 1.5-fold higher peak power than that generated by bare carbon nanotube yarn in phosphate-buffered saline (PBS) buffer. The improved performance is the result of the increased capacitance change and the shifting of the potential of zero charges that are induced by the electrochemically capacitive, positively charged ferritin. As a result, we confirm that the electrical performance of the carbon nanotube harvester can be improved using biomaterials. This carbon nanotube yarn harvester, which contains protein, has the potential to replace batteries in implantable devices.

Recent progress in tissue engineering research led to the generation of different types of cells from a handful of skin tissue. Lineage reprogramming is a nascent field, which holds great potential to expand its use in regenerative medicine and disease modeling. The concept of somatic cell epigenetic stability has been fundamentally reshaped through the report of direct conversion of somatic identity to another lineage by introducing transcription factors. Here, we review recent advances in lineage reprogramming research, especially direct conversion into dopamine neurons from fibroblasts.

A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the 'Warburg effect', which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase. Remarkably, knockdown of SIRT2 in human fibroblasts resulted in significantly decreased OXPHOS and increased glycolysis. In addition, we found that miR-200c-5p specifically targets SIRT2, downregulating its expression. Furthermore, SIRT2 overexpression in hPSCs significantly affected energy metabolism, altering stem cell functions such as pluripotent differentiation properties. Taken together, our results identify the miR-200c-SIRT2 axis as a key regulator of metabolic reprogramming (Warburg-like effect), via regulation of glycolytic enzymes, during human induced pluripotency and pluripotent stem cell function.

The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)‐related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron‐specific manner in AD‐related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1’s expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD mouse model and postmortem human AD subjects. In addition, we performed both gain‐of‐function and loss‐of‐function studies of Nurr1 and its pharmacological activation in 5XFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5XFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD‐related pathophysiology and identify Nurr1 as a novel AD therapeutic target.

Background The quantification of pain intensity in vivo is essential for identifying the mechanisms of various types of pain or for evaluating the effects of different analgesics. A variety of behavioral tests for pain measurement have been devised, but many are limited because animals are physically restricted, which affects pain sensation. In this study, pain assessment was attempted with minimal physical restriction, and voluntary movements of unrestrained animals were used to evaluate the intensities of various types of pain. Results The number of times animals reared or total distances traveled was measured using a motion-tracking device and found to be markedly reduced in carrageenan-induced inflammatory, acetic acid-induced visceral, and streptozotocin-induced neuropathic pain tests. These two voluntary movement parameters were found to be highly correlated with paw withdrawal latency from irradiating heat. In addition, these parameters were markedly reversed by morphine and by non-steroidal anti-inflammatory drugs in inflammatory pain models. These parameters were also useful to detect hypoalgesia in TRPV1−/− mice. Conclusions These results suggest that parameters of voluntary movement, such as, number of rearing and total distance moved, are effective indicators of pain intensity for many types of pain and that they can be used to evaluate degree of pain perception.

Spinal muscular atrophy and hereditary motor and sensory neuropathies are characterized by muscle weakness and atrophy caused by the degenerations of peripheral motor and sensory nerves. Recent advances in genetics have resulted in the identification of missense mutations in TRPV4 in patients with these hereditary neuropathies. Neurodegeneration caused by Ca(2+) overload due to the gain-of-function mutation of TRPV4 was suggested as the molecular mechanism for the neuropathies. Despite the importance of TRPV4 mutations in causing neuropathies, the precise role of TRPV4 in the sensory/motor neurons is unknown. Here, we report that TRPV4 mediates neurotrophic factor-derived neuritogenesis in developing peripheral neurons. TRPV4 was found to be highly expressed in sensory and spinal motor neurons in early development as well as in the adult, and the overexpression or chemical activation of TRPV4 was found to promote neuritogenesis in sensory neurons as well as PC12 cells, whereas its knockdown and pharmacologic inhibition had the opposite effect. More importantly, nerve growth factor or cAMP treatment up-regulated the expression of phospholipase A(2) and TRPV4. Neurotrophic factor-derived neuritogenesis appears to be regulated by the phospholipase A(2)-mediated TRPV4 pathway. These findings show that TRPV4 mediates neurotrophic factor-induced neuritogenesis in developing peripheral nerves. Because neurotrophic factors are essential for the maintenance of peripheral nerves, these findings suggest that aberrant TRPV4 activity may lead to some types of pathology of sensory and motor nerves.

Objective To identify the causal gene in a multi-incident U.S. kindred with Parkinson’s disease (PD). Methods We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. Results We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Conclusions Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0045-4) contains supplementary material, which is available to authorized users.

Bipolar disorder (BD) is a psychiatric disease that causes mood swings between manic and depressed states. Although genetic linkage studies have shown an association between BD and TRPM2, a Ca(2+)-permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of Trpm2 that is frequently found in BD patients, induces loss of function. Trpm2-deficient mice exhibited BD-related behavior such as increased anxiety and decreased social responses, along with disrupted EEG functional connectivity. Moreover, the administration of amphetamine in wild-type mice evoked a notable increase in open-field activity that was reversed by the administration of lithium. However, the anti-manic action of lithium was not observed in the Trpm2(−/−) mice. The brains of Trpm2(−/−) mice showed a marked increase in phosphorylated glycogen synthase kinase-3 (GSK-3), a key element in BD-like behavior and a target of lithium. In contrast, activation of TRPM2 induced the dephosphorylation of GSK-3 via calcineurin, a Ca(2+)-dependent phosphatase. Importantly, the overexpression of the D543E mutant failed to induce the dephosphorylation of GSK-3. Therefore, we conclude that the genetic dysfunction of Trpm2 causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BD. Our findings explain the long-sought etiologic mechanism underlying the genetic link between Trpm2 mutation and BD. SIGNIFICANCE STATEMENT Bipolar disorder (BD) is a mental disorder that causes changes in mood and the etiology is still unknown. TRPM2 is highly associated with BD; however, its involvement in the etiology of BD is still unknown. We show here that TRPM2 plays a central role in causing the pathology of BD. We found that D543E, a mutation of Trpm2 frequently found in BD patients, induces the loss of function. Trpm2-deficient mice exhibited mood disturbances and impairments in social cognition. TRPM2 actively regulates the phosphorylation of GSK-3, which is a main target of lithium, a primary medicine for treating BD. Therefore, abnormal regulation of GSK-3 by hypoactive TRPM2 mutants accounts for the pathology of BD, providing the possible link between BD and TRPM2.

Significance Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate gland, a common disease in elderly men. Excessive testosterone is considered to cause BPH. However, its etiologic mechanisms are elusive. We found that ANO1, a Ca 2+ -activated Cl − channel, is essential for the testosterone-induced BPH. ANO1 was highly expressed in dihydrotestosterone (DHT)-treated prostate epithelial cells. The selective knockdown of ANO1 suppressed DHT-induced cell proliferation. Surprisingly, we found that there were three androgen-response elements in the ANO1 promoter region, which were relevant for the DHT-dependent induction of ANO1. Intraprostate treatment of Ano1 siRNA inhibited the prostate enlargement in vivo. Thus, ANO1 appears essential for the development of prostate hyperplasia and becomes a useful target for treating BPH.

Pedigrees with variants of unknown significance. Pedigrees in which the RAB39B (A) c.428C>G (p.A143G) and (B) c.624_626delGAG (p.R209del) variants were observed. Individuals affected with Parkinsonâ s disease are represented with black symbols, unaffected individuals with open symbols. Age at onset is indicated immediately below each symbol, followed by age at last clinical evaluation. Wt = wild type; Mut = mutation. (PDF 35 kb)