Cell-based therapy is expected as an alternative treatment for Parkinson’s disease. In this issue of Cell Stem Cell, two accompanying papers (Kim et al., 2021; Piao et al., 2021) report the induction ...of clinically applicable dopaminergic neurons from human embryonic stem cells and the results of pre-clinical study toward a clinical trial.
Cell-based therapy is expected as an alternative treatment for Parkinson’s disease. In this issue of Cell Stem Cell, two accompanying papers (Kim et al., 2021; Piao et al., 2021) report the induction of clinically applicable dopaminergic neurons from human embryonic stem cells and the results of pre-clinical study toward a clinical trial.
Following intensive efforts since their discovery little more than 10 years ago, cell replacement therapy using induced pluripotent stem (iPS) cells is now becoming reality. However, there remain ...several obstacles in the translation of basic research to clinical application, obstacles known as the “Valley of Death”. With regards to regenerative medicine using iPS cells for Parkinson's disease, we have developed a method for the 1) efficient induction of dopaminergic neurons from human iPS cells and 2) sorting dopaminergic progenitor cells using a floor plate marker, CORIN. The grafted CORIN+ cells survived well and functioned as midbrain dopaminergic neurons in the Parkinson's disease model rats and monkeys, and showed minimal risk of tumor formation. Based on these results, we performed a pre-clinical study using a clinical-grade iPS cell line and finally started a clinical trial to treat Parkinson's disease patients in August 2018. Here, I discuss the key issues to crossing the Valley of Death: scientific rationale, pre-clinical study, and clinical trial.
Parkinson's disease (PD) is a neurodegenerative disease caused by the progressive loss of dopaminergic (DA) neurons in the midbrain projecting to the striatum, which leads to motor dysfunctions, such ...as bradykinesia (slowed movement), rigidity, and tremors. To replace the lost cells, the transplantation of DA neurons derived from embryonic stem cells or induced pluripotent stem cells (iPSCs) has been considered. In this issue of the JCI, Song et al. report on their development of an iPSC induction and differentiation protocol that can promote the realization of autologous transplantation to treat PD patients with their own cells.
This study identifies exogenous fluctuations (i.e., shocks) in oil prices and examines their causal effects on macroeconomic variables in Japan. Following a recent line of research that identifies ...exogenous changes in oil prices (Kilian, 2009), we decompose fluctuations in real prices into crude oil supply shocks, shocks to the global demand for commodities, and demand shocks to the crude oil market. This study provides three main findings. First, an exogenous change in oil prices on the supply side decreases GDP, consumption, investment, and wages. Second, an exogenous change in oil prices on the demand side increases GDP, consumption, investment, and wages. Third, shocks that cause an increase in oil prices increase aggregate price levels, regardless of whether they originate on the supply or demand side. We provide evidence counter to the conventional wisdom that an increase in oil prices always hampers the Japanese economy.
There is hope for neural regeneration through stem cell-derived neural cell transplantation. In particular, the reconstruction of neural circuits has a different mode of action from that of ...conventional medical treatment or gene therapy and is expected to have more fundamental effects. However, there are many issues to overcome, such as producing appropriate donor cells, controlling neural connections after transplantation, and establishing tumor formation. Cell-based therapy has been developed mainly for Parkinson's disease, and transplantation of ES/iPS cell-derived dopaminergic neurons is already in clinical trials. In addition, developmental research for treating stroke is underway, and further developments using brain organoids are expected.
Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and ...suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.
The recent status of Japan's government-driven project to establish carbon fiber reinforced thermoplastic composites (CFRTP) technology for automotive applications conducted in the National ...Composites Center (NCC) Japan is introduced first. The baseline technology is discontinuous carbon fiber reinforced thermoplastic composites (C-LFT-D: carbon – long fiber thermoplastic-direct) using press compaction. All the components of the target car chassis made of aluminum alloy are replaced by C-LFT-D components and a 10% weight reduction with the same rigidity has been verified. The basic physics of the fiber length distribution mechanism and the experimental procedures to measure fiber length distributions are proposed. A basic theory to predict the flow behavior of extruded raw material of the mixture of melted resin and thermoplastics is proposed, and sophisticated CAE software to predict the flow patterns of the raw material is established. Measured elastic moduli of processed LFT-D plates show strong dependency on local fiber orientations and strong correlations between bending strengths and bending modulus are found. Hence, prediction of fiber orientation in the press compaction is a key point of the design of LFT-D components. The viscoelastic properties of C-LFT-D materials are characterized by using established theories. Certain important parameters, such as the shift factors, are identified by theory and experiments. The basic concepts of joining technology are also established, where ultrasonic fusion bonding is selected as the primary method. Joining procedures are defined and mechanical properties of the joints are evaluated. The essence of the other project conducted in the University of Tokyo for CFRTP applications to automobiles is also introduced. Several new composites are developed and evaluation technologies are developed.
Even though organic light emitting diodes (OLED) have been achieving commercial successes, their device physics have been under debating. In this article, we develop a junction theory of organic ...heterojunctions, which describes the carrier accumulation dynamics in them. We derive an equation, which is the counterpart of the Mott-Schottky relation in the metal-semiconductor contact. We will show that the essence of the carrier transport control in organic devices is the control of the internal electric field and therefore the drift motion, whereas that in the semiconductors is the control of the carrier population by shifting the Fermi energy and therefore the diffusion motion. Tang's invention of organic electronic devices with layered ultrathin layers of small organic molecules was a new paradigm of controlling the carrier transport in polaron conductors rather than only a finding of the substitutes of Si semiconductors.
Display omitted
•A junction theory in organic heterojunctions is presented to describe the carrier accumulation dynamics in them.•The counterpart of the Mott-Schottky relation of the Schottky contact is given for organic heterojunctions.•The quasiconductor concept is proposed to enlighten the distinct nature of the polaron conductors from the semiconductors.
PDF
