Direct Reprogramming of Rat Neural Precursor Cells and Fibroblasts into Pluripotent Stem Cells

Background: Given the usefulness of rats as an experimental system, an efficient method for generating rat induced pluripotent stem (iPS) cells would provide researchers with a powerful tool for studying human physiology and disease. Here, we report direct reprogramming of rat neural precursor (NP) cells and rat embryonic fibroblasts (REF) into iPS cells by retroviral transduction using either three (Oct3/4, Sox2, and Klf4), four (Oct3/4, Sox2, Klf4, and c-Myc), or five (Oct3/4, Sox2, Klf4, c-Myc, and Nanog) genes. Methodology and Principal Findings: iPS cells were generated from both NP and REF using only three (Oct3/4, Sox2, and Klf4) genes without c-Myc. Two factors were found to be critical for efficient derivation and maintenance of rat iPS cells: the use of rat instead of mouse feeders, and the use of small molecules specifically inhibiting mitogen-activated protein kinase and glycogen synthase kinase 3 pathways. In contrast, introduction of embryonic stem cell (ESC) extracts induced partial reprogramming, but failed to generate iPS cells. However, when combined with retroviral transduction, this method generated iPS cells with significantly higher efficiency. Morphology, gene expression, and epigenetic status confirmed that these rat iPS cells exhibited ESC-like properties, including the ability to differentiate into all three germ layers both in vitro and in teratomas. In particular, we found that these rat iPS cells could differentiate to midbrain-like dopamine neurons with a high efficiency. Conclusions/Significance: Given the usefulness of rats as an experimental system, our optimized method would be useful for generating rat iPS cells from diverse tissues and provide researchers with a powerful tool for studying human physiology and disease

Verification of piezoresistive and piezoelectric properties in 2D transition-metal dichalcogenide PtSe2 and PtTe2 materials

Transition-metal dichalcogenide (TMD) materials have promising properties that make them suitable for wearable bioelectronics and biosensors. Specifically, the Platinum based TMD materials, PtSe2 and PtTe2, can be fabricated at low temperatures, allowing for growth on flexible substrates, such as polyimide film. Exploration of piezoresistivity and piezoelectricity in PtSe2 and PtTe2 can enable more applications for the novel 2D material. This report focuses on the experimental setup and results for the verification of the piezoresistive and piezoelectric property in PtSe2 and PtTe2. The piezoresistivity experiment focuses on the change in resistance in the material due to strain induced by bending using a two-point bending fixture. In the piezoelectricity experiment, samples are put in a periodic strain at 2 Hz with the voltage response of the material being measured using a digital oscilloscope. An analysis of the experimental results is discussed along with a proposal for further applications for using piezoelectric materials as energy-harvesting elements of the next-generation bioelectronics.Electrical and Computer Engineerin

Correlation between Crystallinity, Charge Transport, and Electrical Stability in an Ambipolar Polymer Field-Effect Transistor Based on Poly(naphthalene-alt-diketopyrrolopyrrole)

We characterized the electrical properties of ambipolar polymer field-effect transistors (PFETs) based on the low-band-gap polymer, pNAPDO-DPP-EH. The polymer consisted of electron-rich 2,6-di(thienyl)naphthalene units with decyloxy chains (NAPDO) and electron-deficient diketopyrrolopyrrole units with 2-ethylhexyl chains (DPP-EH). The as-spun pNAPDO-DPP-EH PFET device exhibited ambipolar transport properties with a hole mobility of 3.64 X 10(-3) cm(2)/(V s) and an electron mobility of 0.37 X 10(-3) cm(2)/(V s). Thermal annealing of the polymer film resulted in a dramatic increase in the carrier mobility. Annealing at 200 degrees C yielded hole and electron mobilities of 0.078 and 0.002 cm(2)/(V s), respectively. The mechanism by which the mobility had improved was investigated via grazing incidence X-ray diffraction studies, atomic force microscopy, and temperature-dependent transport measurements. These results indicated that thermal annealing improved the polymer film crystallinity and promoted the formation of a longer-range lamellar structure that lowered the thermal activation energy for charge hopping. Thermal annealing, moreover, reduced charge trapping in the films and thus improved the electrical stability of the PFET device. This work underscores the fact that long-range ordering in a crystalline polymer is of great importance for efficient charge transport and high electrical stability

An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models

Abstract The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson’s disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1’s transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD

Correlation between Crystallinity, Charge Transport, and Electrical Stability in an Ambipolar Polymer Field-Effect Transistor Based on Poly(naphthalene-<i>alt</i>-diketopyrrolopyrrole)

We characterized the electrical properties of ambipolar polymer field-effect transistors (PFETs) based on the low-band-gap polymer, pNAPDO-DPP-EH. The polymer consisted of electron-rich 2,6-di­(thienyl)­naphthalene units with decyloxy chains (NAPDO) and electron-deficient diketopyrrolopyrrole units with 2-ethylhexyl chains (DPP-EH). The as-spun pNAPDO-DPP-EH PFET device exhibited ambipolar transport properties with a hole mobility of 3.64 × 10^–3 cm²/(V s) and an electron mobility of 0.37 × 10^–3 cm²/(V s). Thermal annealing of the polymer film resulted in a dramatic increase in the carrier mobility. Annealing at 200 °C yielded hole and electron mobilities of 0.078 and 0.002 cm²/(V s), respectively. The mechanism by which the mobility had improved was investigated via grazing incidence X-ray diffraction studies, atomic force microscopy, and temperature-dependent transport measurements. These results indicated that thermal annealing improved the polymer film crystallinity and promoted the formation of a longer-range lamellar structure that lowered the thermal activation energy for charge hopping. Thermal annealing, moreover, reduced charge trapping in the films and thus improved the electrical stability of the PFET device. This work underscores the fact that long-range ordering in a crystalline polymer is of great importance for efficient charge transport and high electrical stability

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.)

Crystallinity-Controlled Naphthalene-alt-diketopyrrolopyrrole Copolymers for High-Performance Ambipolar Field Effect Transistors

We report high-performance of ambipolar organic field-effect transistors (FETs) based on the low band gap copolymers of pDPPT2NAP-HD and pDPPT2NAP-OD. The polymers are composed of electron-rich 2,6-di(thienyl)naphthalene (T2NAP) and electron-deficient diketopyrrolopyrrole (DPP) units with branched alkyl chains of 2-hexyldecyl (HD) or 2-octyldodecyl (OD). The polymers were polymerized via Suzuki coupling, yielding optical band gaps of similar to 1.4 eV. In the transistor performance test, we observed good ambipolar transport behavior in both polymer films, and pDPPT2NAP-OD displayed hole and electron mobilities 1 order of magnitude higher than the corresponding properties of pDPPT2NAP-HD. Thermal annealing of the polymer films increased the carrier mobilities. Annealing at 150 degrees C provided optimal conditions yielding saturated film crystallinity and maximized carrier mobility. The highest hole and electron mobilities achieved in these polymers were 1.3 and 0.1 cm(2)/(V s), respectively, obtained from pDPPT2NAP-OD. The polymer structure and thermal annealing affected the carrier mobility, and this effect was investigated by fully characterizing the polymer films by grazing incidence X-ray diffraction (GIXD), atomic force microscopy (AFM), and transmission electron microscopy (TEM) experiments. The GLXD data revealed that both polymers formed highly crystalline films with edge-on orientation. pDPPT2NAP-OD, which included longer alkyl chains, showed a higher tendency to form long-range order among the polymer chains. Thermal annealing up to 150 degrees C improved the polymer film crystallinity and promoted the formation of longer-range lamellar structures. AFM and TEM images of the films were consistent with the GI-XD data. Theoretical calculations of the polymer structures provided a rationale for the relationship between the torsional angle between aromatic rings and the carrier mobility. From the intensive electrical measurements and full characterizations, we find that the chemical structure of polymer backbone and side alkyl chain has a profound effect on film crystallinity, morphology, and transistor properties