Investigating pediatric disorders with induced pluripotent stem cells

The study of disease pathophysiology has long relied on model systems, including animal models and cultured cells. In 2006, Shinya Yamanaka achieved a breakthrough by reprogramming somatic cells into induced pluripotent stem cells (iPSCs). This revolutionary discovery provided new opportunities for disease modeling and therapeutic intervention. With established protocols, investigators can generate iPSC lines from patient blood, urine, and tissue samples. These iPSCs retain ability to differentiate into every human cell type. Advances in differentiation and organogenesis move cellular in vitro modeling to a multicellular model capable of recapitulating physiology and disease. Here, we discuss limitations of traditional animal and tissue culture models, as well as the application of iPSC models. We highlight various techniques, including reprogramming strategies, directed differentiation, tissue engineering, organoid developments, and genome editing. We extensively summarize current established iPSC disease models that utilize these techniques. Confluence of these technologies will advance our understanding of pediatric diseases and help usher in new personalized therapies for patients

Novel Roaming and Stationary Tethered Aerial Robots for Continuous Mobile Missions in Nuclear Power Plants

AbstractIn this paper, new tethered aerial robots including roaming tethered aerial robots (RTARs) for radioactive material sampling and stationary tethered aerial robots (STARs) for environment monitoring are proposed to meet extremely-long-endurance missions of nuclear power plants. The flight of the proposed tethered aerial robots may last for a few days or even a few months as long as the tethered cable provides continuous power. A high voltage AC or DC power system was newly adopted to reduce the mass of the tethered cable. The RTAR uses a tethered cable spooled from the aerial robot and an aerial tension control system. The aerial tension control system provides the appropriate tension to the tethered cable, which is accordingly laid down on the ground as the RTAR roams. The STAR includes a tethered cable spooled from the ground and a ground tension control system, which enables the STAR to reach high altitudes. Prototypes of the RTAR and STAR were designed and successfully demonstrated in outdoor environments, where the load power, power type, operating frequency, and flight attitude of the RTAR and STAR were: 180 W, AC 100 kHz, and 20 m; and 300 W, AC or DC 100 kHz, and 80 m, respectively

Decoupled cantilever arms for highly versatile and sensitive temperature and heat flux measurements

Microfabricated cantilever beams have been used in microelectromechanical systems for a variety of sensor and actuator applications. Bimorph cantilevers accurately measure temperature change and heat flux with resolutions several orders of magnitude higher than those of conventional sensors such as thermocouples, semiconductor diodes, as well as resistance and infrared thermometers. The use of traditional cantilevers, however, entails a series of important measurement limitations, because their interactions with the sample and surroundings often create parasitic deflection forces and the typical metal layer degrades the thermal sensitivity of the cantilever. The paper introduces a design to address these issues by decoupling the sample and detector section of the cantilever, along with a thermomechanical model, the fabrication, system integration, and characterization. The custom-designed bi-arm cantilever is over one order of magnitude more sensitive than current commercial cantilevers due to the significantly reduced thermal conductance of the cantilever sample arm. The rigid and immobile sample section offers measurement versatility ranging from photothermal absorption, near-field thermal radiation down to contact, conduction, and material thermal characterization measurements in nearly identical configurations.United States. Dept. of Energy. Division of Materials Sciences and Engineering (DE-FG02-02ER45977)United States. Air Force Office of Scientific Research. Multidisciplinary University Research Initiative (UIUC FA9550-08-1-0407

Directing lineage specification of human mesenchymal stem cells by decoupling electrical stimulation and physical patterning on unmodified graphene

The organization and composition of the extracellular matrix (ECM) have been shown to impact the propagation of electrical signals in multiple tissue types. To date, many studies with electroactive biomaterial substrates have relied upon passive electrical stimulation of the ionic media to affect cell behavior. However, development of cell culture systems in which stimulation can be directly applied to the material – thereby isolating the signal to the cell-material interface and cell–cell contracts – would provide a more physiologically-relevant paradigm for investigating how electrical cues modulate lineage-specific stem cell differentiation. In the present study, we have employed unmodified, directly-stimulated, (un)patterned graphene as a cell culture substrate to investigate how extrinsic electrical cycling influences the differentiation of naïve human mesenchymal stem cells (hMSCs) without the bias of exogenous biochemicals. We first demonstrated that cyclic stimulation does not deteriorate the cell culture media or result in cytotoxic pH, which are critical experiments for correct interpretation of changes in cell behavior. We then measured how the expression of osteogenic and neurogenic lineage-specific markers were altered simply by exposure to electrical stimulation and/or physical patterns. Expression of the early osteogenic transcription factor RUNX2 was increased by electrical stimulation on all graphene substrates, but the mature marker osteopontin was only modulated when stimulation was combined with physical patterns. In contrast, the expression of the neurogenic markers MAP2 and β3-tubulin were enhanced in all electrical stimulation conditions, and were less responsive to the presence of patterns. These data indicate that specific combinations of non- biological inputs – material type, electrical stimulation, physical patterns – can regulate hMSC lineage specification. This study represents a substantial step in understanding how the interplay of electrophysical stimuli regulate stem cell behavior and helps to clarify the potential for graphene substrates in tissue engineering applications

Variability of extracorporeal cardiopulmonary resuscitation utilization for refractory adult out-of-hospital cardiac arrest: an international survey study.

Objective: A growing interest in extracorporeal cardiopulmonary resuscitation (ECPR) as a rescue strategy for refractory adult out-of-hospital cardiac arrest (OHCA) currently exists. This study aims to determine current standards of care and practice variation for ECPR patients in the USA and Korea. Methods: In December 2015, we surveyed centers from the Korean Hypothermia Network (KORHN) Investigators and the US National Post-Arrest Research Consortium (NPARC) on current targeted temperature management and ECPR practices. This project analyzes the subsection of questions addressing ECPR practices. We summarized survey. Results: Overall, 9 KORHN and 4 NPARC centers reported having ECPR programs and had complete survey data available. Two KORHN centers utilized extracorporeal membrane oxygenation only for postarrest circulatory support in patients with refractory shock and were excluded from further analysis. Centers with available ECPR generally saw a high volume of OHCA patients (10/11 centers care for \u3e75 OHCA a year). Location of, and providers trained for cannulation varied across centers. All centers in both countries (KORHN 7/7, NPARC 4/4) treated comatose ECPR patients with targeted temperature management. All NPARC centers and four of seven KORHN centers reported having a standardized hospital protocol for ECPR. Upper age cutoff for eligibility ranged from 60 to 75 years. No absolute contraindications were unanimous among centers. Conclusion: A wide variability in practice patterns exist between centers performing ECPR for refractory OHCA in the US and Korea. Standardized protocols and shared research databases might inform best practices, improve outcomes, and provide a foundation for prospective studies

An Optical Source Catalog of the North Ecliptic Pole Region

We present a five (u*,g',r',i',z') band optical photometry catalog of the sources in the North Ecliptic Pole (NEP) region based on deep observations made with MegaCam at CFHT. The source catalog covers about 2 square degree area centered at the NEP and reaches depths of about 26 mag for u*, g', r' bands, about 25 mag for i' band, and about 24 mag for z' band (4 sigma detection over an 1 arcsec aperture). The total number of cataloged sources brighter than r'= 23 mag is about 56,000 including both point sources and extended sources. From the investigation of photometric properties using the color-magnitude diagrams and color-color diagrams, we have found that the colors of extended sources are mostly (u*-r') 0.5. This can be used to separate the extended sources from the point sources reliably, even for the faint source domain where typical morphological classification schemes hardly work efficiently. We have derived an empirical color-redshift relation of the red sequence galaxies using the Sloan Digital Sky Survey data. By applying this relation to our photometry catalog and searching for any spatial overdensities, we have found two galaxy clusters and one nearby galaxy group.Comment: 34 pages, 15 figures, 2 tables. Accepted for publication in ApJS. The pdf file with high resolution figures can be downloaded from http://astro.snu.ac.kr/~nhwang/index.files/nep.htm

Analysis of the Association between CIMP and BRAFV600E in Colorectal Cancer by DNA Methylation Profiling

A CpG island methylator phenotype (CIMP) is displayed by a distinct subset of colorectal cancers with a high frequency of DNA hypermethylation in a specific group of CpG islands. Recent studies have shown that an activating mutation of BRAF (BRAFV600E) is tightly associated with CIMP, raising the question of whether BRAFV600E plays a causal role in the development of CIMP or whether CIMP provides a favorable environment for the acquisition of BRAFV600E. We employed Illumina GoldenGate DNA methylation technology, which interrogates 1,505 CpG sites in 807 different genes, to further study this association. We first examined whether expression of BRAFV600E causes DNA hypermethylation by stably expressing BRAFV600E in the CIMP-negative, BRAF wild-type COLO 320DM colorectal cancer cell line. We determined 100 CIMP-associated CpG sites and examined changes in DNA methylation in eight stably transfected clones over multiple passages. We found that BRAFV600E is not sufficient to induce CIMP in our system. Secondly, considering the alternative possibility, we identified genes whose DNA hypermethylation was closely linked to BRAFV600E and CIMP in 235 primary colorectal tumors. Interestingly, genes that showed the most significant link include those that mediate various signaling pathways implicated in colorectal tumorigenesis, such as BMP3 and BMP6 (BMP signaling), EPHA3, KIT, and FLT1 (receptor tyrosine kinases) and SMO (Hedgehog signaling). Furthermore, we identified CIMP-dependent DNA hypermethylation of IGFBP7, which has been shown to mediate BRAFV600E-induced cellular senescence and apoptosis. Promoter DNA hypermethylation of IGFBP7 was associated with silencing of the gene. CIMP-specific inactivation of BRAFV600E-induced senescence and apoptosis pathways by IGFBP7 DNA hypermethylation might create a favorable context for the acquisition of BRAFV600E in CIMP+ colorectal cancer. Our data will be useful for future investigations toward understanding CIMP in colorectal cancer and gaining insights into the role of aberrant DNA hypermethylation in colorectal tumorigenesis

The On-Orbit Performance of the Galaxy Evolution Explorer

We report the first year on-orbit performance results for the Galaxy Evolution Explorer (GALEX), a NASA Small Explorer that is performing a survey of the sky in two ultraviolet bands. The instrument comprises a 50 cm diameter modified Ritchey-Chretien telescope with a 1.25 degree field of view, selectable imaging and objective grism spectroscopic modes, and an innovative optical system with a thin-film multilayer dichroic beam splitter that enables simultaneous imaging by a pair of photon counting, microchannel plate, delay line readout detectors. Initial measurements demonstrate that GALEX is performing well, meeting its requirements for resolution, efficiency, astrometry, bandpass definition and survey sensitivity.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issu