Co-shared genomic alterations within tumors from patients with both myeloproliferative neoplasms and lymphoma.

Not available.

FOXA1/2 depletion drives global reprogramming of differentiation state and metabolism in a human liver cell line and inhibits differentiation of human stem cell-derived hepatic progenitor cells.

FOXA factors are critical members of the developmental gene regulatory network (GRN) composed of master transcription factors (TF) which regulate murine cell fate and metabolism in the gut and liver. How FOXA factors dictate human liver cell fate, differentiation, and simultaneously regulate metabolic pathways is poorly understood. Here, we aimed to determine the role of FOXA2 (and FOXA1 which is believed to compensate for FOXA2) in controlling hepatic differentiation and cell metabolism in a human hepatic cell line (HepG2). siRNA mediated knockdown of FOXA1/2 in HepG2 cells significantly downregulated albumin (p < .05) and GRN TF gene expression (HNF4α, HEX, HNF1ß, TBX3) (p < .05) and significantly upregulated endoderm/gut/hepatic endoderm markers (goosecoid [GSC], FOXA3, and GATA4), gut TF (CDX2), pluripotent TF (NANOG), and neuroectodermal TF (PAX6) (p < .05), all consistent with partial/transient reprograming. shFOXA1/2 targeting resulted in similar findings and demonstrated evidence of reversibility of phenotype. RNA-seq followed by bioinformatic analysis of shFOXA1/2 knockdown HepG2 cells demonstrated 235 significant downregulated genes and 448 upregulated genes, including upregulation of markers for alternate germ layers lineages (cardiac, endothelial, muscle) and neurectoderm (eye, neural). We found widespread downregulation of glycolysis, citric acid cycle, mitochondrial genes, and alterations in lipid metabolism, pentose phosphate pathway, and ketogenesis. Functional metabolic analysis agreed with these findings, demonstrating significantly diminished glycolysis and mitochondrial respiration, with concomitant accumulation of lipid droplets. We hypothesized that FOXA1/2 inhibit the initiation of human liver differentiation in vitro. During human pluripotent stem cells (hPSC)-hepatic differentiation, siRNA knockdown demonstrated de-differentiation and unexpectedly, activation of pluripotency factors and neuroectoderm. shRNA knockdown demonstrated similar results and activation of SOX9 (hepatobiliary). These results demonstrate that FOXA1/2 controls hepatic and developmental GRN, and their knockdown leads to reprogramming of both differentiation and metabolism, with applications in studies of cancer, differentiation, and organogenesis.

Quantitative investigation on a period variation reduction method for the fabrication of large-area gratings using two-spherical-beam laser interference lithography.

Gratings produced by two-spherical-beam Laser Interference Lithography (LIL) will have a nonuniform period, and the associated period variation is larger with the increase of the substrate size. This work quantitatively investigates a noninvasive method for improving the period variation on 4-inch silicon wafers. By temporarily deforming the flexible silicon wafer using a customized concave vacuum chuck [J. Vac. Sci. Technol. B19(6), 2347 (2001)10.1116/1.1421558], we show that the fabricated gratings will have improved period uniformity, with the period variation reduced by 86% at the 1000 nm central grating period setting. This process is a simple and efficient way to achieve linear gratings without altering the LIL configuration with two spherical beams. We present experimental results on the impact of a concave vacuum chuck on the chirp reduction at different grating period settings. Then, we compare two different LIL configurations with different wavelength sources concerning their influence on the efficiency of period variation reduction. Finally, the flatness of the 4-inch silicon wafers due to the temporary bending process is verified using optical profilometry measurements.

High Electricity Demand in the Northeast U.S.: PJM Reliability Network and Peaking Unit Impacts on Air Quality.

On high electricity demand days, when air quality is often poor, regional transmission organizations (RTOs), such as PJM Interconnection, ensure reliability of the grid by employing peak-use electric generating units (EGUs). These "peaking units" are exempt from some federal and state air quality rules. We identify RTO assignment and peaking unit classification for EGUs in the Eastern U.S. and estimate air quality for four emission scenarios with the Community Multiscale Air Quality (CMAQ) model during the July 2006 heat wave. Further, we population-weight ambient values as a surrogate for potential population exposure. Emissions from electricity reliability networks negatively impact air quality in their own region and in neighboring geographic areas. Monitored and controlled PJM peaking units are generally located in economically depressed areas and can contribute up to 87% of hourly maximum PM2.5 mass locally. Potential population exposure to peaking unit PM2.5 mass is highest in the model domain's most populated cities. Average daily temperature and national gross domestic product steer peaking unit heat input. Air quality planning that capitalizes on a priori knowledge of local electricity demand and economics may provide a more holistic approach to protect human health within the context of growing energy needs in a changing world.

Temporalization of peak electric generation particulate matter emissions during high energy demand days.

Underprediction of peak ambient pollution by air quality models hinders development of effective strategies to protect health and welfare. The U.S. Environmental Protection Agency's community multiscale air quality (CMAQ) model routinely underpredicts peak ozone and fine particulate matter (PM2.5) concentrations. Temporal misallocation of electricity sector emissions contributes to this modeling deficiency. Hourly emissions are created for CMAQ by use of temporal profiles applied to annual emission totals unless a source is matched to a continuous emissions monitor (CEM) in the National Emissions Inventory (NEI). More than 53% of CEMs in the Pennsylvania-New Jersey-Maryland (PJM) electricity market and 45% nationally are unmatched in the 2008 NEI. For July 2006, a United States heat wave with high electricity demand, peak electric sector emissions, and elevated ambient PM2.5 mass, we match hourly emissions for 267 CEM/NEI pairs in PJM (approximately 49% and 12% of unmatched CEMs in PJM and nationwide) using state permits, electricity dispatch modeling and CEMs. Hourly emissions for individual facilities can differ up to 154% during the simulation when measurement data is used rather than default temporalization values. Maximum CMAQ PM2.5 mass, sulfate, and elemental carbon predictions increase up to 83%, 103%, and 310%, at the surface and 51%, 75%, and 38% aloft (800 mb), respectively.

Broadband pulse compression gratings with measured 99.7% diffraction efficiency.

We present experimental investigations of grating mirrors with high diffraction efficiencies exceeding 99.7% in the -1st order for TE polarization at a wavelength of 1060 nm, and exceeding a diffraction efficiency of 99% in the wavelength range from 1025 nm to at least 1070 nm. The total efficiency of a four-pass compressor for chirped pulse amplification was >96%. The design, fabrication, and characterization of the fully dielectric grating mirrors are presented.

Thermal behavior of resonant waveguide-grating mirrors in Yb:YAG thin-disk lasers.

We present the experimental investigations of different designs of resonant waveguide-grating (RWG) mirrors, used as intracavity folding mirrors in an Yb:YAG thin-disk laser (TDL). The investigation was focused on the rise of the surface temperature due to the coupling of the incident radiation to a waveguide mode as well as on laser efficiency, polarization, and wavelength selectivity. It was found that the damage threshold and efficiency can be increased significantly with a proper design of the structure in comparison to the simplest design with a single waveguide layer. So far, the presented RWG allow the generation of linear polarization with a narrow spectral linewidth down to 25 pm FWHM in a fundamental mode Yb:YAG TDL. Damage thresholds of 60 kW/cm(2) have been reached where only 63 K of surface temperature increase was observed. This showed that the improved mirrors are suitable for the generation of kW-class narrow linewidth, linearly polarized Yb:YAG TDL.

Speech intelligibility in hospitals.

Effective communication between staff members is key to patient safety in hospitals. A variety of patient care activities including admittance, evaluation, and treatment rely on oral communication. Surprisingly, published information on speech intelligibility in hospitals is extremely limited. In this study, speech intelligibility measurements and occupant evaluations were conducted in 20 units of five different U.S. hospitals. A variety of unit types and locations were studied. Results show that overall, no unit had "good" intelligibility based on the speech intelligibility index (SII > 0.75) and several locations found to have "poor" intelligibility (SII < 0.45). Further, occupied spaces were found to have 10%-15% lower SII than unoccupied spaces on average. Additionally, staff perception of communication problems at nurse stations was significantly correlated with SII ratings. In a targeted second phase, a unit treated with sound absorption had higher SII ratings for a larger percentage of time as compared to an identical untreated unit. Taken as a whole, the study provides an extensive baseline evaluation of speech intelligibility across a variety of hospitals and unit types, offers some evidence of the positive impact of absorption on intelligibility, and identifies areas for future research.

Graphene Coating of Nafion Membranes for Enhanced Fuel Cell Performance.

Electrochemically exfoliated graphene (e-G) thin films on Nafion membranes exhibit a selective barrier effect against undesirable fuel crossover. This approach combines the high proton conductivity of state-of-the-art Nafion and the ability of e-G layers to effectively block the transport of methanol and hydrogen. Nafion membranes are coated with aqueous dispersions of e-G on the anode side, making use of a facile and scalable spray process. Scanning transmission electron microscopy and electron energy-loss spectroscopy confirm the formation of a dense percolated graphene flake network, which acts as a diffusion barrier. The maximum power density in direct methanol fuel cell (DMFC) operation with e-G-coated Nafion N115 is 3.9 times higher than that of the Nafion N115 reference (39 vs 10 mW cm-2@0.3 V) at a 5M methanol feed concentration. This suggests the application of e-G-coated Nafion membranes for portable DMFCs, where the use of highly concentrated methanol is desirable.

Linearly polarized, narrow-linewidth, and tunable Yb:YAG thin-disk laser.

We report on the design, fabrication, and implementation of grating-waveguide structures (GWS) for intracavity polarization and wavelength selection as well as wavelength tuning. The GWS discussed in this Letter is a combination of a low-index leaky-mode waveguide, a subwavelength diffraction grating, and a highly reflective mirror that was designed to operate in Littrow configuration. Using our device as the end mirror of an Yb:YAG thin-disk laser allowed the extraction of beams that exhibit an extremely narrow laser emission bandwidth of ≈25 pm FWHM and a high degree of linear polarization of 99±0.5%. Moreover, the GWS allows a wavelength tuning range from 1007 to 1053 nm. The high-power suitability and the low loss of the GWS was demonstrated by the intracavity use in an Yb:YAG thin-disk laser with an output power of 325 W in multimode operation (M(2)=6) and with 110 W in fundamental-mode operation (M(2)≈1.2), exhibiting optical efficiencies of 53.2% and 36.2%, respectively. An output power of 1.8 kW, corresponding to a power density of 125 kW/cm(2) on the grating, was achieved in further higher-power experiments.

A Generative Model for Generic Light Field Reconstruction.

Recently deep generative models have achieved impressive progress in modeling the distribution of training data. In this work, we present for the first time a generative model for 4D light field patches using variational autoencoders to capture the data distribution of light field patches. We develop a generative model conditioned on the central view of the light field and incorporate this as a prior in an energy minimization framework to address diverse light field reconstruction tasks. While pure learning-based approaches do achieve excellent results on each instance of such a problem, their applicability is limited to the specific observation model they have been trained on. On the contrary, our trained light field generative model can be incorporated as a prior into any model-based optimization approach and therefore extend to diverse reconstruction tasks including light field view synthesis, spatial-angular super resolution and reconstruction from coded projections. Our proposed method demonstrates good reconstruction, with performance approaching end-to-end trained networks, while outperforming traditional model-based approaches on both synthetic and real scenes. Furthermore, we show that our approach enables reliable light field recovery despite distortions in the input.

Versatility of composite grafts for nasal defects - a case series.

This retrospective study describes the reconstruction of 18 nasal defects with chondrocutaneous (composite) grafts. Composite grafts are versatile one-stage options for defects ≤2.5 cm at the lower third of the nose and are particularly useful in reconstruction of small full-thickness defects and superficial defects bordering or involving the alar rim.

Basing care reforms on evidence: the Kenya health sector costing model.

BACKGROUND: The Government of the Republic of Kenya is in the process of implementing health care reforms. However, poor knowledge about costs of health care services is perceived as a major obstacle towards evidence-based, effective and efficient health care reforms. Against this background, the Ministry of Health of Kenya in cooperation with its development partners conducted a comprehensive costing exercise and subsequently developed the Kenya Health Sector Costing Model in order to fill this data gap. METHODS: Based on standard methodology of costing of health care services in developing countries, standard questionnaires and analyses were employed in 207 health care facilities representing different trustees (e.g. Government, Faith Based/Nongovernmental, private-for-profit organisations), levels of care and regions (urban, rural). In addition, a total of 1369 patients were randomly selected and asked about their demand-sided costs. A standard step-down costing methodology was applied to calculate the costs per service unit and per diagnosis of the financial year 2006/2007. RESULTS: The total costs of essential health care services in Kenya were calculated as 690 million Euros or 18.65 Euro per capita. 54% were incurred by public sector facilities, 17% by Faith Based and other Nongovernmental facilities and 23% in the private sector. Some 6% of the total cost is due to the overall administration provided directly by the Ministry and its decentralised organs. Around 37% of this cost is absorbed by salaries and 22% by drugs and medical supplies. Generally, costs of lower levels of care are lower than of higher levels, but health centres are an exemption. They have higher costs per service unit than district hospitals. CONCLUSIONS: The results of this study signify that the costs of health care services are quite high compared with the Kenyan domestic product, but a major share are fixed costs so that an increasing coverage does not necessarily increase the health care costs proportionally. Instead, productivity will rise in particular in under-utilized private health care institutions. The results of this study also show that private-for-profit health care facilities are not only the luxurious providers catering exclusively for the rich but also play an important role in the service provision for the poorer population. The study findings also demonstrated a high degree of cost variability across private providers, suggesting differences in quality and efficiencies.

Mitral Valve Segmentation Using Robust Nonnegative Matrix Factorization.

Analyzing and understanding the movement of the mitral valve is of vital importance in cardiology, as the treatment and prevention of several serious heart diseases depend on it. Unfortunately, large amounts of noise as well as a highly varying image quality make the automatic tracking and segmentation of the mitral valve in two-dimensional echocardiographic videos challenging. In this paper, we present a fully automatic and unsupervised method for segmentation of the mitral valve in two-dimensional echocardiographic videos, independently of the echocardiographic view. We propose a bias-free variant of the robust non-negative matrix factorization (RNMF) along with a window-based localization approach, that is able to identify the mitral valve in several challenging situations. We improve the average f1-score on our dataset of 10 echocardiographic videos by 0.18 to a f1-score of 0.56.

Paclitaxel-eluting biodegradable synthetic vascular prostheses: a step towards reduction of neointima formation?

BACKGROUND: Clinical small-caliber vascular prostheses are unsatisfactory. Reasons for failure are early thrombosis and late intimal hyperplasia. We thus prepared biodegradable small-caliber vascular prostheses using electrospun polycaprolactone (PCL) with slow-releasing paclitaxel (PTX), an antiproliferative drug. METHODS AND RESULTS: PCL solutions containing PTX were used to prepare nonwoven nanofibre-based 2-mm ID prostheses. Mechanical morphological properties and drug loading, distribution, and release were studied in vitro. Infrarenal abdominal aortic replacement was carried out with nondrug-loaded and drug-loaded prostheses in 18 rats and followed for 6 months. Patency, stenosis, tissue reaction, and drug effect on endothelialization, vascular remodeling, and neointima formation were studied in vivo. In vitro prostheses showed controlled morphology mimicking extracellular matrix with mechanical properties similar to those of native vessels. PTX-loaded grafts with suitable mechanical properties and controlled drug-release were obtained by factorial design. In vivo, both groups showed 100% patency, no stenosis, and no aneurysmal dilatation. Endothelial coverage and cell ingrowth were significantly reduced at 3 weeks and delayed at 12 and 24 weeks in PTX grafts, but as envisioned, neointima formation was significantly reduced in these grafts at 12 weeks and delayed at 6 months. CONCLUSIONS: Biodegradable, electrospun, nanofibre, polycaprolactone prostheses are promising because in vitro they maintain their mechanical properties (regardless of PTX loading), and in vivo show good patency, reendothelialize, and remodel with autologous cells. PTX loading delays endothelialization and cellular ingrowth. Conversely, it reduces neointima formation until the end point of our study and thus may be an interesting option for small caliber vascular grafts.

Time-resolved near-infrared spectroscopy and imaging of the adult human brain.

Near-infrared spectroscopy (NIRS) of the human brain is aiming at the non-invasive determination of concentration changes of oxy- and deoxyhemoglobin in the cortex. However, it usually relies on the assumption of spatially homogeneous absorption changes. To overcome this limitation we performed instrumental and methodological developments of time-resolved NIRS with the aim to achieve depth resolution. We present our recently developed time-domain near-infrared brain imager based on picosecond diode lasers and time-correlated single photon counting (TCSPC) which can be used at the bedside. To achieve depth localization of absorption changes we analysed statistical moments (integral, mean time of flight and variance) of measured time-of-flight distributions of diffusely reflected photons. In particular, variance has a selective sensitivity to deep absorptions changes and provides a suitable representation of cerebral signals. The separation of cerebral and extracerebral changes of hemoglobin concentrations is demonstrated for a motor stimulation experiment.

Time-Multiplexed Illumination for simultaneous Structural and Functional Voltage Sensitive Dye Recordings with a single Photo Sensor.

The in-vivo optical imaging of the cortical surface provides the ability to record different types of biophysiological signals, e.g., structural information, intrinsic signals, like blood oxygenation coupled reflection changes as well as extrinsic properties of voltage sensitive probes, like fluorescent voltage-sensitive dyes. The recorded data sets have very high temporal and spatial resolutions on a meso- to macroscopic scale, which surpass conventional multi-electrode recordings. Both, intrinsic and functional data sets, each provide unique information about temporal and spatial dynamics of cortical functioning, yet have individual drawbacks. To optimize the informational value it would thus be opportune to combine different types of optical imaging in a near simultaneous recording.Due to the low signal-to-noise ratio of voltage-sensitive dyes it is necessary to reduce stray light pollution below the level of the camera's dark noise. It is thus impossible to record full-spectrum optical data sets. We address this problem by a time-multiplexed illumination, bespoke to the utilized voltage sensitive dye, to record an alternating series of intrinsic and extrinsic frames by a high-frequency CMOS sensor. These near simultaneous data series can be used to compare the mutual influence of intrinsic and extrinsic dynamics (with regards to extracorporeal functional imaging) as well as for motion compensation and thus for minimizing frame averaging, which in turn results in increased spatial precision of functional data and in a reduction of necessary experimental data sets (3R principle).

Degradation and healing characteristics of small-diameter poly(epsilon-caprolactone) vascular grafts in the rat systemic arterial circulation.

BACKGROUND: Long-term patency of conventional synthetic grafts is unsatisfactory below a 6-mm internal diameter. Poly(epsilon-caprolactone) (PCL) is a promising biodegradable polymer with a longer degradation time. We aimed to evaluate in vivo healing and degradation characteristics of small-diameter vascular grafts made of PCL nanofibers compared with expanded polytetrafluoroethylene (ePTFE) grafts. METHODS AND RESULTS: We prepared 2-mm-internal diameter grafts by electrospinning using PCL (M(n)=80, 000 g/mol). Either PCL (n=15) or ePTFE (n=15) grafts were implanted into 30 rats. Rats were followed up for 24 weeks. At the conclusion of the follow-up period, patency and structural integrity were evaluated by digital subtraction angiography. The abdominal aorta, including the graft, was harvested and investigated under light microscopy. Endothelial coverage, neointima formation, and transmural cellular ingrowth were measured by computed histomorphometry. All animals survived until the end of follow-up, and all grafts were patent in both groups. Digital subtraction angiography revealed no stenosis in the PCL group but stenotic lesions in 1 graft at 18 weeks (40%) and in another graft at 24 weeks (50%) in the ePTFE group. None of the grafts showed aneurysmal dilatation. Endothelial coverage was significantly better in the PCL group. Neointimal formation was comparable between the 2 groups. Macrophage and fibroblast ingrowth with extracellular matrix formation and neoangiogenesis were better in the PCL group. After 12 weeks, foci of chondroid metaplasia located in the neointima of PCL grafts were observed in all samples. CONCLUSIONS: Small-diameter PCL grafts represent a promising alternative for the future because of their better healing characteristics compared with ePTFE grafts. Faster endothelialization and extracellular matrix formation, accompanied by degradation of graft fibers, seem to be the major advantages. Further evaluation of degradation and graft healing characteristics may potentially lead to the clinical use of such grafts for revascularization procedures.

Effect of implantation site on outcome of tissue-engineered vascular grafts.

OBJECTIVE: Vascular prostheses for small caliber bypass grafts in cardiac and vascular diseases or for access surgery are still missing. Poly (Ɛ-caprolactone) (PCL) has been previously investigated by our group and showed good biocompatibility and mechanical properties in vitro and rapid endothelialisation, cellular infiltration and vascularisation in vivo yielding optimal patency in the abdominal aortic position. The aim of the present study is to evaluate our PCL graft in the carotid position and to compare its outcome to the grafts implanted in the abdominal aortic position. METHODS: PCL grafts (1 mm ID/10 mm long) were implanted into the left common carotid artery in 20 Sprague-Dawley rats and compared to our previously published series of abdominal aortic implants. The animals were followed up to 3, 6, 12 and 24 weeks. At each time point, in vivo compliance, angiography and histological examination with morphology were performed. RESULTS: PCL grafts showed good mechanical properties and ease of handling. The average graft compliance was 14.5 ±â€¯1.7%/ mmHg compared to 7.8 ±â€¯0.9% for the abdominal position and 45.1 ±â€¯3.2%/ mmHg for the native carotid artery. The overall patency for the carotid position was 65% as compared to 100% in the abdominal position. Complete endothelialisation was achieved at 3 weeks and cell invasion was more rapid than in the aortic position. In contrast, intimal hyperplasia (IH) and vascular density were less pronounced than in the aortic position. CONCLUSION: Our PCL grafts in the carotid position were well endothelialised with early cellular infiltration, higher compliance, lower IH and calcification compared to the similar grafts implanted in the aortic position. However, there was a higher occlusion rate compared to our abdominal aorta series. Anatomical position, compliance mismatch, flow conditions may answer the difference in patency seen.