Intratumoral heterogeneity is a major obstacle to cancer treatment and a significant confounding factor in bulk-tumor profiling. We performed an unbiased analysis of transcriptional heterogeneity in ...colorectal tumors and their microenvironments using single-cell RNA-seq from 11 primary colorectal tumors and matched normal mucosa. To robustly cluster single-cell transcriptomes, we developed reference component analysis (RCA), an algorithm that substantially improves clustering accuracy. Using RCA, we identified two distinct subtypes of cancer-associated fibroblasts (CAFs). Additionally, epithelial-mesenchymal transition (EMT)-related genes were found to be upregulated only in the CAF subpopulation of tumor samples. Notably, colorectal tumors previously assigned to a single subtype on the basis of bulk transcriptomics could be divided into subgroups with divergent survival probability by using single-cell signatures, thus underscoring the prognostic value of our approach. Overall, our results demonstrate that unbiased single-cell RNA-seq profiling of tumor and matched normal samples provides a unique opportunity to characterize aberrant cell states within a tumor.
THE ARCTIC SYSTEM REANALYSIS, VERSION 2 Bromwich, D. H.; Wilson, A. B.; Bai, L. ...
Bulletin of the American Meteorological Society,
04/2018, Letnik:
99, Številka:
4
Journal Article
Recenzirano
The Arctic is a vital component of the global climate, and its rapid environmental evolution is an important element of climate change around the world. To detect and diagnose the changes occurring ...to the coupled Arctic climate system, a state-of-the-art synthesis for assessment and monitoring is imperative. This paper presents the Arctic System Reanalysis, version 2 (ASRv2), a multiagency, university-led retrospective analysis (reanalysis) of the greater Arctic region using blends of the polar-optimized version of the Weather Research and Forecasting (Polar WRF) Model and WRF three-dimensional variational data assimilated observations for a comprehensive integration of the regional climate of the Arctic for 2000–12. New features in ASRv2 compared to version 1 (ASRv1) include 1) higher-resolution depiction in space (15-km horizontal resolution), 2) updated model physics including subgrid-scale cloud fraction interaction with radiation, and 3) a dual outer-loop routine for more accurate data assimilation. ASRv2 surface and pressure-level products are available at 3-hourly and monthly mean time scales at the National Center for Atmospheric Research (NCAR). Analysis of ASRv2 reveals superior reproduction of near-surface and tropospheric variables. Broadscale analysis of forecast precipitation and site-specific comparisons of downward radiative fluxes demonstrate significant improvement over ASRv1. The high-resolution topography and land surface, including weekly updated vegetation and realistic sea ice fraction, sea ice thickness, and snow-cover depth on sea ice, resolve finescale processes such as topographically forced winds. Thus, ASRv2 permits a reconstruction of the rapid change in the Arctic since the beginning of the twenty-first century–complementing global reanalyses. ASRv2 products will be useful for environmental models, verification of regional processes, or siting of future observation networks.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
3.
THE COSMIC/FORMOSAT-3 MISSION Anthes, R. A.; Bernhardt, P. A.; Chen, Y. ...
Bulletin of the American Meteorological Society,
03/2008, Letnik:
89, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The radio occultation (RO) technique, which makes use of radio signals transmitted by the global positioning system (GPS) satellites, has emerged as a powerful and relatively inexpensive approach for ...sounding the global atmosphere with high precision, accuracy, and vertical resolution in all weather and over both land and ocean. On 15 April 2006, the joint Taiwan–U.S. Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC)/Formosa Satellite Mission 3 (COSMIC/FORMOSAT-3, hereafter COSMIC) mission, a constellation of six microsatellites, was launched into a 512-km orbit. After launch the satellites were gradually deployed to their final orbits at 800 km, a process that took about 17 months. During the early weeks of the deployment, the satellites were spaced closely, offering a unique opportunity to verify the high precision of RO measurements. As of September 2007, COSMIC is providing about 2000 RO soundings per day to support the research and operational communities. COSMIC RO data are of better quality than those from the previous missions and penetrate much farther down into the troposphere; 70%–90% of the soundings reach to within 1 km of the surface on a global basis. The data are having a positive impact on operational global weather forecast models.
With the ability to penetrate deep into the lower troposphere using an advanced open-loop tracking technique, the COSMIC RO instruments can observe the structure of the tropical atmospheric boundary layer. The value of RO for climate monitoring and research is demonstrated by the precise and consistent observations between different instruments, platforms, and missions. COSMIC observations are capable of intercalibrating microwave measurements from the Advanced Microwave Sounding Unit (AMSU) on different satellites. Finally, unique and useful observations of the ionosphere are being obtained using the RO receiver and two other instruments on the COSMIC satellites, the tiny ionosphere photometer (TIP) and the tri-band beacon.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Targeted covalent inhibitors have re‐emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the ...structure‐based design of BCR‐ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild‐type and mutant ABL kinases, especially ABLT315I bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non‐covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co‐crystal structures of covalent inhibitor‐ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label‐free mass spectrometry to evaluate off‐targets of our compounds at proteome‐wide level in different mammalian cells.
Using iminoboronate chemistry, we report the first successful examples of catalytic lysine‐targeting reversible covalent BCR‐ABL inhibitors which inhibited both ABLWT and ABLT315I at nanomolar potency. We also demonstrated how the study of off‐targets for this class of compounds could be performed using activity‐based protein profiling and mass spectrometry.
Summary
Chilling restrains the distribution of mangroves. We tested whether foliar phosphorus (P) fractions and gene expression are associated with cold tolerance in mangrove species.
We exposed ...seedlings of six mangrove populations from different latitudes to favorable, chilling and recovery treatments, and measured their foliar P concentrations and fractions, photochemistry, nighttime respiration, and gene expression.
A Kandelia obovata (KO; 26.45°N) population completely and a Bruguiera gymnorhiza (Guangxi) (BGG; 21.50°N) population partially (30%) survived chilling. Avicennia marina (24.29°N), and other B. gymnorhiza (26.66°N, 24.40°N, and 19.62°N) populations died after chilling. Photosystems of KO and photosystem I of BGG were least injured. During chilling, leaf P fractions, except nucleic acid P in three populations, declined and photoinhibition and nighttime respiration increased in all populations, with the greatest impact in B. gymnorhiza. Leaf nucleic acid P was positively correlated with photochemical efficiency during recovery and nighttime respiration across populations for each treatment.
Relatively high concentrations of nucleic acid P and metabolite P were associated with stronger chilling tolerance in KO. Bruguiera gymnorhiza exhibited relatively low concentrations of organic P in favorable and chilling conditions, but its partially survived population showed stronger compensation in nucleic acid P and Pi concentrations and gene expression during recovery.
Objectives/Hypothesis
Benign paroxysmal positional vertigo (BPPV) is the most common vestibular disorder with an incidence between 10.7 and 17.3 per 100,000 persons per year. The mechanism for BPPV ...has been postulated to involve displaced otoconia resulting in canalithiasis. Although particulate matter has been observed in the endolymph of affected patients undergoing posterior canal occlusion surgery, an otoconial origin for the disease is still questioned.
Study Design
In this study, particulate matter was extracted from the posterior semicircular canal of two patients and examined with scanning electron microscopy.
Methods
The samples were obtained from two patients intraoperatively during posterior semicircular canal occlusion. The particles were fixed, stored in ethanol, and chemically dehydrated. The samples were sputter coated and viewed under a scanning electron microscope. Digital images were obtained.
Results
Intact and degenerating otoconia with and without linking filaments were found attached to amorphous particulate matter. Many otoconia appeared to be partially embedded in a gel matrix, presumably that which encases and anchors the otoconia within the otolith membrane, whereas others stood alone with no attached filaments and matrix. The otoconia measured roughly 2 to 8 μm in length and displayed a uniform outer shape with a cylindrical bulbous body and a 3 + 3 rhombohedral plane at each end.
Conclusions
These findings suggest that the source of the particulate matter in the semicircular canals of patients with BPPV is broken off fragments of the utricular otolithic membrane with attached and detached otoconia.
Level of Evidence
NA Laryngoscope, 127:709–714, 2017
Bone is a dynamic tissue that site-specifically adapts to the load that it experiences. In response to increasing load, the cortical bone area is increased, mainly through enhanced periosteal bone ...formation. This increase in area is associated with an increase in the number of bone-forming osteoblasts; however, the origin of the cells involved remains unclear. Alpha-smooth muscle actin (αSMA) is a marker of early osteoprogenitor cells in the periosteum, and we hypothesized that the new osteoblasts that are activated by loading could originate from αSMA-expressing cells. Therefore, we used an in vivo fate-mapping approach in an established axial loading model to investigate the role of αSMA-expressing cells in the load-induced increase in osteoblasts. Histomorphometric analysis was applied to measure the number of cells of different origin on the periosteal surface in the most load-responsive region of the mouse tibia. A single loading session failed to increase the number of periosteal αSMA-expressing cells and osteoblasts. However, in response to multiple episodes of loading, the caudal, but not the cranial, periosteal surface was lined with an increased number of osteoblasts originating from αSMA-expressing cells 5 days after the initial loading session. The proportion of osteoblasts derived from αSMA-labeled progenitors increased by 70% (
p
< 0.05), and the proportion of αSMA-labeled cells that had differentiated into osteoblasts was doubled. We conclude that αSMA-expressing osteoprogenitors can differentiate and contribute to the increase in periosteal osteoblasts induced by mechanical loading in a site-specific manner.
Osteogenesis imperfecta (OI) is a genetic disorder most commonly caused by mutations associated with type I collagen, resulting in a defective collagen bone matrix. Current treatments for OI focus on ...pharmaceutical strategies to increase the amount of defective bone matrix, but do not address the underlying collagen defect. Introducing healthy donor stem cells that differentiate into osteoblasts producing normal collagen in OI patients has the potential to increase bone mass and correct the mutant collagen matrix. In this study, donor bone marrow stromal cells (BMSCs, also known as bone marrow mesenchymal stem cells) expressing both αSMACreERT2/Ai9 progenitor reporter and osteoblast reporter Col2.3GFP were locally transplanted into the femur of OI murine (OIM) mice. One month post‐transplantation, 18% of the endosteal surface was lined by donor Col2.3GFP expressing osteoblasts indicating robust engraftment. Long‐term engraftment in the marrow was observed 3 and 6 months post‐transplantation. The presence of Col1a2‐expressing donor cell‐derived cortical bone matrix was detected in transplanted OIM femurs. Local transplantation of BMSCs increased cortical thickness (+12%), the polar moment of inertia (+14%), bone strength (+30%), and stiffness (+30%) 3 months post‐transplantation. Engrafted cells expressed progenitor markers CD51 and Sca‐1 up to 3 months post‐transplantation. Most importantly, 3 months post‐transplantation donor cells maintained the ability to differentiate into Col2.3GFP+ osteoblasts in vitro, and in vivo following secondary transplantation into OIM animals. Locally transplanted BMSCs can improve cortical structure and strength, and persist as continued source of osteoblast progenitors in the OIM mouse for at least 6 months.
Direct intra‐bone transplantation of bone marrow stromal cells into osteogenesis imperfecta murine (OIM) model resulted in significant improvement of bone parameters. Combination of visual markers for lineage tracing of progenitor cells and osteoblasts showed successful engraftment of donor cells up to 6 months post‐transplantation and indicated the stem cell potential following secondary transplant.
AIM: Mangroves are intertidal plants with sea‐dispersed propagules, hence their population structure can offer valuable insights into the biogeographical processes driving population subdivision in ...coastal species. In this study, we used molecular markers and ocean circulation simulations to examine the effects of ocean currents and land masses on the genetic structure of the major mangrove species Rhizophora mucronata. LOCATION: Southeast Asia. METHODS: We assessed the genetic structure of 13 R. mucronata populations from continental Southeast Asia and Sumatra using 10 microsatellite loci. We first examined the relative effects of geographical distance and land mass (the Malay Peninsula) in shaping the genetic structure of R. mucronata in Southeast Asia. We then characterized the genetic structure of R. mucronata and compared it to the simulated ocean circulation patterns within our study region. RESULTS: Despite the low genetic diversity, significant genetic structuring was detected across R. mucronata populations. Contrary to observations on other mangrove species, genetic differentiation in R. mucronata was not found across the coasts of the Malay Peninsula, nor was it correlated with geographical distance. Instead, the most distinct genetic discontinuity was found at the boundary between the Andaman Sea and the Malacca Strait, and this can be explained by the prevailing ocean currents in this region. MAIN CONCLUSIONS: Our study presents novel evidence that the genetic structure of R. mucronata is maintained by ocean current‐facilitated propagule dispersal.
In this paper, we describe the GPS radio occultation (RO) inversion process currently used at the University Corporation for Atmospheric Research (UCAR) COSMIC (Constellation Observing System for ...Meteorology, Ionosphere and Climate) Data Analysis and Archive Center (CDAAC). We then evaluate the accuracy of RO refractivity soundings of the CHAMP (CHAllenging Minisatellite Payload) and SACC (Satellite de Aplicaciones Cientificas-C) missions processed by CDAAC software, using data primarily from the month of December 2001. Our results show that RO soundings have the highest accuracy from about 5 km to 25 km. In this region of the atmosphere, the observational errors (which include both measurement and representativeness errors) are generally in the range of 0.3% to 0.5% in refractivity. The observational errors in the tropical lower troposphere increase toward the surface, and reach ∼3% in the bottom few kilometers of the atmosphere. The RO observational errors also increase above 25 km, particularly over the higher latitudes of the winter hemisphere. These error estimates are, in general, larger than earlier theoretical predictions. The larger observational errors in the lower tropical troposphere are attributed to the complicated structure of humidity, superrefraction and receiver tracking errors. The larger errors above 25 km are related to observational noise (mainly, uncalibrated ionospheric effects) and the use of ancillary data for noise reduction through an optimization procedure. We demonstrate that RO errors above 25 km can be substantially reduced by selecting only low-noise occultations. Our results show that RO soundings have smaller observational errors of refractivity than radiosondes when compared to analyses and short-term forecasts, even in the tropical lower troposphere. This difference is most likely related to the larger representativeness errors associated with the radiosonde, which provides in situ (point) measurements. The RO observational errors are found to be comparable with or smaller than 12-hour forecast errors of the NCEP (National Centers for Environmental Prediction) Aviation (AVN) model, except in the tropical lower troposphere below 3 km. This suggests that RO observations will improve global weather analysis and prediction. It is anticipated that with the use of an advanced signal tracking technique (open-loop tracking) in future missions, such as COSMIC, the accuracy of RO soundings can be further improved.
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