Genomic prediction in an admixed population of Atlantic salmon (Salmo salar)

Reliability of genomic selection (GS) models was tested in an admixed population of Atlantic salmon, originating from crossing of several wild subpopulations. The models included ordinary genomic BLUP models (GBLUP), using genome-wide SNP markers of varying densities (1 to 220k), a genomic identity-by-descent model (IBD-GS), using linkage analysis of sparse genome-wide markers, as well as a classical pedigree-based model. Reliabilities of the models were compared through 5-fold cross-validation. The traits studied were salmon lice (Lepeophtheirus salmonis) resistance (LR), measured as (log) density on the skin and fillet color (FC), with respective estimated heritabilities of 0.14 and 0.43. All genomic models outperformed the classical pedigree-based model, for both traits and at all marker densities. However, the relative improvement differed considerably between traits, models and marker densities. For the highly heritable FC, the IBD-GS had similar reliability as GBLUP at high marker densities (>22k). In contrast, for the lowly heritable LR, IBD-GS was clearly inferior to GBLUP, irrespective of marker density. Hence, GBLUP was robust to marker density for the lowly heritable LR, but sensitive to marker density for the highly heritable FC. We hypothesize that this phenomenon may be explained by historical admixture of different founder populations, expected to reduce short-range LD and induce long-range LD. The relative importance of LD/relationship information is expected to decrease/increase with increasing heritability of the trait. Still, using the ordinary GBLUP, the typical long-range LD of an admixed population may be effectively captured by sparse markers, while efficient utilization of relationship information may require denser markers (e.g., 22k or more)

Small molecule XIAP inhibitors enhance TRAIL-Lnduced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma

Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-Iinked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAIL-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. © 2009 American Association for Cancer Research

A stratigraphic framework for abrupt climatic changes during the Last Glacial period based on three synchronized Greenland ice-core records: refining and extending the INTIMATE event stratigraphy

Due to their outstanding resolution and well-constrained chronologies, Greenland ice-core records provide a master record of past climatic changes throughout the Last Interglacial–Glacial cycle in the North Atlantic region. As part of the INTIMATE (INTegration of Ice-core, MArine and TErrestrial records) project, protocols have been proposed to ensure consistent and robust correlation between different records of past climate. A key element of these protocols has been the formal definition and ordinal numbering of the sequence of Greenland Stadials (GS) and Greenland Interstadials (GI) within the most recent glacial period. The GS and GI periods are the Greenland expressions of the characteristic Dansgaard–Oeschger events that represent cold and warm phases of the North Atlantic region, respectively. We present here a more detailed and extended GS/GI template for the whole of the Last Glacial period. It is based on a synchronization of the NGRIP, GRIP, and GISP2 ice-core records that allows the parallel analysis of all three records on a common time scale. The boundaries of the GS and GI periods are defined based on a combination of stable-oxygen isotope ratios of the ice (δ18O, reflecting mainly local temperature) and calcium ion concentrations (reflecting mainly atmospheric dust loading) measured in the ice. The data not only resolve the well-known sequence of Dansgaard–Oeschger events that were first defined and numbered in the ice-core records more than two decades ago, but also better resolve a number of short-lived climatic oscillations, some defined here for the first time. Using this revised scheme, we propose a consistent approach for discriminating and naming all the significant abrupt climatic events of the Last Glacial period that are represented in the Greenland ice records. The final product constitutes an extended and better resolved Greenland stratotype sequence, against which other proxy records can be compared and correlated. It also provides a more secure basis for investigating the dynamics and fundamental causes of these climatic perturbations

Radiative transfer modeling of simulation and observational data

Radiative Transfer (RT) is considered to be one of the four Grand Challenges in Computational Astrophysics aside of Astrophysical Fluid Dynamics, N-Body Problems in Astrophysics, and Relativistic Astrophysics. The high dimensionality (7D instead of 4D for MHD) and the underlying integro-differential transport equation have forced coders to implement approximative RT methods in order to fit spectra and images or to treat RT in their HD and MHD codes. The central role of RT in star formation (SF) is based on several facts: a) The dense dusty gas in SF regions alters the radiation substantially making SF one of the most complex applications of RT. b) Radiation transports energy within the object and is therefore an essential part of any dynamical SF model. c) RT calculations tell us which of the processes/structures are visible at what wavelength by which telescope/instrument. Hence, RT is the central tool to analyze simulation results or to explore the scientific capabilities of planned instruments. d) With inverse RT, we can obtain the 1D-3D density and temperature structure from observations, completely decoupled from any (M)HD modeling (and the approximations made within). In this review, we summarize the main difficulties and the currently used computational techniques to calculate the RT in SF regions. Recent applications of 3D continuum RT in molecular clouds and disks around young massive stars are discussed to illustrate the capabilities and limits of current RT modeling

Investigation of strontium transport and strontium quantification in cortical rat bone by time-of-flight secondary ion mass spectrometry

Next-generation bone implants will be functionalized with drugs for stimulating bone growth. Modelling of drug release by such functionalized biomaterials and drug dispersion into bone can be used as predicting tool for biomaterials testing in future. Therefore, the determination of experimental parameters to describe and simulate drug release in bone is essential. Here, we focus on Sr2+ transport and quantification in cortical rat bone. Sr2+ dose-dependently stimulates bone-building osteoblasts and inhibits bone-resorbing osteoclasts. It should be preferentially applied in the case of bone fracture in the context of osteoporotic bone status. Transport properties of cortical rat bone were investigated by dipping experiments of bone sections in aqueous Sr2+ solution followed by time-of-flight secondary ion mass spectrometry (ToF-SIMS) depth profiling. Data evaluation was carried out by fitting a suitable mathematical diffusion equation to the experimental data. An average diffusion coefficient of D = (1.68 ?? 0.57) ?? 10-13 cm2 s-1 for healthy cortical bone was obtained. This value differed only slightly from the value of D = (4.30 ?? 1.43) ?? 10-13 cm2 s-1 for osteoporotic cortical bone. Transmission electron microscopy investigations revealed a comparable nano- and ultrastructure for both types of bone status. Additionally, Sr2+-enriched mineralized collagen standards were prepared for ToF-SIMS quantification of Sr2+ content. The obtained calibration curve was used for Sr2+ quantification in cortical and trabecular bone in real bone sections. The results allow important insights regarding the Sr2+ transport properties in healthy and osteoporotic bone and can ultimately be used to perform a simulation of drug release and mobility in bone

Strontium release from Sr 2+ -loaded bone cements and dispersion in healthy and osteoporotic rat bone

Drug functionalization of biomaterials is a modern and popular approach in biomaterials research. Amongst others this concept is used for the functionalization of bone implants to locally stimulate the bone healing process. For example strontium ions (Sr2+) are administered in osteoporosis therapy to stimulate bone growth and have recently been integrated into bone cements. Based on results of different analytical experiments we developed a two-phase model for the transport of therapeutically active Sr2+-ions in bone in combination with Korsmeyer-Peppas kinetics for the Sr2+ release from bone cement. Data of cement dissolution experiments into water in combination with inductively coupled plasma mass spectrometry (ICP-MS) analysis account for dissolution kinetics following Noyes-Whitney rule. For dissolution in ??-MEM cell culture media the process is kinetically hindered and can be described by Korsmeyer-Peppas kinetics. Time of flight secondary ion mass spectrometry (ToF-SIMS) was used to determine the Sr2+ diffusion coefficient in healthy and osteoporotic trabecular rat bone. Therefore, bone sections were dipped in aqueous Sr2+-solution by one side and the Sr2+-profile was measured by classical SIMS depth profiling. The Sr2+ mobility can be described by a simple diffusion model and we obtained diffusion coefficients of (2.28??2.97)???10-12cm2/s for healthy and of (1.55??0.93)???10-10cm2/s for osteoporotic bone. This finding can be explained by a different bone nanostructure, which was observed by focused ion beam scanning electron microscopy (FIB-SEM) and transmission electron microscopy (TEM). Finally, the time and spatially resolved drug transport was calculated by finite element method for the femur of healthy and osteoporotic rats. The obtained results were compared to mass images that were obtained from sections of in vivo experiments by ToF-SIMS. The simulated data fits quite well to experimental results. The successfully applied model for the description of drug dispersion can help to reduce the number of animal experiments in the future.Copyright ?? 2017 Elsevier B.V. All rights reserved

IMPACT OF SHORT- AND LONG-TERM EXERCISE TRAINING ON BRANCHED-CHAIN AMINO ACID TURNOVER AND INSULIN SENSITIVITY IN PRE-DIABETIC AND NORMAL WEIGHT HUMANS

Introduction: Obesity is associated with reduced insulin sensitivity (IS), reduced branched-chain amino acids (BCAA) catabolism, and elevated plasma BCAA. Physical exercise is known to enhance IS and influence BCAA metabolism.Aim: To investigate the relationship between BCAA metabolism and IS in overweight/dysglycemic (pT2D) and normal weight (control) individuals during short- and long-term exercise.Materials and Methods: We measured IS by hyper-insulinemic-euglycemic clamp, transcriptomics by mRNA sequencing of skeletal muscle and adipose tissue biopsies, and plasma concentration of BCAA by HPLC in 13 control men and 13 men with pT2D. Samples were obtained at rest, directly after and 2h after a bicycle challenge, before as well as after 12 weeks of combined endurance- and strength-exercise intervention. The effect of BCAA on glucose metabolism was analyzed in cultured human myotubes.Results: IS was lower in pT2D vs. controls and increased significantly following exercise in both groups. Plasma concentration of BCAA was higher, whereas BCAA catabolism based on pathway analyses was lower in both skeletal muscle and adipose tissue in pT2D vs. control men. Plasma concentration of BCAA did not change on average with exercise, whereas BCAA catabolism based on transcriptomics increased in both skeletal muscle and adipose tissue. The increase in BCAA catabolism was higher in pT2D vs. control men in both tissues. Increased skeletal muscle catabolism predicted increased IS, the decrease in molar sum of circulating BCAA predicted improvement in HOMA-IR, and the increase in adipose tissue BCAA catabolism predicted increased expression of adipose tissue citric acids cycle enzyme mRNA. The addition of BCAA to cultured myotubes reduced the fractional glucose oxidation.Conclusion: A mechanism involving increased BCAA catabolism in adipose tissue and skeletal muscle, may mediate interactions between exercise, BCAA metabolism and IS

Biofabrication: A Guide to Technology and Terminology

Biofabrication holds the potential to generate constructs that more closely recapitulate the complexity and heterogeneity of tissues and organs than do currently available regenerative medicine therapies. Such constructs can be applied for tissue regeneration or as in vitro 3D models. Biofabrication is maturing and growing, and scientists with different backgrounds are joining this field, underscoring the need for unity regarding the use of terminology. We therefore believe that there is a compelling need to clarify the relationship between the different concepts, technologies, and descriptions of biofabrication that are often used interchangeably or inconsistently in the current literature. Our objective is to provide a guide to the terminology for different technologies in the field which may serve as a reference for the biofabrication community. Biofabrication holds great potential in the fields of regenerative medicine and physiological 3D in vitro models by allowing the manufacture of complex tissue constructs with a higher degree of biomimicry to native tissues than do current biomedical solutions.As the number of biofabrication technologies being developed continues to expand, it is of paramount importance to adopt a concerted terminology framework and avoid generalizations.The ratio between the spatial resolution and the timescale of manufacture could be considered as a reliable measure to aid in the selection of an appropriate biofabrication technology for a desired application