The blood–brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood–brain ...barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer’s disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface. Current research relies heavily on animal models (mostly mice) or on two-dimensional (2D) in vitro models, neither of which fully capture the complexities of the human blood–brain barrier. Physiological differences between humans and mice make translation to the clinic problematic, while monolayer cultures cannot capture the inherently three-dimensional (3D) nature of the blood–brain barrier, which includes close association of the abluminal side of the endothelium with astrocyte foot-processes and pericytes. Here we discuss the central nervous system diseases associated with blood–brain barrier pathology, recent advances in the development of novel 3D blood–brain barrier -on-a-chip systems that better mimic the physiological complexity and structure of human blood–brain barrier, and provide an outlook on how these blood–brain barrier-on-a-chip systems can be used for central nervous system disease modeling.
Impact statement
The field of microphysiological systems is rapidly evolving as new technologies are introduced and our understanding of organ physiology develops. In this review, we focus on Blood–Brain Barrier (BBB) models, with a particular emphasis on how they relate to neurological disorders such as Alzheimer’s disease, multiple sclerosis, stroke, cancer, and vascular malformations. We emphasize the importance of capturing the three-dimensional nature of the brain and the unique architecture of the BBB – something that until recently had not been well modeled by in vitro systems. Our hope is that this review will provide a launch pad for new ideas and methodologies that can provide us with truly physiological BBB models capable of yielding new insights into the function of this critical interface.
The main objective of this study was to evaluate the relationship between circulating anti-Müllerian hormone (AMH) and superovulatory response of dairy cows. Holstein cows (n=72) were milked twice ...daily and housed and fed individually in tiestalls. All animals were synchronized and flushed at 70±3 d in milk (DIM), near peak production (39.6kg/d). Blood samples for AMH analysis were collected at 3 different stages of a synchronized estrous cycle at a random stage (40±3 DIM), proestrus (50±3 DIM), and diestrus (57±3 DIM). Body weights were measured weekly from calving until embryo collection. Statistical analyses were performed with Proc CORR and Proc GLIMMIX of SAS (SAS Institute Inc., Cary, NC). The 3 AMH samples from individual cows were correlated and not influenced by day of cycle. Surprisingly, AMH tended to be negatively correlated with body weight loss from calving to embryo collection (r=−0.22). More importantly, average AMH was highly associated (r=0.65) with superovulation response (number of corpora lutea on the day of the flush, CLN), total structures collected (r=0.48), and total transferable embryos (r=0.37), but not percentage of fertilized embryos (r=−0.20) or degenerate embryos (r=0.02). When cows were classified into quartiles (Q) of circulating AMH (Q1=0.01 to 82.6pg/mL; Q2=91.1 to 132.5pg/mL; Q3=135.3 to 183.8pg/mL; Q4=184.4 to 374.3pg/mL), we observed a >2-fold difference between first and fourth AMH quartiles in superovulation response (CLN: Q1=12.0±1.5; Q2=14.7±2.0; Q3=17.2±1.2; Q4=25.6±1.5) and embryo production. In conclusion, circulating AMH concentration was strongly associated with superovulation response, and evaluation of AMH could be used to identify cows with greater responses to superstimulation and thus improve efficiency of superovulation programs in dairy cows.
Ruminal digestion of neutral detergent fiber (NDF) is affected in part by the proportion of NDF that is indigestible (iNDF), and the rate at which the potentially digestible NDF (pdNDF) is digested. ...Indigestible NDF in forages is commonly determined as the NDF residue remaining after long-term in situ or in vitro incubations. Rate of pdNDF digestion can be determined by measuring the degradation of NDF in ruminal in vitro or in situ incubations at multiple time points, and fitting the change in residual pdNDF by time with log-transformed linear first order or nonlinear mathematical treatments. The estimate of indigestible fiber is important because it sets the pool size of potentially digestible fiber, which in turn affects the estimate of the proportion of potentially digestible fiber remaining in the time series analysis. Our objective was to compare estimates of iNDF based on in vitro (IV) and in situ (IS) measurements at 2 fermentation end points (120 and 288h). Further objectives were to compare the subsequent rate, lag, and estimated total-tract NDF digestibility (TTNDFD) when iNDF from each method was used with a 7 time point in vitro incubation of NDF to model fiber digestion. Thirteen corn silage samples were dried and ground through a 1-mm screen in a Wiley mill. A 2×2 factorial trial was conducted to determine the effect of time of incubation and method of iNDF analysis on iNDF concentration; the 2 factors were method of iNDF analysis (IS vs. IV) and incubation time (120 vs. 288h). Four sample replicates were used, and approximately 0.5g/sample was weighed into each Ankom F 0285 bag (Ankom Technology, Macedon, NY; pore size=25 µm) for all techniques. The IV-120 had a higher estimate of iNDF (37.8% of NDF) than IS-120 (32.1% of NDF), IV-288 (31.2% of NDF), or IS-288 technique (25.7% of NDF). Each of the estimates of iNDF was then used to calculate the rate of degradation of pdNDF from a 7 time point in vitro incubation. When the IV-120 NDF residue was used, the subsequent rates of pdNDF digestion were fastest (2.8% h−1) but the estimate of lag was longest (10.3h), compared with when iNDF was based on the IS-120 or IV-288 NDF residues (rates of 2.3%h−1 and 2.4%h−1; lag times of 9.7 and 9.8 h, respectively). Rate of pdNDF degradation was slowest (2.1% h−1) when IS-288 NDF residue was used as the estimate of iNDF. The estimate of lag based on IS-288 (9.4h) was similar to lag estimates calculated when IS-120 or IV-288 were used as the estimate of iNDF. The TTNDFD estimates did not differ between treatments (35.5%), however, because differences in estimated pools of iNDF resulted in subsequent changes in rates and lag times of fiber digestion that tended to cancel out. Estimates of fiber digestion kinetic parameters and TTNDFD were similar when fit to either the linear or nonlinear fiber degradation models. All techniques also yielded estimates of iNDF that were higher than predicted iNDF based on the commonly used ratio of 2.4 × lignin.
The absence of recent data regarding the nutritional needs of modern soybean Glycine max (L.) Merr. production systems necessitates a greater comprehensive understanding of nutrient uptake, ...partitioning, and remobilization. The objective of this study was to evaluate macro‐ and micronutrient accumulation and partitioning in current soybean cultivars. Across 3 site‐years, plants were sampled at seven growth stages and divided into four plant tissue fractions for quantification of nutrient uptake. Accumulation (per ha) of 275 kg N, 21 kg P (48 kg P2O5), 172 kg K (207 kg K2O), 113 kg Ca, 50 kg Mg, 19 kg S, 335 g Zn, 371 g Mn, 325 g B, 849 g Fe, and 63 g Cu were required to produce approximately 3500 and 9500 kg ha−1 of grain and total biomass, respectively. Supplemental fertility modestly increased biomass and yield (2%), but did not alter nutrient partitioning or harvest index. Nutrients with high harvest index (i.e., percentage of total nutrient accumulation partitioned to grain) values included P (81%), N (73%), Cu (62%), and S (61%), which may serve as a limitation to high yield. Seasonal patterns of nutrient accumulation suggested that K and Fe were acquired primarily during late vegetative growth while the uptake of N, P, Ca, Mg, S, Zn, Mn, B, and Cu were more equally distributed between vegetative and seed‐filling growth phases. These results document the rate and duration of macro‐ and micronutrient accumulation in soybean, and highlight the importance of adequate nutrient availability during key crop growth periods.
Aims/hypothesis The aim of this cohort study was to investigate the risk of malignant neoplasms and mortality in patients with diabetes treated either with human insulin or with one of three insulin ...analogues. Methods Data were provided by the largest German statutory health insurance fund (time-frame: January 1998 to June 2005 inclusive), on patients without known malignant disease who had received first-time therapy for diabetes mellitus exclusively with human insulin, aspart, lispro or glargine. The primary outcome was the diagnosis of a malignant neoplasm. Data were analysed by multiple Cox regression models adjusting for potential confounders. Results A total of 127,031 patients were included, with a mean follow-up time of 1.63 (median 1.41, maximum 4.41) years. A positive association between cancer incidence and insulin dose was found for all insulin types. Because patients receiving combined therapy with insulin analogues and human insulin were excluded, the mean daily dose was much lower for glargine than for human insulin, and a slightly lower cancer incidence in the glargine group was found. After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p < 0.0001): the adjusted HR was 1.09 (95% CI 1.00 to 1.19) for a daily dose of 10 IU, 1.19 (95% CI 1.10 to 1.30) for a daily dose of 30 IU, and 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU. No increased risk was found for aspart (p = 0.30) or lispro (p = 0.96) compared with human insulin. Conclusions/interpretation Considering the overall relationship between insulin dose and cancer, and the lower dose with glargine, the cancer incidence with glargine was higher than expected compared with human insulin. Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients. Prospective long-term studies are needed to further evaluate the safety of insulin analogues, especially glargine.
Aim.
As the nearest large spiral galaxy, M 31 provides a unique opportunity to study the structure and evolutionary history of this galaxy type in great detail. Among the many observing programs ...aimed at M 31 are microlensing studies, which require good three-dimensional models of the stellar mass distribution. Possible non-axisymmetric structures like a bar need to be taken into account. Due to M 31’s high inclination, the bar is difficult to detect in photometry alone. Therefore, detailed kinematic measurements are needed to constrain the possible existence and position of a bar in M 31.
Methods.
We obtained ≈220 separate fields with the optical integral-field unit spectrograph VIRUS-W, covering the whole bulge region of M 31 and parts of the disk. We derived stellar line-of-sight velocity distributions from the stellar absorption lines, as well as velocity distributions and line fluxes of the emission lines H
β
, O
III
and N
I
. Our data supersede any previous study in terms of spatial coverage and spectral resolution.
Results.
We find several features that are indicative of a bar in the kinematics of the stars, we see intermediate plateaus in the velocity and the velocity dispersion, and correlation between the higher moment
h
3 and the velocity. The gas kinematics is highly irregular, but is consistent with non-triaxial streaming motions caused by a bar. The morphology of the gas shows a spiral pattern, with seemingly lower inclination than the stellar disk. We also look at the ionization mechanisms of the gas, which happens mostly through shocks and not through starbursts.
Extremely compact massive galaxies at z ∼ 1.4 Trujillo, I.; Feulner, G.; Goranova, Y. ...
Monthly notices of the Royal Astronomical Society,
November 2006, Volume:
373, Issue:
1
Journal Article
Peer reviewed
Open access
The optical rest-frame sizes of 10 of the most massive (∼5 × 1011 h−270 M⊙) galaxies found in the near-infrared MUNICS survey at 1.2 < z < 1.7 are analysed. Sizes are estimated in both the J and K′ ...filters. These massive galaxies are at least a factor of 4+1.9−1.0 (±1σ) smaller in the rest-frame V-band than local counterparts of the same stellar mass. Consequently, the stellar mass density of these objects is (at least) 60 times larger than that of massive ellipticals today. Although the stellar populations of these objects are passively fading, their structural properties are rapidly changing since that redshift. This observational fact disagrees with a scenario where the more massive and passive galaxies are fully assembled at z∼ 1.4 (i.e. a monolithic scenario) and points towards a dry merger scenario as the responsible mechanism for the subsequent evolution of these galaxies.
Using integral field spectroscopy, we investigate the kinematic properties of 35 massive centrally dense and compact star-forming galaxies (SFGs; \(\mathrm{log}{\overline{M}}_{* }{M}_{\odot }=11.1\), ...\(\mathrm{log}({{\rm{\Sigma }}}_{1\mathrm{kpc}}{M}_{\odot }\,{\mathrm{kpc}}^{-2})\gt 9.5\), \(\mathrm{log}({M}_{* }/{r}_{e}^{1.5}{M}_{\odot }\,{\mathrm{kpc}}^{-1.5})\gt 10.3\)) at z ∼ 0.7–3.7 within the KMOS3D survey. We spatially resolve 23 compact SFGs and find that the majority are dominated by rotational motions with velocities ranging from 95 to 500 km s−1. The range of rotation velocities is reflected in a similar range of integrated Hα line widths, 75–400 km s−1, consistent with the kinematic properties of mass-matched extended galaxies from the full KMOS3D sample. The fraction of compact SFGs that are classified as “rotation-dominated” or “disklike” also mirrors the fractions of the full KMOS3D sample. We show that integrated line-of-sight gas velocity dispersions from KMOS3D are best approximated by a linear combination of their rotation and turbulent velocities with a lesser but still significant contribution from galactic-scale winds. The Hα exponential disk sizes of compact SFGs are, on average, 2.5 ± 0.2 kpc, 1–2נthe continuum sizes, in agreement with previous work. The compact SFGs have a 1.4נhigher active galactic nucleus (AGN) incidence than the full KMOS3D sample at fixed stellar mass with an average AGN fraction of 76%. Given their high and centrally concentrated stellar masses, as well as stellar-to-dynamical mass ratios close to unity, the compact SFGs are likely to have low molecular gas fractions and to quench on a short timescale unless replenished with inflowing gas. The rotation in these compact systems suggests that their direct descendants are rotating passive galaxies.
The vascular endothelial growth factor (VEGF) family is central to cancer angiogenesis. However, targeting VEGF as an anti-cancer therapeutic approach has shown success for some tumor types but not ...others. Here we examine the expression of the expanded VEGF family in prostate cancer, including the Semaphorin (Sema) family members that compete with VEGFs for Neuropilin binding and can themselves have pro- or anti-angiogenic activity.
First, we used multivariate statistical methods, including partial least squares and clustering, to examine VEGF/Sema gene expression variability in previously published prostate cancer microarray datasets. We show that unlike some cancers, such as kidney cancer, primary prostate cancer is characterized by both a down-regulation of the pro-angiogenic members of the VEGF family and a down-regulation of anti-angiogenic members of the Sema family. We found pro-lymphangiogenic signatures, including the genes encoding VEGFC and VEGFD, associated with primary tumors that ultimately became aggressive. In contrast to primary prostate tumors, prostate cancer metastases showed increased expression of key pro-angiogenic VEGF family members and further repression of anti-angiogenic class III Sema family members. Given the lack of success of VEGF-targeting molecules so far in prostate cancer, this suggests that the reduction in anti-angiogenic Sema signaling may potentiate VEGF signaling and even promote resistance to VEGF-targeting therapies. Inhibition of the VEGF 'accelerator' may need to be accompanied by promotion of the Sema 'brake' to block cancer angiogenesis. To leverage our mechanistic understanding, and to link multigene expression changes to outcomes, we performed individualized computational simulations of competitive VEGF and Sema receptor binding across many tumor samples. The simulations suggest that loss of Sema expression promotes angiogenesis by lowering plexin signaling, not by potentiating VEGF signaling via relaxation of competition.
The combined analysis of bioinformatic data with computational modeling of ligand-receptor interactions demonstrated that enhancement of angiogenesis in prostate cancer metastases may occur through two different routes: elevation of VEGFA and reduction of class 3 Semaphorins. Therapeutic inhibition of angiogenesis in metastatic prostate cancer should account for both of these routes.
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