Unbiased Signal Equation for Quantitative Magnetization Transfer Mapping in Balanced Steady-State Free Precession MRI

Purpose: Quantitative magnetization transfer (qMT) imaging can be used to quantify the proportion of protons in a voxel attached to macromolecules. Here, we show that the original qMT balanced steady-state free precession (bSSFP) model is biased due to over-simplistic assumptions made in its derivation. Theory and Methods: We present an improved model for qMT bSSFP, which incorporates finite radio-frequency (RF) pulse effects as well as simultaneous exchange and relaxation. Further, a correction to finite RF pulse effects for sinc-shaped excitations is derived. The new model is compared to the original one in numerical simulations of the Bloch-McConnell equations and in previously acquired in-vivo data. Results: Our numerical simulations show that the original signal equation is significantly biased in typical brain tissue structures (by 7-20 %) whereas the new signal equation outperforms the original one with minimal bias (< 1%). It is further shown that the bias of the original model strongly affects the acquired qMT parameters in human brain structures, with differences in the clinically relevant parameter of pool-size-ratio of up to 31 %. Particularly high biases of the original signal equation are expected in an MS lesion within diseased brain tissue (due to a low T2/T1-ratio), demanding a more accurate model for clinical applications. Conclusion: The improved model for qMT bSSFP is recommended for accurate qMT parameter mapping in healthy and diseased brain tissue structures

Intraluminal Pressure Modulates Vascular Contractility of Perfused Mesenteric Resistance Arteries: Altered Response in Hypertension

Intraluminal pressure may affect vascular contractility in both normotension and hypertension. To test this hypothesis, we studied mesenteric resistance arteries from normotensive humans as well as normotensive (WKY) and spontaneously hypertensive (SHR) rats (internal diameter 214 ± 27, 201 ± 6, and 172 ± 6 μm, mean ± SEM at 10 mm Hg). Vessels were mounted on glass cannulas and perfused in organ chambers filled with buffer solution at intraluminal pressures of 10 to 120 mm Hg; vasomotion was measured using a video dimension analyzer. Under baseline conditions (10 mm Hg), wall thickness was 36 ± 4 μm in humans, 32 ± 4 μm in WKY, and 47 ± 2 μm in SHR (P < .001). With increasing pressure, the diameter of human vessels increased up to 25 mm Hg and remained constant at higher pressures. In contrast, resistance arteries of normotensive and hypertensive rats exhibited an almost linear increase in diameter over the whole pressure range. In SHR, the pressure-diameter relationship was much flatter than that of WKY, indicating reduced compliance. In human arteries, the contraction to KCl was maximal at 25 mm Hg and averaged 40 ± 6%. Both above and below 25 mm Hg, the response declined to a minimum of 17 ± 2% at 120 mm Hg (P < .01). Similar results were obtained in WKY rats. In contrast, the contractile response in SHR remained maximal over the entire pressure range studied (65 ± 5%). Thus, intraluminal pressure profoundly affects vascular reactivity of resistance arteries; low pressure augments and high pressure reduces the contractile response in normotensive human and rat resistance arteries, whereas this pressure-dependent modulation of vascular reactivity is lost in the SHR. Am J Hypertens 1992;5:542-54

Detailed modelling of a large sample of Herschel sources in the Lockman Hole: identification of cold dust and of lensing candidates through their anomalous SEDs

We have studied in detail a sample of 967 SPIRE sources with 5σ detections at 350 and 500 μm and associations with Spitzer-SWIRE 24 μm galaxies in the HerMES-Lockman survey area, fitting theirmid- and far-infrared, and submillimetre, spectral energy distributions (SEDs) in an automatic search with a set of six infrared templates. For almost 300 galaxies,we havemodelled their SEDs individually to ensure the physicality of the fits. We confirm the need for the new cool and cold cirrus templates, and also of the young starburst template, introduced in earlier work. We also identify 109 lensing candidates via their anomalous SEDs and provide a set of colour–redshift constraints which allow lensing candidates to be identified from combined Herschel and Spitzer data. The picture that emerges of the submillimetre galaxy population is complex, comprising ultraluminous and hyperluminous starbursts, lower luminosity galaxies dominated by interstellar dust emission, lensed galaxies and galaxies with surprisingly cold (10–13 K) dust. 11 per cent of 500 μm selected sources are lensing candidates. 70 per cent of the unlensed sources are ultraluminous infrared galaxies and 26 per cent are hyperluminous. 34 per cent are dominated by optically thin interstellar dust (‘cirrus’) emission, but most of these are due to cooler dust than is characteristic of our Galaxy. At the highest infrared luminosities we see SEDs dominated by M82, Arp 220 and young starburst types, in roughly equal proportions

Physiological modeling of isoprene dynamics in exhaled breath

Human breath contains a myriad of endogenous volatile organic compounds (VOCs) which are reflective of ongoing metabolic or physiological processes. While research into the diagnostic potential and general medical relevance of these trace gases is conducted on a considerable scale, little focus has been given so far to a sound analysis of the quantitative relationships between breath levels and the underlying systemic concentrations. This paper is devoted to a thorough modeling study of the end-tidal breath dynamics associated with isoprene, which serves as a paradigmatic example for the class of low-soluble, blood-borne VOCs. Real-time measurements of exhaled breath under an ergometer challenge reveal characteristic changes of isoprene output in response to variations in ventilation and perfusion. Here, a valid compartmental description of these profiles is developed. By comparison with experimental data it is inferred that the major part of breath isoprene variability during exercise conditions can be attributed to an increased fractional perfusion of potential storage and production sites, leading to higher levels of mixed venous blood concentrations at the onset of physical activity. In this context, various lines of supportive evidence for an extrahepatic tissue source of isoprene are presented. Our model is a first step towards new guidelines for the breath gas analysis of isoprene and is expected to aid further investigations regarding the exhalation, storage, transport and biotransformation processes associated with this important compound.Comment: 14 page

Distributed changes of the functional connectome in patients with glioblastoma

Glioblastoma might have widespread effects on the neural organization and cognitive function, and even focal lesions may be associated with distributed functional alterations. However, functional changes do not necessarily follow obvious anatomical patterns and the current understanding of this interrelation is limited. In this study, we used resting-state functional magnetic resonance imaging to evaluate changes in global functional connectivity patterns in 15 patients with glioblastoma. For six patients we followed longitudinal trajectories of their functional connectome and structural tumour evolution using bi-monthly follow-up scans throughout treatment and disease progression. In all patients, unilateral tumour lesions were associated with inter-hemispherically symmetric network alterations, and functional proximity of tumour location was stronger linked to distributed network deterioration than anatomical distance. In the longitudinal subcohort of six patients, we observed patterns of network alterations with initial transient deterioration followed by recovery at first follow-up, and local network deterioration to precede structural tumour recurrence by two months. In summary, the impact of focal glioblastoma lesions on the functional connectome is global and linked to functional proximity rather than anatomical distance to tumour regions. Our findings further suggest a relevance for functional network trajectories as a possible means supporting early detection of tumour recurrence

Tracing the cosmic growth of supermassive black holes to z~3 with Herschel

We study a sample of Herschel selected galaxies within the Great Observatories Origins Deep Survey-South and the Cosmic Evolution Survey fields in the framework of the Photodetector Array Camera and Spectrometer (PACS) Evolutionary Probe project. Starting from the rich multiwavelength photometric data sets available in both fields, we perform a broad-band spectral energy distribution decomposition to disentangle the possible active galactic nucleus (AGN) contribution from that related to the host galaxy. We find that 37 per cent of the Herschel-selected sample shows signatures of nuclear activity at the 99 per cent confidence level. The probability of revealing AGN activity increases for bright (L 1−1000 > 10 11 L ? ) star-forming galaxies at z > 0.3, becoming about 80 per cent for the brightest (L 1−1000 > 10 12 L ? ) Infrared (IR) galaxies at z≥1. Finally, we reconstruct the AGN bolometric luminosity function and the supermassive black hole growth rate across cosmic time up to z ∼ 3 from a far-IR perspective. This work shows general agreement with most of the panchromatic estimates from the literature, with the global black hole growth peaking at z ∼ 2 and reproducing the observed local black hole mass density with consistent values of the radiative efficiency Erad (∼0.07)

Synthesis of six-coordinate mono-, bis-, and tris(tetrazolato) complexes via [3 + 2] cycloadditions of nitriles to silicon-bound azido ligands

A convenient synthetic route to poly(tetrazolato) silicon complexes is described based on the four reactive centres of the N-rich, highly endothermic tetraazides of the type Si(N3)4(L2). Hypercoordinate azido(tetrazolato) silicon complexes Si(N3)2(N4C-R)2(L2), R = CH3, C6H5, 4-C6H4CH3 (4a, 5, 6, 7) and Si(N3)2(N4C-L)2 (9, L = 2-C5H4N), L2 = 2,2'-bipyridine, 1,10-phenanthroline, with SiN6 skeletons were synthesised via multiple [3 + 2] dipolar cycloaddition reactions starting from Si(N3)4(L2) and a nitrile. The isolated new complexes were characterised by standard analytical methods, single crystal X-ray diffraction and differential scanning calorimetry (4a,b). Tetrazolato ligand linkage isomerism was observed for complex 4a. The crystallographically characterised methyl tetrazolato complexes and plausible configurational and linkage isomers were evaluated by DFT calculations at the B3LYP/6-311G(d,p) level

Formation of engineering thinking at school during the lesson-game "solar system"

This paper describes the structure, conduct, and the main stages of the interdisciplinary lesson-game. Some data on the principles of educational technology are given. Methodical recommendations for conducting the lesson, as well as examples of didactic tasks are given. The proposed lesson carries the task - to build a model of the solar system. But this is not a simple design and construction but a deep didactic analysis. The results will be the construction of a model of the solar system, as a result of the application of engineering thinking skills in life, as well as the transfer of the project modeling algorithm from theory to practice

Evolution of the endomembrane systems of trypanosomatids:conservation and specialisation

Parasite surfaces support multiple functions required for survival within their hosts, and maintenance and functionality of the surface depends on membrane trafficking. To understand the evolutionary history of trypanosomatid trafficking, where multiple lifestyles and mechanisms of host interactions are known, we examined protein families central to defining intracellular compartments and mediating transport, namely Rabs, SNAREs and RabGAPs, across all available Euglenozoa genomes. Bodonids possess a large trafficking repertoire, which is mainly retained by the Trypanosoma cruzi group, with extensive losses in other lineages, particularly African trypanosomes and phytomonads. There are no large-scale expansions or contractions from an inferred ancestor, excluding direct associations between parasitism or host range. However, we observe stepwise secondary losses within Rab and SNARE cohorts (but not RabGAPs). Major changes are associated with endosomal and late exocytic pathways, consistent with the diversity in surface proteomes between trypanosomatids and mechanisms of interaction with the host. Along with the conserved core family proteins, several lineage-specific members of the Rab (but not SNARE) family were found. Significantly, testing predictions of SNARE complex composition by proteomics confirms generalised retention of function across eukaryotes

Comprehensive Analysis of MGMT Promoter Methylation: Correlation with MGMT Expression and Clinical Response in GBM

O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation has been identified as a potential prognostic marker for glioblastoma patients. The relationship between the exact site of promoter methylation and its effect on gene silencing, and the patient's subsequent response to therapy, is still being defined. The aim of this study was to comprehensively characterize cytosine-guanine (CpG) dinucleotide methylation across the entire MGMT promoter and to correlate individual CpG site methylation patterns to mRNA expression, protein expression, and progression-free survival. To best identify the specific MGMT promoter region most predictive of gene silencing and response to therapy, we determined the methylation status of all 97 CpG sites in the MGMT promoter in tumor samples from 70 GBM patients using quantitative bisulfite sequencing. We next identified the CpG site specific and regional methylation patterns most predictive of gene silencing and improved progression-free survival. Using this data, we propose a new classification scheme utilizing methylation data from across the entire promoter and show that an analysis based on this approach, which we call 3R classification, is predictive of progression-free survival (HR  = 5.23, 95% CI [2.089–13.097], p<0.0001). To adapt this approach to the clinical setting, we used a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test based on the 3R classification and show that this test is both feasible in the clinical setting and predictive of progression free survival (HR  = 3.076, 95% CI [1.301–7.27], p = 0.007). We discuss the potential advantages of a test based on this promoter-wide analysis and compare it to the commonly used methylation-specific PCR test. Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting