Functional imaging of the nonhuman primate Placenta with endogenous blood oxygen level-dependent contrast.

PURPOSE: To characterize spatial patterns of T2* in the placenta of the rhesus macaque (Macaca mulatta), to correlate these patterns with placental perfusion determined using dynamic contrast-enhanced MRI (DCE-MRI), and to evaluate the potential for using the blood oxygen level-dependent effect to quantify placental perfusion without the use of exogenous contrast reagent. METHODS: MRI was performed on three pregnant rhesus macaques at gestational day 110. Multiecho spoiled gradient echo measurements were used to compute maps of T2*. Spatial maxima in these maps were compared with foci of early enhancement determined by DCE-MRI. RESULTS: Local maxima in T2* maps were strongly correlated with spiral arteries identified by DCE-MRI, with mean spatial separations ranging from 2.34 to 6.11 mm in the three animals studied. Spatial patterns of R2* ( = 1/ T2*) within individual placental lobules can be quantitatively analyzed using a simple model to estimate fetal arterial oxyhemoglobin concentration [Hbo,f] and a parameter viPS/Φ, reflecting oxygen transport to the fetus. Estimated mean values of [Hbo,f] ranged from 4.25 mM to 4.46 mM, whereas viPS/Φ ranged from 2.80 × 105 cm-3 to 1.61 × 106 cm-3 . CONCLUSIONS: Maternal spiral arteries show strong spatial correlation with foci of extended T2* observed in the primate placenta. A simple model of oxygen transport accurately describes the spatial dependence of R2* within placental lobules and enables assessment of placental function and oxygenation without requiring administration of an exogenous contrast reagent. Magn Reson Med 76:1551-1562, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Mechanics of cortical folding: stress, growth and stability.

Cortical folding, or gyrification, coincides with several important developmental processes. The folded shape of the human brain allows the cerebral cortex, the thin outer layer of neurons and their associated projections, to attain a large surface area relative to brain volume. Abnormal cortical folding has been associated with severe neurological, cognitive and behavioural disorders, such as epilepsy, autism and schizophrenia. However, despite decades of study, the mechanical forces that lead to cortical folding remain incompletely understood. Leading hypotheses have focused on the roles of (i) tangential growth of the outer cortex, (ii) spatio-temporal patterns in the birth and migration of neurons, and (iii) internal tension in axons. Recent experimental studies have illuminated not only the fundamental cellular and molecular processes underlying cortical development, but also the stress state, mechanical properties and spatio-temporal patterns of growth in the developing brain. The combination of mathematical modelling and physical measurements has allowed researchers to evaluate hypothesized mechanisms of folding, to determine whether each is consistent with physical laws. This review summarizes what physical scientists have learned from models and recent experimental observations, in the context of recent neurobiological discoveries regarding cortical development. Here, we highlight evidence of a combined mechanism, in which spatio-temporal patterns bias the locations of primary folds (i), but tangential growth of the cortical plate induces mechanical instability (ii) to propagate primary and higher-order folds.This article is part of the Theo Murphy meeting issue 'Mechanics of development'.

Flanking regulatory sequences of the Tetrahymena R deletion element determine the boundaries of DNA rearrangement.

In the ciliate Tetrahymena thermophila, thousands of DNA segments of variable size are eliminated from the developing somatic macronucleus by specific DNA rearrangements. It is unclear whether rearrangement of the many different DNA elements occurs via a single mechanism or via multiple rearrangement systems. In this study, we characterized in vivo cis-acting sequences required for the rearrangement of the 1.1-kbp R deletion element. We found that rearrangement requires specific sequences flanking each side of the deletion element. The required sequences on the left side appear to span roughly a 70-bp region that is located at least 30 bp from the rearrangement boundary. When we moved the location of the left cis-acting sequences closer to the eliminated region, we observed a rightward shift of the rearrangement boundary such that the newly formed deletion junction retained its original distance from this flanking region. Likewise, when we moved the flanking region as much as 500 bp away from the deletion element, the rearrangement boundary shifted to remain in relative juxtaposition. Clusters of base substitutions made throughout this critical flanking region did not affect rearrangement efficiency or accuracy, which suggests a complex nature for this regulatory sequence. We also found that the right flanking region effectively replaced the essential sequences identified on the left side, and thus, the two flanking regions contain sequences of analogous function despite the lack of obvious sequence identity. These data taken together indicate that the R-element flanking regions contain sequences that position the rearrangement boundaries from a short distance away. Previously, a 10-bp polypurine tract flanking the M-deletion element was demonstrated to act from a distance to determine its rearrangement boundaries. No apparent sequence similarity exists between the M and R elements. The functional similarity between these different cis-acting sequences of the two elements is firm support for a common mechanism controlling Tetrahymena rearrangement.

PREDICT: A simple risk score for clinical severity and long-term prognosis after hospitalization for acute myocardial infarction or unstable angina: the Minnesota heart survey.

BACKGROUND: We evaluated short- and long-term mortality risks in 30- to 74-year-old patients hospitalized for acute myocardial infarction or unstable angina and developed a new score called PREDICT. METHODS AND RESULTS: PREDICT was based on information routinely collected in hospital. Predictors abstracted from hospital record items pertaining to the admission day, including shock, heart failure, ECG findings, cardiovascular disease history, kidney function, and age. Comorbidity was assessed from discharge diagnoses, and mortality was determined from death certificates. For 1985 and 1990 hospitalizations, the 6-year death rate in 6134 patients with 0 to 1 score points was 4%, increasing stepwise to 89% for >/=16 points. Score validity was established by only slightly attenuated mortality prediction in 3570 admissions in 1970 and 1980. When case severity was controlled for, 6-year risk declined 32% between 1970 and 1990. When PREDICT was held constant, 24% of those treated with thrombolysis died in 6 years compared with 31% of those not treated. CONCLUSIONS: The simple PREDICT risk score was a powerful prognosticator of 6-year mortality after hospitalization.

Mechanical forces in cerebral cortical folding: a review of measurements and models.

Folding of the cerebral cortical surface is a critical process in human brain development, yet despite decades of indirect study and speculation the mechanics of the process remain incompletely understood. Leading hypotheses have focused on the roles of circumferential expansion of the cortex, radial growth, and internal tension in neuronal fibers (axons). In this article, we review advances in the mathematical modeling of growth and morphogenesis and new experimental data, which together promise to clarify the mechanical basis of cortical folding. Recent experimental studies have illuminated not only the fundamental cellular and molecular processes underlying cortical development, but also the stress state and mechanical behavior of the developing brain. The combination of mathematical modeling and biomechanical data provides a means to evaluate hypothesized mechanisms objectively and quantitatively, and to ensure that they are consistent with physical law, given plausible assumptions and reasonable parameter values.

Retinal input influences the size and corticocortical connectivity of visual cortex during postnatal development in the ferret.

Retinal input plays an important role in the specification of topographically organized circuits and neuronal response properties, but the mechanism and timing of this effect is not known in most species. A system that shows dramatic dependence on retinal influences is the interhemispheric connection through the corpus callosum. Using ferrets, we analyzed the extent to which development of the visual callosal pattern depends on retinal influences, and explored the period during which these influences are required for normal pattern formation. We studied the mature callosal patterns in normal ferrets and in ferrets bilaterally enucleated (BE) at postnatal day 7 (P7) or P20. Callosal patterns were revealed in tangential sections from unfolded and flattened brains following multiple injections of horseradish peroxidase in the opposite hemisphere. We also estimated the effect of enucleation on the surface areas of striate and extrastriate visual cortex by using magnetic resonance imaging (MRI) data from intact brains. In BEP7 ferrets we found that the pattern of callosal connections was highly anomalous and the sizes of both striate and extrastriate visual cortex were significantly reduced. In contrast, enucleation at P20 had no significant effect on the callosal pattern, but it still caused a reduction in the size of striate and extrastriate visual cortex. Finally, retinal deafferentation had no significant effect on the number of visual callosal neurons. These results indicate that the critical period during which the eyes influence the development of callosal patterns, but not the size of visual cortex, ends by P20 in the ferret.

Intracellular water-specific MR of microbead-adherent cells: the HeLa cell intracellular water exchange lifetime.

Quantitative characterization of the intracellular water (1)H MR signal from cultured cells will provide critical biophysical insight into the MR signal from tissues in vivo. Microbeads provide a robust immobilization substrate for the many mammalian cell lines that adhere to surfaces and also provide sufficient cell density for observation of the intracellular water MR signal. However, selective observation of the intracellular water MR signal from perfused, microbead-adherent mammalian cells requires highly effective suppression of the extracellular water MR signal. We describe how high-velocity perfusion of microbead-adherent cells results in short apparent (1)H MR longitudinal and transverse relaxation times for the extracellular water in a thin slice selected orthogonal to the direction of flow. When combined with a spin-echo pulse sequence, this phenomenon provides highly effective suppression of the extracellular water MR signal. This new method is exploited here to quantify the kinetics of water exchange from the intracellular to extracellular spaces of HeLa cells. The time constant describing water exchange from intracellular to extracellular spaces, also known as the exchange lifetime for intracellular water, is 119 +/- 14 ms.

Intracellular water specific MR of microbead-adherent cells: HeLa cell intracellular water diffusion.

The (1)H MR signal arising from flowing extracellular media in a perfused, microbead-adherent cultured cell system can be suppressed with a slice-selective, spin-echo pulse sequence. The signal from intracellular water can, thus, be selectively monitored. Herein, this technique was combined with pulsed field gradients (PFGs) to quantify intracellular water diffusion in HeLa cells. The intracellular water MR diffusion-signal attenuation at various diffusion times was well described by a biophysical model that characterizes the incoherent displacement of intracellular water as a truncated Gaussian distribution of apparent diffusion coefficients (ADCs). At short diffusion times, the water "free" diffusion coefficient and the surface-to-volume ratio of HeLa cells were estimated and were, 2.0 +/- 0.3 microm(2)/ms and 0.48 +/- 0.1 microm(-1) (mean +/- SD), respectively. At long diffusion times, the cell radius of 10.1 +/- 0.4 microm was inferred and was consistent with that measured by optical microscopy. In summary: 1) intracellular water "free" diffusion in HeLa cells was rapid, two-thirds that of pure water; and 2) the cell radius inferred from modeling the incoherent displacement of intracellular water by a truncated Gaussian distribution of ADCs was confirmed by independent optical microscopy measures.

Solution conformations of a peptide containing the cytoplasmic domain sequence of the beta amyloid precursor protein.

The cytoplasmic domain of the beta amyloid precursor protein (betaAPP) may play a role in cellular events that lead to the secretion of the Abeta peptide, the major constituent of amyloid plaques found in the brains of individuals affected by Alzheimer's disease, by interacting with cellular factors involved in betaAPP function or processing. In order to elucidate the structural basis of cytoplasmic domain activity, the conformations adopted in solution by a peptide containing the 47-residue C-terminal sequence of betaAPP have been investigated by NMR and CD spectroscopy. The peptide does not have a stable tertiary structure, but local regions of the polypeptide chain populate defined conformations. In particular, the amino acid sequences TPEE and NPTY form type I reverse turns. These structured regions correspond to sequences within the cytoplasmic domain implicated in the biological activity of betaAPP.

Dietary fiber, weight gain, and cardiovascular disease risk factors in young adults.

CONTEXT: Dietary composition may affect insulin secretion, and high insulin levels, in turn, may increase the risk for cardiovascular disease (CVD). OBJECTIVE: To examine the role of fiber consumption and its association with insulin levels, weight gain, and other CVD risk factors compared with other major dietary components. DESIGN AND SETTING: The Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter population-based cohort study of the change in CVD risk factors over 10 years (1985-1986 to 1995-1996) in Birmingham, Ala; Chicago, III; Minneapolis, Minn; and Oakland, Calif. PARTICIPANTS: A total of 2909 healthy black and white adults, 18 to 30 years of age at enrollment. MAIN OUTCOME MEASURES: Body weight, insulin levels, and other CVD risk factors at year 10, adjusted for baseline values. RESULTS: After adjustment for potential confounding factors, dietary fiber showed linear associations from lowest to highest quintiles of intake with the following: body weight (whites: 174.8-166.7 lb [78.3-75.0 kg], P<.001; blacks: 185.6-177.6 lb [83.5-79.9 kg], P = .001), waist-to-hip ratio (whites: 0.813-0.801, P = .004; blacks: 0.809-0.799, P = .05), fasting insulin adjusted for body mass index (whites: 77.8-72.2 pmol/L [11.2-10.4 microU/mL], P = .007; blacks: 92.4-82.6 pmol/L [13.3-11.9 microU/mL], P = .01) and 2-hour postglucose insulin adjusted for body mass index (whites: 261.1-234.7 pmol/L [37.6-33.8 microU/mL], P = .03; blacks: 370.2-259.7 pmol/L [53.3-37.4 microU/mL], P<.001). Fiber was also associated with blood pressure and levels of triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and fibrinogen; these associations were substantially attenuated by adjustment for fasting insulin level. In comparison with fiber, intake of fat, carbohydrate, and protein had inconsistent or weak associations with all CVD risk factors. CONCLUSIONS: Fiber consumption predicted insulin levels, weight gain, and other CVD risk factors more strongly than did total or saturated fat consumption. High-fiber diets may protect against obesity and CVD by lowering insulin levels.