Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies

Feasibility of an in situ measurement device for bubble size and distribution

The feasibility of in situ measurement device for bubble size and distribution was explored. A novel in situ probe measurement system, the EnviroCam™, was developed. Where possible, this probe incorporated strengths, and minimized weaknesses of historical and currently available real-time measurement methods for bubbles. The system was based on a digital, high-speed, high resolution, modular camera system, attached to a stainless steel shroud, compatible with standard Ingold ports on fermenters. Still frames and/or video were produced, capturing bubbles passing through the notch of the shroud. An LED light source was integral with the shroud. Bubbles were analyzed using customized commercially available image analysis software and standard statistical methods. Using this system, bubble sizes were measured as a function of various operating parameters (e.g., agitation rate, aeration rate) and as a function of media properties (e.g., viscosity, antifoam, cottonseed flour, and microbial/animal cell broths) to demonstrate system performance and its limitations. For selected conditions, mean bubble size changes qualitatively compared favorably with published relationships. Current instrument measurement capabilities were limited primarily to clear solutions that did not contain large numbers of overlapping bubbles

Bmp7 Functions via a Polarity Mechanism to Promote Cloacal Septation

During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood.We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse.Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations

Systematic Analysis of Pleiotropy in C. elegans Early Embryogenesis

Pleiotropy refers to the phenomenon in which a single gene controls several distinct, and seemingly unrelated, phenotypic effects. We use C. elegans early embryogenesis as a model to conduct systematic studies of pleiotropy. We analyze high-throughput RNA interference (RNAi) data from C. elegans and identify “phenotypic signatures”, which are sets of cellular defects indicative of certain biological functions. By matching phenotypic profiles to our identified signatures, we assign genes with complex phenotypic profiles to multiple functional classes. Overall, we observe that pleiotropy occurs extensively among genes involved in early embryogenesis, and a small proportion of these genes are highly pleiotropic. We hypothesize that genes involved in early embryogenesis are organized into partially overlapping functional modules, and that pleiotropic genes represent “connectors” between these modules. In support of this hypothesis, we find that highly pleiotropic genes tend to reside in central positions in protein-protein interaction networks, suggesting that pleiotropic genes act as connecting points between different protein complexes or pathways

The Born supremacy: quantum advantage and training of an Ising Born machine

The search for an application of near-term quantum devices is widespread. Quantum Machine Learning is touted as a potential utilisation of such devices, particularly those which are out of the reach of the simulation capabilities of classical computers. In this work, we propose a generative Quantum Machine Learning Model, called the Ising Born Machine (IBM), which we show cannot, in the worst case, and up to suitable notions of error, be simulated efficiently by a classical device. We also show this holds for all the circuit families encountered during training. In particular, we explore quantum circuit learning using non-universal circuits derived from Ising Model Hamiltonians, which are implementable on near term quantum devices. We propose two novel training methods for the IBM by utilising the Stein Discrepancy and the Sinkhorn Divergence cost functions. We show numerically, both using a simulator within Rigetti's Forest platform and on the Aspen-1 16Q chip, that the cost functions we suggest outperform the more commonly used Maximum Mean Discrepancy (MMD) for differentiable training. We also propose an improvement to the MMD by proposing a novel utilisation of quantum kernels which we demonstrate provides improvements over its classical counterpart. We discuss the potential of these methods to learn `hard' quantum distributions, a feat which would demonstrate the advantage of quantum over classical computers, and provide the first formal definitions for what we call `Quantum Learning Supremacy'. Finally, we propose a novel view on the area of quantum circuit compilation by using the IBM to `mimic' target quantum circuits using classical output data only.Comment: v3 : Close to journal published version - significant text structure change, split into main text & appendices. See v2 for unsplit version; v2 : Typos corrected, figures altered slightly; v1 : 68 pages, 39 Figures. Comments welcome. Implementation at https://github.com/BrianCoyle/IsingBornMachin

Systematic Analysis of Pleiotropy in C. elegans Early Embryogenesis

Pleiotropy refers to the phenomenon in which a single gene controls several distinct, and seemingly unrelated, phenotypic effects. We use C. elegans early embryogenesis as a model to conduct systematic studies of pleiotropy. We analyze high-throughput RNA interference (RNAi) data from C. elegans and identify “phenotypic signatures”, which are sets of cellular defects indicative of certain biological functions. By matching phenotypic profiles to our identified signatures, we assign genes with complex phenotypic profiles to multiple functional classes. Overall, we observe that pleiotropy occurs extensively among genes involved in early embryogenesis, and a small proportion of these genes are highly pleiotropic. We hypothesize that genes involved in early embryogenesis are organized into partially overlapping functional modules, and that pleiotropic genes represent “connectors” between these modules. In support of this hypothesis, we find that highly pleiotropic genes tend to reside in central positions in protein-protein interaction networks, suggesting that pleiotropic genes act as connecting points between different protein complexes or pathways

IL-2 Mediates CD4+ T Cell Help in the Breakdown of Memory-Like CD8+ T Cell Tolerance under Lymphopenic Conditions

Background: Lymphopenia results in the proliferation and differentiation of naïve T cells into memory-like cells in the apparent absence of antigenic stimulation. This response, at least in part due to a greater availability of cytokines, is thought to promote anti-self responses. Although potentially autoreactive memory-like CD8 + T cells generated in a lymphopenic environment are subject to the mechanisms of peripheral tolerance, they can induce autoimmunity in the presence of antigen-specific memory-like CD4 + T helper cells. Methodology/Principal Findings: Here, we studied the mechanisms underlying CD4 help under lymphopenic conditions in transgenic mice expressing a model antigen in the beta cells of the pancreas. Surprisingly, we found that the self-reactivity mediated by the cooperation of memory-like CD8 + and CD4 + T cells was not abrogated by CD40L blockade. In contrast, treatment with anti-IL-2 antibodies inhibited the onset of autoimmunity. IL-2 neutralization prevented the CD4-mediated differentiation of memory-like CD8 + T cells into pathogenic effectors in response to self-antigen cross-presentation. Furthermore, in the absence of helper cells, induction of IL-2 signaling by an IL-2 immune complex was sufficient to promote memory-like CD8 + T cell self-reactivity. Conclusions/Significance: IL-2 mediates the cooperation of memory-like CD4 + and CD8 + T cells in the breakdown of crosstolerance, resulting in effector cytotoxic T lymphocyte differentiation and the induction of autoimmune disease

Expression profiling in transgenic FVB/N embryonic stem cells overexpressing STAT3

BACKGROUND: The transcription factor STAT3 is a downstream target of the LIF signalling cascade. LIF signalling or activation is sufficient to maintain embryonic stem (ES) cells in an undifferentiated and pluripotent state. To further investigate the importance of STAT3 in the establishment of ES cells we have in a first step derived stable pluripotent embryonic stem cells from transgenic FVB mice expressing a conditional tamoxifen dependent STAT3-MER fusion protein. In a second step, STAT3-MER overexpressing cells were used to identify STAT3 pathway-related genes by expression profiling in order to identify new key-players involved in maintenance of pluripotency in ES cells. RESULTS: Transgenic STAT3-MER blastocysts yielded pluripotent germline-competent ES cells at a high frequency in the absence of LIF when established in tamoxifen-containing medium. Expression profiling of tamoxifen-induced transgenic FVB ES cell lines revealed a set of 26 genes that were markedly up- or down-regulated when compared with wild type cells. The expression of four of the up-regulated genes (Hexokinase II, Lefty2, Pramel7, PP1rs15B) was shown to be restricted to the inner cell mass (ICM) of the blastocysts. These differentially expressed genes represent potential candidates for the maintenance of pluripotency of ES cells. We finally overexpressed two candidate genes, Pem/Rhox5 and Pramel7, in ES cells and demonstrated that their overexpression is sufficient for the maintenance of expression of ES cell markers as well as of the typical morphology of pluripotent ES cells in absence of LIF. CONCLUSION: Overexpression of STAT3-MER in the inner cell mass of blastocyst facilitates the establishment of ES cells and induces the upregulation of potential candidate genes involved in the maintenance of pluripotency. Two of them, Pem/Rhox5 and Pramel7, when overexpressed in ES cells are able to maintain the embryonic stem cells in a pluripotent state in a LIF independent manner as STAT3 or Nanog

Structure and dynamics of the shark assemblage off recife, northeastern Brazil

Understanding the ecological factors that regulate elasmobranch abundance in nearshore waters is essential to effectively manage coastal ecosystems and promote conservation. However, little is known about elasmobranch populations in the western South Atlantic Ocean. An 8-year, standardized longline and drumline survey conducted in nearshore waters off Recife, northeastern Brazil, allowed us to describe the shark assemblage and to monitor abundance dynamics using zero-inflated generalized additive models. This region is mostly used by several carcharhinids and one ginglymostomid, but sphyrnids are also present. Blacknose sharks, Carcharhinus acronotus, were mostly mature individuals and declined in abundance throughout the survey, contrasting with nurse sharks, Ginglymostoma cirratum, which proliferated possibly due to this species being prohibited from all harvest since 2004 in this region. Tiger sharks, Galeocerdo cuvier, were mostly juveniles smaller than 200 cm and seem to use nearshore waters off Recife between January and September. No long-term trend in tiger shark abundance was discernible. Spatial distribution was similar in true coastal species (i.e. blacknose and nurse sharks) whereas tiger sharks were most abundant at the middle continental shelf. The sea surface temperature, tidal amplitude, wind direction, water turbidity, and pluviosity were all selected to predict shark abundance off Recife. Interspecific variability in abundance dynamics across spatiotemporal and environmental gradients suggest that the ecological processes regulating shark abundance are generally independent between species, which could add complexity to multi-species fisheries management frameworks. Yet, further research is warranted to ascertain trends at population levels in the South Atlantic Ocean.State Government of Pernambuco, Brazil; Fundacao para a Ciencia e Tecnologia, Portugal [SFRH/BD/37065/2007]info:eu-repo/semantics/publishedVersio