Computational modelling of placental amino acid transfer as an integrated system

AbstractPlacental amino acid transfer is essential for fetal development and its impairment is associated with poor fetal growth. Amino acid transfer is mediated by a broad array of specific plasma membrane transporters with overlapping substrate specificity. However, it is not fully understood how these different transporters work together to mediate net flux across the placenta. Therefore the aim of this study was to develop a new computational model to describe how human placental amino acid transfer functions as an integrated system. Amino acid transfer from mother to fetus requires transport across the two plasma membranes of the placental syncytiotrophoblast, each of which contains a distinct complement of transporter proteins. A compartmental modelling approach was combined with a carrier based modelling framework to represent the kinetics of the individual accumulative, exchange and facilitative classes of transporters on each plasma membrane. The model successfully captured the principal features of transplacental transfer. Modelling results clearly demonstrate how modulating transporter activity and conditions such as phenylketonuria, can increase the transfer of certain groups of amino acids, but that this comes at the cost of decreasing the transfer of others, which has implications for developing clinical treatment options in the placenta and other transporting epithelia

Characterization and wear performance of boride phases over tool steel substrates

This research work was conducted to characterize boride phases, obtained from the powder-pack process, on AISI H13 and D2 steel substrates, and investigate their tribological behavior. The boriding was developed at a temperature of 1273 K with an exposure time of 8 h. X-ray diffraction, scanning electron microscopy, and energy-dispersive X-ray spectroscopy were conducted on the borided material to characterize the presence of the FeB, Fe2B, and CrB phases and the distribution of heavy elements on the surface of the substrates. The adherence of the boride layers was evaluated, in a qualitative form, through the Daimler-Benz Rockwell-C indentation technique. Sliding wear tests were then performed using a reciprocating wear test machine. All tests were conducted in dry conditions at room temperature. A frequency of 10 Hz and 15-mm sliding distance were used. The applied Hertzian pressure was 2.01 GPa. Scanning electron microscopy was used to observe and analyze the wear mechanisms. Additionally, the variation of the friction coefficient versus the number of cycles was obtained. Experimental results showed that the characteristic wear mechanism for the borided surface was plastic deformation and mild abrasive wear; for unborided substrates, cracking and spalling were observed

Constraining slow-roll inflation with WMAP and 2dF

We constrain slow-roll inflationary models using the recent WMAP data combined with data from the VSA, CBI, ACBAR and 2dF experiments. We find the slow-roll parameters to be $0 < \epsilon_1 < 0.032$ and $\epsilon_2 + 5.0 \epsilon_1 = 0.036 \pm 0.025$. For inflation models $V \propto \phi^{\alpha}$ we find that $\alpha< 3.9, 4.3$ at the 2$\sigma$ and $3\sigma$ levels, indicating that the $\lambda\phi^4$ model is under very strong pressure from observations. We define a convergence criterion to judge the necessity of introducing further power spectrum parameters such as the spectral index and running of the spectral index. This criterion is typically violated by models with large negative running that fit the data, indicating that the running cannot be reliably measured with present data.Comment: 8 pages RevTeX4 file with six figures incorporate

Strong duality in conic linear programming: facial reduction and extended duals

The facial reduction algorithm of Borwein and Wolkowicz and the extended dual of Ramana provide a strong dual for the conic linear program $$(P) \sup {<c, x> | Ax \leq_K b}$$ in the absence of any constraint qualification. The facial reduction algorithm solves a sequence of auxiliary optimization problems to obtain such a dual. Ramana's dual is applicable when (P) is a semidefinite program (SDP) and is an explicit SDP itself. Ramana, Tuncel, and Wolkowicz showed that these approaches are closely related; in particular, they proved the correctness of Ramana's dual using certificates from a facial reduction algorithm. Here we give a clear and self-contained exposition of facial reduction, of extended duals, and generalize Ramana's dual: -- we state a simple facial reduction algorithm and prove its correctness; and -- building on this algorithm we construct a family of extended duals when $K$ is a {\em nice} cone. This class of cones includes the semidefinite cone and other important cones.Comment: A previous version of this paper appeared as "A simple derivation of a facial reduction algorithm and extended dual systems", technical report, Columbia University, 2000, available from http://www.unc.edu/~pataki/papers/fr.pdf Jonfest, a conference in honor of Jonathan Borwein's 60th birthday, 201

Improving Persian Information Retrieval Systems Using Stemming and Part of Speech Tagging

With the emergence of vast resources of information, it is necessary to develop methods that retrieve the most relevant information according to needs. These retrieval methods may benefit from natural language constructs to boost their results by achieving higher precision and recall rates. In this study, we have used part of speech properties of terms as extra source of information about document and query terms and have evaluated the impact of such data on the performance of the Persian retrieval algorithms. Also the effect of stemming has been experimented as a complement to this research. Our findings indicate that part of speech tags may have small influence on effectiveness of the retrieved results. However, when this information is combined with stemming it improves the accuracy of the outcomes considerably

Machine Learning in Automated Text Categorization

The automated categorization (or classification) of texts into predefined categories has witnessed a booming interest in the last ten years, due to the increased availability of documents in digital form and the ensuing need to organize them. In the research community the dominant approach to this problem is based on machine learning techniques: a general inductive process automatically builds a classifier by learning, from a set of preclassified documents, the characteristics of the categories. The advantages of this approach over the knowledge engineering approach (consisting in the manual definition of a classifier by domain experts) are a very good effectiveness, considerable savings in terms of expert manpower, and straightforward portability to different domains. This survey discusses the main approaches to text categorization that fall within the machine learning paradigm. We will discuss in detail issues pertaining to three different problems, namely document representation, classifier construction, and classifier evaluation.Comment: Accepted for publication on ACM Computing Survey

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract.

Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4 &lt;sup&gt;+&lt;/sup&gt; (n=4), CD8 &lt;sup&gt;+&lt;/sup&gt; (n=4), CD4 &lt;sup&gt;+&lt;/sup&gt; /CD8 &lt;sup&gt;+&lt;/sup&gt; (n=1) and CD4 &lt;sup&gt;-&lt;/sup&gt; /CD8 &lt;sup&gt;-&lt;/sup&gt; (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4 &lt;sup&gt;+&lt;/sup&gt; , CD4 &lt;sup&gt;+&lt;/sup&gt; /CD8 &lt;sup&gt;+&lt;/sup&gt; , and CD4 &lt;sup&gt;-&lt;/sup&gt; /CD8 &lt;sup&gt;-&lt;/sup&gt; cases harbored frequent alterations of JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8 &lt;sup&gt;+&lt;/sup&gt; cases exhibited structural alterations involving the 3' untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case was a harbinger of disease transformation. The CD4 &lt;sup&gt;+&lt;/sup&gt; and CD4 &lt;sup&gt;+&lt;/sup&gt; /CD8 &lt;sup&gt;+&lt;/sup&gt; lymphoproliferative disorders displayed heterogeneous Th1 (T-bet &lt;sup&gt;+&lt;/sup&gt; ), Th2 (GATA3 &lt;sup&gt;+&lt;/sup&gt; ) or hybrid Th1/Th2 (T-bet &lt;sup&gt;+&lt;/sup&gt; /GATA3 &lt;sup&gt;+&lt;/sup&gt; ) profiles, while the majority of CD8 &lt;sup&gt;+&lt;/sup&gt; disorders and the CD4 &lt;sup&gt;-&lt;/sup&gt; /CD8 &lt;sup&gt;-&lt;/sup&gt; disease showed a type-2 polarized (GATA3 &lt;sup&gt;+&lt;/sup&gt; ) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8 &lt;sup&gt;+&lt;/sup&gt; cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and confirm the heterogeneous nature of these diseases. Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases

The Cosmic Microwave Background in an Inhomogeneous Universe - why void models of dark energy are only weakly constrained by the CMB

The dimming of Type Ia supernovae could be the result of Hubble-scale inhomogeneity in the matter and spatial curvature, rather than signaling the presence of a dark energy component. A key challenge for such models is to fit the detailed spectrum of the cosmic microwave background (CMB). We present a detailed discussion of the small-scale CMB in an inhomogeneous universe, focusing on spherically symmetric `void' models. We allow for the dynamical effects of radiation while analyzing the problem, in contrast to other work which inadvertently fine tunes its spatial profile. This is a surprisingly important effect and we reach substantially different conclusions. Models which are open at CMB distances fit the CMB power spectrum without fine tuning; these models also fit the supernovae and local Hubble rate data which favours a high expansion rate. Asymptotically flat models may fit the CMB, but require some extra assumptions. We argue that a full treatment of the radiation in these models is necessary if we are to understand the correct constraints from the CMB, as well as other observations which rely on it, such as spectral distortions of the black body spectrum, the kinematic Sunyaev-Zeldovich effect or the Baryon Acoustic Oscillations.Comment: 23 pages with 14 figures. v2 has considerably extended discussion and analysis, but the basic results are unchanged. v3 is the final versio

Cosmological parameter estimation and the inflationary cosmology

We consider approaches to cosmological parameter estimation in the inflationary cosmology, focussing on the required accuracy of the initial power spectra. Parametrizing the spectra, for example by power-laws, is well suited to testing the inflationary paradigm but will only correctly estimate cosmological parameters if the parametrization is sufficiently accurate, and we investigate conditions under which this is achieved both for present data and for upcoming satellite data. If inflation is favoured, reliable estimation of its physical parameters requires an alternative approach adopting its detailed predictions. For slow-roll inflation, we investigate the accuracy of the predicted spectra at first and second order in the slow-roll expansion (presenting the complete second-order corrections for the tensors for the first time). We find that within the presently-allowed parameter space, there are regions where it will be necessary to include second-order corrections to reach the accuracy requirements of MAP and Planck satellite data. We end by proposing a data analysis pipeline appropriate for testing inflation and for cosmological parameter estimation from high-precision data.Comment: 15 pages RevTeX file with figures incorporated. Slow-roll inflation module for use with the CAMB program can be found at http://astronomy.cpes.susx.ac.uk/~sleach/inflation/ This version corrects a typo in the definition of z_S (after Eq.1) and supersedes the journal versio

Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles

AbstractPlacental amino acid transport is required for fetal development and impaired transport has been associated with poor fetal growth. It is well known that placental amino acid transport is mediated by a broad array of specific membrane transporters with overlapping substrate specificity. However, it is not fully understood how these transporters function, both individually and as an integrated system. We propose that mathematical modelling could help in further elucidating the underlying mechanisms of how these transporters mediate placental amino acid transport.The aim of this work is to model the sodium independent transport of serine, which has been assumed to follow an obligatory exchange mechanism. However, previous amino acid uptake experiments in human placental microvillous plasma membrane vesicles have persistently produced results that are seemingly incompatible with such a mechanism; i.e. transport has been observed under zero-trans conditions, in the absence of internal substrates inside the vesicles to drive exchange. This observation raises two alternative hypotheses; (i) either exchange is not fully obligatory, or (ii) exchange is indeed obligatory, but an unforeseen initial concentration of amino acid substrate is present within the vesicle which could drive exchange.To investigate these possibilities, a mathematical model for tracer uptake was developed based on carrier mediated transport, which can represent either facilitated diffusion or obligatory exchange (also referred to as uniport and antiport mechanisms, respectively). In vitro measurements of serine uptake by placental microvillous membrane vesicles were carried out and the model applied to interpret the results based on the measured apparent Michaelis–Menten parameters Km and Vmax. In addition, based on model predictions, a new time series experiment was implemented to distinguish the hypothesised transporter mechanisms. Analysis of the results indicated the presence of a facilitated transport component, while based on the model no evidence for substantial levels of endogenous amino acids within the vesicle was found