Human P450 CYP17A1: Control of Substrate Preference by Asparagine 202

CYP17A1 is a key steroidogenic enzyme known to conduct several distinct chemical transformations on multiple substrates. In its hydroxylase activity, this enzyme adds a hydroxyl group at the 17α position of both pregnenolone and progesterone at approximately equal rates. However, the subsequent 17,20 carbon–carbon scission reaction displays variable substrate specificity in the numerous CYP17A1 isozymes operating in vertebrates, manifesting as different Kd and kcat values when presented with 17α-hydroxypregnenlone (OHPREG) versus 17α-hydroxyprogesterone (OHPROG). Here we show that the identity of the residue at position 202 in human CYP17A1, thought to form a hydrogen bond with the A-ring alcohol substituent on the pregnene- nucleus, is a key driver of this enzyme’s native preference for OHPREG. Replacement of asparagine 202 with serine completely reverses the preference of CYP17A1, more than doubling the rate of turnover of the OHPROG to androstenedione reaction and substantially decreasing the rate of formation of dehydroepiandrosterone from OHPREG. In a series of resonance Raman experiments, it was observed that, in contrast with the case for the wild-type protein, in the mutant the 17α alcohol of OHPROG tends to form a H-bond with the proximal rather than terminal oxygen of the oxy–ferrous complex. When OHPREG was a substrate, the mutant enzyme was found to have a H-bonding interaction with the proximal oxygen that is substantially weaker than that of the wild type. These results demonstrate that a single-point mutation in the active site pocket of CYP17A1, even when far from the heme, has profound effects on steroidogenic selectivity in androgen biosynthesis

Phase behavior of a system of particles with core collapse

The pressure-temperature phase diagram of a one-component system, with particles interacting through a spherically symmetric pair potential in two dimensions is studied. The interaction consists of a hard core plus an additional repulsion at low energies. It is shown that at zero temperature, instead of the expected isostructural transition due to core collapse occurring when increasing pressure, the system passes through a series of ground states that are not triangular lattices. In particular, and depending on parameters, structures with squares, chains, hexagons and even quasicrystalline ground states are found. At finite temperatures the solid-fluid coexistence line presents a zone with negative slope (which implies melting with decreasing in volume) and the fluid phase has a temperature of maximum density, similar to that in water.Comment: 11 pages, 15 figures included. To appear in PRE. Some figures in low quality format. Better ones available upon request from [email protected]

Studies on optimizing potential energy functions for maximal intrinsic hyperpolarizability

We use numerical optimization to study the properties of (1) the class of one-dimensional potential energy functions and (2) systems of point charges in two-dimensions that yield the largest hyperpolarizabilities, which we find to be within 30% of the fundamental limit. We investigate the character of the potential energy functions and resulting wavefunctions and find that a broad range of potentials yield the same intrinsic hyperpolarizability ceiling of 0.709.Comment: 9 pages, 9 figure

Detecting Sarcasm in Multimodal Social Platforms

Sarcasm is a peculiar form of sentiment expression, where the surface sentiment differs from the implied sentiment. The detection of sarcasm in social media platforms has been applied in the past mainly to textual utterances where lexical indicators (such as interjections and intensifiers), linguistic markers, and contextual information (such as user profiles, or past conversations) were used to detect the sarcastic tone. However, modern social media platforms allow to create multimodal messages where audiovisual content is integrated with the text, making the analysis of a mode in isolation partial. In our work, we first study the relationship between the textual and visual aspects in multimodal posts from three major social media platforms, i.e., Instagram, Tumblr and Twitter, and we run a crowdsourcing task to quantify the extent to which images are perceived as necessary by human annotators. Moreover, we propose two different computational frameworks to detect sarcasm that integrate the textual and visual modalities. The first approach exploits visual semantics trained on an external dataset, and concatenates the semantics features with state-of-the-art textual features. The second method adapts a visual neural network initialized with parameters trained on ImageNet to multimodal sarcastic posts. Results show the positive effect of combining modalities for the detection of sarcasm across platforms and methods.Comment: 10 pages, 3 figures, final version published in the Proceedings of ACM Multimedia 201

Two Approaches to Solving the Inversion Problem for Eddy Current NDE

The eddy current NDE inversion problem is to determine flaw parameters from eddy current sensor impedance changes. Two approaches to solving this problem are discussed for geometries with two components of eddy current. The first is to use the Finite Element Method of numerical analysis to compute the sensor impedance change for each flaw parameter value. The second approach is to combine the Finite Element Method with an analytical scattering technique. These two approaches are applied to the problem of an infinitely long coil surrounding an infinitely long conducting bar with an infinitely long surface crack. The calculated impedance changes show good agreement with known analytical and experimental results

Water-like anomalies for core-softened models of fluids: One dimension

We use a one-dimensional (1d) core-softened potential to develop a physical picture for some of the anomalies present in liquid water. The core-softened potential mimics the effect of hydrogen bonding. The interest in the 1d system stems from the facts that closed-form results are possible and that the qualitative behavior in 1d is reproduced in the liquid phase for higher dimensions. We discuss the relation between the shape of the potential and the density anomaly, and we study the entropy anomaly resulting from the density anomaly. We find that certain forms of the two-step square well potential lead to the existence at T=0 of a low-density phase favored at low pressures and of a high-density phase favored at high pressures, and to the appearance of a point $C'$ at a positive pressure, which is the analog of the T=0 ``critical point'' in the $1d$ Ising model. The existence of point $C'$ leads to anomalous behavior of the isothermal compressibility $K_T$ and the isobaric specific heat $C_P$.Comment: 22 pages, 7 figure

Eddy-Current Probe Design

This paper describes theoretical and experimental work directed toward finding the optimum probe dimensions and operating frequency for eddy current detection of half-penny surface cracks in nonmagnetic conducting materials. The study applies to probes which excite an approximately uniform spatial field over the length of the crack at the surface of the material. In practical terms, this means that the probe is not smaller than the crack length in any of its critical dimensions

Metastable liquid-liquid phase transition in a single-component system with only one crystal phase and no density anomaly

We investigate the phase behavior of a single-component system in 3 dimensions with spherically-symmetric, pairwise-additive, soft-core interactions with an attractive well at a long distance, a repulsive soft-core shoulder at an intermediate distance, and a hard-core repulsion at a short distance, similar to potentials used to describe liquid systems such as colloids, protein solutions, or liquid metals. We showed [Nature {\bf 409}, 692 (2001)] that, even with no evidences of the density anomaly, the phase diagram has two first-order fluid-fluid phase transitions, one ending in a gas--low-density liquid (LDL) critical point, and the other in a gas--high-density liquid (HDL) critical point, with a LDL-HDL phase transition at low temperatures. Here we use integral equation calculations to explore the 3-parameter space of the soft-core potential and we perform molecular dynamics simulations in the interesting region of parameters. For the equilibrium phase diagram we analyze the structure of the crystal phase and find that, within the considered range of densities, the structure is independent of the density. Then, we analyze in detail the fluid metastable phases and, by explicit thermodynamic calculation in the supercooled phase, we show the absence of the density anomaly. We suggest that this absence is related to the presence of only one stable crystal structure.Comment: 15 pages, 21 figure

Calcium and phosphorus metabolism in peripartal dogs

Recommended allowances for calcium and phosphorus are mostly based on factorial calculations partly set at the level determined adequate for giant breeds (Nutrient requirements of dogs and cats. Washington, DC, USA: The National Academies Press. 2006). Information about appropriateness of supply with both minerals during the peripartal phase is limited. From other species is known that bone mineral stores are used in addition to oral intake of calcium and phosphorus in periods of higher needs such as gestation and lactation. The aim of this study was to determine parameters of calcium and phosphorus homeostasis in female dogs receiving the recommended amount of these minerals according to NRC (Nutrient requirements of dogs and cats. Washington, DC, USA: The National Academies Press. 2006) during the peripartal phase. In five Beagles and four Foxhound crossbreds, all primiparous with a litter size of 1–8 puppies, apparent digestibility of calcium and phosphorus as well as serum parameters of mineral metabolism (total and ionised calcium, phosphorus, parathyroid hormone, bone specific alkaline phosphatase, crosslaps) was determined in the period of 12–9 days before and 4–9 days after parturition. The apparent digestibility of calcium was relatively low and did not differ significantly between both peripartal phases, whereas the apparent digestibility of phosphorus increased during lactation. Serum concentrations of calcium (total as well as ionised), phosphorus and parathyroid hormone did not differ between gestation and lactation. The bone resorption marker serum crosslaps increased in lactating dogs but most individual values were within the reference range for adult female dogs at maintenance. On the other hand, the bone formation marker bone specific alkaline phosphatase decreased from prepartal to postpartal phase with values clearly above reference range in both phases. Based on the results especially of the bone markers, which stayed within the reference range during the peripartal phase without indicating predominant bone resorption, we hypothesise that the applied recommended daily allowances defined for peripartal dogs are appropriate