Absence of Melatonin Induces Night-Time Hepatic Insulin Resistance and Increased Gluconeogenesis Due to Stimulation of Nocturnal Unfolded Protein Response

It is known that the circadian rhythm in hepatic phosphoenolpyruvate carboxykinase expression (a limiting catalytic step of gluconeogenesis) and hepatic glucose production is maintained by both daily oscillation in autonomic inputs to the liver and night feeding behavior. However, increased glycemia and reduced melatonin (Mel) levels have been recently shown to coexist in diabetic patients at the end of the night period. In parallel, pinealectomy (PINX) is known to cause glucose intolerance with increased basal glycemia exclusively at the end of the night. The mechanisms that underlie this metabolic feature are not completely understood. Here, we demonstrate that PINX rats show night-time hepatic insulin resistance characterized by reduced insulin-stimulated RAC-alpha serine/threonine-protein kinase phosphorylation and increased phosphoenolpyruvate carboxykinase expression. In addition, PINX rats display increased conversion of pyruvate into glucose at the end of the night. The regulatory mechanism suggests the participation of unfolded protein response (UPR), because PINX induces night-time increase in activating transcription factor 6 expression and prompts a circadian fashion of immunoglobulin heavy chain-binding protein, activating transcription factor 4, and CCAAT/enhancer-binding protein-homologous protein expression with Zenith values at the dark period. PINX also caused a night-time increase in Tribble 3 and regulatory-associated protein of mammalian target of rapamycin; both were reduced in liver of PINX rats treated with Mel. Treatment of PINX rats with 4-phenyl butyric acid, an inhibitor of UPR, restored night-time hepatic insulin sensitivity and abrogated gluconeogenesis in PINX rats. Altogether, the present data show that a circadian oscillation of UPR occurs in the liver due to the absence of Mel. The nocturnal UPR activation is related with night-time hepatic insulin resistance and increased gluconeogenesis in PINX rats. (Endocrinology 152: 1253-1263, 2011)

Indirect study of (11)B(p,alpha(0))(8)Be and (10)B(p,alpha)(7)Be reactions at astrophysical energies by means of the Trojan Horse Method: recent results

Nuclear (p,alpha) reactions destroying the so-called ""light-elements"" lithium, beryllium and boron have been largely studied in the past mainly because their role in understanding some astrophysical phenomena, i.e. mixing-phenomena occurring in young F-G stars [1]. Such mechanisms transport the surface material down to the region close to the nuclear destruction zone, where typical temperatures of the order of similar to 10(6) K are reached. The corresponding Gamow energy E(0)=1.22 (Z(x)(2)Z(X)(2)T(6)(2))(1/3) [2] is about similar to 10 keV if one considers the ""boron-case"" and replaces in the previous formula Z(x) = 1, Z(X) = 5 and T(6) = 5. Direct measurements of the two (11)B(p,alpha(0))(8)Be and (10)B(p,alpha)(7)Be reactions in correspondence of this energy region are difficult to perform mainly because the combined effects of Coulomb barrier penetrability and electron screening [3]. The indirect method of the Trojan Horse (THM) [4-6] allows one to extract the two-body reaction cross section of interest for astrophysics without the extrapolation-procedures. Due to the THM formalism, the extracted indirect data have to be normalized to the available direct ones at higher energies thus implying that the method is a complementary tool in solving some still open questions for both nuclear and astrophysical issues [7-12].

Trojan Horse Method: a useful tool for electron screening effect investigation

Direct measurements in the last decades have highlighted a new problem related to the lowering of the Coulomb barrier between the interacting nuclei due to the presence of the ""electron screening"" in the laboratory measurements. It was systematically observed that the presence of the electronic cloud around the interacting ions in measurements of nuclear reactions cross sections at astrophysical energies gives rise to an enhancement of the astrophysical S(E)-factor as lower and lower energies are explored [1]. Moreover, at present Such an effect is not well understood as the value of the potential for screening extracted from these measurements is higher than the tipper limit of theoretical predictions (adiabatic limit). On the other hand, the electron screening potential in laboratory measurement is different from that occurring in stellar plasmas thus the quantity of interest in astrophysics is the so-called ""bare nucleus cross section"". This quantity can only be extrapolated in direct measurements. These are the reasons that led to a considerable growth on interest in indirect measurement techniques and in particular the Trojan Horse Method (THM) [2,3]. Results concerning the bare nucleus cross sections measurements will be shown in several cases of astrophysical interest. In those cases the screening potential evaluated by means of the THM will be compared with the adiabatic limit and results arising from extrapolation in direct measurements.

Approximating a class of combinatorial problems with rational objective function

In the late seventies, Megiddo proposed a way to use an algorithm for the problem of minimizing a linear function a(0) + a(1)x(1) + ... + a(n)x(n) subject to certain constraints to solve the problem of minimizing a rational function of the form (a(0) + a(1)x(1) + ... + a(n)x(n))/(b(0) + b(1)x(1) + ... + b(n)x(n)) subject to the same set of constraints, assuming that the denominator is always positive. Using a rather strong assumption, Hashizume et al. extended Megiddo`s result to include approximation algorithms. Their assumption essentially asks for the existence of good approximation algorithms for optimization problems with possibly negative coefficients in the (linear) objective function, which is rather unusual for most combinatorial problems. In this paper, we present an alternative extension of Megiddo`s result for approximations that avoids this issue and applies to a large class of optimization problems. Specifically, we show that, if there is an alpha-approximation for the problem of minimizing a nonnegative linear function subject to constraints satisfying a certain increasing property then there is an alpha-approximation (1 1/alpha-approximation) for the problem of minimizing (maximizing) a nonnegative rational function subject to the same constraints. Our framework applies to covering problems and network design problems, among others.

Repetition-free longest common subsequence

We study the following problem. Given two sequences x and y over a finite alphabet, find a repetition-free longest common subsequence of x and y. We show several algorithmic results, a computational complexity result, and we describe a preliminary experimental study based on the proposed algorithms. We also show that this problem is APX-hard. (C) 2009 Elsevier B.V. All rights reserved.

Three-dimensional packings with rotations

We present approximation algorithms for the three-dimensional strip packing problem, and the three-dimensional bin packing problem. We consider orthogonal packings where 90 degrees rotations are allowed. The algorithms we show for these problems have asymptotic performance bounds 2.64, and 4.89, respectively. These algorithms are for the more general case in which the bounded dimensions of the bin given in the input are not necessarily equal (that is, we consider bins for which the length. the width and the height are not necessarily equal). Moreover, we show that these problems-in the general version-are as hard to approximate as the corresponding oriented version. (C) 2009 Elsevier Ltd. All rights reserved.

Approximation algorithms and hardness results for the clique packing problem

For a fixed family F of graphs, an F-packing in a graph G is a set of pairwise vertex-disjoint subgraphs of G, each isomorphic to an element of F. Finding an F-packing that maximizes the number of covered edges is a natural generalization of the maximum matching problem, which is just F = {K(2)}. In this paper we provide new approximation algorithms and hardness results for the K(r)-packing problem where K(r) = {K(2), K(3,) . . . , K(r)}. We show that already for r = 3 the K(r)-packing problem is APX-complete, and, in fact, we show that it remains so even for graphs with maximum degree 4. On the positive side, we give an approximation algorithm with approximation ratio at most 2 for every fixed r. For r = 3, 4, 5 we obtain better approximations. For r = 3 we obtain a simple 3/2-approximation, achieving a known ratio that follows from a more involved algorithm of Halldorsson. For r = 4, we obtain a (3/2 + epsilon)-approximation, and for r = 5 we obtain a (25/14 + epsilon)-approximation. (C) 2008 Elsevier B.V. All rights reserved.

Minimum cycle cover and Chinese postman problems on mixed graphs with bounded tree-width

Let M = (V, E, A) be a mixed graph with vertex set V, edge set E and arc set A. A cycle cover of M is a family C = {C(1), ... , C(k)} of cycles of M such that each edge/arc of M belongs to at least one cycle in C. The weight of C is Sigma(k)(i=1) vertical bar C(i)vertical bar. The minimum cycle cover problem is the following: given a strongly connected mixed graph M without bridges, find a cycle cover of M with weight as small as possible. The Chinese postman problem is: given a strongly connected mixed graph M, find a minimum length closed walk using all edges and arcs of M. These problems are NP-hard. We show that they can be solved in polynomial time if M has bounded tree-width. (C) 2008 Elsevier B.V. All rights reserved.

Algorithms for two-dimensional cutting stock and strip packing problems using dynamic programming and column generation

We investigate several two-dimensional guillotine cutting stock problems and their variants in which orthogonal rotations are allowed. We first present two dynamic programming based algorithms for the Rectangular Knapsack (RK) problem and its variants in which the patterns must be staged. The first algorithm solves the recurrence formula proposed by Beasley; the second algorithm - for staged patterns - also uses a recurrence formula. We show that if the items are not so small compared to the dimensions of the bin, then these algorithms require polynomial time. Using these algorithms we solved all instances of the RK problem found at the OR-LIBRARY, including one for which no optimal solution was known. We also consider the Two-dimensional Cutting Stock problem. We present a column generation based algorithm for this problem that uses the first algorithm above mentioned to generate the columns. We propose two strategies to tackle the residual instances. We also investigate a variant of this problem where the bins have different sizes. At last, we study the Two-dimensional Strip Packing problem. We also present a column generation based algorithm for this problem that uses the second algorithm above mentioned where staged patterns are imposed. In this case we solve instances for two-, three- and four-staged patterns. We report on some computational experiments with the various algorithms we propose in this paper. The results indicate that these algorithms seem to be suitable for solving real-world instances. We give a detailed description (a pseudo-code) of all the algorithms presented here, so that the reader may easily implement these algorithms. (c) 2007 Elsevier B.V. All rights reserved.

Packing triangles in low degree graphs and indifference graphs

We consider the problems of finding the maximum number of vertex-disjoint triangles (VTP) and edge-disjoint triangles (ETP) in a simple graph. Both problems are NP-hard. The algorithm with the best approximation ratio known so far for these problems has ratio 3/2 + epsilon, a result that follows from a more general algorithm for set packing obtained by Hurkens and Schrijver [On the size of systems of sets every t of which have an SDR, with an application to the worst-case ratio of heuristics for packing problems, SIAM J. Discrete Math. 2(1) (1989) 68-72]. We present improvements on the approximation ratio for restricted cases of VTP and ETP that are known to be APX-hard: we give an approximation algorithm for VTP on graphs with maximum degree 4 with ratio slightly less than 1.2, and for ETP on graphs with maximum degree 5 with ratio 4/3. We also present an exact linear-time algorithm for VTP on the class of indifference graphs. (C) 2007 Elsevier B.V. All rights reserved.

Design of a Modern Liposome and Bee Venom Formulation for the Traditional VIT-Venom Immunotherapy

Traditional venom immunotherapy uses injections of whole bee venom in buffer or adsorbed in Al (OH)(3) in an expensive, time-consuming way. New strategies to improve the safety and efficacy of this treatment with a reduction of injections would, therefore, be of general interest. It would improve patient compliance and provide socio-economic benefits. Liposomes have a long tradition in drug delivery because they increase the therapeutic index and avoid drug degradation and secondary effects. However, bee venom melittin (Mel) and phospholipase (PLA(2)) destroy the phospholipid membranes. Our central idea was to inhibit the PLA(2) and Mel activities through histidine alkylation and or tryptophan oxidation (with pbb, para-bromo-phenacyl bromide, and/or NBSN-bromosuccinimide, respectively) to make their encapsulations possible within stabilized liposomes. We strongly believe that this formulation will be nontoxic but immunogenic. In this paper, we present the whole bee venom conformation characterization during and after chemical modification and after interaction with liposome by ultraviolet, circular dichroism, and fluorescence spectroscopies. The PLA(2) and Mel activities were, measured indirectly by changes in turbidity at 400(nm), rhodamine leak-out, and hemolysis. The native whole bee venom (BV) presented 78.06% of alpha-helical content. The alkylation (A-BV) and succynilation (S-BV) of BV increased 0.44 and 0.20% of its alpha-helical content. The double-modified venom (S-A-BV) had a 0.74% increase of alpha-helical content. The BV chemical modification induced another change on protein conformations observed by Trp that became buried with respect to the native whole BV. It was demonstrated that the liposomal membranes must contain pbb (SPC:Cho:pbb, 26:7:1) as a component to protect them from aggregation and/or fusion. The membranes containing pbb maintained the same turbidity (100%) after incubation with modified venom, in contrast with pbb-free membranes that showed a 15% size decrease. This size decrease was interpreted as membrane degradation and was corroborated by a 50% rhodamine leak-out. Another fact that confirmed our interpretation was the observed 100% inhibition of the hemolytic activity after venom modification with pbb and NBS (S-A-BV). When S-A-BV interacted with liposomes, other protein conformational changes were observed and characterized by the increase of 1.93% on S-A-BV alpha-helical content and the presence of tryptophan residues in a more hydrophobic environment. In other words, the S-A-BV interacted with liposomal membranes, but this interaction was not effective to cause aggregation, leak-out, or fusion. A stable formulation composed by S-A-BV encapsulated within liposomes composed by SPC:Cho:pbb, at a ratio of 26:7:1, was devised. Large unilamellar vesicles of 202.5 nm with a negative surface charge (-24.29 mV) encapsulated 95% of S-A-BV. This formulation can, now, be assayed on VIT.