Membrane Disordering by Eicosapentaenoic Acid in B Lymphomas Is Reduced by Elongation to Docosapentaenoic Acid as Revealed with Solid-State Nuclear Magnetic Resonance Spectroscopy of Model Membranes

BACKGROUND: Plasma membrane organization is a mechanistic target of n-3 (ω-3) polyunsaturated fatty acids. Previous studies show that eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) differentially disrupt plasma membrane molecular order to enhance the frequency and function of B lymphocytes. However, it is not known whether EPA and DHA affect the plasma membrane organization of B lymphomas differently to influence their function. OBJECTIVE: We tested whether EPA and DHA had different effects on membrane order in B lymphomas and liposomes and studied their effects on B-lymphoma growth. METHODS: B lymphomas were treated with 25 μmol EPA, DHA, or serum albumin control/L for 24 h. Membrane order was measured with fluorescence polarization, and cellular fatty acids (FAs) were analyzed with GC. Growth was quantified with a viability assay. (2)H nuclear magnetic resonance (NMR) studies were conducted on deuterated phospholipid bilayers. RESULTS: Treating Raji, Ramos, and RPMI lymphomas for 24 h with 25 μmol EPA or DHA/L lowered plasma membrane order by 10-40% relative to the control. There were no differences between EPA and DHA on membrane order for the 3 cell lines. FA analyses revealed complex changes in response to EPA or DHA treatment and a large fraction of EPA was converted to docosapentaenoic acid (DPA; 22:5n-3). NMR studies, which were used to understand why EPA and DHA had similiar membrane effects, showed that phospholipids containing DPA, similar to DHA, were more ordered than those containing EPA. Finally, treating B lymphomas with 25 μmol EPA or DHA/L did not increase the frequency of B lymphomas compared with controls. CONCLUSIONS: The results establish that 25 μmol EPA and DHA/L equally disrupt membrane order and do not promote B lymphoma growth. The data open a new area of investigation, which is how EPA's conversion to DPA substantially moderates its influence on membrane properties

On the Complexity of Searching in Trees: Average-case Minimization

We focus on the average-case analysis: A function w : V -> Z+ is given which defines the likelihood for a node to be the one marked, and we want the strategy that minimizes the expected number of queries. Prior to this paper, very little was known about this natural question and the complexity of the problem had remained so far an open question. We close this question and prove that the above tree search problem is NP-complete even for the class of trees with diameter at most 4. This results in a complete characterization of the complexity of the problem with respect to the diameter size. In fact, for diameter not larger than 3 the problem can be shown to be polynomially solvable using a dynamic programming approach. In addition we prove that the problem is NP-complete even for the class of trees of maximum degree at most 16. To the best of our knowledge, the only known result in this direction is that the tree search problem is solvable in O(|V| log|V|) time for trees with degree at most 2 (paths). We match the above complexity results with a tight algorithmic analysis. We first show that a natural greedy algorithm attains a 2-approximation. Furthermore, for the bounded degree instances, we show that any optimal strategy (i.e., one that minimizes the expected number of queries) performs at most O(\Delta(T) (log |V| + log w(T))) queries in the worst case, where w(T) is the sum of the likelihoods of the nodes of T and \Delta(T) is the maximum degree of T. We combine this result with a non-trivial exponential time algorithm to provide an FPTAS for trees with bounded degree

A Minimal Periods Algorithm with Applications

Kosaraju in ``Computation of squares in a string'' briefly described a linear-time algorithm for computing the minimal squares starting at each position in a word. Using the same construction of suffix trees, we generalize his result and describe in detail how to compute in O(k|w|)-time the minimal k-th power, with period of length larger than s, starting at each position in a word w for arbitrary exponent $k\geq2$ and integer $s\geq0$. We provide the complete proof of correctness of the algorithm, which is somehow not completely clear in Kosaraju's original paper. The algorithm can be used as a sub-routine to detect certain types of pseudo-patterns in words, which is our original intention to study the generalization.Comment: 14 page

Effects of fish oils on ex vivo B-cell responses of obese subjects upon BCR/TLR stimulation: a pilot study

The long-chain n-3 polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) in fish oil have immunomodulatory properties. B cells are a poorly studied target of EPA/DHA in humans. Therefore, in this pilot study, we tested how n-3 LC-PUFAs influence B-cell responses of obese humans. Obese men and women were assigned to consume four 1-g capsules per day of olive oil (OO, n=12), fish oil (FO, n=12) concentrate or high-DHA-FO concentrate (n=10) for 12 weeks in a parallel design. Relative to baseline, FO (n=9) lowered the percentage of circulating memory and plasma B cells, whereas the other supplements had no effect. There were no postintervention differences between the three supplements. Next, ex vivo B-cell cytokines were assayed after stimulation of Toll-like receptors (TLRs) and/or the B-cell receptor (BCR) to determine if the effects of n-3 LC-PUFAs were pathway-dependent. B-cell IL-10 and TNFα secretion was respectively increased with high DHA-FO (n=10), relative to baseline, with respective TLR9 and TLR9 + BCR stimulation. OO (n=12) and FO (n=12) had no influence on B-cell cytokines compared to baseline, and there were no differences in postintervention cytokine levels between treatment groups. Finally, ex vivo antibody levels were assayed with FO (n=7) after TLR9 + BCR stimulation. Compared to baseline, FO lowered IgM but not IgG levels accompanied by select modifications to the plasma lipidome. Altogether, the results suggest that n-3 LC-PUFAs could modulate B-cell activity in humans, which will require further testing in a larger cohort

Rewriting Systems for Reachability in Vector Addition Systems with Pairs

15 pagesInternational audienceWe adapt hypergraph rewriting system to a generalization of Vector Addition Systems with States (VASS) that we call vector addition systems with pairs (VASP). We give rewriting systems and strategies, that allow us to obtain reachability equivalence results between some classes of VASP and VASS. Reachability for the later is well known be equivalent to reachability in Petri nets. VASP generalize also Branching Extension of VASS (BVASS) for which it is unknown if they are more expressive than VASS. We consider here a more restricted notion of reachability for VASP than that for BVASS. However the reachability decision problem corresponding is already equivalent to decidability of the provability in Multiplicative and Exponential Linear Logic (MELL), a question left open for more than 20 years

Cardiovascular risk estimation and eligibility for statins in primary prevention comparing different strategies.

Recommendations for statin use for primary prevention of coronary heart disease (CHD) are based on estimation of the 10-year CHD risk. It is unclear which risk algorithm and guidelines should be used in European populations. Using data from a population-based study in Switzerland, we first assessed 10-year CHD risk and eligibility for statins in 5,683 women and men 35 to 75 years of age without cardiovascular disease by comparing recommendations by the European Society of Cardiology without and with extrapolation of risk to age 60 years, the International Atherosclerosis Society, and the US Adult Treatment Panel III. The proportions of participants classified as high-risk for CHD were 12.5% (15.4% with extrapolation), 3.0%, and 5.8%, respectively. Proportions of participants eligible for statins were 9.2% (11.6% with extrapolation), 13.7%, and 16.7%, respectively. Assuming full compliance to each guideline, expected relative decreases in CHD deaths in Switzerland over a 10-year period would be 16.4% (17.5% with extrapolation), 18.7%, and 19.3%, respectively; the corresponding numbers needed to treat to prevent 1 CHD death would be 285 (340 with extrapolation), 380, and 440, respectively. In conclusion, the proportion of subjects classified as high risk for CHD varied over a fivefold range across recommendations. Following the International Atherosclerosis Society and the Adult Treatment Panel III recommendations might prevent more CHD deaths at the cost of higher numbers needed to treat compared with European Society of Cardiology guidelines

B cell activity is impaired in human and mouse obesity and is responsive to an essential fatty acid upon murine influenza infection

Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming theWestern diet had diminished Ab titers whereas theWestern diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism