Host-selected mutations converging on a global regulator drive an adaptive leap towards symbiosis in bacteria

Host immune and physical barriers protect against pathogens but also impede the establishment of essential symbiotic partnerships. To reveal mechanisms by which beneficial organisms adapt to circumvent host defenses, we experimentally evolved ecologically distinct bioluminescent Vibrio fischeri by colonization and growth within the light organs of the squid Euprymna scolopes. Serial squid passaging of bacteria produced eight distinct mutations in the binK sensor kinase gene, which conferred an exceptional selective advantage that could be demonstrated through both empirical and theoretical analysis. Squid-adaptive binK alleles promoted colonization and immune evasion that were mediated by cell-associated matrices including symbiotic polysaccharide (Syp) and cellulose. binK variation also altered quorum sensing, raising the threshold for luminescence induction. Preexisting coordinated regulation of symbiosis traits by BinK presented an efficient solution where altered BinK function was the key to unlock multiple colonization barriers. These results identify a genetic basis for microbial adaptability and underscore the importance of hosts as selective agents that shape emergent symbiont populations

The traveling salesman problem on cubic and subcubic graphs

We study the traveling salesman problem (TSP) on the metric completion of cubic and subcubic graphs, which is known to be NP-hard. The problem is of interest because of its relation to the famous 4/3-conjecture for metric TSP, which says that the integrality gap, i.e., the worst case ratio between the optimal value of a TSP instance and that of its linear programming relaxation (the subtour elimination relaxation), is 4/3. We present the first algorithm for cubic graphs with approximation ratio 4/3. The proof uses polyhedral techniques in a surprising way, which is of independent interest. In fact we prove constructively that for any cubic graph on TeX vertices a tour of length TeX exists, which also implies the 4/3-conjecture, as an upper bound, for this class of graph-TSP. Recently, Mömke and Svensson presented an algorithm that gives a 1.461-approximation for graph-TSP on general graphs and as a side result a 4/3-approximation algorithm for this problem on subcubic graphs, also settling the 4/3-conjecture for this class of graph-TSP. The algorithm by Mömke and Svensson is initially randomized but the authors remark that derandomization is trivial. We will present a different way to derandomize their algorithm which leads to a faster running time. All of the latter also works for multigraphs

May measurement month 2018: an analyses of blood pressure screening results from Cabo Verde.

Raised blood pressure (BP) is the biggest contributor to mortality and disease burden in Cabo Verde. May Measurement Month (MMM) is a global campaign set up in 2017 to raise awareness of high BP. In 2018, we aimed to expand the campaign by including a greater number of centres to increase awareness. Nine islands participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 98.0% of screenees provided three BP readings and multiple imputation using chained equations was used to impute missing readings. A total of 8008 individuals (mean age 40.4 years; 68.5% female) were screened. After multiple imputation, 2666 (33.3%) individuals had hypertension, of whom 74.8% were aware of their previous diagnosis and 55.8% were taking antihypertensive medication. Of those on medication, 39.1% were controlled and of all hypertensives, 21.8% were controlled. We detected 44.2% of individuals with untreated hypertension and 60.9% of treated individuals were inadequately treated. The Cape Verdean population is ageing and consequently cardiovascular disease is increasing, with hypertension being an important risk factor. Corrective actions need to be taken by the government. MMM is an ideal initiative to reach the public by raising awareness of this major cardiovascular risk factor

The Orienteering Problem under Uncertainty Stochastic Programming and Robust Optimization compared

The Orienteering Problem (OP) is a generalization of the well-known traveling salesman problem and has many interesting applications in logistics, tourism and defense. To reflect real-life situations, we focus on an uncertain variant of the OP. Two main approaches that deal with optimization under uncertainty are stochastic programming and robust optimization. We will explore the potentialities and bottlenecks of these two approaches applied to the uncertain OP. We will compare the known robust approach for the uncertain OP (the robust orienteering problem) to the new stochastic programming counterpart (the two-stage orienteering problem). The application of both approaches will be explored in terms of their suitability in practice

Predictors of mortality in primary antiphospholipid syndrome. A single-centre cohort study.

The vascular mortality of antiphospholipid syndrome (APS) ranges from 1.4 % to 5.5 %, but its predictors are poorly known. It was the study objective to evaluate the impact of baseline lupus anticoagulant assays, IgG anticardiolipin (aCL), plasma fibrinogen (FNG) and von Willebrand factor (VWF), platelets (PLT) and of genetic polymorphisms of methylenetetrahydrofolate reductase C677T, of prothrombin G20210A and of paraoxonase-1 Q192R on mortality in primary APS (PAPS). Cohort study on 77 thrombotic PAPS and 33 asymptomatic carriers of aPL (PCaPL) seen from 1989 to 2015 and persistently positive for aPL as per annual review. At baseline all participants were tested twice for the ratios of kaolin clotting time (KCTr), activated partial thromboplastin time (aPTTr), dilute Russell viper venom time (DRVVTr), IgG aCL, FNG, VWF and once for PLT. All thrombotic PAPS were on warfarin with regular INR monitoring. During follow-up 11 PAPS deceased (D-PAPS) of recurrent thrombosis despite adequate anticoagulation yielding an overall vascular mortality of 10 %. D-PAPS had the strongest baseline aPTTr and DRVVTr and the highest mean baseline IgG aCL, FNG, VWF and PLT. Cox proportional hazards model identified baseline DRVVTr and FNG as main predictors of mortality with adjusted hazard ratios of 5.75 (95 % confidence interval [CI]: 1.5, 22.4) and of 1.03 (95 %CI: 1.01, 1.04), respectively. In conclusion, plasma DRVVTr and FNG are strong predictors of vascular mortality in PAPS; while FNG lowering agents exist further research should be directed at therapeutic strategies able to dampen aPL production

A Duality Based 2-Approximation Algorithm for Maximum Agreement Forest

We give a 2-approximation algorithm for the Maximum Agreement Forest problem on two rooted binary trees. This NP-hard problem has been studied extensively in the past two decades, since it can be used to compute the rooted Subtree Prune-and-Regraft (rSPR) distance between two phylogenetic trees. Our algorithm is combinatorial and its running time is quadratic in the input size. To prove the approximation guarantee, we construct a feasible dual solution for a novel linear programming formulation. In addition, we show this linear program is stronger than previously known formulations, and we give a compact formulation, showing that it can be solved in polynomial tim

Split scheduling with uniform setup times

We study a scheduling problem in which jobs may be split into parts, where the parts of a split job may be processed simultaneously on more than one machine. Each part of a job requires a setup time, however, on the machine where the job part is processed. During setup, a machine cannot process or set up any other job. We concentrate on the basic case in which setup times are job-, machine- and sequence-independent. Problems of this kind were encountered when modelling practical problems in planning dis- aster relief operations. Our main algorithmic result is a polynomial-time algorithm for minimising total completion time on two parallel identical machines. We argue, why the same problem with threemachines is not an easy extension of the two-machine case, leaving the complexity of this case as a tantalising open problem. We give a constant-factor approximation algorithm for the general case with any number of machines and a polynomial-time approximation scheme for a fixed number of machines. For the version with the objective to minimise total weighted completion time, we prove NP-hardness. Finally, we conclude with an overview of the state of the art for other split scheduling problems with job-, machine- and sequence-independent setup times

The LIFT trial: study protocol for a double-blind, randomised, placebo-controlled trial of K+-binder Lokelma for maximisation of RAAS inhibition in CKD patients with heart failure

Background CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy. Methods We propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants’ RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George’s Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline. Discussion This trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded. Trial registration EudraCT number 2020–002946-18. Registered on 08 June 2020. Online record pending

The acceleration and storage of radioactive ions for a neutrino factory

The term beta-beam has been coined for the production of a pure beam of electron neutrinos or their antiparticles through the decay of radioactive ions circulating in a storage ring. This concept requires radioactive ions to be accelerated to a Lorentz gamma of 150 for 6He and 60 for 18Ne. The neutrino source itself consists of a storage ring for this energy range, with long straight sections in line with the experiment(s). Such a decay ring does not exist at CERN today, nor does a high-intensity proton source for the production of the radioactive ions. Nevertheless, the existing CERN accelerator infrastructure could be used as this would still represent an important saving for a beta-beam facility. This paper outlines the first study, while some of the more speculative ideas will need further investigations.Comment: Accepted for publication in proceedings of Nufact02, London, 200