Blowups with log canonical singularities

We show that the minimum weight of a weighted blowup of Ad with [epsilon]- log canonical singularities is bounded by a constant depending only on [epsilon] and d . This was conjectured by Birkar. Using the recent classification of 4_ dimensional empty simplices by Iglesias-Valiño and Santos, we work out an explicit bound for blowups of A4 with terminal singular-ities: the smallest weight is always at most 32, and at most 6 in all but finitely many cases.Some background on birational geometry was supplied to Sankaran by Anne-Sophie Kaloghiros. The explanations here relating these results to their wider context are largely hers, but errors and omissions in such explanations are definitely ours. Parts of this work were carried out while Sankaran was visiting Fukuoka University and KIAS, Seoul: he thanks both for hospitality and a helpful environment. Work of Santos was supported by grant MTM2017-83750-P of the Spanish Ministry of Economy and Competitiveness and by the Einstein Foundation Berlin under grant EVF-2015-230. We also thank the organisers of MEGA 2019 (Madrid), where the two authors first met and discussed these questions

Regular cylindrical algebraic decomposition

We show that a strong well-based cylindrical algebraic decomposition P of a bounded semi-algebraic set S is a regular cell decomposition, in any dimension and independently of the method by which P is constructed. Being well-based is a global condition on P that holds for the output of many widely used algorithms. We also show the same for S of dimension at most 3 and P a strong cylindrical algebraic decomposition that is locally boundary simply connected: this is a purely local extra condition.</p

Lattice Boltzmann simulations of low-Reynolds-number flows past fluidized spheres : effect of inhomogeneities on the drag force

This work is supported by a grant from the ExxonMobil Research & Engineering Co., and by a fellowship awarded to G.J.R. by the National Science Foundation (DGE-1148900).Peer reviewedPostprin

Antagonism between substitutions in β-lactamase explains a path not taken in the evolution of bacterial drug resistance

CTX-M β-lactamases are widespread in Gram-negative bacterial pathogens and provide resistance to the cephalosporin cefotaxime but not to the related antibiotic ceftazidime. Nevertheless, variants have emerged that confer resistance to ceftazidime. Two natural mutations, causing P167S and D240G substitutions in the CTX-M enzyme, result in 10-fold increased hydrolysis of ceftazidime. Although the combination of these mutations would be predicted to increase ceftazidime hydrolysis further, the P167S/D240G combination has not been observed in a naturally occurring CTX-M variant. Here, using recombinantly expressed enzymes, minimum inhibitory concentration measurements, steady-state enzyme kinetics, and X-ray crystallography, we show that the P167S/D240G double mutant enzyme exhibits decreased ceftazidime hydrolysis, lower thermostability, and decreased protein expression levels compared with each of the single mutants, indicating negative epistasis. X-ray structures of mutant enzymes with covalently trapped ceftazidime suggested that a change of an active-site Ω-loop to an open conformation accommodates ceftazidime leading to enhanced catalysis. 10-μs molecular dynamics simulations further correlated Ω-loop opening with catalytic activity. We observed that the WT and P167S/D240G variant with acylated ceftazidime both favor a closed conformation not conducive for catalysis. In contrast, the single substitutions dramatically increased the probability of open conformations. We conclude that the antagonism is due to restricting the conformation of the Ω-loop. These results reveal the importance of conformational heterogeneity of active-site loops in controlling catalytic activity and directing evolutionary trajectories

Shortening of 3′UTRs Correlates with Poor Prognosis in Breast and Lung Cancer

A major part of the post-transcriptional regulation of gene expression is affected by trans-acting elements, such as microRNAs, binding the 3′ untraslated region (UTR) of their target mRNAs. Proliferating cells partly escape this type of negative regulation by expressing shorter 3′ UTRs, depleted of microRNA binding sites, compared to non-proliferating cells. Using large-scale gene expression datasets, we show that a similar phenomenon takes place in breast and lung cancer: tumors expressing shorter 3′ UTRs tend to be more aggressive and to result in shorter patient survival. Moreover, we show that a gene expression signature based only on the expression ratio of alternative 3′ UTRs is a strong predictor of survival in both tumors. Genes undergoing 3′UTR shortening in aggressive tumors of the two tissues significantly overlap, and several of them are known to be involved in tumor progression. However the pattern of 3′ UTR shortening in aggressive tumors in vivo is clearly distinct from analogous patterns involved in proliferation and transformation

African Trypanosomiasis-associated anemia : the contribution of the interplay between parasites and the mononuclear phagocyte system

African trypanosomosis (AT) is a chronically debilitating parasitic disease of medical and economic importance for the development of sub-Saharan Africa. The trypanosomes that cause this disease are extracellular protozoan parasites that have developed efficient immune escape mechanisms to manipulate the entire host immune response to allow parasite survival and transmission. During the early stage of infection, a profound pro-inflammatory type 1 activation of the mononuclear phagocyte system (MPS), involving classically activated macrophages (i.e., M1), is required for initial parasite control. Yet, the persistence of this M1-type MPS activation in trypanosusceptible animals causes immunopathology with anemia as the most prominent pathological feature. By contrast, in trypanotolerant animals, there is an induction of IL-10 that promotes the induction of alternatively activated macrophages (M2) and collectively dampens tissue damage. A comparative gene expression analysis between M1 and M2 cells identified galectin-3 (Gal-3) and macrophage migration inhibitory factor (MIF) as novel M1-promoting factors, possibly acting synergistically and in concert with TNF-alpha during anemia development. While Gal-3 enhances erythrophagocytosis, MIF promotes both myeloid cell recruitment and iron retention within the MPS, thereby depriving iron for erythropoiesis. Hence, the enhanced erythrophagocytosis and suppressed erythropoiesis lead to anemia. Moreover, a thorough investigation using MIF-deficient mice revealed that the underlying mechanisms in AT-associated anemia development in trypanosusceptible and tolerant animals are quite distinct. In trypanosusceptible animals, anemia resembles anemia of inflammation, while in trypanotolerant animals' hemodilution, mainly caused by hepatosplenomegaly, is an additional factor contributing to anemia. In this review, we give an overview of how trypanosome-and host-derived factors can contribute to trypanosomosis-associated anemia development with a focus on the MPS system. Finally, we will discuss potential intervention strategies to alleviate AT-associated anemia that might also have therapeutic potential