Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (Berenil®), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (MPXR) is the result of loss of a separate High Affinity Pentamidine Transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the “selectivity region” of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this remarkable ability

Redox control of multidrug resistance and Its possible modulation by antioxidants

Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic enzymes with a temporal redox-regulated axis. This results in rapid metabolic transformation and elimination of a toxin. This metabolic axis is tightly interconnected with the inducible Nrf2-linked pathway, a key switch-on mechanism for upregulation of endogenous antioxidant enzymes and detoxifying systems. As a result, chemotherapeutics and cytotoxic by-products of their metabolism (ROS, hydroperoxides, and aldehydes) are inactivated and MDR occurs. On the other hand, tumour cells are capable of mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells. The multiple redox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) or inhibitors of inducible antioxidant defence as a novel approach to diminish MDR. Pitfalls and progress in this direction are discussed

The Ineludible non-Gaussianity of the Primordial Black Hole Abundance

We study the formation of primordial black holes when they are generated by the collapse of large overdensities in the early universe. Since the density contrast is related to the comoving curvature perturbation by a nonlinear relation, the overdensity statistics is unavoidably non-Gaussian. We show that the abundance of primordial black holes at formation may not be captured by a perturbative approach which retains the first few cumulants of the non-Gaussian probability distribution. We provide two techniques to calculate the non-Gaussian abundance of primordial black holes at formation, one based on peak theory and the other on threshold statistics. Our results show that the unavoidable non-Gaussian nature of the inhomogeneities in the energy density makes it harder to generate PBHs. We provide simple (semi-)analytical expressions to calculate the non-Gaussian abundances of the primordial black holes and show that for both narrow and broad power spectra the gaussian case from threshold statistics is reproduced by increasing the amplitude of the power spectrum by a factor ${\cal O}(2\div 3)$.Comment: 26 pages, 10 figures, matching published versio

Christoffel words and the Calkin-Wilf tree

In this note we present some results on the Calkin-Wilf tree of irreducible fractions, giving an insight on the duality relating it to the Stern-Brocot tree, and proving noncommutative versions of known results relating labels of the Calkin-Wilf trees to hyperbinary expansions of positive integers. The main tool is the Christoffel tree introduced in a paper by Berstel and de Luca

The Naples Systematic Series – Second part: Irregular waves, seakeeping in head sea

Abstract The main aim of this study is to characterize the dynamic behavior of the Naples Systematic Series (NSS) in irregular head sea. A further aim of the study is to provide data to detect the influence of hull form on the sea-keeping performances in the planing and semi-planing speed range. The NSS derives from a parent hull that has shown to behave well in rough seas, characterized by high deadrise angles of the bottom at the bow, to reduce acceleration. All the models of NSS were tested in three different sea states and in Fr range from 0.515 to 1.197. The relatively high Froude numbers associated with the forms of the series make inappropriate the statistical analysis usually carried out to describe the behavior of the displacement ships. To overcome these unsuitableness, Cartwright Lounguet Higgins, extreme value and normal distribution fittings have been furnished for heave and pitch maxima and minima; gamma and extreme value have been furnished to represent acceleration in the centre of gravity and bow. Finally, a case study is presented to show a useful procedure for designer evaluation

Ising transition driven by frustration in a 2D classical model with SU(2) symmetry

We study the thermal properties of the classical antiferromagnetic Heisenberg model with both nearest ($J_1$) and next-nearest ($J_2$) exchange couplings on the square lattice by extensive Monte Carlo simulations. We show that, for $J_2/J_1 > 1/2$, thermal fluctuations give rise to an effective $Z_2$ symmetry leading to a {\it finite-temperature} phase transition. We provide strong numerical evidence that this transition is in the 2D Ising universality class, and that $T_c\to 0$ with an infinite slope when $J_2/J_1\to 1/2$.Comment: 4 pages with 4 figure

A new international measure of social stratification

In this paper we present a new international measure of social stratification, the ICAMS (International Cambridge Scale). Our aim is to bring new evidence to the hypothesis that the construct that underlies measures of social stratification as different as prestige scales, socioeconomic indexes, social distance and social status scales is actually unidimensional. We evaluate the new scale according to both criterion-related and construct validity. Our analysis shows that the ICAMS is a valid indicator of social stratification, being almost as valid as International Socio-Economic Index (ISEI) in what we termed the generic, the homogamy and the social mobility models, and being better than ISEI in the cultural consumption model. The second key result is that all continuous measures we consider (ICAMS, ISEI and Standard International Occupational Prestige Scale) are indicators of the same latent dimension, which is unidimensional. This latter result is compatible with morethan one explanation, hence calling for further research

Insulin resistance and HCV virologic response to peg-interferons (Peg-IFN) with ribavirin (RBV) in HIV/HCV co-infected patients

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