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

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

Kerr black hole lensing for generic observers in the strong deflection limit

We generalize our previous work on gravitational lensing by a Kerr black hole in the strong deflection limit, removing the restriction to observers on the equatorial plane. Starting from the Schwarzschild solution and adding corrections up to the second order in the black hole spin, we perform a complete analytical study of the lens equation for relativistic images created by photons passing very close to a Kerr black hole. We find out that, to the lowest order, all observables (including shape and shift of the black hole shadow, caustic drift and size, images position and magnification) depend on the projection of the spin on a plane orthogonal to the line of sight. In order to break the degeneracy between the black hole spin and its inclination relative to the observer, it is necessary to push the expansion to higher orders. In terms of future VLBI observations, this implies that very accurate measures are needed to determine these two parameters separately.Comment: 17 pages, 4 figures, one section added, to appear on Physical Review

Covalency, double-counting and the metal-insulator phase diagram in transition metal oxides

Dynamical mean field theory calculations are used to show that for late transition-metal-oxides a critical variable for the Mott/charge-transfer transition is the number of d-electrons, which is determined by charge transfer from oxygen ions. Insulating behavior is found only for a narrow range of d-occupancy, irrespective of the size of the intra-d Coulomb repulsion. The result is useful in interpreting 'density functional +U' and 'density functional plus dynamical mean field' methods in which additional correlations are applied to a specific set of orbitals and an important role is played by the 'double counting correction' which dictates the occupancy of these correlated orbitals. General considerations are presented and are illustrated by calculations for two representative transition metal oxide systems: layered perovskite Cu-based "high-Tc" materials, an orbitally non-degenerate electronically quasi-two dimensional systems, and pseudocubic rare earch nickelates, an orbitally degenerate electronically three dimensional system. Density functional calculations yield d-occupancies very far from the Mott metal-insulator phase boundary in the nickelate materials, but closer to it in the cuprates, indicating the sensitivity of theoretical models of the cuprates to the choice of double counting correction and corroborating the critical role of lattice distortions in attaining the experimentally observed insulating phase in the nickelates.Comment: 10+ pages, 5 figure

The 2013–2018 matese and beneventano seismic sequences (Central–Southern apennines). New constraints on the hypocentral depth determination

The Matese and Beneventano areas coincide with the transition from the central to the southern Apennines and are characterized by both SW-and NE-dipping normal faulting seismogenic structures, responsible for the large historical earthquakes. We studied the Matese and Beneventano seismicity by means of high-precision locations of earthquakes spanning from 29 December 2013 to 4 September 2018. Events were located by using all of the available data from temporary and permanent stations in the area and a 1D computed velocity model, inverting the dataset with the Velest code. For events M > 2.8 we used P-and S-waves arrival times of the strong motion stations located in the study area. A constant value of 1.83 for Vp/Vs was computed with a modified Wadati method. The dataset consists of 2378 earthquakes, 18,715 P-and 12,295 S-wave arrival times. We computed 55 new fault plane solutions. The mechanisms show predominantly normal fault movements, with T-axis trends oriented NE–SW. Only relatively small E–W trending clusters in the eastern peripheral zones of the Apenninic belt show right-lateral strike-slip kinematics similar to that observed in the Potenza (1990–1991) and Molise (2002 and 2018) sequences. These belong to transfer zones associated with differential slab retreat of the Adriatic plate subduction beneath the Apennines. The Matese sequence (December 2013–February 2014; main shock Mw 5.0) is the most relevant part of our dataset. Hypocentral depths along the axis of the Apenninic belt are in agreement with previous seismological studies that place most of the earthquakes in the brittle upper crust. We confirm a general deepening of seismicity moving from west to the east along the Apennines. Seismicity depth is controlled by heat-flow, which is lower in the eastern side, thus causing a deeper brittle–ductile transition

Testing the specificity of predictors of reading, spelling and maths: a new model of the association among learning skills based on competence, performance and acquisition

In a previous study (Zoccolotti et al., 2020) we examined reading, spelling, and maths skills in an unselected group of 129 Italian children attending fifth grade by testing various cognitive predictors; results showed a high degree of predictors’ selectivity for each of these three behaviors. In the present study, we focused on the specificity of the predictors by performing cross-analyses on the same dataset; i.e., we predicted spelling and maths skills based on reading predictors, reading based on maths predictors and so on. Results indicated that some predictors, such as the Orthographic Decision and the Arithmetic Facts tests, predicted reading, spelling and maths skills in similar ways, while others predicted different behaviors but only for a specific parameter, such as fluency but not accuracy (as in the case of RAN), and still others were specific for a single behavior (e.g., Visual-auditory Pseudo-word Matching test predicted only spelling skills). To interpret these results, we propose a novel model of learning skills separately considering factors in terms of competence, performance and acquisition (automatization). Reading, spelling and calculation skills would depend on the development of discrete and different abstract competences (accounting for the partial dissociations among learning disorders reported in the literature). By contrast, overlap among behaviors would be accounted for by defective acquisition in automatized responses to individual “instances”; this latter skill is item specific but domain independent. Finally, performance factors implied in task’s characteristics (such as time pressure) may contribute to the partial association among learning skills. It is proposed that this new model may provide a useful base for interpreting the diffuse presence of comorbidities among learning disorders

Search for the Optical Counterpart of the Vela Pulsar X-ray Nebula

Observations of the Vela pulsar region with the Chandra X-ray observatory have revealed the fine structure of its synchrotron pulsar-wind nebula (PWN), which showed an overall similarity with the Crab PWN. However, contrary to the Crab, no firm detection of the Vela PWN in optical has been reported yet. To search for the optical counterpart of the X-ray PWN, we analyzed deep optical observations performed with different telescopes. We compared the optical images with those obtained with the Chandra ACIS to search for extended emission patterns which could be identified as counterparts of the X-ray nebula elements. Although some features are seen in the optical images, we find no correlation with the X-ray structure. Thus, we conclude that the diffuse optical emission is more likely associated with filaments in the host Vela SNR. The derived upper limits on the optical flux from the PWN are compatibile, within the uncertainties, with the values expected on the basis of the extrapolations of the X-ray data.Comment: 19 pages, 6 figures. Accepted for publication in Ap

Multi-wavelength observations of 3FGL J2039.6-5618: a candidate redback millisecond pulsar

We present multi-wavelength observations of the unassociated gamma-ray source 3FGL J2039.6-5618 detected by the Fermi Large Area Telescope. The source gamma-ray properties suggest that it is a pulsar, most likely a millisecond pulsar, for which neither radio nor $\gamma$-ray pulsations have been detected yet. We observed 3FGL J2039.6-5618 with XMM-Newton and discovered several candidate X-ray counterparts within/close to the gamma-ray error box. The brightest of these X-ray sources is variable with a period of 0.2245$\pm$0.0081 d. Its X-ray spectrum can be described by a power law with photon index $\Gamma_X =1.36\pm0.09$, and hydrogen column density $N_{\rm H} < 4 \times 10^{20}$ cm$^{-2}$, which gives an unabsorbed 0.3--10 keV X-ray flux of $1.02 \times 10^{-13}$ erg cm$^{-2}$ s$^{-1}$. Observations with the Gamma-Ray Burst Optical/Near-Infrared Detector (GROND) discovered an optical counterpart to this X-ray source, with a time-average magnitude $g'\sim 19.5$. The counterpart features a flux modulation with a period of 0.22748$\pm$0.00043 d that coincides, within the errors, with that of the X-ray source, confirming the association based on the positional coincidence. We interpret the observed X-ray/optical periodicity as the orbital period of a close binary system where one of the two members is a neutron star. The light curve profile of the companion star, with two asymmetric peaks, suggests that the optical emission comes from two regions at different temperatures on its tidally-distorted surface. Based upon its X-ray and optical properties, we consider this source as the most likely X-ray counterpart to 3FGL J2039.6-5618, which we propose to be a new redback system.Comment: 35 pages, 8 figures, accepted for publication on Astrophysical Journa

The patient-physician relationship in the face of oncological disease: A review of literature on the emotional and psychological reactions of patients and physician

The physician-patient relationship is daily destabilized by emotional reactions and psychic defenses that cancer arises in the two partners. Continued scientific and technological progresses which were reached by medicine in recent years, and particularly oncologic clinical discoveries, increased the chance of not only survival but also healing. Nevertheless, cancer diagnosis is still a hard existential text that destabilizes everyday life, all the psychic and relational balance, inevitably causing a psychological and social change not only in the patient who is affected but also into the wide social network around him (family, friends, doctors, healthcare team). The aim of this review is to understand how problems, feelings, emotions, distresses or defense mechanisms could garble the relation and the communication dynamics between physician and patients and then prejudicing the efficacy of oncologic therapeutic compliance. Pubmed and Scopus were searched, using strings related to "cancer", "physician-patient relations", burn-out", "compliance", and "communication", identifying literature published from 2000 to January 2015. Extracted papers were assessed for their relevance (10 of 412 papers initially reviewed). Results indicate that a good and empathetic relationship between physician and patient were related to good therapeutic adherence. In particular, a good physician-patient relation maximizes the impact of clinical therapies and reduces psychophysical implications