Salivarian Trypanosomes Have Adopted Intricate Host-Pathogen Interaction Mechanisms That Ensure Survival in Plain Sight of the Adaptive Immune System

Salivarian trypanosomes are extracellular parasites affecting humans, livestock and game animals. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are human infective sub-species of T. brucei causing human African trypanosomiasis (HAT—sleeping sickness). The related T. b. brucei parasite lacks the resistance to survive in human serum, and only inflicts animal infections. Animal trypanosomiasis (AT) is not restricted to Africa, but is present on all continents. T. congolense and T. vivax are the most widespread pathogenic trypanosomes in sub-Saharan Africa. Through mechanical transmission, T. vivax has also been introduced into South America. T. evansi is a unique animal trypanosome that is found in vast territories around the world and can cause atypical human trypanosomiasis (aHT). All salivarian trypanosomes are well adapted to survival inside the host’s immune system. This is not a hostile environment for these parasites, but the place where they thrive. Here we provide an overview of the latest insights into the host-parasite interaction and the unique survival strategies that allow trypanosomes to outsmart the immune system. In addition, we review new developments in treatment and diagnosis as well as the issues that have hampered the development of field-applicable anti-trypanosome vaccines for the implementation of sustainable disease control.</jats:p

Uniform Random Sampling Product Configurations of Feature Models That Have Numerical Features

Analyses of Software Product Lines (SPLs) rely on automated solvers to navigate complex dependencies among features and find legal configurations. Often these analyses do not support numerical features with constraints because propositional formulas use only Boolean variables. Some automated solvers can represent numerical features natively, but are limited in their ability to count and Uniform Random Sample (URS) conigurations, which are key operations to derive unbiased statistics on configuration spaces. Bit-blasting is a technique to encode numerical constraints as propositional formulas. We use bit-blasting to encode Boolean and numerical constraints so that we can exploit existing #SAT solvers to count and URS conigurations. Compared to state-of-art Satisfiability Modulo Theory and Constraint Programming solvers, our approach has two advantages: 1) faster and more scalable coniguration counting and 2) reliable URS of SPL configurations. We also show that our work can be used to extend prior SAT-based SPL analyses to support numerical features and constraints.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The influence of the preparation methods on the inclusion of model drugs in a β-cyclodextrin cavity

NOTICE: this is the author’s version of a work that was accepted for publication in European Journal of Pharmaceutics and Biopharmaceutics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Eur J Pharm Biopharm. 2009 Feb;71(2):377-386. Epub 2008 Oct 17.The work aims to prove the complexation of two model drugs (ibuprofen, IB and indomethacin, IN) by bcyclodextrin (bCD), and the effect of water in such a process, and makes a comparison of their complexation yields. Two methods were considered: kneading of a binary mixture of the drug, bCD, and inclusion of either IB or IN in aqueous solutions of bCD. In the latter method water was removed by air stream, spray-drying and freeze-drying. To prove the formation of complexes in final products, optical microscopy, UV spectroscopy, IR spectroscopy, DSC, X-ray and NMR were considered. Each powder was added to an acidic solution (pH = 2) to quantify the concentration of the drug inside bCD cavity. Other media (pH = 5 and 7) were used to prove the existence of drug not complexed in each powder, as the drugs solubility increases with the pH. It was observed that complexation occurred in all powders, and that the fraction of drug inside the bCD did not depend neither on the method of complexation nor on the processes of drying considered

The Dark Matter Density in the Solar Neighborhood reconsidered

Both the gas flaring and the dip in the rotation curve, which was recently reconfirmed with precise measurements using the VERA VLBI array in Japan, suggest doughnut-like substructure in the dark matter (DM) halo. A global fit to all available data shows that the data are indeed best described by an NFW DM profile complemented by two doughnut-like DM substructures with radii of 4.2 and 12.4 kpc, which coincide with the local dust ring and the Monocerus ring of stars, respectively. Both regions have been suggested as regions with tidal streams from "shredded" satellites. If real, the radial extensions of these nearby ringlike structures enhance the local dark matter density by a factor of four to about 1.3$\pm0.3$ GeV/cm$^3$. It is shown that i) this higher DM density is perfectly consistent with the local gravitational potential determining the surface density and the local matter density (Oort limit), ii) previous determinations of the surface density were biased by the assumption of a smoothly varying DM halo and iii) the s-shaped gas flaring is explained. Such a possible enhancement of the local DM density is of great interest for direct DM searches and would change the directional dependence for indirect DM searches.Comment: 14 pages, 4 figures, extended version, accepted for publication in JCA

Palpation Device for the Identification of Kidney and Bladder Cancer: A Pilot Study

PURPOSE: To determine the ability of a novel palpation device to differentiate between benign and malignant tissues of the kidney and bladder by measuring tissue elasticity. MATERIALS AND METHODS: A novel palpation device was developed, mainly composed of a micromotor, a linear position sensor, a force transducer, and a hemisphere tip and cylindrical body probe. Motion calibration as well as performance validation was done. The tissue elasticity of both benign and malignant tissues of the kidney and bladder was measured using this device. A single investigator performed the ex-vivo palpation experiment in twelve kidneys and four bladder specimens. Malignant tissues were made available from partial nephrectomy specimens and radical cystectomy specimens. Palpations for benign renal parenchyma tissue were carried out on nephroureterectomy specimens while non-involved areas in the radical cystectomy specimens were used for benign bladder samples. Elastic modulus (Young's modulus) of tissues was estimated using the Hertz-Sneddon equation from the experimental results. These were then compared using a t-test for independent samples. RESULTS: Renal cell carcinoma tissues appear to be softer than normal kidney tissues, whereas tissues from urothelial carcinoma of the bladder appear to be harder than normal bladder tissues. The results from renal cell carcinoma differed significantly from those of normal kidney tissues (p=0.002), as did urothelial carcinoma of the bladder from normal bladder tissues (p=0.003). CONCLUSION: Our novel palpation device can potentially differentiate between malignant and benign kidney and bladder tissues. Further studies are necessary to verify our results and define its true clinical utility.ope

The Impact of Cognitive and Behavioral Symptoms on ALS Patients and Their Caregivers

Previously thought to be a pure motor disease, amyotrophic lateral sclerosis (ALS) is now established as multisystem neurodegenerative disorder that lies on a continuum with frontotemporal dementia (FTD). Cognitive and behavioral symptoms primarily extend to executive function, personality, social conduct, and emotion processing. The assessment and management of cognitive and behavioral symptoms is complicated as they must be differentiated from psychological responses to a terminal diagnosis and progressive physical impairment. This is made more difficult by the limited number of studies investigating how these symptoms specifically affect patients and caregivers well-being. The current review focuses on the impact of cognitive and behavioral symptoms on patient and caregiver well-being and their implications for future research and interventions in ALS. This is an important area of research that could form the basis for more tailored, and potentially more successful, non-pharmacological interventions to improve psychological well-being among patients with ALS and their caregivers

Distinct regulation of c-myb gene expression by HoxA9, Meis1 and Pbx proteins in normal hematopoietic progenitors and transformed myeloid cells

The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells