Antileishmanial and antitrypanosomal activity of symmetrical dibenzyl-substituted α,β-unsaturated carbonyl-based compounds.

Human African Trypanosomiasis (HAT) and leishmaniasis are two of the most neglected challenging tropical diseases, caused by the kinetoplastid parasites and species, respectively. For both of these complex disease spectra, treatment options are limited and threatened by drug resistance, justifying urgent new drug discovery efforts. In the present study we investigated the antitrypanosomal and antileishmanial activity of a series of 21 symmetrical α,β-unsaturated carbonyl-based compounds, each featuring two 3-methoxybenzene attached to a central cyclohexanone, tetrahydro-4-pyranone scaffold or 4-piperidone ring. Structure-activity relationships were explored with respect to substitution on positions 3, 4 and 6 of the terminal 3-methoxybenzyl groups, and seven types of central ring. Compounds and , showed broad anti-kinetoplastid activity against all species and strains tested. Compound featuring -methyl-4-piperidone was found to be the most potent analog and therefore can serve as a potential lead for the development of new drug candidates for trypanosomiasis and leishmaniasis

Theoretical study of the thermodynamic and kinetic properties of self-interstitials in aluminum and nickel

The formation thermodynamics and migration properties of self-interstitials in aluminum and nickel are investigated as a function of temperature using atomistic simulation techniques and embedded-atom-type interatomic potentials. Molecular dynamics and nonequilibrium free-energy techniques are employed to investigate anharmonic effects on the H-O dumbbell formation properties. The equilibrium concentration of this defect is compared to those of vacancies and divacancies. The results are then analyzed in the framework of the interstitialcy model, according to which very high vibrational formation entropies should be expected for self-interstitials at high temperatures. The kinetics of self-interstitial migration is also investigated using different atomistic techniques, revealing the simultaneous activity of more than one distinct interstitial configuration as the temperature increases.731

Generalized approach to translating exercise tests and prescribing exercise

Although there is evidence supporting the benefit of regular exercise, and recommendations about exercise and physical activity, the process of individually prescribing exercise following exercise testing is more difficult. Guidelines like % heart rate (HR) reserve (HRR) require an anchoring maximal test and do not always provide a homogenous training experience. When prescribing HR on the basis of % HRR, rating of perceived exertion or Talk Test, cardiovascular/perceptual drift during sustained exercise makes prescription of the actual workload difficult. To overcome this issue, we have demonstrated a strategy for "translating" exercise test responses to steady state exercise training on the basis of % HRR or the Talk Test that appeared adequate for individuals ranging from cardiac patients to athletes. However, these methods depended on the nature of the exercise test details. In this viewpoint, we combine these data with workload expressed as Metabolic Equivalent Task (METs). We demonstrate that there is a regular stepdown between the METs during training to achieve the same degree of homeostatic disturbance during testing. The relationship was linear, was highly-correlated (r = 0.89), and averaged 71.8% (Training METs/Test METs). We conclude that it appears possible to generate a generalized approach to correctly translate exercise test responses to exercise training

Home advantage in the Winter Paralympic Games 1976–2014

Purpose: There is a limited amount of home advantage research concerned with winter sports. There is also a distinct lack of studies that investigate home advantage in the context of para-sport events. This paper addresses this gap in the knowledge by examining home advantage in the Winter Paralympic Games. Methods: Using a standardised measure of success, we compared the performances of host nations at home with their own performances away from home between 1976 and 2014. Both country level and individual sport level analysis is conducted for this time period. Comparisons are also drawn with the Winter Olympic Games since 1992, the point from which both the Winter Olympic Games and the Winter Paralympic Games have been hosted by the same nations and in the same years. Results: Clear evidence of a home advantage effect in the Winter Paralympic Games was found at country level. When examining individual sports, only alpine skiing and cross country skiing returned a significant home advantage effect. When comparing home advantage in the Winter Paralympic Games with the Winter Olympic Games for the last seven host nations (1992–2014), we found that home advantage was generally more pronounced (although not a statistically significant difference) in the case of the former. Conclusion: The causes of home advantage in the Winter Paralympic Games are unclear and should be investigated further

Hyperthermia and Thermosensitive Liposomes for Improved Delivery of Chemotherapeutic Drugs to Solid Tumors

Lipid-based nanocarriers or liposomes have been proven successful in the delivery of chemotherapeutic agents and are currently applied clinically in the treatment of various types of cancer. Liposomes offer the advantage of a high drug payload, decreased drug toxicity and enhanced drug accumulation at tumor sites. Increased accumulation is due to the relatively leaky tumor vasculature that allows liposome extravasation. Between different types of tumors and even within one tumor, vascular permeability and thus liposome extravasation may differ greatly. Furthermore, upon accumulation of liposomes in the tumor area, drug bioavailability is not guaranteed. At present, these are the major issues for clinically used liposomal drugs

Transition of plasmodium sporozoites into liver stage-like forms is regulated by the RNA binding protein pumilio

Many eukaryotic developmental and cell fate decisions that are effected post-transcriptionally involve RNA binding proteins as regulators of translation of key mRNAs. In malaria parasites (Plasmodium spp.), the development of round, non-motile and replicating exo-erythrocytic liver stage forms from slender, motile and cell-cycle arrested sporozoites is believed to depend on environmental changes experienced during the transmission of the parasite from the mosquito vector to the vertebrate host. Here we identify a Plasmodium member of the RNA binding protein family PUF as a key regulator of this transformation. In the absence of Pumilio-2 (Puf2) sporozoites initiate EEF development inside mosquito salivary glands independently of the normal transmission-associated environmental cues. Puf2- sporozoites exhibit genome-wide transcriptional changes that result in loss of gliding motility, cell traversal ability and reduction in infectivity, and, moreover, trigger metamorphosis typical of early Plasmodium intra-hepatic development. These data demonstrate that Puf2 is a key player in regulating sporozoite developmental control, and imply that transformation of salivary gland-resident sporozoites into liver stage-like parasites is regulated by a post-transcriptional mechanism

Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

From Oxford to Hawaii Ecophysiological Barriers Limit Human Progression in Ten Sport Monuments

In order to understand the determinants and trends of human performance evolution, we analyzed ten outdoor events among the oldest and most popular in sports history. Best performances of the Oxford-Cambridge boat race (since 1836), the channel crossing in swimming (1875), the hour cycling record (1893), the Elfstedentocht speed skating race (1909), the cross country ski Vasaloppet (1922), the speed ski record (1930), the Streif down-hill in Kitzbühel (1947), the eastward and westward sailing transatlantic records (1960) and the triathlon Hawaii ironman (1978) all follow a similar evolutive pattern, best described through a piecewise exponential decaying model (r2 = 0.95±0.07). The oldest events present highest progression curvature during their early phase. Performance asymptotic limits predicted from the model may be achieved in fourty years (2049±32 y). Prolonged progression may be anticipated in disciplines which further rely on technology such as sailing and cycling. Human progression in outdoor sports tends to asymptotic limits depending on physiological and environmental parameters and may temporarily benefit from further technological progresses

Number and mode of inheritance of QTL influencing backfat thickness on SSC2p in Sino-European pig pedigrees

<p>Abstract</p> <p>Background</p> <p>In the pig, multiple QTL associated with growth and fatness traits have been mapped to chromosome 2 (SSC2) and among these, at least one shows paternal expression due to the IGF2-intron3-G3072A substitution. Previously published results on the position and imprinting status of this QTL disagree between analyses from French and Dutch F2 crossbred pig populations obtained with the same breeds (Meishan crossed with Large White or Landrace).</p> <p>Methods</p> <p>To study the role of paternal and maternal alleles at the IGF2 locus and to test the hypothesis of a second QTL affecting backfat thickness on the short arm of SSC2 (SSC2p), a QTL mapping analysis was carried out on a combined pedigree including both the French and Dutch F2 populations, on the progeny of F1 males that were heterozygous (A/G) and homozygous (G/G) at the IGF2 locus. Simulations were performed to clarify the relations between the two QTL and to understand to what extent they can explain the discrepancies previously reported.</p> <p>Results</p> <p>The QTL analyses showed the segregation of at least two QTL on chromosome 2 in both pedigrees, i.e. the IGF2 locus and a second QTL segregating at least in the G/G F1 males and located between positions 30 and 51 cM. Statistical analyses highlighted that the maternally inherited allele at the IGF2 locus had a significant effect but simulation studies showed that this is probably a spurious effect due to the segregation of the second QTL.</p> <p>Conclusions</p> <p>Our results show that two QTL on SSC2p affect backfat thickness. Differences in the pedigree structures and in the number of heterozygous females at the IGF2 locus result in different imprinting statuses in the two pedigrees studied. The spurious effect observed when a maternally allele is present at the IGF2 locus, is in fact due to the presence of a second closely located QTL. This work confirms that pig chromosome 2 is a major region associated with fattening traits.</p