Evaluation of α,β-unsaturated ketones as antileishmanial agents

In this study, we assessed the antileishmanial activity of 126 α,β-unsaturated ketones. The compounds NC901, NC884, and NC2459 showed high leishmanicidal activity for both the extracellular (50% effective concentration [EC(50)], 456 nM, 1,122 nM, and 20 nM, respectively) and intracellular (EC(50), 1,870 nM, 937 nM, and 625 nM, respectively) forms of Leishmania major propagated in macrophages, with little or no toxicity to mammalian cells. Bioluminescent imaging of parasite replication showed that all three compounds reduced the parasite burden in the murine model, with no apparent toxicity

17‐α estradiol ameliorates age‐associated sarcopenia and improves late‐life physical function in male mice but not in females or castrated males

Pharmacological treatments can extend mouse lifespan, but lifespan effects often differ between sexes. 17‐α estradiol (17aE2), a less feminizing structural isomer of 17‐β estradiol, produces lifespan extension only in male mice, suggesting a sexually dimorphic mechanism of lifespan regulation. We tested whether these anti‐aging effects extend to anatomical and functional aging—important in late‐life health—and whether gonadally derived hormones control aging responses to 17aE2 in either sex. While 17aE2 started at 4 months of age diminishes body weight in both sexes during adulthood, in late‐life 17aE2‐treated mice better maintain body weight. In 17aE2‐treated male mice, the higher body weight is associated with heavier skeletal muscles and larger muscle fibers compared with untreated mice during aging, while treated females have heavier subcutaneous fat. Maintenance of skeletal muscle in male mice is associated with improved grip strength and rotarod capacity at 25 months, in addition to higher levels of most amino acids in quadriceps muscle. We further show that sex‐specific responses to 17aE2—metabolomic, structural, and functional—are regulated by gonadal hormones in male mice. Castrated males have heavier quadriceps than intact males at 25 months, but do not respond to 17aE2, suggesting 17aE2 promotes an anti‐aging skeletal muscle phenotype similar to castration. Finally, 17aE2 treatment benefits can be recapitulated in mice when treatment is started at 16 months, suggesting that 17aE2 may be able to improve aspects of late‐life function even when started after middle age.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148386/1/acel12920_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148386/2/acel12920.pd

Técnicas de protección del patrimonio arqueológico excavado

Los yacimientos arqueológicos presentan problemas para la protección ambiental de los restos que se hallan en ellos. Los materiales de las excavaciones suelen ser adobe, tapiales o piedras, materiales que sufren una gran degradación a la intemperie. Generalmente durante el proceso de degradación las construcciones pierden en primer lugar la techumbre por lo que el agua de lluvia penetra directamente sobre el interior de los yacimientos, actuando sobre revestimientos, bajorrelieves, pinturas, etc. También la cota de los restos arqueológicos suele ser inferior a los niveles actuales de las calles, por lo que el agua freática o de lluvia termina acumulándose en ellos, e incluso el viento termina transportando basuras y materiales finos sobre los restos, ayudado especialmente por los a veces maleducados visitantes

PHANGS CO kinematics: disk orientations and rotation curves at 150 pc resolution

We present kinematic orientations and high resolution (150 pc) rotation curves for 67 main sequence star-forming galaxies surveyed in CO (2-1) emission by PHANGS-ALMA. Our measurements are based on the application of a new fitting method tailored to CO velocity fields. Our approach identifies an optimal global orientation as a way to reduce the impact of non-axisymmetric (bar and spiral) features and the uneven spatial sampling characteristic of CO emission in the inner regions of nearby galaxies. The method performs especially well when applied to the large number of independent lines-of-sight contained in the PHANGS CO velocity fields mapped at 1'' resolution. The high resolution rotation curves fitted to these data are sensitive probes of mass distribution in the inner regions of these galaxies. We use the inner slope as well as the amplitude of our fitted rotation curves to demonstrate that CO is a reliable global dynamical mass tracer. From the consistency between photometric orientations from the literature and kinematic orientations determined with our method, we infer that the shapes of stellar disks in the mass range of log($\rm M_{\star}(M_{\odot})$)=9.0-10.9 probed by our sample are very close to circular and have uniform thickness.Comment: 19 figures, 36 pages, accepted for publication in ApJ. Table of PHANGS rotation curves available from http://phangs.org/dat

Development of an in vitro periodontal biofilm model for assessing antimicrobial and host modulatory effects of bioactive molecules

Background: Inflammation within the oral cavity occurs due to dysregulation between microbial biofilms and the host response. Understanding how different oral hygiene products influence inflammatory properties is important for the development of new products. Therefore, creation of a robust host-pathogen biofilm platform capable of evaluating novel oral healthcare compounds is an attractive option. We therefore devised a multi-species biofilm co-culture model to evaluate the naturally derived polyphenol resveratrol (RSV) and gold standard chlorhexidine (CHX) with respect to anti-biofilm and anti-inflammatory properties.<p></p> Methods: An in vitro multi-species biofilm containing <i>S. mitis, F. nucleatum, P. Gingivalis</i> and <i>A. Actinomycetemcomitans</i> was created to represent a disease-associated biofilm and the oral epithelial cell in OKF6-TERT2. Cytotoxicity studies were performed using RSV and CHX. Multi-species biofilms were either treated with either molecule, or alternatively epithelial cells were treated with these prior to biofilm co-culture. Biofilm composition was evaluated and inflammatory responses quantified at a transcriptional and protein level.<p></p> Results: CHX was toxic to epithelial cells and multi-species biofilms at concentrations ranging from 0.01-0.2%. RSV did not effect multi-species biofilm composition, but was toxic to epithelial cells at concentrations greater than 0.01%. In co-culture, CHX-treated biofilms resulted in down regulation of the inflammatory chemokine IL-8 at both mRNA and protein level. RSV-treated epithelial cells in co-culture were down-regulated in the release of IL-8 protein, but not mRNA.<p></p> Conclusions: CHX possesses potent bactericidal properties, which may impact downstream inflammatory mediators. RSV does not appear to have bactericidal properties against multi-species biofilms, however it did appear to supress epithelial cells from releasing inflammatory mediators. This study demonstrates the potential to understand the mechanisms by which different oral hygiene products may influence gingival inflammation, thereby validating the use of a biofilm co-culture model.<p></p&gt

Propulsion Wheel Motor for an Electric Vehicle

A wheel assembly for an electric vehicle includes a wheel rim that is concentrically disposed about a central axis. A propulsion-braking module is disposed within an interior region of the wheel rim. The propulsion-braking module rotatably supports the wheel rim for rotation about the central axis. The propulsion-braking module includes a liquid cooled electric motor having a rotor rotatable about the central axis, and a stator disposed radially inside the rotor relative to the central axis. A motor-wheel interface hub is fixedly attached to the wheel rim, and is directly attached to the rotor for rotation with the rotor. The motor-wheel interface hub directly transmits torque from the electric motor to the wheel rim at a 1:1 ratio. The propulsion-braking module includes a drum brake system having an electric motor that rotates a cam device, which actuates the brake shoes

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual\u27s risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig\u27s potential to enhance clinical therapeutic innovation to improve human health. (Figure presented.)

An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma

: Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered