477 research outputs found
A high throughput screen for next-generation leads targeting malaria parasite transmission
Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2â1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting maleâfemale and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population
La participaciĂłn laboral de las mujeres: un reto para el bienestar social.
Este trabajo ha sido posible gracias a la cobertura de los proyectos de investigaciĂłn âRiesgos y
oportunidades a lo largo del curso de la vida en las sociedades postindustrialesâ (CICYT. Sec2003-06799), dirigido por Esping-Andersen (Universitat Pompeu Fabra) y âNuevos Riesgos Sociales y Trayectorias de las PolĂticas del Bienestarâ (NURSOPOB) (MEC, Plan Nacional de I+D+I), dirigidos por Luis Moreno (Unidad de PolĂticas Comparadas, CSIC). Agradezco a ambos el apoyo que me han prestado para poderle llevar a cabo, y de forma muy particular, a Ana Arriba y Luis Moreno, por sus comentarios y colaboraciĂłn en versiones anteriores del mismo
Performance of the CMS Cathode Strip Chambers with Cosmic Rays
The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device
in the CMS endcaps. Their performance has been evaluated using data taken
during a cosmic ray run in fall 2008. Measured noise levels are low, with the
number of noisy channels well below 1%. Coordinate resolution was measured for
all types of chambers, and fall in the range 47 microns to 243 microns. The
efficiencies for local charged track triggers, for hit and for segments
reconstruction were measured, and are above 99%. The timing resolution per
layer is approximately 5 ns
Performance and Operation of the CMS Electromagnetic Calorimeter
The operation and general performance of the CMS electromagnetic calorimeter
using cosmic-ray muons are described. These muons were recorded after the
closure of the CMS detector in late 2008. The calorimeter is made of lead
tungstate crystals and the overall status of the 75848 channels corresponding
to the barrel and endcap detectors is reported. The stability of crucial
operational parameters, such as high voltage, temperature and electronic noise,
is summarised and the performance of the light monitoring system is presented
HTLV-1 infection in solid organ transplant donors and recipients in Spain
Background: HTLV-1 infection is a neglected disease, despite infecting 10â15 million people worldwide and
severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1
associated illnesses due to immunosuppression, screening is being widely considered in the transplantation
setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ
transplants in a survey conducted in Spain.
Methods: All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV
antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients
attended since the year 2008.
Results: A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312
(42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards
represented nearly 80%.
Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients.
Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from
Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed
within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be
removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in
dialysis but otherwise asymptomatic.
Conclusion: The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in
Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ
transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along
with the rapid development of subacute myelopath
Rapid subacute myelopathy following kidney transplantation from HTLV-1 donors: role of immunosuppresors and failure of antiretrovirals
Two kidney transplant recipients from a single donor became infected with HTLV-1 (human T-lymphotropic virus type 1) in Spain. One developed myelopathy 8 months following surgery despite early prescription of antiretroviral therapy. The allograft was removed from the second recipient at month 8 due to rejection and immunosuppressors discontinued. To date, 3 years later, this patient remains infected but asymptomatic. HTLV-1 infection was recognized retrospectively in the donor, a native Spaniard who had sex partners from endemic regions. Our findings call for a reappraisal of screening policies on donor-recipient organ transplantation. Based on the high risk of disease development and the large flux of persons from HTLV-1 endemic regions, pre-transplant HTLV-1 testing should be mandatory in Spain
Adjuvant chemotherapy for stage III colon cancer: Relative dose intensity and survival among veterans
Background: Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS). Methods: Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations. Results: 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p70% RDI at the first year (HR=0.58; 95% CI=0.37-0.89) and married status (HR=0.66; 95% CI=0.45-0.97) were associated with significantly decreased risk of death, while age â„75 (versus 55-64) (HR=2.06; 95% CI=1.25-3.40), Charlson Comorbidity Index (HR=1.17; 95% CI=1.06-1.30), T4 tumor status (versus T1/T2) (HR=5.88; 95% CI=2.69-12.9), N2 node status (HR=1.68; 95% CI=1.12-2.50) and bowel obstruction (HR=2.32, 95% CI=1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS. Conclusion: Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA
Erratum: âSearches for Gravitational Waves from Known Pulsars at Two Harmonics in 2015â2017 LIGO Dataâ (2019, ApJ, 879, 10)
Due to an error at the publisher, in the published article the number of pulsars presented in the paper is incorrect in multiple places throughout the text. Specifically, "222" pulsars should be "221." Additionally, the number of pulsars for which we have EM observations that fully overlap with O1 and O2 changes from "168" to "167." Elsewhere, in the machine-readable table of Table 1 and in Table 2, the row corresponding to pulsar J0952-0607 should be excised as well. Finally, in the caption for Table 2 the number of pulsars changes from "188" to "187.
Searches for gravitational waves from known pulsars at two harmonics in 2015-2017 LIGO data
International audienceWe present a search for gravitational waves from 222 pulsars with rotation frequencies âł10 Hz. We use advanced LIGO data from its first and second observing runs spanning 2015â2017, which provides the highest-sensitivity gravitational-wave data so far obtained. In this search we target emission from both the l = m = 2 mass quadrupole mode, with a frequency at twice that of the pulsarâs rotation, and the l = 2, m = 1 mode, with a frequency at the pulsar rotation frequency. The search finds no evidence for gravitational-wave emission from any pulsar at either frequency. For the l = m = 2 mode search, we provide updated upper limits on the gravitational-wave amplitude, mass quadrupole moment, and fiducial ellipticity for 167 pulsars, and the first such limits for a further 55. For 20 young pulsars these results give limits that are below those inferred from the pulsarsâ spin-down. For the Crab and Vela pulsars our results constrain gravitational-wave emission to account for less than 0.017% and 0.18% of the spin-down luminosity, respectively. For the recycled millisecond pulsar J0711â6830 our limits are only a factor of 1.3 above the spin-down limit, assuming the canonical value of 1038 kg m2 for the starâs moment of inertia, and imply a gravitational-wave-derived upper limit on the starâs ellipticity of 1.2 Ă 10â8. We also place new limits on the emission amplitude at the rotation frequency of the pulsars
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