The evolution of hematopoietic cells under cancer therapy

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Asociación Española Contra el Cáncer (AECC) (GC16173697BIGA); Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain); CERCA (Generalitat de Catalunya); Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia; Barcelona Institute of Science and Technology (BIST); Hartwig Medical Foundation; Center for Personalized Cancer Treatment (CPCT).Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs

Googling Insomnia, Light, Metabolism, and Circadian. A Population Interest Simple Report

Exposure to light at night, insomnia, and disrupted circadian patterns could be considered risk factors for developing noncommunicable diseases. Understanding the awareness of the general population about the abovementioned factors could be essential to predict noncommunicable diseases. This report aimed to investigate the general community’s interest in circadian, insomnia, metabolism, and light using Google Trends, and to evaluate results from different geographic areas. Relative search volumes (RSVs) for the factors mentioned, filtered by the “Health” category, were collected between 2007 and 2021. Moreover, RSVs were analysed in five different European languages. Worldwide mean RSVs for “Circadian”, “Insomnia”, “Light”, and “Metabolism” during the study period were 2%, 13.4%, 62.2%, and 10%, respectively. In different developed countries, searching for light, insomnia, and metabolism were different, suggesting a variable level of awareness. Limited knowledge about the circadian pattern of human activities was detected. The highest correlation coefficient was calculated. Our results suggest the potential role of extensive data analysis in understanding the public interest and awareness about these risk factors. Moreover, it should be interpreted as the onset of stimulus for researchers to use comprehensible language for reaching comprehensive media coverage to prevent sleep and circadian system disturbances

Transcription of toll-like receptors 2, 3, 4 and 9, FoxP3 and Th17 cytokines in a susceptible experimental model of canine Leishmania infantum infection

Canine leishmaniosis (CanL) due to Leishmania infantum is a chronic zoonotic systemic disease resulting from complex interactions between protozoa and the canine immune system. Toll-like receptors (TLRs) are essential components of the innate immune system and facilitate the early detection of many infections. However, the role of TLRs in CanL remains unknown and information describing TLR transcription during infection is extremely scarce. The aim of this research project was to investigate the impact of L. infantum infection on canine TLR transcription using a susceptible model. The objectives of this study were to evaluate transcription of TLRs 2, 3, 4 and 9 by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) in skin, spleen, lymph node and liver in the presence or absence of experimental L. infantum infection in Beagle dogs. These findings were compared with clinical and serological data, parasite densities in infected tissues and transcription of IL-17, IL-22 and FoxP3 in different tissues in non-infected dogs (n = 10), and at six months (n = 24) and 15 months (n = 7) post infection. Results revealed significant down regulation of transcription with disease progression in lymph node samples for TLR3, TLR4, TLR9, IL-17, IL-22 and FoxP3. In spleen samples, significant down regulation of transcription was seen in TLR4 and IL-22 when both infected groups were compared with controls. In liver samples, down regulation of transcription was evident with disease progression for IL-22. In the skin, upregulation was seen only for TLR9 and FoxP3 in the early stages of infection. Subtle changes or down regulation in TLR transcription, Th17 cytokines and FoxP3 are indicative of the silent establishment of infection that Leishmania is renowned for. These observations provide new insights about TLR transcription, Th17 cytokines and Foxp3 in the liver, spleen, lymph node and skin in CanL and highlight possible markers of disease susceptibility in this model

ALMA Observations of Asteroid 3 Juno at 60 Kilometer Resolution

We present Atacama Large Millimeter/submillimeter Array (ALMA) 1.3 mm continuum images of the asteroid 3 Juno obtained with an angular resolution of 0.042 arcseconds (60 km at 1.97 AU). The data were obtained over a single 4.4 hr interval, which covers 60% of the 7.2 hr rotation period, approximately centered on local transit. A sequence of ten consecutive images reveals continuous changes in the asteroid's profile and apparent shape, in good agreement with the sky projection of the three-dimensional model of the Database of Asteroid Models from Inversion Techniques. We measure a geometric mean diameter of 259pm4 km, in good agreement with past estimates from a variety of techniques and wavelengths. Due to the viewing angle and inclination of the rotational pole, the southern hemisphere dominates all of the images. The median peak brightness temperature is 215pm13 K, while the median over the whole surface is 197pm15 K. With the unprecedented resolution of ALMA, we find that the brightness temperature varies across the surface with higher values correlated to the subsolar point and afternoon areas, and lower values beyond the evening terminator. The dominance of the subsolar point is accentuated in the final four images, suggesting a reduction in the thermal inertia of the regolith at the corresponding longitudes, which are possibly correlated to the location of the putative large impact crater. These results demonstrate ALMA's potential to resolve thermal emission from the surface of main belt asteroids, and to measure accurately their position, geometric shape, rotational period, and soil characteristics.Comment: 8 pages, 3 figures, 2 tables, accepted for publication in the Astrophysical Journal Letter

ALMA Long Baseline Observations of the Strongly Lensed Submillimeter Galaxy HATLAS J090311.6+003906 at z=3.042

We present initial results of very high resolution Atacama Large Millimeter/submillimeter Array (ALMA) observations of the $z$=3.042 gravitationally lensed galaxy HATLAS J090311.6+003906 (SDP.81). These observations were carried out using a very extended configuration as part of Science Verification for the 2014 ALMA Long Baseline Campaign, with baselines of up to 15 km. We present continuum imaging at 151, 236 and 290 GHz, at unprecedented angular resolutions as fine as 23 milliarcseconds (mas), corresponding to an un-magnified spatial scale of ~180 pc at z=3.042. The ALMA images clearly show two main gravitational arc components of an Einstein ring, with emission tracing a radius of ~1.5". We also present imaging of CO(10-9), CO(8-7), CO(5-4) and H2O line emission. The CO emission, at an angular resolution of ~170 mas, is found to broadly trace the gravitational arc structures but with differing morphologies between the CO transitions and compared to the dust continuum. Our detection of H2O line emission, using only the shortest baselines, provides the most resolved detection to date of thermal H2O emission in an extragalactic source. The ALMA continuum and spectral line fluxes are consistent with previous Plateau de Bure Interferometer and Submillimeter Array observations despite the impressive increase in angular resolution. Finally, we detect weak unresolved continuum emission from a position that is spatially coincident with the center of the lens, with a spectral index that is consistent with emission from the core of the foreground lensing galaxy.Comment: 9 pages, 5 figures and 3 tables, accepted for publication in the Astrophysical Journal Letter

First Results from High Angular Resolution ALMA Observations Toward the HL Tau Region

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations from the 2014 Long Baseline Campaign in dust continuum and spectral line emission from the HL Tau region. The continuum images at wavelengths of 2.9, 1.3, and 0.87 mm have unprecedented angular resolutions of 0.075 arcseconds (10 AU) to 0.025 arcseconds (3.5 AU), revealing an astonishing level of detail in the circumstellar disk surrounding the young solar analogue HL Tau, with a pattern of bright and dark rings observed at all wavelengths. By fitting ellipses to the most distinct rings, we measure precise values for the disk inclination (46.72pm0.05 degrees) and position angle (+138.02pm0.07 degrees). We obtain a high-fidelity image of the 1.0 mm spectral index ($\alpha$), which ranges from $\alpha\sim2.0$ in the optically-thick central peak and two brightest rings, increasing to 2.3-3.0 in the dark rings. The dark rings are not devoid of emission, we estimate a grain emissivity index of 0.8 for the innermost dark ring and lower for subsequent dark rings, consistent with some degree of grain growth and evolution. Additional clues that the rings arise from planet formation include an increase in their central offsets with radius and the presence of numerous orbital resonances. At a resolution of 35 AU, we resolve the molecular component of the disk in HCO+ (1-0) which exhibits a pattern over LSR velocities from 2-12 km/s consistent with Keplerian motion around a ~1.3 solar mass star, although complicated by absorption at low blue-shifted velocities. We also serendipitously detect and resolve the nearby protostars XZ Tau (A/B) and LkHa358 at 2.9 mm.Comment: 11 pages, 5 figures, 2 tables, accepted for publication in the Astrophysical Journal Letter

Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation

Introductions of West Nile Virus Strains to Mexico

Complete genome sequencing of 22 West Nile virus isolates suggested 2 independent introductions into Mexico. A previously identified mouse-attenuated glycosylation variant was introduced into southern Mexico through the southeastern United States, while a common US genotype appears to have been introduced incrementally into northern Mexico through the southwestern United States

An Overview of the 2014 ALMA Long Baseline Campaign

A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to ~15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from September to late November 2014, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at ~350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy.Comment: 11 pages, 7 figures, 2 tables; accepted for publication in the Astrophysical Journal Letters; this version with small changes to affiliation