Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

Summary: The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma. : Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer. Keywords: medulloblastoma, protein-signaling, protein synthesis, MYC, TP53, proteome, phosphoproteom

High proportion of cactus species threatened with extinction

This is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record.Consejo Nacional de Ciencia y Tecnologí

Three Short Period Jupiters from TESS

We report the confirmation and mass determination of three hot Jupiters discovered by the Transiting Exoplanet Survey Satellite (TESS) mission: HIP 65Ab (TOI-129, TIC-201248411) is an ultra-short-period Jupiter orbiting a bright (V=11.1 mag) K4-dwarf every 0.98 days. It is a massive 3.213 +/- 0.078 Mjup planet in a grazing transit configuration with an impact parameter of b = 1.17 +0.10/-0.08. As a result the radius is poorly constrained, 2.03 +0.61/-0.49 Rjup. The planet's distance to its host star is less than twice the separation at which it would be destroyed by Roche lobe overflow. It is expected to spiral into HIP 65A on a timescale ranging from 80 Myr to a few gigayears, assuming a reduced tidal dissipation quality factor of Qs' = 10^7 - 10^9. We performed a full phase-curve analysis of the TESS data and detected both illumination- and ellipsoidal variations as well as Doppler boosting. HIP 65A is part of a binary stellar system, with HIP 65B separated by 269 AU (3.95 arcsec on sky). TOI-157b (TIC 140691463) is a typical hot Jupiter with a mass of 1.18 +/- 0.13 Mjup and a radius of 1.29 +/- 0.02 Rjup. It has a period of 2.08 days, which corresponds to a separation of just 0.03 AU. This makes TOI-157 an interesting system, as the host star is an evolved G9 sub-giant star (V=12.7). TOI-169b (TIC 183120439) is a bloated Jupiter orbiting a V=12.4 G-type star. It has a mass of 0.79 +/- 0.06 Mjup and a radius of 1.09 +0.08/-0.05 Rjup. Despite having the longest orbital period (P = 2.26 days) of the three planets, TOI-169b receives the most irradiation and is situated on the edge of the Neptune desert. All three host stars are metal rich with [Fe/H] ranging from 0.18 - 0.24.Comment: Published in A&

The impact of SARS-CoV-2 in dementia across Latin America : A call for an urgent regional plan and coordinated response

The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS-CoV-2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently call for a coordinated action plan, including the development of inexpensive mass testing and multilevel regional coordination for dementia care and related actions. Brain health diplomacy should lead to a shared and escalated response across the region, coordinating leadership, and triangulation between governments and international multilateral networks

Three Short Period Jupiters from TESS. HIP 65Ab, TOI-157b and TOI-169b

We report the confirmation and mass determination of three hot Jupiters discovered by the Transiting Exoplanet Survey Satellite (TESS) mission: HIP 65Ab (TOI-129, TIC-201248411) is an ultra-short-period Jupiter orbiting a bright (V = 11.1 mag) K4-dwarf every 0.98 days. It is a massive 3.213 ± 0.078 M_J planet in a grazing transit configuration with an impact parameter of b = 1.17_(−0.08)^(+0.10). As a result the radius is poorly constrained, 2.03_(−0.49)^(+0.61)R_J. The planet’s distance to its host star is less than twice the separation at which it would be destroyed by Roche lobe overflow. It is expected to spiral into HIP 65A on a timescale ranging from 80 Myr to a few gigayears, assuming a reduced tidal dissipation quality factor of Qs′ = 10⁷ − 10⁹. We performed a full phase-curve analysis of the TESS data and detected both illumination- and ellipsoidal variations as well as Doppler boosting. HIP 65A is part of a binary stellar system, with HIP 65B separated by 269 AU (3.95 arcsec on sky). TOI-157b (TIC 140691463) is a typical hot Jupiter with a mass of 1.18 ± 0.13 M_J and a radius of 1.29 ± 0.02 R_J. It has a period of 2.08 days, which corresponds to a separation of just 0.03 AU. This makes TOI-157 an interesting system, as the host star is an evolved G9 sub-giant star (V = 12.7). TOI-169b (TIC 183120439) is a bloated Jupiter orbiting a V = 12.4 G-type star. It has a mass of 0.79 ±0.06 M_J and a radius of 1.09_(−0.05)^(+0.08)R_J. Despite having the longest orbital period (P = 2.26 days) of the three planets, TOI-169b receives the most irradiation and is situated on the edge of the Neptune desert. All three host stars are metal rich with [Fe / H] ranging from 0.18 to 0.24

Optical and infrared flares from a transient Galactic soft gamma-ray repeater

Soft gamma-ray repeaters (SGRs) are a rare type of gamma-ray transient sources that are ocasionally detected as bursts in the high-energy sky. They are thought to be produced by magnetars, young neutron stars with very strong magnetic fields of the order of 10^(14-15) G. Only three such objects are known in our Galaxy, and a fourth one is associated with the supernova remnant N49 in the Large Magellanic Cloud. In none of these cases has an optical counterpart to either the gamma-ray flares or the quiescent source been identified. Here we present multi-wavelength observations of a puzzling source, SWIFT J195509+261406, for which we detected more than 40 flaring episodes in the optical band over a time span of 3 days, plus a faint infrared flare 11 days later, after which it returned to quiescence. We propose that SWIFT J195509+261406 is a member of a subgroup of SGRs for which the long-term X-ray emission is transient in nature. Furthermore, it is the first SGR for which bursts have been detected in the optical and near-infrared bands and maybe the link between the "persistent" SGRs and the dim isolated neutron stars.Comment: Version submitted to Nature on 31 Jan 2008. A substantially revised version of this work has been published in Nature, vol. 455 issue 7212 pp 506-509 under the title "Flares from a Galactic magnetar suggest a missing link to dim isolated neutron stars

Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists: A New Paradigm for Treating Sepsis and Other Diseases

Abstract. Sepsis remains the most common cause of death in intensive care units in the USA, with a current estimate of at least 750,000 cases per year, and 215,000 deaths annually. Despite extensive research still we do not quite understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury. Endotoxin (lipopolysaccharide from Gram-negative bacteria, or LPS) has been implicated as a major cause of this syndrome. Inflammatory shock as a consequence of LPS release remains a serious clinical concern. In humans, inflammatory responses to LPS result in the release of cytokines and other cell mediators from monocytes and macrophages, which can cause fever, shock, organ failure and death. A number of different approaches have been investigated to try to treat and/or prevent the septic shock associated with infections caused by Gram-negative bacteria, including blockage of one or more of the cytokines induced by LPS. Recently several novel amphipathic compounds have been developed as direct LPS antagonists at the LPS receptor, TLR4. This review article will outline the current knowledge on the TLR4-LPS synthesis and discuss the signaling, in vitro pre-clinical and in vivo clinical evaluation of TLR4 antagonists and their potential use in sepsis and a variety of diseases such as atherosclerosis as well as hepatic and renal malfunction. KEY WORDS: drug discovery; LPS; sepsis; toll-like receptor antagonists

The Magellan-TESS Survey I: Survey Description and Mid-Survey Results

One of the most significant revelations from Kepler is that roughly one-third of Sun-like stars host planets which orbit their stars within 100 days and are between the size of Earth and Neptune. How do these super-Earth and sub-Neptune planets form, what are they made of, and do they represent a continuous population or naturally divide into separate groups? Measuring their masses and thus bulk densities can help address these questions of their origin and composition. To that end, we began the Magellan-TESS Survey (MTS), which uses Magellan II/PFS to obtain radial velocity (RV) masses of 30 transiting exoplanets discovered by TESS and develops an analysis framework that connects observed planet distributions to underlying populations. In the past, RV measurements of small planets have been challenging to obtain due to the faintness and low RV semi-amplitudes of most Kepler systems, and challenging to interpret due to the potential biases in the existing ensemble of small planet masses from non-algorithmic decisions for target selection and observation plans. The MTS attempts to minimize these biases by focusing on bright TESS targets and employing a quantitative selection function and multi-year observing strategy. In this paper, we (1) describe the motivation and survey strategy behind the MTS, (2) present our first catalog of planet mass and density constraints for 25 TESS Objects of Interest (TOIs; 20 in our population analysis sample, five that are members of the same systems), and (3) employ a hierarchical Bayesian model to produce preliminary constraints on the mass-radius (M-R) relation. We find qualitative agreement with prior mass-radius relations but some quantitative differences (abridged). The the results of this work can inform more detailed studies of individual systems and offer a framework that can be applied to future RV surveys with the goal of population inferences.Comment: 101 pages (39 of main text and references, the rest an appendix of figures and tables). Submitted to AAS Journal

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

BACKGROUND Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia (N = 11,095), using a single image analysis protocol. METHODS We included T1-weighted data from 46 datasets (5,080 affected individuals and 6,015 controls) from the ENIGMA Consortium. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Analyses were also performed with respect to the use of antipsychotic medication and other clinical variables, as well as age and sex. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029). RESULTS Small average differences between cases and controls were observed for asymmetries in cortical thickness, specifically of the rostral anterior cingulate (d = −0.08, pFDR = 0.047) and the middle temporal gyrus (d = −0.07, pFDR = 0.048), both driven primarily by thinner cortices in the left hemisphere in schizophrenia. These asymmetries were not significantly associated with the use of antipsychotic medication or other clinical variables. Older individuals with schizophrenia showed a stronger average leftward asymmetry of pallidum volume than older controls (d = 0.08, pFDR = 9.0 × 10−3). The multivariate analysis revealed that 7% of the variance across all structural asymmetries was explained by case-control status (F = 1.87, p = 1.25 × 10−5). CONCLUSIONS Altered trajectories of asymmetrical brain development and/or lifespan asymmetry may contribute to schizophrenia pathophysiology. Small case-control differences of brain macro-structural asymmetry may manifest due to more substantial differences at the molecular, cytoarchitectonic or circuit levels, with functional relevance for lateralized cognitive processes