Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

Leber congenital amaurosis (LCA) and early‐onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10‐18 deletion

Two centuries of masting data for European beech and Norway spruce across the European continent

Tree masting is one of the most intensively studied ecological processes. It affects nutrient fluxes of trees, regeneration dynamics in forests, animal population densities, and ultimately influences ecosystem services. Despite a large volume of research focused on masting, its evolutionary ecology, spatial and temporal variability and environmental drivers are still matter of debate. Understanding the proximate and ultimate causes of masting at broad spatial and temporal scales will enable us to predict tree reproductive strategies and their response to changing environment. Here we provide broad spatial (distribution range-wide) and temporal (century) masting data for the two main masting tree species in Europe, European beech (Fagus sylvatica L.) and Norway spruce (Picea abies (L.) H. Karst.). We collected masting data from a total of 359 sources through an extensive literature review and from unpublished surveys. The dataset has a total of 1747 series and 18348 yearly observations from 28 countries and covering a time span of years 1677-2016 and 1791-2016 for beech and spruce, respectively. For each record, the following information is available: identification code; species; year of observation; proxy of masting (flower, pollen, fruit, seed, dendrochronological reconstructions); statistical data type (ordinal, continuous); data value; unit of measurement (only in case of continuous data); geographical location (country, Nomenclature of Units for Territorial Statistics NUTS-1 level, municipality, coordinates); first and last record year and related length; type of data source (field survey, peer reviewed scientific literature, grey literature, personal observation); source identification code; date when data were added to the database; comments. To provide a ready-to-use masting index we harmonized ordinal data into five classes. Furthermore, we computed an additional field where continuous series with length >4 years where converted into a five classes ordinal index. To our knowledge, this is the most comprehensive published database on species-specific masting behaviour. It is useful to study spatial and temporal patterns of masting and its proximate and ultimate causes, to refine studies based on tree-ring chronologies, to understand dynamics of animal species and pests vectored by these animals affecting human health, and it may serve as calibration-validation data for dynamic forest models.The paper was partly funded by the “Fondo di Ricerca Locale 2015-2016” of the University of Torino and by the Stiftelsen Stina Werners fond (grant SSWF 10-1/29-3 to I.D.)

Accreting Black Holes

This chapter provides a general overview of the theory and observations of black holes in the Universe and on their interpretation. We briefly review the black hole classes, accretion disk models, spectral state classification, the AGN classification, and the leading techniques for measuring black hole spins. We also introduce quasi-periodic oscillations, the shadow of black holes, and the observations and the theoretical models of jets.Comment: 41 pages, 18 figures. To appear in "Tutorial Guide to X-ray and Gamma-ray Astronomy: Data Reduction and Analysis" (Ed. C. Bambi, Springer Singapore, 2020). v3: fixed some typos and updated some parts. arXiv admin note: substantial text overlap with arXiv:1711.1025

The BINGO Project: III. Optical design and optimization of the focal plane

Context. The Baryon Acoustic Oscillations from Integrated Neutral Gas Observations (BINGO) telescope was designed to measure the fluctuations of the 21 cm radiation arising from the hyperfine transition of neutral hydrogen. It is also aimed at measuring the baryon acoustic oscillations (BAO) from such fluctuations, thereby serving as a pathfinder to future, deeper intensity mapping surveys. The requirements for the Phase 1 of the projects consider a large reflector system (two 40 m-class dishes in a crossed-Dragone configuration) illuminating a focal plane with 28 horns to measure the sky, with two circular polarizations in a drift scan mode to produce measurements of the radiation in intensity (I) as well as the circular (V) polarization. Aims. In this paper, we present the optical design for the instrument. We describe the optical arrangement of the horns in the focal plane to produce a homogeneous and well-sampled map after the end of Phase 1, as well as the intensity and polarization properties of the beams. Our analysis provides an optimal model for the location of the horns in the focal plane, producing a homogeneous and Nyquist-sampled map after the nominal survey time. Methods. We used the GRASP package to model the focal plane arrangement and performed several optimization tasks to arrive at the current configuration, including an estimation of the sidelobes corresponding to the diffraction patterns of the two mirrors. The final model for the focal plane was defined through a combination of neural network and other direct optimization methods. Results. We arrived at an optimal configuration for the optical system that includes the focal plane positioning and the beam behavior of the instrument. We present an estimate of the expected sidelobes both for intensity and polarization, as well as the effect of band averaging on the final sidelobes, as well as an estimation of the cross-polarization leakage for the final configuration. Conclusions. We conclude that the chosen optical design meets the requirements for the project in terms of polarization purity and area coverage as well as a homogeneity of coverage so that BINGO can perform a successful BAO experiment. We further conclude that the requirements on the placement and rms error on the mirrors are also achievable so that a successful experiment can be conducted

The BINGO project: II. Instrument description

Context. The measurement of diffuse 21-cm radiation from the hyperfine transition of neutral hydrogen (Hi signal) in different redshifts is an important tool for modern cosmology. However, detecting this faint signal with non-cryogenic receivers in single-dish telescopes is a challenging task. The BINGO (Baryon Acoustic Oscillations from Integrated Neutral Gas Observations) radio telescope is an instrument designed to detect baryonic acoustic oscillations (BAOs) in the cosmological Hi signal, in the redshift interval 0:127 ≤ z ≤ 0:449. Aims. This paper describes the BINGO radio telescope, including the current status of the optics, receiver, observational strategy, calibration, and the site. Methods. BINGO has been carefully designed to minimize systematics, being a transit instrument with no moving dishes and 28 horns operating in the frequency range 980 ≤ v ≤ 1260 MHz. Comprehensive laboratory tests were conducted for many of the BINGO subsystems and the prototypes of the receiver chain, horn, polarizer, magic tees, and transitions have been successfully tested between 2018-2020. The survey was designed to cover ∼13% of the sky, with the primary mirror pointing at declination δ = -15°. The telescope will see an instantaneous declination strip of 14:75. Results. The results of the prototype tests closely meet those obtained during the modeling process, suggesting BINGO will perform according to our expectations. After one year of observations with a 60% duty cycle and 28 horns, BINGO should achieve an expected sensitivity of 102μK per 9.33MHz frequency channel, one polarization, and be able to measure the Hi power spectrum in a competitive time frame

The BINGO project: I. Baryon acoustic oscillations from integrated neutral gas observations

Context. Observations of the redshifted 21-cm line of neutral hydrogen (HI) are a new and powerful window of observation that offers us the possibility to map the spatial distribution of cosmic HI and learn about cosmology. Baryon Acoustic Oscillations from Integrated Neutral Gas Observations (BINGO) is a new unique radio telescope designed to be one of the first to probe baryon acoustic oscillations (BAO) at radio frequencies. Aims. BINGO has two science goals: cosmology and astrophysics. Cosmology is the main science goal and the driver for BINGO's design and strategy. The key of BINGO is to detect the low redshift BAO to put strong constraints on the dark sector models and test the ICDM (cold dark matter) model. Given the versatility of the BINGO telescope, a secondary goal is astrophysics, where BINGO can help discover and study fast radio bursts (FRB) and other transients, as well as study Galactic and extragalactic science. In this paper, we introduce the latest progress of the BINGO project, its science goals, describing the scientific potential of the project for each goal and the new developments obtained by the collaboration. Methods. BINGO is a single dish transit telescope that will measure the BAO at low-z by making a 3D map of the HI distribution through the technique of intensity mapping over a large area of the sky. In order to achieve the project's goals, a science strategy and a specific pipeline for cleaning and analyzing the produced maps and mock maps was developed by the BINGO team, which we generally summarize here. Results. We introduce the BINGO project and its science goals and give a general summary of recent developments in construction, science potential, and pipeline development obtained by the BINGO Collaboration in the past few years. We show that BINGO will be able to obtain competitive constraints for the dark sector. It also has the potential to discover several FRBs in the southern hemisphere. The capacity of BINGO in obtaining information from 21-cm is also tested in the pipeline introduced here. Following these developments, the construction and observational strategies of BINGO have been defined. Conclusions. There is still no measurement of the BAO in radio, and studying cosmology in this new window of observations is one of the most promising advances in the field. The BINGO project is a radio telescope that has the goal to be one of the first to perform this measurement and it is currently being built in the northeast of Brazil. This paper is the first of a series of papers that describe in detail each part of the development of the BINGO project

Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial

Abstract Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.</jats:p

The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer

The availability of bromodomain and extra-terminal inhibitors (BETi) has enabled translational epigenetic studies in cancer. BET proteins regulate transcription by selectively recognizing acetylated lysine residues on chromatin. BETi compete with this process leading to both downregulation and upregulation of gene expression. Hypoxia enables progression of triple negative breast cancer (TNBC), the most aggressive form of breast cancer, partly by driving metabolic adaptation, angiogenesis and metastasis through upregulation of hypoxia-regulated genes (for example, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A). Responses to hypoxia can be mediated epigenetically, thus we investigated whether BETi JQ1 could impair the TNBC response induced by hypoxia and exert anti-tumour effects. JQ1 significantly modulated 44% of hypoxia-induced genes, of which two-thirds were downregulated including CA9 and VEGF-A. JQ1 prevented HIF binding to the hypoxia response element in CA9 promoter, but did not alter HIF expression or activity, suggesting some HIF targets are BET-dependent. JQ1 reduced TNBC growth in vitro and in vivo and inhibited xenograft vascularization. These findings identify that BETi dually targets angiogenesis and the hypoxic response, an effective combination at reducing tumour growth in preclinical studies