The 1989 and 2015 outbursts of V404 Cygni: a global study of wind-related optical features

The black hole transient V404 Cygni exhibited a bright outburst in June 2015 that was intensively followed over a wide range of wavelengths. Our team obtained high time resolution optical spectroscopy (~90 s), which included a detailed coverage of the most active phase of the event. We present a database consisting of 651 optical spectra obtained during this event, that we combine with 58 spectra gathered during the fainter December 2015 sequel outburst, as well as with 57 spectra from the 1989 event. We previously reported the discovery of wind-related features (P-Cygni and broad-wing line profiles) during both 2015 outbursts. Here, we build diagnostic diagrams that enable us to study the evolution of typical emission line parameters, such as line fluxes and equivalent widths, and develop a technique to systematically detect outflow signatures. We find that these are present throughout the outburst, even at very low optical fluxes, and that both types of outflow features are observed simultaneously in some spectra, confirming the idea of a common origin. We also show that the nebular phases depict loop patterns in many diagnostic diagrams, while P-Cygni profiles are highly variable on time-scales of minutes. The comparison between the three outbursts reveals that the spectra obtained during June and December 2015 share many similarities, while those from 1989 exhibit narrower emission lines and lower wind terminal velocities. The diagnostic diagrams presented in this work have been produced using standard measurement techniques and thus may be applied to other active low-mass X-ray binaries.Comment: Accepted for publication in MNRAS. 23 pages paper, plus a 9 pages appendix with extra tables and figures. 18 figures are included in the paper and 8 in the appendi

Discovery of the optical counterpart to the X-ray pulsar SAX J2103.5+4545

We report optical and infrared photometric and spectroscopic observations that identify the counterpart to the 358.6-s X-ray transient pulsar SAX J2103.5+4545 with a moderately reddened V=14.2 B0Ve star. This identification makes SAX J2103.5+4545 the Be/X-ray binary with the shortest orbital period known, Porb= 12.7 days. The amount of absorption to the system has been estimated to be Av=4.2+-0.3, which for such an early-type star implies a distance of about 6.5 kpc. The optical spectra reveal major and rapid changes in the strength and shape of the Halpha line. The Halpha line was initially observed as a double peak profile with the ratio of the intensities of the blue over the red peak greater than one (V/R > 1). Two weeks later this ratio reversed (V/R< 1). Subsequently, in less than a month, the emission ceased and Halpha appeared in absorption. This fast spectral variability is interpreted within the viscous decretion disc model and demonstrates the significant role of the neutron star on the evolution of the circumstellar disc around the Be star. The implications of the small orbit and moderate eccentricity on the spin period of the neutron star are discussed.Comment: 9 pages, 6 figures, accepted for publication in A&

Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted. (C) 2022 by American Society of Clinical Oncolog

Ornato e despojamento no mundo fabril

O artigo investiga algumas das tendências da arquitetura gerada por fábricas - galpões industriais, moradias, igrejas, escolas, clubes etc. -, erguida no Brasil entre as duas últimas décadas do século XIX e as primeiras do XX. Apoia-se em amplo inventário, como base para um esforço de análise que se propõe a identificar os temas e usos predominantes dos ornatos aplicados a construções geradas por fábricas, as referências historicistas mobilizadas e eventuais rupturas de signos arquitetônicos tipológicos, e, no limite, a abolição de ornatos e dos referidos signos. Assim, de um lado, trata da penetração da linguagem eclética nessas construções, investigando o repertório formal utilizado em diferentes tipologias. De outro, trata da simultânea difusão de uma estética tipicamente fabril, fundamentada em noções de economia, eficiência, utilidade e funcionalidade. Mostra como tais noções se expressam ora em uma simplificação ou ausência de ornatos, ora no uso de ornatos cujos temas remetem ao mundo das máquinas; às vezes, no distanciamento ou abandono de signos arquitetônicos tipológicos consagrados; ou, ainda, no emprego de materiais produzidos industrialmente e que se difundiram a partir, sobretudo, da arquitetura de fábricas.The article examines some aspects of the architecture created for factories - warehouses, houses, churches, schools, clubs etc. -, built in Brazil between the two last decades of the nineteenth century and early of the twentieth century. The research relies on extensive inventory, the basis on which an analysis effort is realized that aims to identify the themes and predominant use of ornament applied to constructions produced by factories, the historicist references mobilized and eventual disruption of typological architectural signs, and, ultimately, the elimination of ornament and of those signs. Therefore, on one side, it deals with the penetration of the eclectic language in these buildings, by examining the formal repertoire used in different typologies. On the other side, it deals with simultaneous diffusion of a typical manufacturing aesthetic, based on notions of economy, efficiency, utility and functionality. It shows how such notions are expressed in either a simplification or the lack of ornament, sometimes in the use of ornament whose themes relate to the world of machines, sometimes in the detachment or abandonment of embodied architectural typological signs, or even the use of industrially produced materials that have spread from mainly the architecture of factories

A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

A first update on mapping the human genetic architecture of COVID-19

peer reviewe