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"Hidalgo, Daniel"
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Star Wars year by year : a visual history
The definitive history of \"Star Wars\" chronicling four decades of the world of \"Star Wars\"; decade by decade, year-by-year, month-by-month. Everything is covered, from the influences and creation of all six \"Star Wars\" movies, to the toys, books and video games that have shaped the \"Star Wars\" dynasty. The month-by-month format is brought to life by images from the movies, TV series, comic books and more.
Book
An Equivalence Approach to Balance and Placebo Tests
Recent emphasis on credible causal designs has led to the expectation that scholars justify their research designs by testing the plausibility of their causal identification assumptions, often through balance and placebo tests. Yet current practice is to use statistical tests with an inappropriate null hypothesis of no difference, which can result in equating nonsignificant differences with significant homogeneity. Instead, we argue that researchers should begin with the initial hypothesis that the data are inconsistent with a valid research design, and provide sufficient statistical evidence in favor of a valid design. When tests are correctly specified so that difference is the null and equivalence is the alternative, the problems afflicting traditional tests are alleviated. We argue that equivalence tests are better able to incorporate substantive considerations about what constitutes good balance on covariates and placebo outcomes than traditional tests. We demonstrate these advantages with applications to natural experiments.
Journal Article
Norms versus Action: Why Voters Fail to Sanction Malfeasance in Brazil
We show that Brazilian voters strongly sanction malfeasant mayors when presented with hypothetical scenarios but take no action when given the same information about their own mayor. Partnering with the State Accounts Court of Pernambuco, we conducted a field experiment during the 2016 municipal elections in which the treatment group received information about official wrongdoing by their mayor. The treatment has no effect on self-reported voting behavior after the election, yet when informing about malfeasance in the context of a vignette experiment, we are able to replicate the strong negative effect found in prior studies. We argue that voters' behavior in the abstract reflects the comparatively strong norm against corruption in Brazil. Yet on Election Day, their behavior is constrained by factors such as attitudes toward local political dynasties and the greater salience of more pressing concerns like employment and health services.
Journal Article
Delayed vasopressor initiation is associated with increased mortality in patients with septic shock
Mortality rate for septic shock, despite advancements in knowledge and treatment, remains high. Treatment includes administration of broad-spectrum antibiotics and stabilization of the mean arterial pressure (MAP) with intravenous fluid resuscitation. Fluid-refractory shock warrants vasopressor initiation. There is a paucity of evidence regarding the timing of vasopressor initiation and its effect on patient outcomes.
This retrospective, single-centered, cohort study included patients with septic shock from January 2017 to July 2017. Time from initial hypotension to vasopressor initiation was measured for each patient. The primary outcome was 30-day mortality.
Of 530 patients screened,119 patients were included. There were no differences in baseline patient characteristics. Thirty-day mortality was higher in patients who received vasopressors after 6 h (51.1% vs 25%, p < .01). Patients who received vasopressors within the first 6 h had more vasopressor-free hours at 72 h (34.5 h vs 13.1, p = .03) and shorter time to MAP of 65 mmHg (1.5 h vs 3.0, p < .01).
Vasopressor initiation after 6 h from shock recognition is associated with a significant increase in 30-day mortality. Vasopressor administration within 6 h was associated with shorter time to achievement of MAP goals and higher vasopressor-free hours within the first 72 h.
•Delays in vasopressors lead to longer times to shock resolution.•Early initiation does not result in increases in cumulative vasopressor doses.•Higher mortality seen when vasopressors started after 6 h from hypotension.
Journal Article
Population snapshots predict early haematopoietic and erythroid hierarchies
The formation of red blood cells begins with the differentiation of multipotent haematopoietic progenitors. Reconstructing the steps of this differentiation represents a general challenge in stem-cell biology. Here we used single-cell transcriptomics, fate assays and a theory that allows the prediction of cell fates from population snapshots to demonstrate that mouse haematopoietic progenitors differentiate through a continuous, hierarchical structure into seven blood lineages. We uncovered coupling between the erythroid and the basophil or mast cell fates, a global haematopoietic response to erythroid stress and novel growth factor receptors that regulate erythropoiesis. We defined a flow cytometry sorting strategy to purify early stages of erythroid differentiation, completely isolating classically defined burst-forming and colony-forming progenitors. We also found that the cell cycle is progressively remodelled during erythroid development and during a sharp transcriptional switch that ends the colony-forming progenitor stage and activates terminal differentiation. Our work showcases the utility of linking transcriptomic data to predictive fate models, and provides insights into lineage development
in vivo
.
Single-cell transcriptomics, fate assays and a computational theory enable prediction of cell fates during haematopoiesis, discovery of regulators of erythropoiesis and reveal coupling between the erythroid, basophil and mast cell fates.
The hierarchy of blood cell lineages
Allon Klein, Merav Socolovsky and colleagues examine the emergence of distinct blood cell lineages from mouse haematopoietic progenitors. Their approach combines single-cell transcriptomics, cell fate potential assays and population balance analysis—a computational method for predicting cell fate probabilities from population snapshots. They use a new flow-cytometry strategy to sort cells with newly defined markers of erythroid differentiation and validate the findings at the single-cell level. The results show that differentiation is a continuous, albeit hierarchical, process. They also reveal that erythroid and mast cell fates are coupled, and that remodelling the expression of cell cycle regulators is very important as erythroid cells proceed to terminal differentiation.
Journal Article
Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing
NGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD).
A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken.
Genetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation.
The diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes.
Journal Article
Compulsory Voting Can Increase Political Inequality: Evidence from Brazil
One of the most robust findings on political institutions is that compulsory voting (CV) reduces the participation gap between poorer and wealthier voters. We present evidence that in Brazil, the largest country to use such a rule, CV increases inequality in turnout. We use individual-level data on 140 million Brazilian citizens and two age-based discontinuities to estimate the heterogeneous effects of CV by educational achievement, a strong proxy for socioeconomic status. Evidence from both thresholds shows that the causal effect of CV on turnout among the more educated is at least twice the size of the effect among those with less education. To explain this result, which is the opposite of what is predicted by the existing literature, we argue that nonmonetary penalties for abstention primarily affect middle- and upper-class voters and thus increase their turnout disproportionately. Survey evidence from a national sample provides evidence for the mechanism. Our results show that studies of CV should consider nonmonetary sanctions, as their effects can reverse standard predictions.
Journal Article
Dynamics of the 4D genome during in vivo lineage specification and differentiation
Mammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of specific contacts between enhancers and promoters. Our high-resolution data show that these enhancer-promoter interactions are not established prior to gene expression, but formed gradually during differentiation, concomitant with progressive upregulation of gene activity. Together, these results provide new insight into the close, interdependent relationship between chromatin architecture and gene regulation during development.
The relationship between regulatory elements, chromatin interactions and gene expression during development remains poorly understood. Here the authors present Tiled-C, a low-input 3C approach to study genome architecture at high resolution, and apply it to mouse erythroid differentiation in vivo, finding that enhancer-promoter interactions are formed gradually during differentiation, concomitant with progressive upregulation of gene activity.
Journal Article
H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death
DNA single-strand break (SSB) repair defects lead to hereditary neurological syndromes. Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1), is caused by the homozygous H493R mutation in tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that initiates the repair of DNA topoisomerase 1 (TOP1)-induced SSBs by unlinking the TOP1 peptide from the break. Although TDP1 also initiates the repair of TOP1-induced DNA double-strand breaks (DSBs) associated with transcription, the role of TOP1-induced DSBs in SCAN1 pathology remains unclear. Here, we have addressed the impact of the SCAN1/H493R mutation on the repair of TOP1-induced DSBs. We demonstrate that while TDP1 loss delays the repair of these breaks, SCAN1/H493R completely blocks it in RPE-1 quiescent cells. This blockage is specific to DSBs and is accompanied by a prolonged trapping of mutated TDP1 on DNA, but not of TOP1 cleavage complexes (TOP1cc). Intriguingly, the H263A inactivating mutation of TDP1, which accumulates TOP1cc, also blocks TOP1-induced DSB repair. Importantly, both SCAN1/H493R and H263A mutations exhibit genome instability and cell death. Moreover, we demonstrate that tyrosyl-DNA phosphodiesterase 2 (TDP2) can compensate for TDP1 loss in RPE-1 quiescent cells. Collectively, our data support the potential role of TOP1-induced DSBs as a main contributor to certain hereditary neurological syndromes.
Journal Article