Long-range ballistic propagation of carriers in methylammonium lead iodide perovskite thin films

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. The performance of semiconductor devices is fundamentally governed by charge-carrier dynamics within the active materials1–6. Although advances have been made towards understanding these dynamics under steady-state conditions, the importance of non-equilibrium phenomena and their effect on device performances remains elusive7,8. In fact, the ballistic propagation of carriers is generally considered to not contribute to the mechanism of photovoltaics (PVs) and light-emitting diodes, as scattering rapidly disrupts such processes after carrier generation via photon absorption or electric injection9. Here we characterize the spatiotemporal dynamics of carriers immediately after photon absorption in methylammonium lead iodide perovskite films using femtosecond transient absorption microscopy (fs-TAM) with a 10 fs temporal resolution and 10 nm spatial precision. We found that non-equilibrium carriers propagate ballistically over 150 nm within 20 fs of photon absorption. Our results suggest that in a typical perovskite PV device operating under standard conditions, a large fraction of carriers can reach the charge collection layers ballistically. The ballistic transport distance appears to be limited by energetic disorder within the materials, probably due to disorder-induced scattering. This provides a direct route towards optimization of the ballistic transport distance via improvements in materials and by minimizing the energetic disorder. Our observations reveal an unexplored regime of carrier transport in perovskites, which could have important consequences for device performance

The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals

INTRODUCTION AND OBJECTIVES: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. Mutations in CSRP3 have been associated with HCM, but evidence supporting pathogenicity is inconclusive. In this study, we describe an HCM cohort with a missense variant in CSRP3 (p.Cys150Tyr) with supporting evidence for pathogenicity and a description of the associated phenotype. METHODS: CSRP3 was sequenced in 6456 index cases with a diagnosis of HCM and in 5012 probands with other cardiomyopathies. In addition, 3372 index cases with hereditary cardiovascular disorders other than cardiomyopathies (mainly channelopathies and aortopathies) were used as controls. RESULTS: The p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6456 HCM probands, and it was not identified in patients with other cardiomyopathies (p < 0.0001) or in our control population (p < 0.0001). Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype. Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease. The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm. The variant showed highly age-dependent penetrance. After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients. CONCLUSIONS: The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene

BACKGROUND: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. METHODS: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). RESULTS: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). CONCLUSIONS: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes

Reporting of Methodologic Information on Trial Registries for Quality Assessment: A Study of Trial Records Retrieved from the WHO Search Portal

Background: Although randomized clinical trials (RCTs) are considered the gold standard of evidence, their reporting is often suboptimal. Trial registries have the potential to contribute important methodologic information for critical appraisal of study results. Methods and Findings: The objective of the study was to evaluate the reporting of key methodologic study characteristics in trial registries. We identified a random sample (n = 265) of actively recruiting RCTs using the World Health Organization International Clinical Trials Registry Platform (ICTRP) search portal in 2008. We assessed the reporting of relevant domains from the Cochrane Collaboration’s ‘Risk of bias’ tool and other key methodological aspects. Our primary outcomes were the proportion of registry records with adequate reporting of random sequence generation, allocation concealment, blinding, and trial outcomes. Two reviewers independently assessed each record. Weighted overall proportions in the ICTRP search portal for adequate reporting of sequence generation, allocation concealment, blinding (including and excluding open label RCT) and primary outcomes were 5.7% (95% CI 3.0–8.4%), 1.4% (0–2.8%), 41% (35–47%), 8.4% (4.1–13%), and 66% (60–72%), respectively. The proportion of adequately reported RCTs was higher for registries that used specific methodological fields for describing methods of randomization and allocation concealment compared to registries that did not. Concerning other key methodological aspects, weighted overall proportions of RCTs with adequately reported items were as follows: eligibility criteria (81%), secondary outcomes (46%), harm (5%) follow-up duration (62%), description of the interventions (53%) and sample size calculation (1%). Conclusions: Trial registries currently contain limited methodologic information about registered RCTs. In order to permit adequate critical appraisal of trial results reported in journals and registries, trial registries should consider requesting details on key RCT methods to complement journal publications. Full protocols remain the most comprehensive source of methodologic information and should be made publicly available

Litterfall, litter decomposition and associated nutrient fluxes in Pinus halepensis: influence of tree removal intensity in a Mediterranean forest

The online version of this article (doi:10.1007/s10342-015-0893-z) contains supplementary material, which is available to authorized users[EN] Our knowledge about the influence of silvicultural treatments on nutrient cycling processes in Mediterranean forests is still limited. Four levels of tree removal were compared in an Aleppo pine forest in eastern Spain to determine the effects on litterfall, litter decomposition and the associated nutrient fluxes after 12 years. Removal treatments included clearfelling, two shelterwood intensities (60 and 75 % of basal area removed) and untreated controls. Twelve years later, the basal area removed still explained 60 % of litterfall mass variance and 60 % of C, 52 % of N, 45 % of P, 17 % of K, 47 % of Ca and 60 % of Mg return variances. Litter decomposed somewhat more slowly in clearfellings compared to controls (p = 0.049), accumulated more Ca and released less K compared to the other three treatments. This was explained by contamination with mineral particles due to the poorly developed O horizon in clearfellings. We conclude that the management practices reduced the nutrient return via litterfall, but the nutrient release through decomposition seems poorly sensitive to canopy disturbance. In order to accurately quantify the harvesting impacts on nutrient cycling in this Mediterranean forest system, it is necessary to measure the litterfall of the understory layer.This work has been supported by a fellowship from the Generalitat Valenciana, Conselleria de Educacion, Formacion y Empleo awarded to L. Lado-Monserrat (BFPI/2008/041). Silvicultural treatments were carried out by the Mediterranean Centre for Environmental Studies (CEAM) through programme "I + D en relacion con la restauracion de la cubierta vegetal y otros aspectos de investigacion forestal". Dataloggers and probes were provided by the Generalitat Valenciana through Project "Efecto de diferentes sistemas de aclareo de masa forestal sobre la disponibilidad de agua, nutrientes y la regeneracion de la masa arborea y arbustiva en parcelas de pinar" (GV06/126). We acknowledge Joana Oliver, Ruth M. Tavera and Daniel Fortanet for their help in the laboratory and in the field. The authors wish to thank Francisco Galiana for his assistance, including help in fieldwork and providing information about the experimental design of the silvicultural treatments. Thanks also go to Rafael Herrera from the Centro de Ecologia, Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela and two anonymous reviewers for critically reviewing the manuscript.Lado Monserrat, L.; Lidón, A.; Bautista, I. (2015). Litterfall, litter decomposition and associated nutrient fluxes in Pinus halepensis: influence of tree removal intensity in a Mediterranean forest. 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Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

<p>Abstract</p> <p>Background</p> <p><it>MyBPC3 </it>mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of <it>MyBPC3 </it>mutations and determine their associated clinical characteristics in our patients.</p> <p>Methods</p> <p>Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the <it>MyBPC3 </it>gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.</p> <p>Results</p> <p>16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with <it>MYH7 </it>mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].</p> <p>Conclusions</p> <p>Mutations in <it>MyBPC3 </it>are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of <it>MyBPC3 </it>mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.</p

Nuclear Translocation of β-Catenin during Mesenchymal Stem Cells Differentiation into Hepatocytes Is Associated with a Tumoral Phenotype

Wnt/β-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/β-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, β-catenin nuclear translocation, up-regulation of genes related to the Wnt/β-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/β-catenin inactivation. Hepatocytes with nuclear translocation of β-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase β-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin β-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/β-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy

BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels