| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Ruilope, LM, et al.
(author)
-
Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
-
In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
-
Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Callaway, EM, et al.
(author)
-
A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
-
Journal article (peer-reviewed)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
|
|
| 11. |
|
|
| 12. |
- Menden, MP, et al.
(author)
-
Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
-
Journal article (peer-reviewed)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
|
|
| 13. |
|
|
| 14. |
- Ren, WC, et al.
(author)
-
Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma
- 2018
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 131:24, s. 2670-2681
-
Journal article (peer-reviewed)abstract
- Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Clark, DW, et al.
(author)
-
Associations of autozygosity with a broad range of human phenotypes
- 2019
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
-
Journal article (peer-reviewed)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
|
|
| 18. |
|
|
| 19. |
- Fang, MY, et al.
(author)
-
T Cell Repertoire Abnormality in Immunodeficiency Patients with DNA Repair and Methylation Defects
- 2022
-
In: Journal of clinical immunology. - : Springer Science and Business Media LLC. - 1573-2592 .- 0271-9142. ; 42:2, s. 375-393
-
Journal article (peer-reviewed)abstract
- Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B,ZBTB24,RAG1,DCLRE1C, andJAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients withDNMT3BandZBTB24mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
- Huang, HP, et al.
(author)
-
Long latency of evoked quantal transmitter release from somata of locus coeruleus neurons in rat pontine slices
- 2007
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 104:4, s. 1401-1406
-
Journal article (peer-reviewed)abstract
- The locus coeruleus (LC) harbors a compact group of noradrenergic cell bodies projecting to virtually all parts of the central nervous system. By using combined measurements of amperometry and patch-clamp, quantal vesicle release of noradrenaline (NA) was detected as amperometric spikes, after depolarization of the LC neurons. After a pulse depolarization, the average latency of amperometric spikes was 1,870 ms, whereas the latency of glutamate-mediated excitatory postsynaptic currents was 1.6 ms. A substantial fraction of the depolarization-induced amperometric spikes originated from the somata. In contrast to glutamate-mediated excitatory postsynaptic currents, NA secretion was strongly modulated by the action potential frequency (0.5–50 Hz). Somatodendritic NA release from LC upon enhanced cell activity produced autoinhibition of firing and of NA release. We conclude that, in contrast to classic synaptic transmission, quantal NA release from LC somata is characterized by a number of distinct properties, including long latency and high sensitivity to action potential frequency.
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
- Mishra, A, et al.
(author)
-
Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
-
Journal article (peer-reviewed)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
- Wu, K, et al.
(author)
-
Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
- 2015
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 10131-
-
Journal article (peer-reviewed)abstract
- The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.
|
|
| 31. |
- Wu, ZC, et al.
(author)
-
Tumor suppressor ZHX2 inhibits NAFLD-HCC progression via blocking LPL-mediated lipid uptake
- 2020
-
In: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 27:5, s. 1693-1708
-
Journal article (peer-reviewed)abstract
- Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD–HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD–HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
- Cao, LY, et al.
(author)
-
Deciphering Molecular Mechanism Underlying Self-Flocculation of Zymomonas mobilis for Robust Production
- 2022
-
In: Applied and environmental microbiology. - : American Society for Microbiology. - 1098-5336 .- 0099-2240. ; 88:9, s. e0239821-
-
Journal article (peer-reviewed)abstract
- Stress tolerance is a prerequisite for microbial cell factories to be robust in production, particularly for biorefinery of lignocellulosic biomass to produce biofuels, bioenergy, and bio-based chemicals for sustainable socioeconomic development, since various inhibitors are released during the pretreatment to destroy the recalcitrant lignin-carbohydrate complex for sugar production through enzymatic hydrolysis of the cellulose component, and their detoxification is too costly for producing bulk commodities. Although tolerance to individual stress has been intensively studied, the progress seems less significant since microbial cells are inevitably suffering from multiple stresses simultaneously under production conditions.
|
|
| 40. |
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
- Ji, FL, et al.
(author)
-
The Genetic Architecture of the Clustering of Cardiometabolic Risk Factors: A Study of 8- to 17-Year-Old Chinese Twins
- 2020
-
In: Twin research and human genetics : the official journal of the International Society for Twin Studies. - : Cambridge University Press (CUP). - 1832-4274. ; 23:5, s. 283-291
-
Journal article (peer-reviewed)abstract
- We explored the genetic architecture of metabolic risk factors of cardiovascular diseases (CVDs) and their clustering in Chinese boys and girls. Seven metabolic traits (body mass index [BMI], waist circumference [WC], systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol [TC], triglyceride [TG], and uric acid [UA]) were measured in a sample of 1016 twins between 8 and 17 years of age, recruited from the Qingdao Twin Registry. Cholesky, independent pathway, and common pathway models were used to identify the latent genetic structure behind the clustering of these metabolic traits. Genetic architecture of these metabolic traits was largely similar in boys and girls. The highest heritability was found for BMI (a2 = 0.63) in boys and TC (a2 = .69) in girls. Three heritable factors, adiposity (BMI and WC), blood pressure (SBP and DBP), and metabolite factors (TC, TG, and UA), which formed one higher-order latent phenotype, were identified. Latent genetic, common environmental, and unique environmental factors indirectly impacted the three factors through one single latent factor. Our results suggest that there is one latent factor influencing several metabolic traits, which are known risk factors of CVDs in young Chinese twins. Latent genetic, common environmental, and unique environmental factors indirectly imposed on them. These results inform strategies for gene pleiotropic discovery and intervening of CVD risk factors during childhood and adolescence.
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
- Loley, C, et al.
(author)
-
No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis
- 2016
-
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 35278-
-
Journal article (peer-reviewed)abstract
- In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
|
|
| 49. |
|
|
| 50. |
|
|
