| 1. |
- Glasbey, JC, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 2. |
- Sungnak, W., et al.
(författare)
-
SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes
- 2020
-
Ingår i: Nature Medicine. - : Nature Research. - 1078-8956 .- 1546-170X. ; 26:5, s. 681-687
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.
|
|
| 3. |
- Sikkema, Lisa, et al.
(författare)
-
An integrated cell atlas of the lung in health and disease
- 2023
-
Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
-
Tidskriftsartikel (refereegranskat)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
|
|
| 4. |
- Michel, M., et al.
(författare)
-
Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
-
Ingår i: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
-
Tidskriftsartikel (refereegranskat)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
|
|
| 5. |
|
|
| 6. |
- Armistead, B., et al.
(författare)
-
Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene's toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens. Granadaene, produced by Group B Streptococcus (GBS), is a long polyene lipid involved in cellular toxicity and hemolytic activity. Here, the authors synthesize and characterize granadaene-like compounds and show that a non-toxic analog diminishes GBS infection in mice when incorporated into a vaccine formulation.
|
|
| 7. |
- Rizik, David G., et al.
(författare)
-
Long-term Outcomes of Transcatheter Aortic Valve Replacement With the Lotus Valve vs CoreValve/EvolutR : A Secondary Analysis of the REPRISE III Randomized Clinical Trial
- 2022
-
Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 5:10, s. 1-11
-
Tidskriftsartikel (refereegranskat)abstract
- Importance: Long-term follow-up after transcatheter aortic valve replacement (TAVR) is of interest given that longitudinal data on mortality and durability of transcatheter heart valves are limited. The REPRISE III (Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System-Randomized Clinical Evaluation) randomized clinical trial compared the mechanically expanded Lotus valve with the self-expanding CoreValve/EvolutR TAVR platforms. Objective: To describe the final 5-year outcomes of the REPRISE III trial. Design, Setting, and Participants: This prespecified secondary analysis assessed the final 5-year clinical, functional, and echocardiographic outcomes of 912 patients from the REPRISE III trial, which was conducted at 55 centers in North America, Europe, and Australia between September 22, 2014, and December 24, 2015. Patients had high risk for aortic stenosis or severe or symptomatic aortic stenosis. Data were analyzed from September 22, 2014, to May 21, 2021. Intervention: Lotus valve or CoreValve/EvolutR TAVR platforms. Main Outcomes and Measures: Valve Academic Research Consortium-2 end points, hemodynamic measures, functional status, and health status were examined through the 5-year follow-up. Results: A total of 912 patients (mean [SD] age, 82.8 [7.3] years; 463 women [50.8%]) were randomized to either the Lotus valve group (n = 607) or CoreValve/EvolutR group (n = 305), with a baseline Society of Thoracic Surgeons risk score of 6.8%. Clinical follow-up data from the REPRISE III trial were available for 581 patients (95.7%) in the Lotus valve group and 285 patients (93.4%) in the CoreValve/EvolutR group. At 5 years, the cumulative event rate for all-cause mortality was 50.9% in the Lotus valve group vs 52.8% in the CoreValve/EvolutR group (P = .59). Disabling stroke was less frequent with the Lotus valve vs CoreValve/EvolutR (cumulative event rates, 8.3% vs 12.2%; P = .04), whereas the cumulative event rates for overall stroke were similar in both groups (14.1% vs 15.3%; P = .38). Insertion of a new permanent pacemaker (38.9% vs 27.3%; P < .001) and detection of prosthetic aortic valve thrombosis (5.8% vs 1.8%; P = .007) were more common in the Lotus valve group than in the CoreValve/EvolutR group. A smaller proportion of patients who received the Lotus valve experienced valve malpositioning (0% vs 2.6%; P < .001) and required the use of a second valve (1.0% vs 3.8%; P < .001) during the procedure compared with those who received the CoreValve/EvolutR. Compared with the Lotus valve group, the CoreValve/EvolutR group had a significantly lower mean (SD) aortic gradient (7.8 [4.2] mm Hg vs 12.6 [6.7] mm Hg; P < .001) and larger valve areas (1.57 [0.56] cm2 vs 1.42 [0.42] cm2; P = .10). After 5 years, the proportion of patients with moderate or greater paravalvular leak was not significantly higher with the CoreValve/EvolutR than with the Lotus valve (1.9% vs 0%; P = .31); however, the proportion of patients with mild paravalvular leak was higher in the CoreValve/EvolutR group compared with the Lotus valve group (23.1% vs 7.8%; P = .006). Long-term, similar improvements in New York Heart Association class and Kansas City Cardiomyopathy Questionnaire score were observed in both groups. Conclusions and Relevance: The REPRISE III trial found that, at 5 years, the clinical outcomes of the Lotus valve were comparable to those of the CoreValve/EvolutR and that the Lotus valve was safe and effective. Trial Registration: ClinicalTrials.gov Identifier: NCT02202434.
|
|
| 8. |
- Coleman, M., et al.
(författare)
-
Hyaluronidase Impairs Neutrophil Function and Promotes Group B Streptococcus Invasion and Preterm Labor in Nonhuman Primates
- 2021
-
Ingår i: Mbio. - 2150-7511. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Invasive bacterial infections during pregnancy are a major risk factor for preterm birth, stillbirth, and fetal injury. Group B streptococci (GBS) are Gram-positive bacteria that asymptomatically colonize the lower genital tract but infect the amniotic fluid and induce preterm birth or stillbirth. Experimental models that closely emulate human pregnancy are pivotal for the development of successful strategies to prevent these adverse pregnancy outcomes. Using a unique nonhuman primate model that mimics human pregnancy and informs temporal events surrounding amniotic cavity invasion and preterm labor, we show that the animals inoculated with hyaluronidase (HylB)-expressing GBS consistently exhibited microbial invasion into the amniotic cavity, fetal bacteremia, and preterm labor. Although delayed cytokine responses were observed at the maternal-fetal interface, increased prostaglandin and matrix metalloproteinase levels in these animals likely mediated pre term labor. HylB-proficient GBS dampened reactive oxygen species production and exhibited increased resistance to neutrophils compared to an isogenic mutant. Together, these findings demonstrate how a bacterial enzyme promotes GBS amniotic cavity invasion and preterm labor in a model that closely resembles human pregnancy. IMPORTANCE Group B streptococci (GBS) are bacteria that commonly reside in the female lower genital tract as asymptomatic members of the microbiota. However, during pregnancy, GBS can infect tissues at the maternal-fetal interface, leading to preterm birth, stillbirth, or fetal injury. Understanding how GBS evade host defenses during pregnancy is key to developing improved preventive therapies for these adverse outcomes. In this study, we used a unique nonhuman primate model to show that an enzyme secreted by GBS, hyaluronidase (HylB) promotes bacterial invasion into the amniotic cavity and fetus. Although delayed immune responses were seen at the maternal-fetal interface, animals infected with hyaluronidase-expressing GBS exhibited premature cervical ripening and preterm labor. These observations reveal that HylB is a crucial GBS virulence factor that promotes bacterial invasion and preterm labor in a pregnancy model that closely emulates human pregnancy. Therefore, hyaluronidase inhibitors may be useful in therapeutic strategies against ascending GBS infection.
|
|
| 9. |
- Kosmidou, Ioanna, et al.
(författare)
-
Sex-Specific Outcomes of Transcatheter Mitral-Valve Repair and Medical Therapy for Mitral Regurgitation in Heart Failure.
- 2021
-
Ingår i: JACC. Heart failure. - 2213-1787.
-
Tidskriftsartikel (refereegranskat)abstract
- This study sought to assess the sex-specific outcomes in patients with heart failure (HF) with 3+ and 4+ secondary mitral regurgitation (SMR) treated with transcatheter mitral valve repair (TMVr) plus guideline-directed medical therapy (GDMT) versus GDMT alone in the COAPT trial.The impact of sex in patients with HF and severe SMR treated with TMVr with the MitraClip compared with GDMT alone is unknown.Patients were randomized 1:1 to TMVr versus GDMT alone. Two-year outcomes were examined according to sex.Among 614 patients, 221 (36.0%) were women. Women were younger than men and had fewer comorbidities, but reduced quality of life and functional capacity at baseline. In a joint frailty model accounting for the competing risk of death, the 2-year cumulative incidence of the primary endpoint of all HF hospitalizations (HFH) was higher in men compared with women treated with GDMT alone. However, the relative reduction in HFHs with TMVr was greater in men (HR: 0.43; 95% CI: 0.34-0.54) than women (HR: 0.78; 95% CI: 0.57-1.05) (Pinteraction = 0.002). A significant interaction between TMVr versus GDMT alone treatment and time was present for all HFHs in women (HR: 0.57; 95% CI: 0.39-0.84, and HR: 1.39; 95% CI: 0.83-2.33 between 0-1 year and 1-2 years after randomization, respectively, Pinteraction = 0.007) but not in men (HR: 0.48; 95% CI: 0.36-0.64, and HR: 0.33; 95% CI: 0.21-0.51; Pinteraction = 0.16). Female sex was independently associated with a lower adjusted risk of death at 2 years (HR: 0.64; 95% CI: 0.46-0.90; P = 0.011). TMVr consistently reduced 2-year mortality compared with GDMT alone, irrespective of sex (Pinteraction = 0.99).In the COAPT trial, TMVr with the MitraClip resulted in improved clinical outcomes compared with GDMT alone, irrespective of sex. However, the impact of TMVr in reducing HFH was less pronounced in women compared with men beyond the first year after treatment. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Tria] [COAPT]) NCT01626079.
|
|
| 10. |
- Demontis, D, et al.
(författare)
-
Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder
- 2021
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 576-
-
Tidskriftsartikel (refereegranskat)abstract
- Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.
|
|
