The aim of this study was to assess the power of the polygenic risk score (PRS) in estimating the overall genetic risk of women carrying germline
pathogenic variants (PVs) c.4035del or c.5266dup to ...develop breast (BC) or ovarian cancer (OC) due to additional genetic variations. In this study, PRSs previously developed from two joint models using summary statistics of age-at-onset (BayesW model) and case-control data (BayesRR-RC model) from a genome-wide association analysis (GWAS) were applied to 406 germline
PV (c.4035del or c.5266dup) carriers affected by BC or OC, compared with unaffected individuals. A binomial logistic regression model was used to assess the association of PRS with BC or OC development risk. We observed that the best-fitting BayesW PRS model effectively predicted the individual's BC risk (OR = 1.37; 95% CI = 1.03-1.81,
= 0.02905 with AUC = 0.759). However, none of the applied PRS models was a good predictor of OC risk. The best-fitted PRS model (BayesW) contributed to assessing the risk of developing BC for germline
PV (c.4035del or c.5266dup) carriers and may facilitate more precise and timely patient stratification and decision-making to improve the current BC treatment or even prevention strategies.
Some studies have found increased coronavirus disease-19 (COVID-19)-related morbidity and mortality in patients with primary antibody deficiencies. Immunization against COVID-19 may, therefore, be ...particularly important in these patients. However, the durability of the immune response remains unclear in such patients. In this study, we evaluated the cellular and humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in a cross-sectional study of 32 patients with primary antibody deficiency (
= 17 with common variable immunodeficiency (CVID) and
= 15 with selective IgA deficiency) and 15 healthy controls. Serological and cellular responses were determined using enzyme-linked immunosorbent assay and interferon-gamma release assays. The subsets of B and T lymphocytes were measured using flow cytometry. Of the 32 patients, 28 had completed the vaccination regimen with a median time after vaccination of 173 days (IQR = 142): 27 patients showed a positive spike-peptide-specific antibody response, and 26 patients showed a positive spike-peptide-specific T-cell response. The median level of antibody response in CVID patients (5.47 ratio (IQR = 4.08)) was lower compared to healthy controls (9.43 ratio (IQR = 2.13)). No difference in anti-spike T-cell response was found between the groups. The results of this study indicate that markers of the sustained SARS-CoV-2 spike-specific immune response are detectable several months after vaccination in patients with primary antibody deficiencies comparable to controls.
Atrial fibrillation (AF) is the most common arrhythmia and typically occurs in elderly patients with other cardiovascular and extracardiac diseases. However, up to 15% of AF develops without any ...related risk factors. Recently, the role of genetic factors has been highlighted in this particular form of AF.
The aims of this study were to determine the prevalence of pathogenic variants in early-onset AF in patients without known disease-related risk factors and to identify any structural cardiac abnormalities in these patients.
We conducted exome sequencing and interpretation in 54 risk factor-free early-onset AF patients and further validated our findings in a similar AF patient cohort from the UK Biobank.
Pathogenic/likely pathogenic variants were found in 13/54 (24%) patients. The variants were identified in cardiomyopathy-related and not arrhythmia-related genes. The majority of the identified variants were TTN gene truncating variants (TTNtvs) (9/13 (69%) patients). We also observed two TTNtvs founder variants in the analysed population-c.13696C>T p.(Gln4566Ter) and c.82240C>T p.(Arg27414Ter). Pathogenic/likely pathogenic variants were found in 9/107 (8%) individuals from an independent similar AF patient cohort from the UK Biobank. In correspondence with our Latvian patients, only variants in cardiomyopathy-associated genes were identified. In five (38%) of the thirteen Latvian patients with pathogenic/likely pathogenic variants, dilation of one or both ventricles was identified on a follow-up cardiac magnetic resonance scan.
We observed a high prevalence of pathogenic/likely pathogenic variants in cardiomyopathy-associated genes in patients with risk factor-free early-onset AF. Moreover, our follow-up imaging data indicate that these types of patients are at risk of developing ventricular dilation. Furthermore, we identified two TTNtvs founder variants in our Latvian study population.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Non-coding RNAs have already been linked to CVD development and progression. While microRNAs (miRs) have been ...well studied in blood samples, there is little data on tissue-specific miRs in cardiovascular relevant tissues and their relation to cardiovascular risk factors. Tissue-specific miRs derived from
(IMA) from 192 coronary artery disease (CAD) patients undergoing coronary artery bypass grafting (CABG) were analyzed. The aims of the study were 1) to establish a reference atlas which can be utilized for identification of novel diagnostic biomarkers and potential therapeutic targets, and 2) to relate these miRs to cardiovascular risk factors. Overall, 393 individual miRs showed sufficient expression levels and passed quality control for further analysis. We identified 17 miRs-miR-10b-3p, miR-10-5p, miR-17-3p, miR-21-5p, miR-151a-5p, miR-181a-5p, miR-185-5p, miR-194-5p, miR-199a-3p, miR-199b-3p, miR-212-3p, miR-363-3p, miR-548d-5p, miR-744-5p, miR-3117-3p, miR-5683 and miR-5701-significantly correlated with cardiovascular risk factors (correlation coefficient >0.2 in both directions,
-value (
< 0.006, false discovery rate (FDR) <0.05). Of particular interest, miR-5701 was positively correlated with hypertension, hypercholesterolemia, and diabetes. In addition, we found that miR-629-5p and miR-98-5p were significantly correlated with acute myocardial infarction. We provide a first atlas of miR profiles in IMA samples from CAD patients. In perspective, these miRs might play an important role in improved risk assessment, mechanistic disease understanding and local therapy of CAD.
Background:
Biofilms, when formed on the surfaces of water pipes, can be responsible for a wide range of water quality and operational problems. We sought to assess the bacterial and free-living ...protozoa (FLP) diversity, in relation to the presence of Legionnaire's disease-causing bacteria
Legionella pneumophila
(
L. pneumophila
) in 45 biofilms of hot water distribution system pipes of apartment buildings in Riga, the capital city of Latvia.
Results:
16S rRNA amplicon sequencing (metataxonomics) revealed that each biofilm contained 224 rather evenly distributed bacterial genera and that most common and most abundant were two genera, completely opposites in terms of their oxygen requirements: the obligately anaerobic
Thermodesulfovibrio
and the strictly aerobic
Phenylobacterium
. Water temperature and north-south axis (i.e., different primary water sources) displayed the most significant effect on the inter-sample variations, allowing us to re-construct three sub-networks (modules) of co-occurring genera, one involving (potentially FLP-derived)
Legionella
spp. Pangenome-based functional profile predictions suggested that all three may be dominated by pathways related to the development and maintenance of biofilms, including quorum sensing and nutrient transport, as well as the utilization of various energy sources, such as carbon and nitrogen. In our 18S rRNA amplicon sequencing data, potential hosts of
L. pneumophila
were detected in 11 out of 12 biofilm samples analyzed, however, in many cases, their relative abundance was very low (<1%). By validating our findings using culture-based methods, we detected
L. pneumophila
(serogroups 2, 3, 6 and 9) in nine (20%) biofilms, whereas FLP (mostly
Acanthamoeba, Vahlkampfidae
and
Vermamoeba
spp.) were present in six (~13%) biofilms. In two biofilms,
L. pneumophila
and its potential hosts were detected simultaneously, using culture-based methods.
Conclusions:
Overall, our study sheds light on the community diversity of hot water biofilms and predicts how several environmental factors, such as water temperature and source might shape it.
Pleiotrophin (Ptn) is strongly expressed by stromal cells which maintain HSCs. However, in vivo, Ptn deficiency does not alter steady-state hematopoiesis. However, knockdown of Ptn (PtnKD) in stromal ...cells increases production of hematopoietic progenitors as well as HSC activity in cocultures, suggesting that Ptn may have a role in HSC activation. Indeed, transplantations of wild-type (Ptn+/+) HSCs into Ptn−/− mice show increased donor cell production in serial transplantations and dominant myeloid regeneration caused by Ptn-dependent regulation of HSC repopulation behavior. This regulation of Lin−Kit+Sca1+ function is associated with increased proliferation and, on a molecular level, with up-regulated expression of cyclin D1 (Ccnd1) and C/EBPα (Cepba), but reduced of PPARγ. The known HSC regulator β-catenin is, however, not altered in the absence of Ptn. In conclusion, our results point to different Ptn-mediated regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. Moreover, our results support the idea that microenvironmental Ptn regulates hematopoietic regeneration through β-catenin–independent regulation of Ccnd1 and Cebpa.
Remaining a major healthcare concern with nearly 29 million confirmed cases worldwide at the time of writing, novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused more than ...920 thousand deaths since its outbreak in China, December 2019. First case of a person testing positive for SARS-CoV-2 infection within the territory of the Republic of Latvia was registered on 2nd of March 2020, 9 days prior to the pandemic declaration by WHO. Since then, more than 277,000 tests were carried out confirming a total of 1,464 cases of coronavirus disease 2019 (COVID-19) in the country as of 12th of September 2020. Rapidly reacting to the spread of the infection, an ongoing sequencing campaign was started mid-March in collaboration with the local testing laboratories, with an ultimate goal in sequencing as much local viral isolates as possible, resulting in first full-length SARS-CoV-2 isolate genome sequences from the Baltics region being made publicly available in early April. With 133 viral isolates representing ~9.1% of the total COVID-19 cases during the "first coronavirus wave" in the country (early March, 2020-mid-September, 2020) being completely sequenced as of today, here, we provide a first report on the genetic diversity of Latvian SARS-CoV-2 isolates.
•A simple and rapid UHPLC-HRMS multi-class polyphenol analysis method was developed.•Authentic raw mono- and polyfloral Latvian honey samples (n = 393) was analysed.•High-quality occurrence data of ...34 polyphenols in honey samples was obtained.
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The phenolic compound profiles of 393 raw mono- and polyfloral Latvian honey samples were investigated using a targeted ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) method. This strategy allowed simultaneous determination of the content of 11 phenolic acids, 18 flavonoids, 2 plant hormones, and 3 water-soluble vitamins in honey samples of botanically diverse origin, including buckwheat (Fagopyrum esculentum), heather (Calluna vulgaris), linden (Tilia cordata), and rapeseed (Brassica napus). Honey samples were collected directly from the beekeepers and were analyzed in their natural, raw form. A selective high-throughput analysis was implemented using sugaring-out assisted liquid-liquid extraction (SULLE) combined with the pentafluorophenyl (PFP) stationary phase. The robustness of the method was evaluated by using the design of experiments (DoE) approach and validated. Pooled quality control (QC) samples allowed monitoring of the method performance across the analysis sequences and principal components analysis (PCA) of QC samples resulted in a small amount of total variance in the total projection, indicating that the data were of good quality. The acquired occurrence data were compiled and compared with other studies. To the best of our knowledge, this study is the first of this scale and purpose, providing unique insights into the phenolic compound composition of fresh, regional European honey.
Hematopoietic stem cells (HSCs) are preserved in co-cultures with UG26-1B6 stromal cells or their conditioned medium. We performed a genome-wide study of gene expression changes of UG26-1B6 stromal ...cells in contact with Lineage− SCA-1+ KIT+ (LSK) cells. This analysis identified connective tissue growth factor (CTGF) to be upregulated in response to LSK cells. We found that co-culture of HSCs on CTGF knockdown stroma (shCtgf) shows impaired engraftment and long-term quality. Further experiments demonstrated that CD34− CD48− CD150+ LSK (CD34− SLAM) cell numbers from shCtgf co-cultures increase in G0 and senescence and show delayed time to first cell division. To understand this observation, a CTGF signaling network model was assembled, which was experimentally validated. In co-culture experiments of CD34− SLAM cells with shCtgf stromal cells, we found that SMAD2/3-dependent signaling was activated, with increasing p27Kip1 expression and downregulating cyclin D1. Our data support the view that LSK cells modulate gene expression in the niche to maintain repopulating HSC activity.
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•LSK cells induce the expression of CTGF in stromal cells•Stromal CTGF drives cell-cycle progression and proliferation of CD34− LSK cells•Decreased stromal CTGF activates TGFB signaling to decrease LSK cell cycle•Stromal CTGF improves maintenance of HSCs with long-term repopulating activity
Oostendorp and colleagues show that hematopoietic stem cells (HSCs) induce expression of connective tissue growth factor (CTGF) in stromal cells. A decrease in stromal CTGF impairs the maintenance of HSC activity in co-culture by rapid modulation of HSC signaling and cell-cycle entry. Thus, HSCs regulate their own cell cycle by modulating gene expression in stromal cells.
Abstract
Aims
Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of ...these contributions since they remain largely unclear.
Methods and results
Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques.
Conclusion
Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability.
Graphical Abstract
This study provides novel mechanistic insights into how acute mental stress fuels vascular inflammation and promotes plaque rupture. EC, endothelial cells; HPA, hypothalamic-pituitary-adrenal axis; MACS, macrophages; SAM, sympathetic-adrenal-medullary axis.
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