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In this review, we focus on the role of MAMs in the regulation of AD pathologies and the potential molecular mechanisms related to MAM-mediated pathological changes in AD. An enhanced recognition of the preclinical pathogenesis in AD could provide new therapeutic strategies, shifting the modality from treatment to prevention.Although the numbers of patients affected by cardiorenal syndrome keeps increasing, we lack a complete understanding of the molecular pathways involved in its development and progression. Nitric oxide synthase (NOS) may play a role in cardiorenal syndrome, particularly cardiorenal syndrome type 2 (CRS2). However, complexities and paradoxical clinical findings have limited translation. In the current Clinical Science, Giam et al. (Clinical Science (2020) 134, 2755-2769) highlight the role of a key NOS substrate transporter, the cationic amino acid transporter-1, in preserving renal function in CRS2. In this commentary, we introduce the cardiorenal syndrome and the putative role that nitric oxide (NO) may play in the development of this disease and discuss the exciting findings of Giam et al. (Clinical Science (2020) 134, 2755-2769) and their tantalizing translational implications.Most scientific investigators conduct well-designed and controlled preclinical experiments generating data that are difficult to explain, contrast with existing scientific dogma, or represent a perceived negative result. It is common for these findings to remain hidden away in a drawer from the greater scientific community. However, these unseen results can lead to publication bias, have the potential to significantly advance scientific disciplines if they are published, and can help investigators avoid repeating experiments that have already been done, thus saving money and time. Moreover, these unexpected data may actually have significance if re-interpreted leading to new hypotheses. This editorial commentary highlights a novel user-friendly tool developed by Bernard and colleagues (REF) to help investigators determine appropriate options for disseminating unpublished data in order to make them available to the broader scientific community. In addition, this commentary serves as an announcement for an upcoming special call for papers on meta-research to be published in Clinical Science. Meta-research is the evaluation and study of existing scientific literature and data. It is an evolving field dedicated to improving rigor and reproducibility in science, an endeavor to which Clinical Science and Portland Press are committed.Previous research has demonstrated the usefulness of hierarchical modeling for incorporating a flexible array of prior information in genetic association studies. When this prior information consists of estimates from association analyses of single nucleotide polymorphisms (SNP)-intermediate or SNP-gene expression, a hierarchical model is equivalent to a two-stage instrumental or transcriptome-wide association study (TWAS) analysis, respectively. We propose to extend our previous approach for the joint analysis of marginal summary statistics to incorporate prior information via a hierarchical model (hJAM). In this framework, the use of appropriate estimates as prior information yields an analysis similar to Mendelian Randomization (MR) and TWAS approaches. hJAM is applicable to multiple correlated SNPs and intermediates to yield conditional estimates for the intermediates on the outcome, thus providing advantages over alternative approaches. We investigate the performance of hJAM in comparison to existing MR and TWAS approaches and demonstrate that hJAM yields an unbiased estimate, maintains correct type-I error and has increased power across extensive simulations. We apply hJAM to two examples estimating the causal effects of body mass index (GIANT consortium) and type 2 diabetes (DIAGRAM, GERA, and UKB) on myocardial infarction (UK Biobank) and estimating the causal effects of the expressions of gene NUCKS1 and PM20D1 on the risk of prostate cancer (PRACTICAL and GTEx).
Patients with tetralogy of Fallot (TOF) are often affected by right ventricular fibrosis, which has been associated with arrhythmias. This study aimed to assess fibrosis distribution in right ventricular outflow tract (RVOT) myocardium of TOF patients to evaluate the utility of single histology-section analyses, and to explore the possibility of fibrosis quantification in unlabelled tissue by second harmonic generation imaging (SHGI) as an alternative to conventional histology-based assays.

We quantified fibrosis in 11 TOF RVOT samples, using a tailor-made automated image analysis method on Picrosirius red-stained sections. In a subset of samples, histology- and SHGI-based fibrosis quantification approaches were compared. Fibrosis distribution was highly heterogeneous, with significant and comparable variability between and within samples. Ceftaroline nmr We found that, on average, 67.8 mm2 of 10 µm thick, histologically processed tissue per patient had to be analysed for accurate fibrosis quantification. SHGI provided data faster and on live tissue, additionally enabling quantification of collagen anisotropy.

Given the high intra-individual heterogeneity, fibrosis quantification should not be conducted on single sections of TOF RVOT myectomies. We provide an analysis algorithm for fibrosis quantification in histological images, which enables the required extended volume analyses in these patients.
Given the high intra-individual heterogeneity, fibrosis quantification should not be conducted on single sections of TOF RVOT myectomies. We provide an analysis algorithm for fibrosis quantification in histological images, which enables the required extended volume analyses in these patients.Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats ( less then 6 fmol/g).
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