Expression quantitative trait loci are highly sensitive to cellular differentiation state

Blood cell development from multipotent hematopoietic stem cells to specialized blood cells is accompanied by drastic changes in gene expression for which the triggers remain mostly unknown. Genetical genomics is an approach linking natural genetic variation to gene expression variation, thereby allowing the identification of genomic loci containing gene expression modulators (eQTLs). In this paper, we used a genetical genomics approach to analyze gene expression across four developmentally close blood cell types collected from a large number of genetically different but related mouse strains. We found that, while a significant number of eQTLs (365) had a consistent “static” regulatory effect on gene expression, an even larger number were found to be very sensitive to cell stage. As many as 1,283 eQTLs exhibited a “dynamic” behavior across cell types. By looking more closely at these dynamic eQTLs, we show that the sensitivity of eQTLs to cell stage is largely associated with gene expression changes in target genes. These results stress the importance of studying gene expression variation in well-defined cell populations. Only such studies will be able to reveal the important differences in gene regulation between different ce

Dose-dependent effects of Allopurinol on human foreskin fibroblast cell and human umbilical vein endothelial cell under hypoxia

Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1α protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1α mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl-hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells

Evaluation of the Novel Folate Receptor Ligand [18F] Fluoro-PEG-Folate for Macrophage Targeting in a Rat Model of Arthritis.

Introduction Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[11C]PK11195 and positron emission tomography (PET). Images, however, also showed significant peri-articular background activity. The folate receptor (FR)-β is a potential alternative target for imaging activated macrophages. Therefore, the PET tracer [18F]fluoro-PEG-folate was synthesized and evaluated in both in vitro and ex vivo studies using a methylated BSA induced arthritis model. Methods [18F]fluoro-PEG-folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5-methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo [18F]fluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic and normal rats and results were compared with those of the established macrophage tracer (R)-[11C]PK11195. Results [18F]fluoro-PEG-folate was synthesized with a purity \u3e97%, a yield of 300 to 1,700 MBq and a specific activity between 40 and 70 GBq/µmol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8-fold lower than that of folic acid, but 3-fold higher than that of 5-Me-THF. In the rat model, [18F]fluoro-PEG-folate uptake in arthritic knees was increased compared with both contralateral knees and knees of normal rats. Uptake in arthritic knees could be blocked by an excess of glucosamine-folate, consistent with [18F]fluoro-PEG-folate being specifically bound to FR. Arthritic knee-to-bone and arthritic knee-to-blood ratios of [18F]fluoro-PEG-folate were increased compared with those of (R)-[11C]PK11195. Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels increased absolute [18F]fluoro-PEG-folate uptake in arthritic joints, but without improving target-to-background ratios. Conclusions The novel PET tracer [18F]fluoro-PEG-folate, designed to target FR on activated macrophages provided improved contrast in a rat model of arthritis compared with the accepted macrophage tracer (R)-[11C]PK11195. These results warrant further exploration of [18F]fluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients

Using the Pneumatic method to estimate embolism resistance in species with long vessels: A commentary on the article “A comparison of five methods to assess embolism resistance in trees”

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordComparisons among methods are essential to validate plant traits measured across studies. However, a rigorous analysis is a complex task that needs to take into account not only the principle of the method and its correct use, but also inherent intraspecific trait variability, something we feel is not fully considered by Sergent et al. (2020). They compared the Bench dehydration, MicroCT, and Pneumatic methods using three long-vesseled species and found divergence among these methods. As a key finding, Sergent and colleagues reported unreliable estimates of Ψ50 for Olea europaea when using the Pneumatic method in a such long-vesseled species. Here, we tested this finding by measuring independently vulnerability curves for O. europaea. Our results reinforce the viability of the Pneumatic method to estimate embolism vulnerability in long-vesseled species, as already found by others. Briefly, we also discuss important procedures when using the Pneumatic method and encourage further experiments, as the only way to know better the limitations of available methods and improve our understanding about plant water relations.São Paulo Research Foundation (FAPESP)Royal SocietyNational Council for Scientific and Technological Development (CNPq, Brazil

Polymorphisms in gene encoding TRPV1-receptor involved in pain perception are unrelated to chronic pancreatitis

Contains fulltext : 79505.pdf (publisher's version ) (Open Access

Prevalence of and risk factors for different measures of low back pain among female nursing aides in Taiwanese nursing homes

<p>Abstract</p> <p>Background</p> <p>Although low back pain (LBP) among nursing staff, especially in nursing aides (NAs), has been a major health problem around the world, there is limited information on its prevalence in Taiwan. In addition, various measurements have been used to determine LBP; understanding the risk factors for each measurement of LBP is essential for prevention. This study aimed to assess the prevalence of and risk factors for different measures of LBP among NAs in Taiwan.</p> <p>Methods</p> <p>A cross-sectional study was conducted among 244 female NAs from 31 nursing homes in central Taiwan. A self-administered questionnaire, including the Nordic questionnaire and the Karasek's job content questionnaire, was used to collect data regarding five different measures of LBP and about demographic, physical and psychosocial factors. Also, on-site observation at the workplace was conducted to measure the frequency of five high risk patient-handling tasks.</p> <p>Results</p> <p>Based on the subjects' reports on the previous twelve months, the prevalence rates for pain lasting for at least one day, seeking of medical care, intense pain, sick leave, and chronic pain were 66.0%, 43.9%, 38.1%, 10.7%, and 8.6%, respectively. While multiple logistic regression analyses indicated that the risk factors varied with different measures of LBP, at least one high risk patient-handling task and one psychosocial factor were observed to be associated each LBP related measure. Three risk factors, including manual transfer of patients between bed/wheelchair and bath cart, perceived physical exertion, and psychological demands, were consistently associated with different measures of LBP. Besides, age was found to be associated with an increased risk of only chronic pain.</p> <p>Conclusion</p> <p>The prevalence of LBP among NAs in Taiwan is high and should be actively addressed. Certain manual patient-transfer tasks and psychological demands seemed to play more important roles in severe LBP (such as care seeking, intense pain, and sick leave) than in minor LBP (pain lasting for at least one day). Because different LBP related measures might be involved with different etiological risk factors, any LBP reduction interventions that aim to improve ergonomic and psychosocial work environments for NAs should take this information into consideration.</p

Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown. In the current study, we used multiplex ligation-dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA

Many quality measurements, but few quality measures assessing the quality of breast cancer care in women: A systematic review

BACKGROUND: Breast cancer in women is increasingly frequent, and care is complex, onerous and expensive, all of which lend urgency to improvements in care. Quality measurement is essential to monitor effectiveness and to guide improvements in healthcare. METHODS: Ten databases, including Medline, were searched electronically to identify measures assessing the quality of breast cancer care in women (diagnosis, treatment, followup, documentation of care). Eligible studies measured adherence to standards of breast cancer care in women diagnosed with, or in treatment for, any histological type of adenocarcinoma of the breast. Reference lists of studies, review articles, web sites, and files of experts were searched manually. Evidence appraisal entailed dual independent assessments of data (e.g., indicators used in quality measurement). The extent of each quality indicator's scientific validation as a measure was assessed. The American Society of Clinical Oncology (ASCO) was asked to contribute quality measures under development. RESULTS: Sixty relevant reports identified 58 studies with 143 indicators assessing adherence to quality breast cancer care. A paucity of validated indicators (n = 12), most of which assessed quality of life, only permitted a qualitative data synthesis. Most quality indicators evaluated processes of care. CONCLUSION: While some studies revealed patterns of under-use of care, all adherence data require confirmation using validated quality measures. ASCO's current development of a set of quality measures relating to breast cancer care may hold the key to conducting definitive studies