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Article: Performance of the fecal immunochemical test for colorectal cancer and advanced neoplasia in individuals under age 50.

Heer, Emily / Ruan, Yibing / Pader, Joy / Mah, Brittany / Ricci, Christina / Nguyen, Teresa / Chow, Kristian / Ford-Sahibzada, Chelsea / Gogna, Priyanka / Poirier, Abbey / Forbes, Nauzer / Heitman, Steve J / Hilsden, Robert J / Brenner, Darren R

Preventive medicine reports

2023 Volume 32, Page(s) 102124

Abstract: The increased demand for colonoscopy combined with increased incidence of colorectal cancer (CRC) among younger populations presents a need to determine FIT performance among individuals in this age group. We conducted a systematic review to assess test ... ...

Abstract	The increased demand for colonoscopy combined with increased incidence of colorectal cancer (CRC) among younger populations presents a need to determine FIT performance among individuals in this age group. We conducted a systematic review to assess test performance characteristics of FIT in detecting CRC and advanced neoplasia in younger age populations. A search through December 2022 identified published articles assessing the sensitivity and specificity of FIT for advanced neoplasia or CRC among populations under age 50. Following the search, 3 studies were included in the systematic review. Sensitivity to detect advanced neoplasia ranged from 0.19 to 0.36 and specificity between 0.94 and 0.97 and the overall sensitivity and specificity were 0.23 (0.17-0.30) and 0.96 (0.94-0.98), respectively. Two studies that assessed these metrics in multiple age categories found similar sensitivity and specificity across all age groups 30-49. Sensitivity and specificity to detect CRC was assessed in one study and found no significant differences by age groups. These results suggest that FIT performance may be lower for younger individuals compared to those typically screened for CRC. However, there were few studies available for analysis. Given increasing recommendations to expand screening in younger age groups, more research is needed to determine whether FIT is an adequate screening tool in this population.
Language	English
Publishing date	2023-02-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2785569-7
ISSN	2211-3355
ISSN	2211-3355
DOI	10.1016/j.pmedr.2023.102124
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Article ; Online: Validity of the Modified Dyspnea Index for the French-Canadian Population.

Dore, Michel / Provencher, Steve / Poirier, Paul / Gélinas, Celine / Stoller, James K / de Oliveira, Elaine Machado / Gallani, Maria Cecilia

Journal of nursing measurement

2021 Volume 29, Issue 1, Page(s) 121–139

Abstract: Background and purpose: Multidimensional tools could evaluate the dyspnea of patients with chronic lung disease. The aim was to validate the use of the French-Canadian version of the modified dyspnea index (MDI) among patients with pulmonary arterial ... ...

Abstract	Background and purpose: Multidimensional tools could evaluate the dyspnea of patients with chronic lung disease. The aim was to validate the use of the French-Canadian version of the modified dyspnea index (MDI) among patients with pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). Methods: The Spearman test analyzed the convergent validation of the MDI with pulmonary function tests (PFTs), New York Heart Association (NYHA) functional classification, the Modified Borg Scale, the Veterans Specific Activity Questionnaire (VSAQ), physical capacity, physical activity (Godin-Shephard Leisure-Time Physical Activity Questionnaire [GSLTPAQ]), and quality of life (SF-12). Results: The MDI had a low correlation with PFT and physical activity; a moderate with physical capacity; a high with the physical dimension (SF-12). Conclusion: The results support the convergent validation of the MDI French-Canadian version with PAH or ILD.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Canada ; Diagnostic Techniques and Procedures/standards ; Diagnostic Techniques and Procedures/statistics & numerical data ; Dyspnea/diagnosis ; Dyspnea/etiology ; Female ; France ; Humans ; Lung Injury/complications ; Lung Injury/nursing ; Male ; Middle Aged ; Nursing Assessment/methods ; Psychometrics/standards ; Psychometrics/statistics & numerical data ; Reproducibility of Results ; Surveys and Questionnaires/standards ; Surveys and Questionnaires/statistics & numerical data ; Translations
Language	English
Publishing date	2021-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1180408-7
ISSN	1945-7049 ; 1061-3749
ISSN (online)	1945-7049
ISSN	1061-3749
DOI	10.1891/JNM-D-19-00042
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Article ; Online: The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol.

Poirier, Steve / Mayer, Gaétan

Drug design, development and therapy

2013 Volume 7, Page(s) 1135–1148

Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) directly binds to the epidermal growth factor-like repeat A domain of low-density lipoprotein receptor and induces its degradation, thereby controlling circulating low-density lipoprotein cholesterol ( ...

Abstract	Proprotein convertase subtilisin/kexin type 9 (PCSK9) directly binds to the epidermal growth factor-like repeat A domain of low-density lipoprotein receptor and induces its degradation, thereby controlling circulating low-density lipoprotein cholesterol (LDL-C) concentration. Heterozygous loss-of-function mutations in PCSK9 can decrease the incidence of coronary heart disease by up to 88%, owing to lifelong reduction of LDL-C. Moreover, two subjects with PCSK9 loss-of-function mutations on both alleles, resulting in a total absence of functional PCSK9, were found to have extremely low circulating LDL-C levels without other apparent abnormalities. Accordingly, PCSK9 could represent a safe and effective pharmacological target to increase clearance of LDL-C and to reduce the risk of coronary heart disease. Recent clinical trials using anti-PCSK9 monoclonal antibodies that block the PCSK9:low-density lipoprotein receptor interaction were shown to considerably reduce LDL-C levels by up to 65% when given alone and by up to 72% in patients already receiving statin therapy. In this review, we will discuss how major scientific breakthroughs in PCSK9 cell biology have led to the development of new and forthcoming LDL-C-lowering pharmacological agents.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Anticholesteremic Agents/pharmacology ; Cholesterol, LDL/blood ; Coronary Disease/physiopathology ; Coronary Disease/prevention & control ; Drug Design ; Endoplasmic Reticulum/metabolism ; Humans ; Lysosomes/metabolism ; Molecular Targeted Therapy ; Mutation ; Proprotein Convertase 9 ; Proprotein Convertases/antagonists & inhibitors ; Proprotein Convertases/genetics ; Proprotein Convertases/metabolism ; Receptors, LDL/metabolism ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism
Chemical Substances	Antibodies, Monoclonal ; Anticholesteremic Agents ; Cholesterol, LDL ; Receptors, LDL ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Proprotein Convertases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2013-10-04
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S36984
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Article ; Online: Spindles insufficiency in sleepwalkers' deep sleep.

Carpentier, Nicolas / O'Reilly, Christian / Carrier, Julie / Poirier, Gaétan / Paquet, Jean / Gibbs, Steve A / Zadra, Antonio / Desautels, Alex

Neurophysiologie clinique = Clinical neurophysiology

2020 Volume 50, Issue 5, Page(s) 339–343

Abstract: Objectives: Sleepwalkers have consistently shown N3 sleep discontinuity, especially after sleep deprivation. In healthy subjects, sleep spindles activity has been positively correlated to sleep stability. We aimed to compare spindles density during N3 ... ...

Abstract	Objectives: Sleepwalkers have consistently shown N3 sleep discontinuity, especially after sleep deprivation. In healthy subjects, sleep spindles activity has been positively correlated to sleep stability. We aimed to compare spindles density during N3 sleep between sleepwalkers and healthy controls. Methods: Two cohorts of 10 and 21 adult sleepwalkers respectively controlled with 10 and 18 healthy volunteers underwent one baseline and one recovery sleep recording after 38h (cohort 1) and 25h (cohort 2) of sleep deprivation. For the two recordings, we performed an automatic detection of spindles (11-16Hz) from EEG signal during N3 sleep, restricted to the first sleep cycle and repeated for all cycles. For better interpretation of results, we extended the analysis to N2 sleep and we also measured the density of slow waves oscillation (SWO) (0.5-4Hz) during the same periods. Results: Compared to controls, sleepwalkers showed significantly lower spindle densities during N3 sleep considering the first sleep cycle (both cohorts) or all cycles (cohort 1). SWO densities did not differ (cohort 1) or were lower (cohort 2) for sleepwalkers. The effect of sleep deprivation did not interact with the effect of group on spindles and SWO densities. Conclusion: This work suggests that the instability of N3 sleep inherent to sleepwalkers may be underpinned by a specific alteration of spindles activity.
MeSH term(s)	Adult ; Electroencephalography ; Humans ; Polysomnography ; Sleep, Slow-Wave ; Somnambulism
Language	English
Publishing date	2020-09-04
Publishing country	France
Document type	Journal Article
ZDB-ID	639421-8
ISSN	1769-7131 ; 0987-7053
ISSN (online)	1769-7131
ISSN	0987-7053
DOI	10.1016/j.neucli.2020.08.003
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Article ; Online: Pilot project: Physiologic responses to a high-intensity active video game with COPD patients-Tools for home rehabilitation.

Parent, Andrée-Anne / Gosselin-Boucher, Vincent / Houle-Peloquin, Marilyn / Poirier, Claude / Comtois, Alain-Steve

The clinical respiratory journal

2018 Volume 12, Issue 5, Page(s) 1927–1936

Abstract: Introduction: Chronic obstructive pulmonary disease (COPD) is a respiratory condition that causes a significant deterioration of the quality of life. However, exercise can improve the quality of life for COPD patients and it is for this reason previous ... ...

Abstract	Introduction: Chronic obstructive pulmonary disease (COPD) is a respiratory condition that causes a significant deterioration of the quality of life. However, exercise can improve the quality of life for COPD patients and it is for this reason previous study observed the effects of active video games to increase exercise. Using motion capture devices with short bursts of exercise never been tried with COPD patients. Objectives: The objective was to observe the feasibility of using this device safely and easily with COPD patients. Methods: A total of 14 participants (8 men, 69 ± 6 years, 6 women, 74 ± 6 years), with a moderate to severe COPD diagnosis performed exercise games (Shape-Up, Ubisoft, Mtl) adapted under supervision. Gaming sessions of 10-15 min duration were composed of four games of about 1.5 min separated by rest. Results: Average and peak minute ventilation, and METs peak were, respectively: Stunt Run game (lifting knees on spot) 25.3 ± 6.8, 33.5 ± 8.2 L/min and 4.2 ± 1.5 METs; Arctic Punch game (punching targets): 23.1 ± 5.6, 31.8 ± 9.8 L/min and 3.7 ± 1.2 METs; To the Core game (core twist), 22.2 ± 7.3, 29.2 ± 9.9 L/min and 3.3 ± 1.1 METs; and Squat me to the Moon game (sitting to standing), 27.8 ± 6.7, 36.8 ± 11.1 L/min and 4.4 ± 1.1 METs. Conclusion: Knowing the pleasure reported by the participants, the safety, and the ability to use it with assistance, it seems that the games could be a good tool in order for COPD patients to exercise at home. However, further investigation needs to be completed in order to observe the benefits in comparison to a traditional training program.
MeSH term(s)	Aged ; Aged, 80 and over ; Exercise/physiology ; Exercise Therapy/methods ; Feasibility Studies ; Female ; Humans ; Male ; Middle Aged ; Observational Studies as Topic ; Pilot Projects ; Pulmonary Disease, Chronic Obstructive/physiopathology ; Pulmonary Disease, Chronic Obstructive/psychology ; Pulmonary Disease, Chronic Obstructive/rehabilitation ; Quality of Life ; Video Games/adverse effects ; Video Games/statistics & numerical data
Language	English
Publishing date	2018-02-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2442214-9
ISSN	1752-699X ; 1752-6981
ISSN (online)	1752-699X
ISSN	1752-6981
DOI	10.1111/crj.12760
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Article ; Online: Impacts of water level fluctuations on mercury concentrations in hydropower reservoirs: A microcosm experiment.

Ni, Felicity J / Bhavsar, Satyendra P / Poirier, David / Branfireun, Brian / Petro, Steve / Arts, Michael T / Chong-Kit, Richard / Mitchell, Carl P J / Arhonditsis, George B

Ecotoxicology and environmental safety

2021 Volume 220, Page(s) 112354

Abstract: Hydropower generation, a renewable source of electricity, has been linked to elevated methylmercury (MeHg) concentrations in impoundments and aquatic biota. This study investigates the impact of water level fluctuations (WLF) on MeHg concentrations in ... ...

Abstract	Hydropower generation, a renewable source of electricity, has been linked to elevated methylmercury (MeHg) concentrations in impoundments and aquatic biota. This study investigates the impact of water level fluctuations (WLF) on MeHg concentrations in water, sediment, and fish. Using a set of controlled microcosm experiments emulating the drawdown/refill dynamics and subsequent sediment exposure to air experienced in reservoirs, we demonstrate that less frequent WLFs, and/or increased exposure of sediment to air, can lead to elevated MeHg concentrations in sediment, and total mercury (THg) and MeHg concentrations in water. In examining the effects of WLF frequency (two-day, weekly, and monthly), the monthly treatment displayed the highest THg and MeHg water levels, while the weekly treatment was characterized by the highest MeHg levels in the sediment. Our work supports emerging evidence that longer duration between WLF creates a larger surface area of sediment exposed to air leading to conditions conducive to higher MeHg concentrations in sediments and water. In contrast, THg, MeHg, and fatty acid trends in fish were largely inconclusive characterized by similar among-treatment effects and minimal temporal variability over the course of our experiment. This result could partly be attributed to overall low mercury levels and simple "worm-forage fish" food web in our experiment. To elucidate the broader impacts of water fluctuations on aquatic chemistry and biota, other factors (e.g., longer WLF cycles, dissolved organic matter, temperature, more complex food webs) which modulate both methylation rates and food web dynamics must be considered.
MeSH term(s)	Animals ; Environmental Monitoring ; Fishes/metabolism ; Food Chain ; Geologic Sediments/chemistry ; Mercury/analysis ; Methylmercury Compounds/analysis ; Water/chemistry ; Water Movements ; Water Pollutants, Chemical/analysis
Chemical Substances	Methylmercury Compounds ; Water Pollutants, Chemical ; Water (059QF0KO0R) ; Mercury (FXS1BY2PGL)
Language	English
Publishing date	2021-06-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	436536-7
ISSN	1090-2414 ; 0147-6513
ISSN (online)	1090-2414
ISSN	0147-6513
DOI	10.1016/j.ecoenv.2021.112354
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Zs.A 1418: Show issues

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Article: Comparison of Preparation Methods for the Determination of Metals in Petroleum Fractions (1000 Â°F+) by Microwave Plasma Atomic Emission Spectroscopy

Poirier, Laura / Nelson Jenny / Gilleland Greg / Wall Steve / Berhane Lidia / Lopez-Linares Francisco

Energy & Fuels. 2017 Aug. 17, v. 31, no. 8

2017

Abstract: Microwave induced plasma atomic emission spectroscopy (MP-AES) with nitrogen gas was employed for the determination of trace elements in petroleum fractions with a boiling point above 1000 Â°F, using direct dilution in an organic solvent. Nitrogen ... ...

Abstract	Microwave induced plasma atomic emission spectroscopy (MP-AES) with nitrogen gas was employed for the determination of trace elements in petroleum fractions with a boiling point above 1000 Â°F, using direct dilution in an organic solvent. Nitrogen produces robust plasma for the analysis of fractions having an American Petroleum Institute (API) gravity range from â2Â° up to 9.7Â° and elemental composition as follows: S (1.0â5.5 wt %) and N (200â14â¯000 mg kgâÂ¹). A satisfactory limit of quantification and spike recoveries at low and high concentration levels were determined for Na, K, Ca, V, Fe, Ni, and Mo present in different residua samples. The recoveries obtained from the analysis of three QC test materials were within Â±10% of the actual and or certified values. It was found that V, Fe, and Ni are the most predominant elements present in these samples and the effect of the source of sustained plasma gas as well as sample preparation method was focused on the quantification of these three elements. Using a direct dilution method, V calculated recoveries using NIST 8505 CRM (104% and 109%) are found independently of the plasma sustained gas source (argon vs nitrogen). Comparing sample preparation methods (wet ashing vs direct dilution), recoveries of 99% and 109% were determined. Furthermore, for Ni, regardless of the fact that the NIST 8505 CRM reference value is not available, the calculations using our measured value of 51 mg kgâÂ¹, indicate that that nickel quantification is not sensitive to either sample preparation or detection methods, giving recovery of 100% in all cases. For Fe, the quantification is susceptible to a sample preparation method; microparticles, which are possible to be present in such fractions, cannot be homogeneously dispersed into the organic media, leading to bias to low measurements in most cases. It seems that better results are obtained using wet acid digestion. Finally, it was shown that, when using nitrogen-based plasma (MP-AES) versus argon-based plasma (ICP-OES), excellent agreement in all cases for vanadium and nickel was determined, indicating that MP-AES represents an alternative for analysis of these complex samples.
Keywords	argon (noble gases) ; ashing ; boiling point ; calcium ; elemental composition ; gravity ; iron ; molybdenum ; nickel ; nitrogen ; petroleum ; potassium ; sodium ; solvents ; spectroscopy ; vanadium ; wet digestion method
Language	English
Dates of publication	2017-0817
Size	p. 7809-7815.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1483539-3
ISSN	1520-5029 ; 0887-0624
ISSN (online)	1520-5029
ISSN	0887-0624
DOI	10.1021%2Facs.energyfuels.7b00654
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Article ; Online: Impacts of water level fluctuations on mercury concentrations in hydropower reservoirs

Felicity J. Ni / Satyendra P. Bhavsar / David Poirier / Brian Branfireun / Steve Petro / Michael T. Arts / Richard Chong-Kit / Carl P.J. Mitchell / George B. Arhonditsis

Ecotoxicology and Environmental Safety, Vol 220, Iss , Pp 112354- (2021)

A microcosm experiment

2021

Abstract	Hydropower generation, a renewable source of electricity, has been linked to elevated methylmercury (MeHg) concentrations in impoundments and aquatic biota. This study investigates the impact of water level fluctuations (WLF) on MeHg concentrations in water, sediment, and fish. Using a set of controlled microcosm experiments emulating the drawdown/refill dynamics and subsequent sediment exposure to air experienced in reservoirs, we demonstrate that less frequent WLFs, and/or increased exposure of sediment to air, can lead to elevated MeHg concentrations in sediment, and total mercury (THg) and MeHg concentrations in water. In examining the effects of WLF frequency (two-day, weekly, and monthly), the monthly treatment displayed the highest THg and MeHg water levels, while the weekly treatment was characterized by the highest MeHg levels in the sediment. Our work supports emerging evidence that longer duration between WLF creates a larger surface area of sediment exposed to air leading to conditions conducive to higher MeHg concentrations in sediments and water. In contrast, THg, MeHg, and fatty acid trends in fish were largely inconclusive characterized by similar among-treatment effects and minimal temporal variability over the course of our experiment. This result could partly be attributed to overall low mercury levels and simple “worm-forage fish” food web in our experiment. To elucidate the broader impacts of water fluctuations on aquatic chemistry and biota, other factors (e.g., longer WLF cycles, dissolved organic matter, temperature, more complex food webs) which modulate both methylation rates and food web dynamics must be considered.
Keywords	Mercury ; Methylation ; Water level fluctuations ; Dam management ; Hydropower ; Environmental pollution ; TD172-193.5 ; Environmental sciences ; GE1-350
Subject code	333
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Trafficking Dynamics of PCSK9-Induced LDLR Degradation: Focus on Human PCSK9 Mutations and C-Terminal Domain.

Poirier, Steve / Hamouda, Hocine Ait / Villeneuve, Louis / Demers, Annie / Mayer, Gaétan

PloS one

2016 Volume 11, Issue 6, Page(s) e0157230

Abstract: PCSK9 is a secreted ligand and negative post-translational regulator of low-density lipoprotein receptor (LDLR) in hepatocytes. Gain-of-function (GOF) or loss-of-function (LOF) mutations in PCSK9 are directly correlated with high or low plasma LDL- ... ...

Abstract	PCSK9 is a secreted ligand and negative post-translational regulator of low-density lipoprotein receptor (LDLR) in hepatocytes. Gain-of-function (GOF) or loss-of-function (LOF) mutations in PCSK9 are directly correlated with high or low plasma LDL-cholesterol levels, respectively. Therefore, PCSK9 is a prevailing lipid-lowering target to prevent coronary heart diseases and stroke. Herein, we fused monomeric fluorescent proteins to PCSK9 and LDLR to visualize their intra- and extracellular trafficking dynamics by live confocal microscopy. Fluorescence recovery after photobleaching (FRAP) showed that PCSK9 LOF R46L mutant and GOF mutations S127R and D129G, but not the LDLR high-affinity mutant D374Y, significantly accelerate PCSK9 exit from the endoplasmic reticulum (ER). Quantitative analysis of inverse FRAP revealed that only R46L presented a much slower trafficking from the trans-Golgi network (TGN) to the plasma membrane and a lower mobile fraction likely suggesting accumulation or delayed exit at the TGN as an underlying mechanism. While not primarily involved in LDLR binding, PCSK9 C-terminal domain (CTD) was found to be essential to induce LDLR degradation both upon its overexpression in cells or via the extracellular pathway. Our data revealed that PCSK9 CTD is required for the localization of PCSK9 at the TGN and increases its LDLR-mediated endocytosis. Interestingly, intracellular lysosomal targeting of PCSK9-ΔCTD was able to rescue its capacity to induce LDLR degradation emphasizing a role of the CTD in the sorting of PCSK9-LDLR complex towards late endocytic compartments. Finally, we validated our dual fluorescence system as a cell based-assay by preventing PCSK9 internalization using a PCSK9-LDLR blocking antibody, which may be expended to identify protein, peptide or small molecule inhibitors of PCSK9.
MeSH term(s)	Hep G2 Cells ; Humans ; Mutation ; Proprotein Convertase 9/antagonists & inhibitors ; Proprotein Convertase 9/metabolism ; Protein Domains ; Protein Transport ; Proteolysis ; Receptors, LDL/genetics ; Receptors, LDL/metabolism
Chemical Substances	LDLR protein, human ; Receptors, LDL ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0157230
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Article ; Online: Trafficking Dynamics of PCSK9-Induced LDLR Degradation

Steve Poirier / Hocine Ait Hamouda / Louis Villeneuve / Annie Demers / Gaétan Mayer

PLoS ONE, Vol 11, Iss 6, p e

Focus on Human PCSK9 Mutations and C-Terminal Domain.

2016 Volume 0157230

Abstract	PCSK9 is a secreted ligand and negative post-translational regulator of low-density lipoprotein receptor (LDLR) in hepatocytes. Gain-of-function (GOF) or loss-of-function (LOF) mutations in PCSK9 are directly correlated with high or low plasma LDL-cholesterol levels, respectively. Therefore, PCSK9 is a prevailing lipid-lowering target to prevent coronary heart diseases and stroke. Herein, we fused monomeric fluorescent proteins to PCSK9 and LDLR to visualize their intra- and extracellular trafficking dynamics by live confocal microscopy. Fluorescence recovery after photobleaching (FRAP) showed that PCSK9 LOF R46L mutant and GOF mutations S127R and D129G, but not the LDLR high-affinity mutant D374Y, significantly accelerate PCSK9 exit from the endoplasmic reticulum (ER). Quantitative analysis of inverse FRAP revealed that only R46L presented a much slower trafficking from the trans-Golgi network (TGN) to the plasma membrane and a lower mobile fraction likely suggesting accumulation or delayed exit at the TGN as an underlying mechanism. While not primarily involved in LDLR binding, PCSK9 C-terminal domain (CTD) was found to be essential to induce LDLR degradation both upon its overexpression in cells or via the extracellular pathway. Our data revealed that PCSK9 CTD is required for the localization of PCSK9 at the TGN and increases its LDLR-mediated endocytosis. Interestingly, intracellular lysosomal targeting of PCSK9-ΔCTD was able to rescue its capacity to induce LDLR degradation emphasizing a role of the CTD in the sorting of PCSK9-LDLR complex towards late endocytic compartments. Finally, we validated our dual fluorescence system as a cell based-assay by preventing PCSK9 internalization using a PCSK9-LDLR blocking antibody, which may be expended to identify protein, peptide or small molecule inhibitors of PCSK9.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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