388 results on '"J. Roelofs"'
Search Results
2. Experiences of people with dual sensory loss in various areas of life: A qualitative study.
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E Veenman, A A J Roelofs, M L Stolwijk, A M Bootsma, and R M A van Nispen
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Medicine ,Science - Abstract
Individuals with dual sensory loss (DSL) appear to have limited ability to compensate for their visual impairment with residual hearing, or for their hearing impairment with residual vision, resulting in challenges in various areas of life. The aim of this qualitative study was to explore the diverse experiences facing individuals with DSL as well as to determine how they experience sensory compensation. Semi-structured interviews were carried out in twenty adults with DSL (13 females and 7 males, mean age 47 years). The causes of DSL severity varied amongst participants. Sensory compensation and experiences in regards to access to information, mobility, communication and fatigue were discussed. Interviews were audio recorded and transcribed verbatim. Framework analysis was used to summarize and interpret the data. In relation to access to information, our results show that, despite various challenges, the use of assistive technology such as voice command functions, enabled participants to operate effectively. Regarding mobility, most participants were capable of finding their way in familiar environments. However, if the setting was unfamiliar, assistance from others or reliance on navigation applications was necessary. Participants experienced little issues with having conversations in quiet settings, however, crowded settings were considered very difficult. The final results showed that most participants suffered from fatigue. Carefully considering which daily activities were feasible and having a daily routine helped to cope with fatigue. This study revealed the experiences of individuals with DSL in important areas of life. The results suggest that, even though many challenges are experienced, individuals with DSL are resourceful in finding compensation strategies. However, capturing participants' sensory compensation experiences was challenging.
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- 2023
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3. Total and regional dual X-ray absorptiometry derived four-compartment model
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Madeline A. Czeck, William T. Juckett, Erica J. Roelofs, and Donald R. Dengel
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Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism - Published
- 2023
4. U-Net-and-a-half: Convolutional network for biomedical image segmentation using multiple expert-driven annotations.
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Yichi Zhang, Jesper Kers, Clarissa A. Cassol, Joris J. Roelofs, Najia Idrees, Alik Farber, Samir Haroon, Kevin P. Daly, Suvranu Ganguli, Vipul C. Chitalia, and Vijaya B. Kolachalama
- Published
- 2021
5. Dual X-ray absorptiometry-derived total and regional body volume
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Madeline A. Czeck, Erica J. Roelofs, William T. Juckett, and Donald R. Dengel
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Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism - Abstract
Although dual X-ray absorptiometry (DXA) has been used to determine total body volume, using DXA to determine regional (i.e., arm and leg) volumes needs further assessment. Thus, the aim of the present study is to evaluate the validity of total and regional DXA-derived body volume compared to a traditional method for measuring body volume.A total of 30 males and females (Age: 25.9 ± 4.0 yrs; Height: 1.75 ± 0.10 m; Weight: 70.98 ± 14.02 kg) underwent one whole body DXA scan, underwater weighing, and regional measures of volume via water displacement. Manually created DXA region of interest boxes were used to determine regional DXA body composition. Total body volume was calculated by taking the participant's dry weight and dividing it by the average density from underwater weighing. Linear regression models with body volume from underwater weighing for total body volume and water displacement for regional volume as the dependent variable and DXA lean mass, fat mass, and bone mass as independent variables created total and regional DXA-derived body volume. T-tests assessed DXA-derived body volume to the traditional method of body volume assessment. Regression models were cross-validated using the Repeated k-fold Cross Validation method.DXA-derived total body volume was not significantly (p = 0.999) different from total body volume measured via total body water displacement. In addition, both arm and leg regional DXA-derived volume was not significantly different (p = 0.999) compared to regional volume measured by regional water displacement. Cross-validation of each model produced RThe DXA may be used as valid method for estimating total and regional body volume. Thus, these results expand the DXA's capabilities and potentially allow for a convenient regional four-compartment model with DXA-derived regional volume.
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- 2022
6. Taxonomy of fibroblasts and progenitors in the synovial joint at single-cell resolution
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Fraser L Collins, Anke J Roelofs, Rebecca A Symons, Karolina Kania, Ewan Campbell, Elaina S R Collie-duguid, Anna H K Riemen, Susan M Clark, and Cosimo De Bari
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
ObjectivesFibroblasts in synovium include fibroblast-like synoviocytes (FLS) in the lining andThy1+ connective-tissue fibroblasts in the sublining. We aimed to investigate their developmental origin and relationship with adult progenitors.MethodsTo discriminate betweenGdf5-lineage cells deriving from the embryonic joint interzone and otherPdgfrα-expressing fibroblasts and progenitors, adultGdf5-Cre;Tom;Pdgfrα-H2BGFPmice were used and cartilage injury was induced to activate progenitors. Cells were isolated from knees, fibroblasts and progenitors were sorted by fluorescence-activated cell-sorting based on developmental origin, and analysed by single-cell RNA-sequencing. Flow cytometry and immunohistochemistry were used for validation. Clonal-lineage mapping was performed usingGdf5-Cre;Confettimice.ResultsIn steady state,Thy1+ sublining fibroblasts were of mixed ontogeny. In contrast,Thy1-Prg4+ lining fibroblasts predominantly derived from the embryonic joint interzone and includedPrg4-expressing progenitors distinct from molecularly defined FLS. Clonal-lineage tracing revealed compartmentalisation ofGdf5-lineage fibroblasts between lining and sublining. Following injury, lining hyperplasia resulted from proliferation and differentiation ofPrg4-expressing progenitors, with additional recruitment of non-Gdf5-lineage cells, into FLS. Consistent with this, a second population of proliferating cells, enriched near blood vessels in the sublining, supplied activated multipotent cells predicted to give rise toThy1+ fibroblasts, and to feed into the FLS differentiation trajectory. Transcriptional programmes regulating fibroblast differentiation trajectories were uncovered, identifying Sox5 and Foxo1 as key FLS transcription factors in mice and humans.ConclusionsOur findings blueprint a cell atlas of mouse synovial fibroblasts and progenitors in healthy and injured knees, and provide novel insights into the cellular and molecular principles governing the organisation and maintenance of adult synovial joints.
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- 2022
7. Spatial Lipidomic Profiling of Mouse Joint Tissue Demonstrates the Essential Role of PHOSPHO1 in Growth Plate Homeostasis
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Jordan Tzvetkov, Louise A. Stephen, Scott Dillon, Jose Luis Millan, Anke J. Roelofs, Cosimo De Bari, Colin Farquharson, Tony Larson, Paul Genever, Tzvetkov, Jordan [0000-0002-0172-716X], Dillon, Scott [0000-0001-5609-8009], Millan, Jose Luis [0000-0002-1547-2671], Roelofs, Anke J [0000-0001-8993-1984], De Bari, Cosimo [0000-0002-5113-862X], Farquharson, Colin [0000-0002-4970-4039], Larson, Tony [0000-0003-1337-3482], Genever, Paul [0000-0002-5730-8976], and Apollo - University of Cambridge Repository
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MATRIX MINERALIZATION ,Mice, Knockout ,Endocrinology, Diabetes and Metabolism ,BONE MODELING AND REMODELING ,DISORDERS OF CALCIUM/PHOSPHATE METABOLISM ,Phosphoric Monoester Hydrolases ,Mice ,STATISTICAL METHODS ,Lipidomics ,Animals ,Homeostasis ,Orthopedics and Sports Medicine ,Growth Plate ,Phospholipids - Abstract
Funder: Biotechnology and Biological Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000268, Funder: Versus Arthritis; Id: http://dx.doi.org/10.13039/501100012041, Lipids play a crucial role in signaling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesized to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralization. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome. Lipids spanning 17 subclasses were mapped across the knee joints of healthy juvenile and adult mice using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS), with annotation supported by shotgun lipidomics. Multivariate analysis identified 96 and 80 lipid ions with differential abundances across joint tissues in juvenile and adult mice, respectively. In both ages, marrow was enriched in phospholipid platelet activating factors (PAFs) and related metabolites, cortical bone had a low lipid content, whereas lysophospholipids were strikingly enriched in the growth plate, an active site of mineralization and PHOSPHO1 activity. Spatially-resolved profiling of PHOSPHO1-knockout (KO) mice across the resting, proliferating, and hypertrophic growth plate zones revealed 272, 306, and 296 significantly upregulated, and 155, 220, and 190 significantly downregulated features, respectively, relative to wild-type (WT) controls. Of note, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, lysophosphatidylethanolamine, and phosphatidylethanolamine derived lipid ions were upregulated in PHOSPHO1-KO versus WT. Our imaging pipeline has established a spatially-resolved lipid signature of joint tissues and has demonstrated that PHOSPHO1 ablation significantly alters the growth plate lipidome, highlighting an essential role of the PHOSPHO1-mediated membrane phospholipid metabolism in lipid and bone homeostasis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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- 2023
8. Body Composition and On-Ice Skate Times for National Collegiate Athletic Association Division I Collegiate Male and Female Ice Hockey Athletes
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Erica J. Roelofs, Donald R. Dengel, Tyler A. Bosch, Madeline A. Czeck, and Calvin C. Dietz
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Male ,biology ,Athletes ,Physical Therapy, Sports Therapy and Rehabilitation ,General Medicine ,biology.organism_classification ,Ice hockey ,Absorptiometry, Photon ,Hockey ,Skating ,Body Composition ,Humans ,Female ,Orthopedics and Sports Medicine ,Skate ,Psychology ,Demography - Abstract
Czeck, MA, Roelofs, EJ, Dietz, C, Bosch, TA, and Dengel, DR. Body composition and on-ice skate times for NCAA Division I collegiate male and female ice hockey athletes. J Strength Cond Res 36(1): 187-192, 2022-This study's purpose was to explore positional differences for an on-ice timed skate test and its relationship to body composition. Male (n = 15) and female (n = 18) collegiate hockey players participated in this study (total n = 33). Each player was categorized by position of forward or defensemen. Dual x-ray absorptiometry assessed total body composition variables of lean, fat, and bone mass as well as regional measures of lean mass, fat mass, and visceral adipose tissue. Total time and section times were determined for the on-ice skating test through a gated automatic timing system at 9, 18, 24, 42, 48, 66, 82, 132, and 148 m. Analysis of variance and Tukey's honest significance difference assessed on-ice skate time differences between positions (p ≤ 0.05). Correlations between body composition variables and skate times were determined for change of direction, skating time, linear skate time, and total skate time. There were no significant differences between positions for skate times (p0.05). Body fat percent (p = 0.007; r = 0.55), total fat mass (p = 0.027; r = 0.46), and leg fat mass (p = 0.019; 0.49) were significantly correlated with total skate time in men, whereas only body fat percent was significantly correlated with change of direction (p = 0.022; r = 0.54) and total skate times (p = 0.016; r = 0.56) in women. The total upper-body mass to leg lean mass ratio was significantly correlated with change of direction (p = 0.036; r = 0.50) in women. In conclusion, the results from this study suggest no differences between on-ice skating times between forwards and defensemen. However, body fat percentage was correlated with on-ice skate times in male and female collegiate hockey players.
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- 2021
9. Differential effects and success stories of distance education in Covid-19 lockdowns on the development of reading comprehension in primary schools
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Eliane Segers, M. In ’t Zandt, J. Stoep, L. Daniels, J. Roelofs, and J. Gubbels
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Speech and Hearing ,Linguistics and Language ,Neuropsychology and Physiological Psychology ,Learning and Plasticity ,Education - Abstract
Contains fulltext : 283810.pdf (Publisher’s version ) (Open Access) In the current study, the development in reading comprehension performance of students in lower-SES versus higher-SES schools during and after school closures due to Covid-19 lockdowns was examined, and compared to a normed reference group. Furthermore, we explored protective factors against negative effects at the time of school closures, by pinpointing successful practices in a sub sample of resilient lower-SES schools. The total sample consisted of 2202 students followed from grade 2-4. Overall, we found that students in lower-SES schools made less progress over time than students in higher-SES schools. On average, students made less progress during the lockdowns, but here, the interaction with SES was not significant. Students' reading comprehension levels partially recovered after the lockdowns. Questionnaire-data revealed that schools were better prepared during the second lockdown, with teachers making more use of digital means, and providing more online reading instruction. In addition, collaboration with the parents seemed to have improved. The in depth interviews with resilient lower-SES schools revealed that the introduction of online education and investing in educational partnerships with parents may have helped to minimize the negative impact of lockdowns. We conclude that lockdowns have a negative effect on the development of reading education, but that students are resilient. Digital means and partnership with parents may be seen as protective factors to attenuate the negative effects of emergency remote teaching. 24 p.
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- 2022
10. The Role of Platelets in Diabetic Kidney Disease
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Ukhti Jamil Rustiasari and Joris J. Roelofs
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Blood Platelets ,Inflammation ,diabetes ,diabetic nephropathy ,Organic Chemistry ,General Medicine ,antiplatelet ,Kidney ,Catalysis ,diabetic kidney disease ,Computer Science Applications ,Inorganic Chemistry ,platelets ,platelet activation ,Diabetes Mellitus ,biomarker ,Animals ,Kidney Failure, Chronic ,Diabetic Nephropathies ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
Diabetic kidney disease (DKD) is among the most common microvascular complications in patients with diabetes, and it currently accounts for the majority of end-stage kidney disease cases worldwide. The pathogenesis of DKD is complex and multifactorial, including systemic and intra-renal inflammatory and coagulation processes. Activated platelets play a pivotal role in inflammation, coagulation, and fibrosis. Mounting evidence shows that platelets play a role in the pathogenesis and progression of DKD. The potentially beneficial effects of antiplatelet agents in preventing progression of DKD has been studied in animal models and clinical trials. This review summarizes the current knowledge on the role of platelets in DKD, including the potential therapeutic effects of antiplatelet therapies.
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- 2022
11. Male and Female Collegiate Ice Hockey Athletes’ Body Composition Over Competitive Seasons
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Donald R. Dengel, Madeline A. Czeck, Tyler A. Bosch, and Erica J. Roelofs
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Male ,Universities ,Adipose tissue ,Physical Therapy, Sports Therapy and Rehabilitation ,Intra-Abdominal Fat ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Ice hockey ,Absorptiometry, Photon ,0302 clinical medicine ,Animal science ,Bone Density ,Humans ,Orthopedics and Sports Medicine ,Dual x-ray absorptiometry ,Total fat ,Bone mineral ,biology ,Athletes ,030229 sport sciences ,biology.organism_classification ,Hockey ,Body Composition ,Lean body mass ,Female ,Composition (visual arts) ,Seasons - Abstract
Eighty-three male and female (49/34) athletes underwent determination of total fat mass (FM), lean mass (LM), bone mineral density (BMD) and visceral adipose tissue (VAT) by dual X-ray absorptiometry during the pre-season, in-season and off-season. Athletes were classified by position of Goalie (G; M/F=7/6), Forward (F; M/F=26/18), or Defenseman (D; M/F=16/10). In males, all positions were similar in weight, FM, LM, BMD and VAT. In females, F weighed less than D and G. FM and VAT was lower in F than D and G, but D was not different from G. LM was lower in F compared to D, but not G, with no differences between D and G. There were no differences in BMD between positions. There were no seasonal changes in males for body composition variables. In females, FM, LM and VAT decreased from pre-season to in-season, while BMD increased. From in-season to off-season, LM increased and BMD decreased. From off-season to pre-season, FM and VAT increased. In conclusion, there were no differences across position or seasonal changes in body composition in males. However, there were positional and seasonal changes in body composition in females, indicating possible differences in training regimens during the off-season compared to males.
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- 2021
12. Post-Exercise Ingestion of Low or High Molecular Weight Glucose Polymer Solution Does Not Improve Cycle Performance in Female Athletes
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Eric T. Trexler, Erica J. Roelofs, Abbie E. Smith-Ryan, Malia N.M. Blue, Katie R. Hirsch, and Meredith G. Mock
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Adult ,Male ,medicine.medical_specialty ,Polymers ,Body water ,Physical Therapy, Sports Therapy and Rehabilitation ,030204 cardiovascular system & hematology ,Placebo ,Article ,Eating ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Time trial ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Ingestion ,Orthopedics and Sports Medicine ,Glucans ,Respiratory exchange ratio ,Cross-Over Studies ,biology ,Athletes ,food and beverages ,Fructose ,030229 sport sciences ,General Medicine ,biology.organism_classification ,Bicycling ,Molecular Weight ,Endocrinology ,chemistry ,Female ,Bioelectrical impedance analysis - Abstract
Mock, MG, Hirsch, KR, Blue, MNM, Trexler, ET, Roelofs, EJ, and Smith-Ryan, AE. Postexercise ingestion of low or high molecular weight glucose polymer solution does not improve cycle performance in female athletes. J Strength Cond Res 35(1): 124-131, 2021-The current study sought to evaluate the effects of postexercise ingestion of a high molecular weight (HMW) glucose polymer solution compared with an isocaloric low molecular weight (LMW) solution or placebo (PLA) on subsequent cycling performance in female athletes. In a randomized, double-blind, placebo-controlled, cross-over design, 10 competitive female cyclists (Mean ± SD; Age = 25.7 ± 5.0 years; V̇o2peak = 49.7 ± 4.3 ml·kg-1·min-1) completed 3 testing sessions separated by 7-10 days. Visits consisted of a ride-to-exhaustion (RTE) at 75% V̇o2peak, followed by immediate consumption of 700 ml containing either: 1.2 g·kg-1 LMW (maltodextrin/dextrose/fructose); 1.2 g·kg-1 HMW (Vitargo); or 0.066 g·kg-1 PLA (noncaloric flavoring). After 2 hours of rest, subjects performed a 15-minute time trial (TT). Respiratory exchange ratio (RER) was assessed via indirect calorimetry during exercise. Total body water (TBW) was measured using bioelectrical impedance to assess fluid balance. When covaried for estrogen, there was no treatment effect on distance (km; p = 0.632) or power output (watts; p = 0.974) during the 15-minute TT. Respiratory exchange ratio was not significantly different during the LMW and HWM TTs (p0.999), but both were significantly higher than PLA (p = 0.039, p = 0.001, respectively). Changes in total body water pre-exercise to postexercise were not significantly different between trials (p = 0.777). Despite benefits of HMW on cycling performance previously reported in males, current results demonstrate no ergogenic effect of HMW or LMW in females. Sex differences in substrate utilization may account for the discrepancy, and further research involving performance nutrition for female athletes is merited.
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- 2021
13. LP-64 Fine particulate matters from air pollution exacerbate renal ischemia reperfusion injury
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T. Sanches, A.C. Parra, M. Veras, L.M. Butter, N. Claessen, J. Roelofs, S. Florquin, J. Kers, L. Andrade, and A. Tammaro
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General Medicine ,Toxicology - Published
- 2022
14. No Changes in Body Composition in NCAA Division I Collegiate Football Players because of COVID-19 Restrictions
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Madeline A. Czeck, Erica J. Roelofs, Nicholas G. Evanoff, and Donald R. Dengel
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Absorptiometry, Photon ,Adipose Tissue ,Athletes ,Bone Density ,Body Composition ,Football ,COVID-19 ,Humans ,Physical Therapy, Sports Therapy and Rehabilitation ,Orthopedics and Sports Medicine ,General Medicine - Abstract
Czeck, MA, Roelofs, EJ, Evanoff, NG, and Dengel, DR. No Changes in body composition in NCAA Division I Collegiate Football Players due to COVID-19 restrictions. J Strength Cond Res 36(6): 1749-1752, 2022-The purpose of this study was to explore the impact of coronavirus disease 2019 (COVID-19) restrictions on body composition, assessed by dual x-ray absorptiometry (DXA), between the 2020 postseason (pre-COVID-19 restrictions) and the 2021 postseason (post-COVID-19 restrictions) in collegiate football players (n = 50). In addition, a subset of athletes (n = 23) was used to explore body composition variables across 4 postseason time points. Body composition variables assessed were total and regional body fat percent, total mass, lean mass, fat mass, bone mineral content, bone mineral density, and visceral adipose tissue mass. Paired t-tests were used to determine differences between the 2020 postseason and the 2021 postseason in body composition variables. Analysis of variance with Tukey HSD post hoc tests assessed significant differences in total and regional body composition across 4 years while adjusting for multiple comparisons. There were no significant differences (p0.05) between postseason 2020 and postseason 2021 for all measures of body composition. In a subset of athletes, body composition was analyzed over a 4-year period of time. There were no significant differences between all 4 time points for all measures of body composition. In conclusion, body composition variables in this study's subjects were not affected because of coronavirus disease 2019 restrictions or over 4 years of their collegiate football career.
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- 2022
15. The Role of Follicle-Stimulating Hormone in Vascular Dysfunction Observed in Hematopoietic Cell Transplant Recipients
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Julia Steinberger, Qi Wang, Donald R. Dengel, Erica J. Roelofs, James S. Hodges, and K. Scott Baker
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medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Gastroenterology ,Article ,Follicle-stimulating hormone ,Cancer Survivors ,immune system diseases ,hemic and lymphatic diseases ,medicine.artery ,Internal medicine ,medicine ,Endocrine system ,Humans ,Brachial artery ,Child ,Ultrasonography ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Transplant Recipients ,Transplantation ,Compliance (physiology) ,surgical procedures, operative ,Oncology ,Pediatrics, Perinatology and Child Health ,Carotid artery structure ,Gonadotropin ,Follicle Stimulating Hormone ,business ,Hormone - Abstract
Childhood cancer survivors who receive a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a substantial negative impact on vascular function. The purpose of this study was to examine the association of vascular function with FSH in HCT recipients, non-HCT recipients and healthy controls. The study included childhood cancer survivors who were HCT recipients (n=24) and non-HCT recipients (n=308), and a control group of healthy siblings (n=211) all aged between 9 and 18 years. Vascular measures of carotid artery structure and function (compliance and distensibility), brachial artery flow-mediated dilation and endothelial-independent dilation were measured using ultrasound imaging. A fasting blood sample was collected to measure hormone levels. FSH was significantly higher in HCT recipients compared with non-HCT recipients and healthy controls (P
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- 2022
16. Treatment with ddAVP improves platelet-based coagulation in a rat model of traumatic hemorrhagic shock
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Mathijs R Wirtz, Joris J Roelofs, J Carel Goslings, Nicole P Juffermans, AII - Inflammatory diseases, AMS - Amsterdam Movement Sciences, Pathology, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, AMS - Musculoskeletal Health, Surgery, and Intensive Care Medicine
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Surgery ,hemorrhage ,Critical Care and Intensive Care Medicine ,multiple trauma ,hormones, hormone substitutes, and hormone antagonists ,animal experimentation ,blood coagulation - Abstract
ObjectivesTrauma-induced hemorrhagic shock is characterized by increased endothelial permeability and coagulopathy. Vasopressin analog ddAVP (desmopressin) acts by reorganizing and redistributing adhesive and tight junction molecules, enhancing endothelial barrier function. Furthermore, ddAVP increases von Willebrand factor (vWF) plasma levels and thereby potentially enhances platelet-based coagulation. The objective of this study was to assess whether the use of ddAVP results in improvement of both endothelial barrier function and platelet-based coagulation, thereby improving shock reversal and reduce organ failure in a rat model of trauma and transfusion.MethodsBlood products were prepared from syngeneic rat blood according to blood bank standards. Polytrauma was induced in Sprague Dawley rats by a fractured femur and crush injury to the intestines and liver. The rats were hemorrhaged until a mean arterial pressure of 40 mm Hg and transfused with RBCs, fresh frozen plasmas and platelets in a 1:1:1 ratio, and randomized to receive a single dose of ddAVP (n=7 per group). Blood samples were taken up to 6 hours after trauma to assess biochemistry, markers of endothelial injury and coagulation status by rotational thromboelastometry (ROTEM). Organ damage was assessed by histopathology.ResultsRats receiving ddAVP showed significantly better shock reversal compared with controls. Also, coagulation parameters remained stable in the ddAVP treated group, whereas rats in the control group showed deterioration of coagulation parameters, including decreased clot strength and decreased platelet functioning (89% (IQR 82% to 92%) of baseline values). Platelet count and vWF antigen levels at exsanguination did not differ between groups. ddAVP did not reduce markers of endothelial dysfunction nor markers of organ injury.ConclusionsThe use of ddAVP in a rat trauma-transfusion model improved shock parameters and ROTEM parameters of clot formation. However, this did not abrogate the amount of organ failure.Level of evidenceLevel III.
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- 2022
17. Oea Signaling Pathways and the Metabolic Benefits of Vertical Sleeve Gastrectomy
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Darleen A. Sandoval, Chelsea R. Hutch, Joshua W. Pressler, Daniela Cota, Silvana Obici, Danielle R. Trakimas, Karen J. Roelofs, and Joyce Sorrell
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Male ,medicine.medical_specialty ,CD36 ,Gene Expression ,Alpha (ethology) ,Oleic Acids ,Article ,Receptors, G-Protein-Coupled ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gastrectomy ,Weight loss ,Internal medicine ,parasitic diseases ,medicine ,Animals ,PPAR alpha ,Obesity ,Mice, Knockout ,Glucose tolerance test ,medicine.diagnostic_test ,Triglyceride ,biology ,business.industry ,Cholesterol ,Lipid metabolism ,Glucose Tolerance Test ,Scavenger Receptors, Class B ,Lipids ,Rats ,Up-Regulation ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Ethanolamines ,030220 oncology & carcinogenesis ,Anorectic ,biology.protein ,030211 gastroenterology & hepatology ,Surgery ,medicine.symptom ,business ,Endocannabinoids ,Signal Transduction - Abstract
Objective The aim of this study was to determine whether downstream [peroxisome proliferator-activated-receptor alpha (PPARα) and the G-protein coupled receptor, GPR119] and upstream (a fatty acid translocase, CD36) signaling targets of N-oleoylethanolamide (OEA) were necessary for weight loss, metabolic improvements, and diet preference following vertical sleeve gastrectomy (VSG). Summary background data OEA is an anorectic N-acylethanolamine produced from dietary fats within the intestinal lumen that can modulate lipid metabolism, insulin secretion, and energy expenditure by activating targets such as PPARα and GPR119. Methods Diet-induced obese mice, including wild-type or whole body knockout (KO) of PPARα, GPR119, and CD36, were stratified to either VSG or sham surgery before body weight, body composition, diet preference, and glucose and lipid metabolic endpoints were assessed. Results We found increased duodenal production of OEA and expression of both GPR119 and CD36 were upregulated in wild-type mice after VSG. However, weight loss and glucose tolerance were improved in response to VSG in PPARαKO, GPR119KO, and CD36KO mice. In fact, VSG corrected hepatic triglyceride dysregulation in CD36KO mice, and circulating triglyceride and cholesterol levels in PPARαKO mice. Lastly, we found PPARα-mediated signaling contributes to macronutrient preference independent of VSG, while removal of CD36 signaling blunts the VSG-induced shift toward carbohydrate preference. Conclusions In the search for more effective and less invasive therapies to help reverse the global acceleration of obesity and obesity-related disease OEA is a promising candidate; however, our data indicate that it is not an underlying mechanism of the effectiveness of VSG.
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- 2020
18. The role of FSH in body composition in hematopoietic cell transplant recipients
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Julia Steinberger, Scott Baker, Erica J. Roelofs, Qi Wang, Donald R. Dengel, and James S. Hodges
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Male ,medicine.medical_specialty ,Adolescent ,Adipose tissue ,Gastroenterology ,Bone Density ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Child ,Bone mineral ,Transplantation ,Hematopoietic cell ,business.industry ,Hematopoietic Stem Cell Transplantation ,surgical procedures, operative ,Increased risk ,Case-Control Studies ,Pediatrics, Perinatology and Child Health ,Body Composition ,Linear Models ,Lean body mass ,Bone mineral content ,Female ,Follicle Stimulating Hormone ,business ,Biomarkers ,Hormone - Abstract
BACKGROUND Childhood cancer survivors who received a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a significant negative impact on bone health and body composition. This study's purpose was to examine FSH and body composition in HCT recipients, non-HCT recipients and healthy controls. METHODS The study included HCT recipients (n = 24), non-HCT recipients (n = 309), and a control group of healthy siblings (n = 211) all aged 9-18 years. A fasting blood sample was collected to measure FSH. All participants underwent a dual X-ray absorptiometry scan to assess total and regional percent fat, lean mass (LM), fat mass (FM), bone mineral content (BMC), bone mineral density (BMD), and visceral adipose tissue (VAT) mass. RESULTS FSH was significantly higher in HCT recipients compared to non-HCT recipients and healthy controls. HCT recipients had significantly lower total body weight, total LM, arm and leg LM, BMC and BMD compared to non-HCT recipients and healthy controls (p
- Published
- 2021
19. Human Mesenchymal Stromal Cells Enhance Cartilage Healing in a Murine Joint Surface Injury Model
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Karina T. Wright, Sally Roberts, Alison Richmond, Helen S. McCarthy, Claire Mennan, Jade Perry, Anna H. K. Riemen, Cosimo De Bari, Anke J. Roelofs, and Susan Clark
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Cartilage, Articular ,Male ,Pathology ,Endogeny ,Osteoarthritis ,Bioreactors ,Pregnancy ,Medicine ,Biology (General) ,Cells, Cultured ,Bone Marrow Transplantation ,education.field_of_study ,Cell Differentiation ,General Medicine ,allogeneic cell therapy ,medicine.anatomical_structure ,Female ,cartilage repair ,Inflammation Mediators ,Joint Diseases ,mesenchymal stromal cells ,Chondrogenesis ,Adult ,medicine.medical_specialty ,bone marrow ,QH301-705.5 ,Population ,Transplantation, Heterologous ,Mice, Transgenic ,Mesenchymal Stem Cell Transplantation ,Article ,Young Adult ,Animals ,Humans ,mouse models ,education ,Cell Proliferation ,Wound Healing ,business.industry ,Cartilage ,Mesenchymal stem cell ,medicine.disease ,Embryonic stem cell ,R1 ,Mice, Inbred C57BL ,Disease Models, Animal ,osteoarthritis ,umbilical cord ,Bone marrow ,business ,Immunostaining ,RC - Abstract
Human umbilical cord (hUC)- or bone marrow (hBM)-derived mesenchymal stromal cells (MSCs) were evaluated as an allogeneic source of cells for cartilage repair. We aimed to determine if they could enhance healing of chondral defects with or without the recruitment of endogenous cells. hMSCs were applied into a focal joint surface injury in knees of adult mice expressing tdTomato fluorescent protein in cells descending from Gdf5-expressing embryonic joint interzone cells. Three experimental groups were used: (i) hUC-MSCs, (ii) hBM-MSCs and (iii) PBS (vehicle) without cells. Cartilage repair was assessed after 8 weeks and tdTomato-expressing cells were detected by immunostaining. Plasma levels of pro-inflammatory mediators and other markers were measured by electrochemiluminescence. Both hUC-MSC (n = 14, p = 0.009) and hBM-MSC (n = 13, p = 0.006) treatment groups had significantly improved cartilage repair compared to controls (n = 18). While hMSCs were not detectable in the repair tissue at 8 weeks post-implantation, increased endogenous Gdf5-lineage cells were detected in repair tissue of hUC-MSC-treated mice. This xenogeneic study indicates that hMSCs enhance intrinsic cartilage repair mechanisms in mice. Hence, hMSCs, particularly the more proliferative hUC-MSCs, could represent an attractive allogeneic cell population for treating patients with chondral defects and perhaps prevent the onset and progression of osteoarthritis.
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- 2021
20. The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice
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Karen J. Roelofs, Darleen A. Sandoval, Chelsea R. Hutch, Kyle Leix, Thomas Klein, April Haller, David D. D’Alessio, Robert Augustin, Randy J. Seeley, and Joyce Sorrell
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Blood Glucose ,Male ,0301 basic medicine ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,Dipeptidyl Peptidase 4 ,Endocrinology, Diabetes and Metabolism ,Incretin ,Linagliptin ,030209 endocrinology & metabolism ,Gastric Inhibitory Polypeptide ,Proglucagon ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Glucagon-Like Peptide 1 ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Glucose homeostasis ,Receptor ,Pancreas ,Dipeptidyl peptidase-4 ,Dipeptidyl-Peptidase IV Inhibitors ,Chemistry ,digestive, oral, and skin physiology ,Postprandial Period ,Receptor antagonist ,030104 developmental biology ,Postprandial ,medicine.anatomical_structure ,Endocrinology ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis. METHODS: We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRA(ΔNull)) or is expressed exclusively in the intestine (GcgRA(ΔVilCre)) or pancreas and duodenum (GcgRA(ΔPDX1Cre)). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists. RESULTS: Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRA(Δnull) mice and control littermates and in GcgRA(ΔVilCre) and GcgRA(ΔPDX1Cre) mice. The potent GLP-1 receptor antagonist, exendin-[9–39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRA(ΔPDX1Cre) mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRA(ΔNull) or in GcgRA(ΔVilCre) mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRA(ΔNull) mice. CONCLUSIONS/INTERPRETATION: Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.
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- 2019
21. Tenascin-C Deficiency Is Associated With Reduced Bacterial Outgrowth During Klebsiella pneumoniae-Evoked Pneumosepsis in Mice
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Mariska T. Meijer, Alex F. de Vos, Brendon P. Scicluna, Joris J. Roelofs, Chérine Abou Fayçal, Gertraud Orend, Fabrice Uhel, Tom van der Poll, Center of Experimental and Molecular Medicine, Graduate School, AII - Infectious diseases, Epidemiology and Data Science, Pathology, ACS - Diabetes & metabolism, Infectious diseases, ACS - Pulmonary hypertension & thrombosis, Amsterdam University Medical Centers (Amsterdam UMC), University of Amsterdam [Amsterdam] (UvA), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nouvel Hôpital Civil de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), and univOAK, Archive ouverte
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0301 basic medicine ,Lipopolysaccharide ,Klebsiella pneumoniae ,sepsis ,chemistry.chemical_compound ,0302 clinical medicine ,Immunology and Allergy ,innate immunity ,Original Research ,Mice, Knockout ,biology ,Mice as laboratory animals ,alarmins ,Tenascin C ,tenascin C ,Tenascin ,musculoskeletal system ,030220 oncology & carcinogenesis ,Systemic administration ,medicine.symptom ,Septicemia -- Diagnosis ,lcsh:Immunologic diseases. Allergy ,mice ,Immunology ,Inflammation ,Microbiology ,Sepsis ,03 medical and health sciences ,Immune system ,Pneumonia, Bacterial ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,pneumonia ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Innate immune system ,biology.organism_classification ,medicine.disease ,Natural immunity ,Klebsiella pneumoniae (K. pneumoniae) ,Klebsiella Infections ,immune system ,030104 developmental biology ,chemistry ,Pneumonia -- Diagnosis ,biology.protein ,Tenascin -- Physiological effect ,lcsh:RC581-607 - Abstract
Tenascin C (TNC) is an extracellular matrix glycoprotein that recently emerged as an immunomodulator. TNC-deficient (TNC-/-) mice were reported to have a reduced inflammatory response upon systemic administration of lipopolysaccharide, the toxic component of gram-negative bacteria. Here, we investigated the role of TNC during gram-negative pneumonia derived sepsis. TNC+/+ and TNC-/- mice were infected with Klebsiella pneumoniae via the airways and sacrificed 24 and 42 h thereafter for further analysis. Pulmonary TNC protein levels were elevated 42 h after infection in TNC+/+ mice and remained undetectable in TNC-/- mice. TNC-/- mice showed modestly lower bacterial loads in lungs and blood, and a somewhat reduced local-but not systemic-inflammatory response. Moreover, TNC-/- and TNC+/+ mice did not differ with regard to neutrophil recruitment, lung pathology or plasma markers of distal organ injury. These results suggest that while TNC shapes the immune response during lipopolysaccharide-induced inflammation, this role may be superseded during pneumosepsis caused by a common gram-negative pathogen., peer-reviewed
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- 2021
22. BMP signaling: A significant player and therapeutic target for osteoarthritis
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H. Wang, Anna H. K. Riemen, Nanasaheb Sv, Jaswal Ap, De Bari C, Kumar B, Agnihotri N, Anke J. Roelofs, Avinash Singh, Iqbal Sf, Ashraf S, and Amitabha Bandyopadhyay
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business.industry ,Cartilage ,Wnt signaling pathway ,Context (language use) ,Osteoarthritis ,medicine.disease ,Embryonic stem cell ,Cell biology ,Pathogenesis ,medicine.anatomical_structure ,medicine ,business ,Endochondral ossification ,Progenitor - Abstract
ObjectiveTo investigate the role of BMP signaling in osteoarthritis' pathogenesis and propose a disease-modifying therapy for OA.MethodsC57BL6/J mouse line was used to perform ACLT surgery at P120 to study the expression pattern of the BMP signaling readout pSMAD1/5/9. To investigate whether activation of BMP signaling is sufficient and necessary to induce osteoarthritis, we have used conditional GOF and LOF mouse lines in which BMP signaling can be activated or depleted, respectively, upon intra-peritoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. Most of the analysis has been done through immunohistochemistry, histopathological staining, and micro-CT to evaluate the status of the pathogenesis of the disease.ResultsWe observed concomitant activation of BMP signaling, as judged by pSMAD1/5/9 immunoreactivity in the articular cartilage, upon induction of osteoarthritis with simultaneous depletion of SMURF1, an intra-cellular BMP signaling inhibitor in articular cartilage. Even without surgical induction of osteoarthritis, only BMP gain-of-function mutation induces OA in mouse articular cartilage. Also, genetic, or pharmacological inhibition of BMP signaling offered significant protection against OA pathogenesis. Interestingly, post-onset of the disease, inhibition of BMP signaling by intra-articular injection of LDN-193189 retarded OA progression with a significant reduction in inflammatory markers.ConclusionOur study demonstrated that BMP signaling plays an essential role in the pathogenesis of OA and that local BMP inhibition can be an effective therapeutic strategy to mitigate osteoarthritis.
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- 2021
23. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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D. KLIONSKY, A. ABDEL-AZIZ, S. ABDELFATAH, M. ABDELLATIF, A. ABDOLI, S. ABEL, H. ABELIOVICH, M. ABILDGAARD, Y. ABUDU, A. ACEVEDO-AROZENA, I. ADAMOPOULOS, K. ADELI, T. ADOLPH, A. ADORNETTO, E. AFLAKI, G. AGAM, A. AGARWAL, B. AGGARWAL, M. AGNELLO, P. AGOSTINIS, J. AGREWALA, A. AGROTIS, P. AGUILAR, S. AHMAD, Z. AHMED, U. AHUMADA-CASTRO, S. AITS, S. AIZAWA, Y. AKKOC, T. AKOUMIANAKI, H. AKPINAR, A. AL-ABD, L. AL-AKRA, A. AL-GHARAIBEH, M. ALAOUI-JAMALI, S. ALBERTI, E. ALCOCER-GOMEZ, C. ALESSANDRI, M. ALI, M. AL-BARI, S. ALIWAINI, J. ALIZADEH, E. ALMACELLAS, A. ALMASAN, A. ALONSO, G. ALONSO, N. ALTAN-BONNET, D. ALTIERI, S. ALVES, C. DA COSTA, M. ALZAHARNA, M. AMADIO, C. AMANTINI, C. AMARAL, S. AMBROSIO, A. AMER, V. AMMANATHAN, Z. AN, S. ANDERSEN, S. ANDRABI, M. ANDRADE-SILVA, A. ANDRES, S. ANGELINI, D. ANN, U. ANOZIE, M. ANSARI, P. ANTAS, A. ANTEBI, Z. ANTON, T. ANWAR, L. APETOH, N. APOSTOLOVA, T. ARAKI, Y. ARAKI, K. ARASAKI, W. ARAUJO, J. ARAYA, C. ARDEN, M. AREVALO, S. ARGUELLES, E. ARIAS, J. ARIKKATH, H. ARIMOTO, A. ARIOSA, D. ARMSTRONG-JAMES, L. ARNAUNE-PELLOQUIN, A. AROCA, D. ARROYO, I. ARSOV, R. ARTERO, D. ASARO, M. ASCHNER, M. ASHRAFIZADEH, O. ASHUR-FABIAN, A. ATANASOV, A. AU, P. AUBERGER, H. AUNER, L. AURELIAN, R. AUTELLI, L. AVAGLIANO, Y. AVALOS, S. AVEIC, C. AVELEIRA, T. AVINWITTENBERG, Y. AYDIN, S. AYTON, S. AYYADEVARA, M. AZZOPARDI, M. BABA, J. BACKER, S. BACKUES, D. BAE, O. BAE, S. BAE, E. BAEHRECKE, A. BAEK, S. BAEK, G. BAGETTA, A. BAGNIEWSKA-ZADWORNA, H. BAI, J. BAI, X. BAI, Y. BAI, N. BAIRAGI, S. BAKSI, T. BALBI, C. BALDARI, W. BALDUINI, A. BALLABIO, M. BALLESTER, S. BALAZADEH, R. BALZAN, R. BANDOPADHYAY, S. BANERJEE, Y. BAO, M. BAPTISTA, A. BARACCA, C. BARBATI, A. BARGIELA, D. BARILA, P. BARLOW, S. BARMADA, E. BARREIRO, G. BARRETO, J. BARTEK, B. BARTEL, A. BARTOLOME, G. BARVE, S. BASAGOUDANAVAR, D. BASSHAM, R. JR, A. BASU, H. BATOKO, I. BATTEN, E. BAULIEU, B. BAUMGARNER, J. BAYRY, R. BEALE, I. BEAU, F. BEAUMATIN, L. BECHARA, G. BECK, M. BEERS, J. BEGUN, C. BEHRENDS, G. BEHRENS, R. BEI, E. BEJARANO, S. BEL, C. BEHL, A. BELAID, N. BELGAREH-TOUZE, C. BELLAROSA, F. BELLEUDI, M. PEREZ, R. BELLO-MORALES, J. BELTRAN, S. BELTRAN, D. BENBROOK, M. BENDORIUS, B. BENITEZ, I. BENITO-CUESTA, J. BENSALEM, M. BERCHTOLD, S. BEREZOWSKA, D. BERGAMASCHI, M. BERGAMI, A. BERGMANN, L. BERLIOCCHI, C. BERLIOZ-TORRENT, A. BERNARD, L. BERTHOUX, C. BESIRLI, S. BESTEIRO, V. BETIN, R. BEYAERT, J. BEZBRADICA, K. BHASKAR, I. BHATIA-KISSOVA, R. BHATTACHARYA, S. BHATTACHARYA, S. BHATTACHARYYA, M. BHUIYAN, S. BHUTIA, L. BI, X. BI, T. BIDEN, K. BIJIAN, V. BILLES, N. BINART, C. BINCOLETTO, A. BIRGISDOTTIR, G. BJORKOY, G. BLANCO, A. BLAS-GARCIA, J. BLASIAK, R. BLOMGRAN, K. BLOMGREN, J. BLUM, E. BOADA-ROMERO, M. BOBAN, K. BOESZEBATTAGLIA, P. BOEUF, B. BOLAND, P. BOMONT, P. BONALDO, S. BONAM, L. BONFILI, J. BONIFACINO, B. BOONE, M. BOOTMAN, M. BORDI, C. BORNER, B. BORNHAUSER, G. BORTHAKUR, J. BOSCH, S. BOSE, L. BOTANA, J. BOTAS, C. BOULANGER, M. BOULTON, M. BOURDENX, B. BOURGEOIS, N. BOURKE, G. BOUSQUET, P. BOYA, P. BOZHKOV, L. BOZI, T. BOZKURT, D. BRACKNEY, C. BRANDTS, R. BRAUN, G. BRAUS, R. BRAVO-SAGUA, J. BRAVO-SAN PEDRO, P. BREST, M. BRINGER, A. BRIONES-HERRERA, V. BROADDUS, P. BRODERSEN, E. ALVAREZ, J. BRODSKY, S. BRODY, P. BRONSON, J. BRONSTEIN, C. BROWN, R. BROWN, P. BRUM, J. BRUMELL, N. BRUNETTI-PIERRI, D. BRUNO, R. BRYSON-RICHARDSON, C. BUCCI, C. BUCHRIESER, M. BUENO, L. BUITRAGO-MOLINA, S. BURASCHI, S. BUCH, J. BUCHAN, E. BUCKINGHAM, H. BUDAK, M. BUDINI, G. BULTYNCK, F. BURADA, J. BURGOYNE, M. BURON, V. BUSTOS, S. BUTTNER, E. BUTTURINI, A. BYRD, I. CABAS, S. CABRERA-BENITEZ, K. CADWELL, J. CAI, L. CAI, Q. CAI, M. CAIRO, J. CALBET, G. CALDWELL, K. CALDWELL, J. CALL, R. CALVANI, A. CALVO, M. BARRERA, N. CAMARA, J. CAMONIS, N. CAMOUGRAND, M. CAMPANELLA, E. CAMPBELL, F. CAMPBELL-VALOIS, S. CAMPELLO, I. CAMPESI, J. CAMPOS, O. CAMUZARD, J. CANCINO, D. DE ALMEIDA, L. CANESI, I. CANIGGIA, B. CANONICO, C. CANTI, B. CAO, M. CARAGLIA, B. CARAMES, E. CARCHMAN, E. CARDENAL-MUNOZ, C. CARDENAS, L. CARDENAS, S. CARDOSO, J. CAREW, G. CARLE, G. CARLETON, S. CARLONI, D. CARMONA-GUTIERREZ, L. CARNEIRO, O. CARNEVALI, J. CAROSI, S. CARRA, A. CARRIER, L. CARRIER, B. CARROLL, A. CARTER, A. CARVALHO, M. CASANOVA, C. CASAS, J. CASAS, C. CASSIOLI, E. CASTILLO, K. CASTILLO, S. CASTILLO-LLUVA, F. CASTOLDI, M. CASTORI, A. CASTRO, M. CASTRO-CALDAS, J. CASTRO-HERNANDEZ, S. CASTRO-OBREGON, S. CATZ, C. CAVADAS, F. CAVALIERE, G. CAVALLINI, M. CAVINATO, M. CAYUELA, P. RICA, V. CECARINI, F. CECCONI, M. CECHOWSKA-PASKO, S. CENCI, V. CEPERUELO-MALLAFRE, J. CERQUEIRA, J. CERUTTI, D. CERVIA, V. CETINTAS, S. CETRULLO, H. CHAE, A. CHAGIN, C. CHAI, G. CHAKRABARTI, O. CHAKRABARTI, T. CHAKRABORTY, M. CHAMI, G. CHAMILOS, D. CHAN, E. CHAN, H. CHAN, M. CHAN, Y. CHAN, P. CHANDRA, C. CHANG, H. CHANG, K. CHANG, J. CHAO, T. CHAPMAN, N. CHARLET-BERGUERAND, S. CHATTERJEE, S. CHAUBE, A. CHAUDHARY, S. CHAUHAN, E. CHAUM, F. CHECLER, M. CHEETHAM, C. CHEN, G. CHEN, J. CHEN, L. CHEN, M. CHEN, N. CHEN, Q. CHEN, R. CHEN, S. CHEN, W. CHEN, X. CHEN, Y. CHEN, Z. CHEN, H. CHENG, J. CHENG, S. CHENG, W. CHENG, X. CHENG, Y. CHENG, Z. CHENG, H. CHEONG, J. CHEONG, B. CHERNYAK, S. CHERRY, C. CHEUNG, K. CHEUNG, E. CHEVET, R. CHI, A. CHIANG, F. CHIARADONNA, R. CHIARELLI, M. CHIARIELLO, N. CHICA, S. CHIOCCA, M. CHIONG, S. CHIOU, A. CHIRAMEL, V. CHIURCHIU, D. CHO, S. CHOE, A. CHOI, M. CHOI, K. CHOUDHURY, N. CHOW, C. CHU, J. CHUA, H. CHUNG, K. CHUNG, S. CHUNG, Y. CHUNG, V. CIANFANELLI, I. CIECHOMSKA, M. CIFUENTES, L. CINQUE, S. CIRAK, M. CIRONE, M. CLAGUE, R. CLARKE, E. CLEMENTI, E. COCCIA, P. CODOGNO, E. COHEN, M. COHEN, T. COLASANTI, F. COLASUONNO, R. COLBERT, A. COLELL, N. COLL, M. COLLINS, M. COLOMBO, D. COLON-RAMOS, L. COMBARET, S. COMINCINI, M. COMINETTI, A. CONSIGLIO, A. CONTE, F. CONTI, V. CONTU, M. COOKSON, K. COOMBS, I. COPPENS, M. CORASANITI, D. CORKERY, N. CORDES, K. CORTESE, M. COSTA, S. COSTANTINO, P. COSTELLI, A. COTO-MONTES, P. CRACK, J. CRESPO, A. CRIOLLO, V. CRIPPA, R. CRISTOFANI, T. CSIZMADIA, A. CUADRADO, B. CUI, J. CUI, Y. CUI, E. CULETTO, A. CUMINO, A. CYBULSKY, M. CZAJA, S. CZUCZWAR, S. D'ADAMO, M. D'AMELIO, D. D'ARCANGELO, A. D'LUGOS, G. D'ORAZI, J. DA SILVA, H. DAFSARI, R. DAGDA, Y. DAGDAS, M. DAGLIA, X. DAI, Y. DAI, J. DAL COL, P. DALHAIMER, L. DALLA VALLE, T. DALLENGA, G. DALMASSO, M. DAMME, I. DANDO, N. DANTUMA, A. DARLING, H. DAS, S. DASARATHY, S. DASARI, S. DASH, O. DAUMKE, A. DAUPHINEE, J. DAVIES, V. DAVILA, R. DAVIS, T. DAVIS, S. NAIDU, F. DE AMICIS, K. DE BOSSCHER, F. DE FELICE, L. DE FRANCESCHI, C. DE LEONIBUS, M. BARBOSA, G. DE MEYER, A. DE MILITO, C. DE NUNZIO, C. DE PALMA, M. DE SANTI, C. DE VIRGILIO, D. DE ZIO, J. DEBNATH, B. DEBOSCH, J. DECUYPERE, M. DEEHAN, G. DEFLORIAN, J. DEGREGORI, B. DEHAY, G. DEL RIO, J. DELANEY, L. DELBRIDGE, E. DELORME-AXFORD, M. DELPINO, F. DEMARCHI, V. DEMBITZ, N. DEMERS, H. DENG, Z. DENG, J. DENGJEL, P. DENT, D. DENTON, M. DEPAMPHILIS, C. DER, V. DERETIC, A. DESCOTEAUX, L. DEVIS, S. DEVKOTA, O. DEVUYST, G. DEWSON, M. DHARMASIVAM, R. DHIMAN, D. DI BERNARDO, M. DI CRISTINA, F. DI DOMENICO, P. DI FAZIO, A. DI FONZO, G. DI GUARDO, G. DI GUGLIELMO, L. DI LEO, C. DI MALTA, A. DI NARDO, M. DI RIENZO, F. DI SANO, G. DIALLINAS, J. DIAO, G. DIAZ-ARAYA, I. DIAZ-LAVIADA, J. DICKINSON, M. DIEDERICH, M. DIEUDE, I. DIKIC, S. DING, W. DING, L. DINI, M. DINIC, A. DINKOVA-KOSTOVA, M. DIONNE, J. DISTLER, A. DIWAN, I. DIXON, M. DJAVAHERI-MERGNY, I. DOBRINSKI, O. DOBROVINSKAYA, R. DOBROWOLSKI, R. DOBSON, S. EMRE, M. DONADELLI, B. DONG, X. DONG, Z. DONG, G. II, V. DOTSCH, H. DOU, J. DOU, M. DOWAIDAR, S. DRIDI, L. DRUCKER, A. DU, C. DU, G. DU, H. DU, L. DU, A. DU TOIT, S. DUAN, X. DUAN, S. DUARTE, A. DUBROVSKA, E. DUNLOP, N. DUPONT, R. DURAN, B. DWARAKANATH, S. DYSHLOVOY, D. EBRAHIMI-FAKHARI, L. ECKHART, C. EDELSTEIN, T. EFFERTH, E. EFTEKHARPOUR, L. EICHINGER, N. EID, T. EISENBERG, N. EISSA, S. EISSA, M. EJARQUE, A. EL ANDALOUSSI, N. EL-HAGE, S. EL-NAGGAR, A. ELEUTERI, E. EL-SHAFEY, M. ELGENDY, A. ELIOPOULOS, M. ELIZALDE, P. ELKS, H. ELSASSER, E. ELSHERBINY, B. EMERLING, N. EMRE, C. ENG, N. ENGEDAL, A. ENGELBRECHT, A. ENGELSEN, J. ENSERINK, R. ESCALANTE, A. ESCLATINE, M. ESCOBAR-HENRIQUES, E. ESKELINEN, L. ESPERT, M. EUSEBIO, G. FABRIAS, C. FABRIZI, A. FACCHIANO, F. FACCHIANO, B. FADEEL, C. FADER, A. FAESEN, W. FAIRLIE, A. FALCO, B. FALKENBURGER, D. FAN, J. FAN, Y. FAN, E. FANG, Y. FANG, M. FANTO, T. FARFEL-BECKER, M. FAURE, G. FAZELI, A. FEDELE, A. FELDMAN, D. FENG, J. FENG, L. FENG, Y. FENG, W. FENG, T. ARAUJO, T. FERGUSON, J. FERNANDEZ-CHECA, S. FERNANDEZVELEDO, A. FERNIE, A. FERRANTE, A. FERRARESI, M. FERRARI, J. FERREIRA, S. FERRO-NOVICK, A. FIGUERAS, R. FILADI, N. FILIGHEDDU, E. FILIPPICHIELA, G. FILOMENI, G. FIMIA, V. FINESCHI, F. FINETTI, S. FINKBEINER, E. FISHER, P. FISHER, F. FLAMIGNI, S. FLIESLER, T. FLO, I. FLORANCE, O. FLOREY, T. FLORIO, E. FODOR, C. FOLLO, E. FON, A. FORLINO, F. FORNAI, P. FORTINI, A. FRACASSI, A. FRALDI, B. 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TAM, D. TAMPELLINI, A. TAMURA, C. TAN, E. TAN, Y. TAN, M. TANAKA, D. TANG, J. TANG, T. TANG, I. TANIDA, Z. TAO, M. TAOUIS, L. TATENHORST, N. TAVERNARAKIS, A. TAYLOR, G. TAYLOR, J. TAYLOR, E. TCHETINA, A. TEE, I. TEGEDER, D. TEIS, N. TEIXEIRA, F. TEIXEIRA-CLERC, K. TEKIRDAG, T. TENCOMNAO, S. TENREIRO, A. TEPIKIN, P. TESTILLANO, G. TETTAMANTI, P. THARAUX, K. THEDIECK, A. THEKKINGHAT, S. THELLUNG, J. THINWA, V. THIRUMALAIKUMAR, S. THOMAS, P. THOMES, A. THORBURN, L. THUKRAL, T. THUM, M. THUMM, L. TIAN, A. TICHY, A. TILL, V. TIMMERMAN, V. TITORENKO, S. TODI, K. TODOROVA, J. TOIVONEN, L. TOMAIPITINCA, D. TOMAR, C. TOMAS-ZAPICO, B. TONG, C. TONG, X. TONG, S. TOOZE, M. TORGERSEN, S. TORII, L. TORRES-LOPEZ, A. TORRIGLIA, C. TOWERS, R. TOWNS, S. TOYOKUNI, V. TRAJKOVIC, D. TRAMONTANO, Q. TRAN, L. TRAVASSOS, C. TRELFORD, S. TREMEL, I. TROUGAKOS, B. TSAO, M. TSCHAN, H. TSE, T. TSE, H. TSUGAWA, A. TSVETKOV, D. TUMBARELLO, Y. TUMTAS, M. TUNON, S. TURCOTTE, B. TURK, V. TURK, B. TURNER, R. 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flux ,macroautophagy ,phagophore ,stress ,vacuole ,Autophagosome ,LC3 ,lysosome ,neurodegeneration ,cancer - Abstract
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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- 2021
24. Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis
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Magdalena Kaneva, B.L. Thomas, D. Strachan, Anne-Sophie Thorup, S. Caxaria, Kanatheepan Shanmuganathan, Anke J. Roelofs, Ahmed Ali, S.E. Eldridge, Andrew McCaskie, Aida Barawi, Costantino Pitzalis, James R. Whiteford, Francesco Dell'Accio, Beatriz F. Fernandez, Frances Henson, Helen Lydon, H. Wang, Zeyu Guan, Cosimo De Bari, Eldridge, Suzanne E [0000-0002-1630-6261], Barawi, Aida [0000-0001-5504-9184], Kaneva, Magdalena [0000-0003-3822-749X], Guan, Zeyu [0000-0003-3050-4210], Lydon, Helen [0000-0003-4012-7631], Thorup, Anne-Sophie [0000-0002-0435-4071], Fernandez, Beatriz F [0000-0002-8612-0251], Caxaria, Sara [0000-0002-8434-8332], Strachan, Danielle [0000-0002-9544-6341], Ali, Ahmed [0000-0002-2750-399X], Shanmuganathan, Kanatheepan [0000-0003-2731-9508], Pitzalis, Costantino [0000-0003-1326-5051], Whiteford, James R [0000-0002-8967-7389], Henson, Frances [0000-0002-3518-1492], McCaskie, Andrew W [0000-0001-6476-0832], Dell'Accio, Francesco [0000-0003-4137-3770], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Cartilage, Articular ,animal structures ,Cellular differentiation ,Osteoarthritis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Chondrocytes ,medicine ,Animals ,Agrin ,Progenitor cell ,030203 arthritis & rheumatology ,Sheep ,Tissue Scaffolds ,Chemistry ,Regeneration (biology) ,Cartilage ,Cell Differentiation ,General Medicine ,Chondrogenesis ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Stem cell - Abstract
Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface. Agrin attracted joint resident progenitor cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signaling downstream of β-catenin, induced expression of the chondrogenic stem cell marker GDF5 and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, an agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity. Our findings support the therapeutic use of agrin for joint surface regeneration.
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- 2020
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25. Body Composition of National Collegiate Athletic Association (NCAA) Division I Female Soccer Athletes through Competitive Seasons
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Christopher W. Bach, Tyler A. Bosch, Philip R. Stanforth, Aaron F. Carbuhn, Donald R. Dengel, Jonathan M. Oliver, April Bockin, and Erica J. Roelofs
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Competitive Behavior ,Adipose tissue ,Physical Therapy, Sports Therapy and Rehabilitation ,030204 cardiovascular system & hematology ,Body fat percentage ,Body Mass Index ,Fat mass ,Young Adult ,03 medical and health sciences ,Absorptiometry, Photon ,0302 clinical medicine ,Animal science ,Soccer ,Body Fat Distribution ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Total fat ,biology ,business.industry ,Athletes ,030229 sport sciences ,biology.organism_classification ,On resistance ,Lean body mass ,Female ,Composition (visual arts) ,Seasons ,business ,Physical Conditioning, Human - Abstract
The purpose of this study was to examine body composition of National Collegiate Athletic Association Division I female soccer players by position and season. One hundred seventy-five female athletes were categorized by positions of forward (n=47), midfielder (n=51), defender (n=57), and goalkeeper (n=20). A dual X-ray absorptiometry scan assessed percent body fat, total lean mass, total fat mass, arm and leg lean mass and fat mass, and visceral adipose tissue. Goalkeepers had significantly higher total, arm, and leg lean mass and fat mass compared to all other positions (p
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- 2020
26. 196-LB: Synergetic and Distinct Roles in the Control of Food Intake and Energy Balance for Subpopulations of NTS Neurons
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Randy J. Seeley, Christopher J. Rhodes, Wenwen C. Cheng, Karen J. Roelofs, Martin G. Myers, Darleen A. Sandoval, Ermelinda Ndoka, David P. Olson, and Basma Maerz
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medicine.medical_specialty ,education.field_of_study ,Leptin receptor ,Endocrinology, Diabetes and Metabolism ,Population ,Hindbrain ,Anorexia ,Biology ,medicine.disease ,Obesity ,Endocrinology ,Internal medicine ,Internal Medicine ,medicine ,Taste aversion ,medicine.symptom ,Calcitonin receptor ,education ,Cholecystokinin - Abstract
To understand hindbrain pathways involved in the control of food intake, we initially defined markers for distinct subsets of nucleus tractus solitarius (NTS) neurons that respond to food intake, including those that express calcitonin receptor (Calcr), leptin receptor (LepRb), or cholecystokinin (CCK). While the chemogenetic activation of each of these NTS populations decreased short- and long-term food intake and body weight, only CCKNTS cells activated aversive CGRP-containing neurons of the parabrachial nucleus (CGRPPBN cells) and promoted a conditioned taste aversion. Indeed, the combined activation of CalcrNTS+LepRbNTS (LCNTS) cells provoked a stronger and more durable suppression of food intake and body weight than any single population but failed to promote aversive responses. Thus, while CCKNTS cells provoke aversive anorexia, CalcrNTS and LepRbNTS cells cooperatively suppress food intake without engaging aversive systems. To understand the roles for these NTS neurons in the physiologic control of food intake and energy balance, we chronically silenced them and examined food intake and energy balance. We found that silencing any single NTS population not only interfered with the response to gut peptide-mimetics, but also increased food intake and body weight, and that high-calorie food accentuated this effect. Additionally, simultaneously silencing multiple populations further increased food intake and body weight, promoting greater adiposity. These findings not only reveal the importance of both aversive and non-aversive brainstem circuits for the control of long-term energy balance, but also identify multiple synergistic hindbrain circuits that non-aversively suppress feeding. These non-aversive systems represent ideal targets for the potential treatment of obesity and associated metabolic diseases. Disclosure W.C. Cheng: None. E. Ndoka: None. B. Maerz: None. K.J. Roelofs: None. C.J. Rhodes: Employee; Self; AstraZeneca. R.J. Seeley: Consultant; Self; Ionis Pharmaceuticals, Inc., Kintai, Kintai, Novo Nordisk A/S, Sanofi, Scohia Pharma Inc. Research Support; Self; AstraZeneca, Novo Nordisk A/S, Pfizer Inc. Stock/Shareholder; Self; Redesign Health. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S. D. Olson: Research Support; Self; MedImmune, Inc, Novo Nordisk A/S. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. Funding American Diabetes Association (1-16-PDF-021 to W.C.C.)
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- 2020
27. Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice
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Christopher J. Rhodes, Basma Khoury, Andrew MacKinnon, David P. Olson, Darleen A. Sandoval, Wenwen Cheng, Ki-Suk Kim, Ermelinda Ndoka, Chelsea R. Hutch, Karen J. Roelofs, Jack Magrisso, Martin G. Myers, and Randy J. Seeley
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0301 basic medicine ,Food intake ,medicine.medical_specialty ,Nucleus tractus solitarius ,Neurotransmission ,Biology ,Eating ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Glucagon-Like Peptide 1 ,Internal medicine ,Solitary Nucleus ,medicine ,Animals ,Receptor ,Mice, Knockout ,Neurons ,Leptin receptor ,Leptin ,digestive, oral, and skin physiology ,General Medicine ,Metabolism ,respiratory system ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,nervous system ,030220 oncology & carcinogenesis ,Receptors, Leptin ,sense organs ,circulatory and respiratory physiology ,Research Article - Abstract
Leptin receptor–expressing (LepRb-expressing) neurons of the nucleus tractus solitarius (NTS; LepRb(NTS) neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and that produce the food intake–suppressing PPG cleavage product glucagon-like peptide-1 [GLP1]) represent a subpopulation of mouse LepRb(NTS) cells. Using Lepr(cre), Ppg(cre), and Ppg(fl) mouse lines, along with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we examined roles for Ppg in GLP1(NTS) and LepRb(NTS) cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppg(fl) early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1(NTS) cells decreased food intake, LepRb(NTS) cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppg(fl) blunted the ability of GLP1(NTS) neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRb(NTS) cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1(NTS) cells, additional pathways engaged by LepRb(NTS) cells dominate for the suppression of food intake.
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- 2020
28. Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis
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Thomas Aigner, Karolina Kania, Kenneth A. Howard, Anke J. Roelofs, H. Wang, Francesco Dell'Accio, Cosimo De Bari, Fabio Colella, Anna H. K. Riemen, and Terence D. Capellini
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0301 basic medicine ,Cartilage, Articular ,Male ,Knee Joint ,PROTEINS ,lcsh:Medicine ,Osteoarthritis ,Stem cells ,SUSCEPTIBILITY ,Biology ,GDF5 ,Menisci, Tibial ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Growth Differentiation Factor 5 ,Synovial joint ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,SYNOVIAL JOINT ,lcsh:Science ,030203 arthritis & rheumatology ,Regulation of gene expression ,BRACHYPODISM ,Multidisciplinary ,MUTATIONS ,Microarray analysis techniques ,Cartilage ,lcsh:R ,ARTICULAR-CARTILAGE FORMATION ,ALLELIC EXPRESSION ,Chondrogenesis ,medicine.disease ,Cell biology ,MICE ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Regulatory sequence ,MORPHOGENESIS ,Musculoskeletal models ,GROWTH ,lcsh:Q ,Female - Abstract
Growth and Differentiation Factor 5 (GDF5) is a key risk locus for osteoarthritis (OA). However, little is known regarding regulation of Gdf5 expression following joint tissue damage. Here, we employed Gdf5-LacZ reporter mouse lines to assess the spatiotemporal activity of Gdf5 regulatory sequences in experimental OA following destabilisation of the medial meniscus (DMM) and after acute cartilage injury and repair. Gdf5 expression was upregulated in articular cartilage post-DMM, and was increased in human OA cartilage as determined by immunohistochemistry and microarray analysis. Gdf5 expression was also upregulated during cartilage repair in mice and was switched on in injured synovium in prospective areas of cartilage formation, where it inversely correlated with expression of the transcriptional co-factor Yes-associated protein (Yap). Indeed, overexpression of Yap suppressed Gdf5 expression in chondroprogenitors in vitro. Gdf5 expression in both mouse injury models required regulatory sequence downstream of Gdf5 coding exons. Our findings suggest that Gdf5 upregulation in articular cartilage and synovium is a generic response to knee injury that is dependent on downstream regulatory sequence and in progenitors is associated with chondrogenic specification. We propose a role for Gdf5 in tissue remodelling and repair after injury, which may partly underpin its association with OA risk.
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- 2020
29. Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis
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Lynn Rowley, Thomas Pap, Karolina Kania, Maxwell A Serowoky, René Gronewold, J. Sherwood, H. Wang, Alexandra J Rafipay, Simón Méndez-Ferrer, Fraser L. Collins, Anke J. Roelofs, Chrysa Kapeni, J. Gage Crump, Christopher B. Little, Cosimo De Bari, Stephanie T Kuwahara, Francesca V. Mariani, M. Sambale, Joanna Smeeton, John F. Bateman, Roelofs, Anke J [0000-0001-8993-1984], Little, Christopher B [0000-0002-0353-7634], Bateman, John F [0000-0001-8542-0730], Mariani, Francesca V [0000-0003-1619-8763], Crump, J Gage [0000-0002-3209-0026], De Bari, Cosimo [0000-0002-5113-862X], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,experimental ,Immunology ,chondrocytes ,Osteoarthritis ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,fibroblasts ,Periosteum ,medicine ,Animals ,Immunology and Allergy ,Cell Lineage ,Progenitor cell ,business.industry ,Stem Cells ,Cartilage ,Synovial Membrane ,Mesenchymal stem cell ,Osteophyte ,medicine.disease ,Embryonic stem cell ,3. Good health ,osteoarthritis ,030104 developmental biology ,medicine.anatomical_structure ,arthritis ,Synovial membrane ,Stem cell ,business ,030217 neurology & neurosurgery - Abstract
ObjectivesOsteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA.MethodsFluorescent genetic cell-labelling and tracing mouse models were induced with tamoxifen to switch on reporter expression, as appropriate, followed by surgery to induce destabilisation of the medial meniscus. Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining and RNA in situ hybridisation. Pdgfrα-H2BGFP mice and Pdgfrα-CreER mice crossed with multicolour Confetti reporter mice were used for identification and clonal tracing of mesenchymal progenitors. Mice carrying Col2-CreER, Nes-CreER, LepR-Cre, Grem1-CreER, Gdf5-Cre, Sox9-CreER or Prg4-CreER were crossed with tdTomato reporter mice to lineage-trace chondrocytes and stem/progenitor cell subpopulations.ResultsArticular chondrocytes, or skeletal stem cells identified by Nes, LepR or Grem1 expression, did not give rise to osteophytes. Instead, osteophytes derived from Pdgfrα-expressing stem/progenitor cells in periosteum and synovium that are descendants from the Gdf5-expressing embryonic joint interzone. Further, we show that Sox9-expressing progenitors in periosteum supplied hybrid skeletal cells to the early osteophyte, while Prg4-expressing progenitors from synovial lining contributed to cartilage capping the osteophyte, but not to bone.ConclusionOur findings reveal distinct periosteal and synovial skeletal progenitors that cooperate to form osteophytes in OA. These cell populations could be targeted in disease modification for treatment of OA.
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- 2020
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30. Stem and Progenitor Cells in Synovium
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Anke J. Roelofs and Cosimo De Bari
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musculoskeletal diseases ,Stromal cell ,Cartilage ,Mesenchymal stem cell ,Osteoarthritis ,Biology ,medicine.disease ,Embryonic stem cell ,Cell biology ,medicine.anatomical_structure ,medicine ,Synovial fluid ,Stem cell ,Progenitor cell - Abstract
The synovium is a thin membrane that lines the cavity of synovial joints. It produces the synovial fluid for joint lubrication and cartilage nutrition. The adult synovium contains a heterogeneous population of mesenchymal stromal/stem cells (MSCs). A subset of MSCs in the joint that descends from the embryonic joint interzone naturally repairs articular cartilage defects in mice in vivo. MSCs in synovium are easy to access and attractive in regenerative cell-based therapy for cartilage repair and osteoarthritis via local delivery of exogenous MSCs or via pharmacological targeting of endogenous MSCs in the joint to trigger and enhance repair.
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- 2020
31. The burden of metabolic syndrome on osteoarthritic joints
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Anke J. Roelofs, Justin J. Rochford, Heather M. Wilson, Cosimo De Bari, and Bruce M. Dickson
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0301 basic medicine ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Knee Joint ,Macrophage ,Population ,Adipose tissue ,Adipokine ,mTORC1 ,Review ,03 medical and health sciences ,0302 clinical medicine ,Chondrocytes ,Adipokines ,Internal medicine ,Osteoarthritis ,medicine ,Humans ,Obesity ,education ,030203 arthritis & rheumatology ,Metabolic Syndrome ,education.field_of_study ,Adiponectin ,Catabolism ,business.industry ,Leptin ,Macrophages ,Synovial Membrane ,medicine.disease ,Chondrocyte ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,lcsh:RC925-935 ,Metabolic syndrome ,business - Abstract
Background The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes. Main text A skewing of macrophages towards a pro-inflammatory M1 phenotype within synovial and adipose tissues is thought to play a role in OA pathogenesis. The metabolic perturbations typical of MetS are important drivers of pro-inflammatory macrophage polarisation and activity. This is mediated via alterations in the levels and activities of the cellular nutrient sensors 5′ adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1), intracellular accumulation of metabolic intermediates such as succinate and citrate, and increases in free fatty acids (FFAs) and hyperglycaemia-induced advanced glycation end-products (AGEs) that bind to receptors on the macrophage surface. Altered levels of adipokines, including leptin and adiponectin, further influence macrophage polarisation. The metabolic alterations in MetS also affect the cartilage through direct effects on chondrocytes by stimulating the production of pro-inflammatory and catabolic factors and possibly by suppressing autophagy and promoting cellular senescence. Conclusions The influence of MetS on OA pathogenesis involves a wide range of metabolic alterations that directly affect macrophages and chondrocytes. The relative burden of intra-articular versus systemic adipose tissue in the MetS-associated OA remains to be clarified. Understanding how altered metabolism interacts with joints affected by OA is crucial for the development of further strategies for treating this debilitating condition, such as supplementing existing therapies with metformin and utilising ω-3 fatty acid derivatives to restore imbalances in ω-3 and ω-6 fatty acids.
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- 2019
32. Examination of muscle morphology and neuromuscular function in normal weight and overfat children aged 7-10 years
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Michael A. Trevino, Gena R. Gerstner, Erica J. Roelofs, Eric D. Ryan, Martin Kohlmeier, and Trent J. Herda
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Male ,Recruitment, Neurophysiological ,Muscle tissue ,medicine.medical_specialty ,Subcutaneous Fat ,Action Potentials ,Physical Therapy, Sports Therapy and Rehabilitation ,Electromyography ,Isometric exercise ,Overweight ,Quadriceps Muscle ,03 medical and health sciences ,0302 clinical medicine ,Isometric Contraction ,Internal medicine ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Muscle Strength ,Child ,Adiposity ,Ultrasonography ,medicine.diagnostic_test ,business.industry ,Skeletal muscle ,030229 sport sciences ,Confidence interval ,Motor unit ,medicine.anatomical_structure ,Torque ,Case-Control Studies ,Cardiology ,Female ,medicine.symptom ,business ,Body mass index ,030217 neurology & neurosurgery - Abstract
Neuromuscular function in young overweight/obese (OF) children is not well described. AIM This study examined isometric and isokinetic leg extensor strength, muscle size (mCSA) and tissue composition as measured via echo intensity (mEI), and motor unit (MU) firing rates in normal weight (NW) and OF children aged 7-10 years. METHODS Fourteen NW (eight girls and six boys, BMI: 15.8 ± 1.4 kg/m2 ) and 15 OF (10 girls and five boys, BMI: 20.8 ± 2.3 kg/m2 ) children volunteered to perform this study. Percentage body fat (%BF) was measured, and mCSA, mEI, and subcutaneous fat (sFAT) of the vastus lateralis (VL) was assessed. MU mean firing rates (MFRs) in relation to recruitment threshold (RT) of the VL were assessed during submaximal isometric contractions. Maximal isokinetic contractions were performed at 1.05 and 4.20 rad/s. The 95% confidence intervals (CI) from the statistical tests are presented. RESULTS The OF children had greater %BF (95% CI = -15.1 to -7.2), mCSA (95% CI = -4.1 to -1.2), mEI (95% CI = -22.3 to -5.9), and sFAT (95% CI = -0.5 to -0.1), greater rate of strength loss with increasing isokinetic velocities (95% CI = 0.4 to 5.4), and a smaller range of MFRs (95% CI = 0.007 to 7.136) at the steady torque than the NW children. CONCLUSIONS The OF children had poorer muscle tissue composition, greater velocity-related impairments in muscle strength, and a smaller range of MFRs at the targeted torque that may suggest altered MU recruitment strategies. Interventions in OF children should include exercises and recruit higher-threshold MUs, such as high-intensity resistance exercises.
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- 2018
33. Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis
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Cosimo De Bari and Anke J. Roelofs
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Cartilage, Articular ,0301 basic medicine ,Osteoarthritis ,Chondrocyte ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Regeneration ,Progenitor cell ,Autologous chondrocyte implantation ,Pharmacology ,030222 orthopedics ,business.industry ,Cartilage ,Mesenchymal stem cell ,Recovery of Function ,medicine.disease ,Chondrogenesis ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Stem cell ,business ,Signal Transduction ,Stem Cell Transplantation - Abstract
The gold standard cell therapy for repair of articular cartilage defects is autologous chondrocyte implantation, with good outcomes long-term. Mesenchymal stromal/stem cells (MSCs) from bone marrow or connective tissues such as fat are being pursued as alternatives for cartilage repair, and are trialled via intra-articular administration in patients with knee osteoarthritis. Early-phase clinical studies concur on safety and provide some promising insight into efficacy, but the mechanism of action remains unclear. Recent studies implicate extracellular vesicles as important mediators of MSC action, offering exciting therapeutic prospects. Our increasing understanding of the mechanisms underlying intrinsic articular cartilage maintenance and repair fosters hope that novel/repurposed therapeutics could elicit repair through activation of endogenous stem/progenitor cells to maintain healthy joints and prevent osteoarthritis.
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- 2018
34. Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease
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Robert Wallace, Mirela Delibegovic, Weiping Han, Bo Bai, Wulin Yang, George D. Mcilroy, Anke J. Roelofs, William P. Cawthorn, Karla J. Suchacki, Yanyun Fu, Justin J. Rochford, and Cosimo De Bari
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Male ,0301 basic medicine ,medicine.medical_specialty ,lcsh:Internal medicine ,Lipodystrophy ,BSCL2 ,Adipose tissue ,White adipose tissue ,Seipin ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Insulin resistance ,GTP-Binding Protein gamma Subunits ,Adipocyte ,Internal medicine ,Adipocytes ,medicine ,Animals ,lcsh:RC31-1245 ,Molecular Biology ,2. Zero hunger ,Adipogenesis ,CGL2 ,business.industry ,Cell Biology ,medicine.disease ,Heterotrimeric GTP-Binding Proteins ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,chemistry ,Original Article ,Browning ,Steatosis ,Energy Metabolism ,business - Abstract
Objective Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans. Here we examined whether loss of Bscl2 specifically in developing adipocytes in vivo is sufficient to prevent adipose tissue development and cause all features observed with congenital BSCL2 disruption. Methods We generated and characterised a novel mouse model of Bscl2 deficiency in developing adipocytes (Ad-B2(−/−)) using the adipose-specific Adiponectin-Cre line. Results We demonstrate that Ad-B2(−/−) mice display early onset lipodystrophy, in common with congenital Bscl2 null mice and CGL2 patients. However, glucose intolerance, insulin resistance, and severe hepatic steatosis are not apparent. Food intake and energy expenditure are unchanged, but Ad-B2(−/−) mice exhibit significantly altered substrate utilisation. We also find differential effects of seipin loss between specific adipose depots revealing new insights regarding their varied characteristics. When fed a high-fat diet, Ad-B2(−/−) mice entirely fail to expand adipose mass but remain glucose tolerant. Conclusions Our findings demonstrate that disruption of Bscl2 specifically in developing adipocytes is sufficient to cause the early-onset generalised lipodystrophy observed in patients with mutations in BSCL2. However, this significant reduction in adipose mass does not cause the overt metabolic dysfunction seen in Bscl2 knockout mice, even following a high-fat diet challenge., Highlights • Seipin loss only in developing adipocytes drives severe early-onset lipodystrophy. • This leads to significantly altered use of metabolic substrates. • We uncover developmental differences between poorly characterised adipose depots. • Despite severely reduced adipose mass mice do not show overt metabolic disease.
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- 2018
35. Vertical sleeve gastrectomy corrects metabolic perturbations in a low-exercise capacity rat model
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Steven L. Britton, Darleen A. Sandoval, Lauren G. Koch, Landon Wood, and Karen J. Roelofs
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0301 basic medicine ,Blood Glucose ,lcsh:Internal medicine ,medicine.medical_specialty ,Sleeve gastrectomy ,medicine.medical_treatment ,030209 endocrinology & metabolism ,White adipose tissue ,Carbohydrate metabolism ,Brief Communication ,Running ,03 medical and health sciences ,chemistry.chemical_compound ,Eating ,0302 clinical medicine ,Weight loss ,Gastrectomy ,Internal medicine ,Brown adipose tissue ,parasitic diseases ,medicine ,Animals ,lcsh:RC31-1245 ,Molecular Biology ,Exercise ,Triglycerides ,Adiposity ,2. Zero hunger ,Bariatric surgery ,business.industry ,Cholesterol ,Insulin ,Cell Biology ,Rats ,Oxygen ,030104 developmental biology ,medicine.anatomical_structure ,Postprandial ,Endocrinology ,Metabolism ,chemistry ,Female ,Basal Metabolism ,medicine.symptom ,business - Abstract
Objective Bariatric surgery is currently our most effective strategy at weight loss, yet the mechanisms for its success remain unknown. Low exercise capacity, in humans and rodents, predicts poor metabolic outcome. The objective of this manuscript was to determine if bariatric surgery could restore metabolic perturbations in rats with low intrinsic exercise capacity. Methods We performed vertical sleeve gastrectomy (VSG) or sham surgery in high fat-fed rats selectively bred for low running capacity. Results We found that VSG reduced body mass through a reduction in fat mass, caused early reductions in food intake, and shifted macronutrient preference away from fat and toward carbohydrates. VSG had no impact on basal glucose but did improve the return to baseline after an oral glucose load. As has been shown previously, VSG increased postprandial insulin, GLP-1, and bile acids. There was no significant impact of VSG on plasma triglycerides, hepatic triglycerides, or cholesterol. Interestingly, the brown adipose tissue to white adipose tissue ratio tended to be greater in VSG compared to sham surgery animals. While VSG positively impacted several aspects of metabolism, it did not enhance maximal oxygen capacity and seemed to lower metabolic efficiency as indicated by lower resting oxygen consumption and fat and carbohydrate oxidation. Conclusion VSG can improve the metabolic status of animals with a low exercise capacity independently of exercise capacity., Highlights • The mechanisms that underscore the success of bariatric surgery are unknown. • Low exercise capacity is associated with poor metabolism in humans and rodents. • Bariatric surgery improves body mass but lowers basal energy expenditure in LCR.
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- 2018
36. Infliximab Exerts No Direct Hepatotoxic Effect on HepG2 Cells In Vitro
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de Vries, Hilbert S., Heij, Tineke de, J. Roelofs, Henie M., M. te Morsche, Rene H., M. Peters, Wilbert H., and de Jong, Dirk J.
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- 2012
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37. OP0036 IL-6 ACTIVATES YES-ASSOCIATED PROTEIN (YAP) IN FIBROBLASTS AND INDUCES YAP-SNAIL COMPLEX FORMATION TO DRIVE SYNOVIAL LINING PATHOLOGY IN INFLAMMATORY ARTHRITIS
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Fabio Colella, Anke J. Roelofs, Fraser L. Collins, C. De Bari, and R. Symons
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musculoskeletal diseases ,Stromal cell ,biology ,business.industry ,Inflammatory arthritis ,Immunology ,Arthritis ,Proximity ligation assay ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,CTGF ,Rheumatology ,Cancer research ,medicine ,biology.protein ,Immunology and Allergy ,Immunohistochemistry ,Interleukin 6 ,business - Abstract
Background:In rheumatoid arthritis (RA), the fibroblast-like synoviocytes (FLS) in synovial lining become invasive and cause joint destruction. The molecular mechanisms underpinning this pathogenic FLS phenotype are incompletely understood. The FLS descend from Growth differentiation factor 5 (Gdf5)-expressing joint interzone cells in the embryo, and we showed that conditional ablation of the transcriptional co-activator Yes associated protein (Yap) in Gdf5-lineage cells prevents synovial lining hyperplasia after traumatic cartilage injury in mice [1].Objectives:Here, we investigated a potential role for Yap in pathogenic FLS in immune-mediated inflammatory arthritis.Methods:Immunohistochemistry was used to detect Yap in human RA synovium and Yap, Snail and Ctgf in mouse synovium following antigen-induced arthritis (AIA). To determine the effect of Yap knockout (KO) in synovial stromal cells, AIA was induced in Gdf5-Cre;tdTomato;Yapfl/fl (Yap cKO) and Gdf5-Cre;tdTomato;Yapwt/wt (control) mice, or in Pdgfrα-CreER;Yapfl/fl (Yap ciKO, targeting Pdgfrα-expressing fibroblasts) and Yapfl/fl or YapWT/fl (control) mice after adult tamoxifen induction. Yap KO in both models was confirmed by immunohistochemistry. After nine days, arthritis severity was determined by histological scoring of synovial lining hyperplasia, immune infiltrates, cellular exudate, and marginal erosions. TdTomato+ Gdf5-lineage cells in synovium were quantified. In vitro, Yap reporter cells were treated with inflammatory cytokines to evaluate their ability to stimulate Yap-induced GFP expression by flow cytometry. Snail overexpression, siRNA-mediated Yap knockdown, and IL-6/sIL-6R stimulation were performed on normal mouse FLS, AIA-FLS or human RA-FLS, and cell invasion through a matrigel-coated transwell was quantified. A proximity ligation assay was utilised to detect Yap/Snail complex formation.Results:Average expression levels of Yap (pGdf5-lineage synovial cells after AIA, with no significant difference between control and Yap cKO mice. In vitro, Yap knockdown prevented IL-6/sIL-6R-induced invasion of normal mouse FLS (p=0.037) and decreased the invasiveness of AIA-FLS (p=0.0057). Using Yap reporter cells, we found that Yap was activated by IL-6/sIL-6R (p=0.016), but not TNFα or IL-1β. Finally, IL-6/sIL-6R treatment of normal mouse FLS (p=0.033) or human RA-FLS (p=0.036) induced Yap-Snail complex formation, and Yap knockdown prevented FLS invasion induced by Snail overexpression (p=0.027).Conclusion:These data demonstrate that via activation by IL-6, and co-operation with the transcription factor Snail, Yap acts as a key modulator of the invasive and destructive phenotype of FLS in inflammatory arthritis. Therapeutic targeting of Yap could reduce joint destruction in RA.References:[1]A. J. Roelofs et al., “Joint morphogenetic cells in the adult mammalian synovium,” Nat. Commun., vol. 8, no. May, p. 15040, 2017. DOI: 10.1136/annrheumdis-2018-213799Acknowledgements:This work was funded by the Medical Research Council (MR/L020211/1 and MR/L022893/1) and Versus Arthritis (20775 and 21156).Disclosure of Interests:None declared
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- 2021
38. AB0039 AGRIN REPAIRS BONE AND CARTILAGE IN VIVO
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B.L. Thomas, Anke J. Roelofs, S.E. Eldridge, Ahmed Ali, Aida Barawi, K. Shanmuganathan, Magdalena Kaneva, Zeyu Guan, C. De Bari, Andrew McCaskie, S. Caxaria, Francesco Dell'Accio, Anne-Sophie Thorup, H. Wang, D. Strachan, Costantino Pitzalis, James R. Whiteford, Helen Lydon, Beatriz F. Fernandez, and Frances Henson
- Subjects
medicine.anatomical_structure ,Agrin ,Rheumatology ,In vivo ,business.industry ,Cartilage ,Immunology ,medicine ,Immunology and Allergy ,business ,General Biochemistry, Genetics and Molecular Biology ,Cell biology - Abstract
Background:Cartilage defects in the joints are reported in 61% of all arthroscopies1&2. The size of the cartilage repair market is estimated to be $2.195 million by 20253. Cartilage defects can evolve into osteoarthritis, in which abnormal load results in cartilage breakdown, joint pain and reduced mobility. Osteoarthritis is the leading cause of permanent disability and absenteeism and affects up to 1/3 of the people over 60yrs. In western countries osteoarthritis costs 1.5-2% of the GDP4. Joint replacement with a prosthesis restores some degree of independence but in up to 20% of patients it does not meet expectations 5 and has a limited life span. There is no pharmacological intervention that arrests or reverts the course of osteoarthritis, despite the desperate need.We previously published that agrin plays an important role in cartilage homeostasis6. The addition of agrin to chondrocytes in vivo resulted in enhanced cartilage formation, suggesting a potential role for agrin in cartilage repair.Objectives:Investigate the potential of agrin for use in cartilage repair.Methods:Critical size osteochondral defects were generated in mice and sheep and injected intraarticularly with type I collagen gel containing agrin or vehicle. Animals were monitored for 8 weeks or 6 months respectively. MicroCT, histological analysis, qPCR, linage tracking, reporter assays, chondrogenesis assay, immunohistochemistry were performed.Results:A single intraarticular administration of agrin induced regeneration of critical-size osteochondral defects in mice, restoring the tissue architecture and bone-cartilage interface. Agrin stem cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signalling, induced GDF5 expression and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, agrin treatment resulted in regeneration of bone and cartilage, which promoted increased ambulatory activity.Conclusion:Agrin orchestrates repair morphogenesis at the joint surface by modulating multiple signalling pathways, supporting the therapeutic use of agrin for joint surface regeneration.References:[1]Curl, W. W. et al. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 13, 456–460 (1997).[2]Hjelle, K., Solheim, E., Strand, T., Muri, R. & Brittberg, M. Articular cartilage defects in 1,000 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 18, 730–734 (2002).[3]Cartilage Repair Market Size, Share, Industry Analysis 2018-2025 | AMR. Allied Market Research https://www.alliedmarketresearch.com/cartilage-repair-market.[4]Hiligsmann, M. et al. Health economics in the field of osteoarthritis: an expert’s consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin. Arthritis Rheum. 43, 303–313 (2013).[5]Dieppe, P., Lim, K. & Lohmander, S. Who should have knee joint replacement surgery for osteoarthritis? Int. J. Rheum. Dis. 14, 175–180 (2011).[6]Eldridge, S., et al. Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in vivo. Annals of the rheumatic diseases 75 (6), 1228-1235 (2016).Acknowledgements:We thank the technical staff in the ARM Lab and Staff at the University of Aberdeen’s Animal Facility and Microscopy and Histology Facility for support. Funding: We gratefully acknowledge funding support of this work by the MRC (MR/L022893/1, MR/N010973/1,and MR/P026362/1), Versus Arthritis (19667, 21515, 20886, and 21621), Rosetrees Trust (A1205), the Medical College of St Bartholomew’s Hospital Trust, and the William Harvey Research Foundation.Disclosure of Interests:Suzanne Eldridge: None declared, Aida Barawi: None declared, Hui Wang: None declared, Anke Roelofs: None declared, Magdalena Kaneva: None declared, Zeyu Guan: None declared, Helen Lydon: None declared, Bethan Thomas: None declared, Anne-Sophie Thorup: None declared, Beatriz F Fernandez: None declared, Sara Caxaria: None declared, Danielle Strachan: None declared, Ahmed Ali: None declared, Kanatheepan Shanmuganathan: None declared, Costantino Pitzalis: None declared, James Whiteford: None declared, Fran Henson: None declared, Andrew McCaskie: None declared, Cosimo De Bari: None declared, Francesco Dell’Accio Consultant of: F.D. has received consultancy fees from Samumed and UCB.
- Published
- 2021
39. Anemia in young children living in the Surinamese interior
- Author
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A. J. Roelofs, C. W. R. Zijlmans, M. S. MacDonald-Ottevanger, A. Stuursma, and B. C. Jubitana
- Subjects
Gerontology ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,Anemia ,Ethnic group ,malnutrition ,Logistic regression ,RACIAL/ETHNIC DISPARITIES ,Maroon ,Amerindian ,children ,Medicine ,Original Research ,General Environmental Science ,business.industry ,General Engineering ,stunting ,Odds ratio ,Anthropometry ,hemoglobin ,medicine.disease ,anemia ,Confidence interval ,Research and Reports in Tropical Medicine ,nutritional status ,IRON-DEFICIENCY ,Malnutrition ,age ,ethnicity ,General Earth and Planetary Sciences ,Observational study ,younger age ,business ,Demography - Abstract
CWR Zijlmans,1 A Stuursma,2 AJ Roelofs,2 BC Jubitana,3 MS MacDonald-Ottevanger1 1Department of Mother & Child Health Care, Scientific Research Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname; 2Faculty of Medicine, University Medical Center Groningen, Groningen, the Netherlands; 3Department of Monitoring Evaluation Surveillance & Research, Medical Mission PHCS, Paramaribo, Suriname Purpose: This study investigates the prevalence of anemia in young children living in the interior of Suriname and the influence of the associated factors age, nutritional status and ethnicity. Patients and methods: In this cross-sectional observational study, 606 children aged 1–5years from three different regions of Suriname’s interior were included, and hemoglobin levels and anthropometric measurements were collected. Logistic regression models were computed to examine independent associations between anemic and nonanemic groups and to measure the influence of age, nutritional status and ethnicity. Results: A total of 606 children were included, of whom 330 (55%) were aged 1–3years and 276 were aged 4–5years. The overall prevalence of anemia was 63%. Younger age was associated with anemia (odds ratio [OR]=1.78; 95% confidence interval [CI]: 1.27–2.51). Anemia was less prevalent in Amerindian than in Maroon children (OR=0.51; 95% CI: 0.34–0.76). Hemoglobin level was not influenced by nutritional status nor by sex. Conclusion: The prevalence of anemia in children aged 1–5 years living in Suriname’s interior is high (63%) compared to that in similar aged children in Latin America and the Caribbean (4–45%). Children aged 1–3years were more affected than those aged 4–5 years as were Maroon children compared to Amerindian children. Nutritional status and sex were not of influence. Keywords: Maroon, Amerindian, hemoglobin, malnutrition, stunting, younger age
- Published
- 2017
40. Muscle cross-sectional area and motor unit properties of the medial gastrocnemius and vastus lateralis in normal weight and overfat children
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Jonathan D. Miller, Eric D. Ryan, Michael A. Trevino, Gena R. Gerstner, Trent J. Herda, Martin Kohlmeier, and Erica J. Roelofs
- Subjects
Male ,Recruitment, Neurophysiological ,medicine.medical_specialty ,Pediatric Obesity ,Physiology ,Medial gastrocnemius ,Action Potentials ,Electromyography ,Isometric exercise ,030204 cardiovascular system & hematology ,Muscle hypertrophy ,Quadriceps Muscle ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Child ,Muscle, Skeletal ,Exercise ,Nutrition and Dietetics ,medicine.diagnostic_test ,business.industry ,Ultrasound ,Body Weight ,General Medicine ,Intensity (physics) ,Motor unit ,Normal weight ,Cardiology ,Female ,business ,030217 neurology & neurosurgery - Abstract
New findings What is the central question of this study? Are differences in muscle size and motor unit properties between normal weight and overfat children muscle specific? What is the main finding and its importance? Muscle cross-sectional area and motor unit action potential amplitudes and firing rates were similar between overfat and normal weight children for both the medial gastrocnemius and vastus lateralis muscles. There was no evidence that the chronic mechanical overload provided by the greater body mass resulted in significant hypertrophy of contractile tissue or motor units that would be used during lower-to-moderate intensity activities. Abstract This study examined the possible differences in muscle cross-sectional area (mCSA), motor unit action potential amplitudes (MUAPAMPS ) and interspike intervals (ISIs) of the firing instances of the medial gastrocnemius (MG) and vastus lateralis (VL) between normal weight (NW) and overfat (OF) children aged 7-10 years. Fourteen NW (age = 8.6 ± 1.1 years, BMI = 15.8 ± 1.4 kg m-2 ) and 12 OF (age = 8.8 ± 0.9 years, BMI = 21.8 ± 2.4 kg m-2 ) children performed isometric trapezoidal muscle actions at 40% of maximal voluntary contraction of the plantar flexors and knee extensors. Surface electromyography was recorded from the MG and VL and decomposed into the firing events of motor units (MUs). Statistical procedures were performed on the composite recruitment thresholds (RTs), ISIs and MUAPAMPS of recorded MUs collapsed across subjects and the y-intercepts and slopes calculated from each subject's ISI and MUAPAMP vs. RT relationships. Ultrasound was used to assess mCSA, echo intensity (mEI), and subcutaneous fat (sFAT) of the MG and VL. The OF had greater mCSAs, mEI and sFAT (P = 0.004-0.024), but there were no differences in mCSA when accounting for mEI for the MG (P = 0.506) and VL (P = 0.326). The NW children had significantly greater composite MUAPAMPS for the VL and MG (P 0.05). These findings suggest that the OF children did not undergo significant muscle or MU hypertrophy that would be routinely activated during activities of daily living.
- Published
- 2019
41. Neuroimaging in Functional Movement Disorders
- Author
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Mark J. Edwards, Tiago Teodoro, and Jacob J. Roelofs
- Subjects
0301 basic medicine ,Agency (philosophy) ,Neuroimaging ,Dysfunctional family ,Imaging ,03 medical and health sciences ,Functional movement disorders ,0302 clinical medicine ,medicine ,Humans ,Psychogenic disease ,Functional movement disorder ,Conversion disorder ,Cognitive science ,Dyskinesias ,Movement Disorders ,Sense of agency ,Neuroimaging (N Pavese, Section Editor) ,General Neuroscience ,fMRI ,Brain ,Psychogenic ,Freudian slip ,medicine.disease ,030104 developmental biology ,Neurology (clinical) ,Psychology ,030217 neurology & neurosurgery ,MRI - Abstract
Purpose of Review Functional movement disorders are common and disabling causes of abnormal movement control. Here, we review the current state of the evidence on the use of neuroimaging in Functional movement disorders, particularly its role in helping to unravel the pathophysiology of this enigmatic condition. Recent Findings In recent years, there has been a shift in thinking about functional movement disorder, away from a focus on high-level psychological precipitants as in Freudian conversion theories, or even an implicit belief they are ‘put-on’ for secondary gain. New research has emphasised novel neurobiological models incorporating emotional processing, self-representation and agency. Summary Neuroimaging has provided new insights into functional movement disorders, supporting emerging neurobiological theories implicating dysfunctional emotional processing, self-image and sense of agency. Recent studies have also found subtle structural brain changes in patients with functional disorders, arguing against a strict functional/structural dichotomy.
- Published
- 2019
42. Immunostaining of Skeletal Tissues
- Author
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Anke J, Roelofs and Cosimo, De Bari
- Subjects
Mice ,Bone Demineralization Technique ,Paraffin Embedding ,Tissue Fixation ,Knee Joint ,Formaldehyde ,Animals ,Fluorescent Antibody Technique ,Frozen Sections ,Fluorescent Dyes - Abstract
Immunohistochemistry (IHC) is a routinely used technique in clinical diagnosis of pathological conditions and in basic and translational research. It combines anatomical, immunological, and biochemical methods and relies on the specific binding of an antibody to an antigen. Using the technique with mineralized tissues is more challenging than with soft tissues. Demineralizing the samples allows for embedding in paraffin wax, and also facilitates cryosectioning. This chapter describes methods for IHC on formaldehyde-fixed, demineralized, paraffin-embedded, or frozen sections to detect antigens in skeletal tissues.
- Published
- 2019
43. Immunostaining of Skeletal Tissues
- Author
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Anke J. Roelofs and Cosimo De Bari
- Published
- 2019
44. Diabetic Nephropathy : Pathophysiology and Clinical Aspects
- Author
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Joris J. Roelofs, Liffert Vogt, Joris J. Roelofs, and Liffert Vogt
- Subjects
- Diabetic nephropathies
- Abstract
This book provides an overview of the most up-to-date research on diabetic nephropathy and the current understanding of its pathogenesis, clinical features and socio-economic developments. Written by leading experts in the field, it provides a comprehensive synthesis of clinical and pathophysiological aspects from a mechanism-based point of view, and reviews evidence-based treatment modalities for the prevention and management of diabetic nephropathy. In addition, closely related areas such as diabesity, diabetic eye disease and macrovascular involvement in diabetes are addressed. Diabetic Nephropathy will be of interest for nephrologists, diabetologists, internists, transplant physicians, public health professionals, basic scientists, geneticists, epidemiologists, pathologists, and molecular and cell biologists working in the field of diabetes and its complications.
- Published
- 2019
45. Effects of pomegranate extract on blood flow and vessel diameter after high-intensity exercise in young, healthy adults
- Author
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Katie R. Hirsch, Abbie E. Smith-Ryan, Eric T. Trexler, Meredith G. Mock, and Erica J. Roelofs
- Subjects
Adult ,Male ,medicine.medical_specialty ,Physical Therapy, Sports Therapy and Rehabilitation ,030204 cardiovascular system & hematology ,Article ,Running ,Young Adult ,03 medical and health sciences ,Oxygen Consumption ,0302 clinical medicine ,Internal medicine ,medicine.artery ,Heart rate ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Brachial artery ,Leg press ,Exercise ,Oxygen saturation (medicine) ,Lythraceae ,Plant Extracts ,business.industry ,Hemodynamics ,030229 sport sciences ,General Medicine ,Blood flow ,Crossover study ,Surgery ,Blood pressure ,Sprint ,Cardiology ,Female ,business - Abstract
The effects of pomegranate extract (PE) supplementation were evaluated on high-intensity exercise performance, blood flow, vessel diameter, oxygen saturation (SPO2), heart rate (HR), and blood pressure (BP). In a randomized, crossover design, nineteen recreationally resistance trained participants were randomly assigned to PE (1000 mg) or placebo (PL), which were consumed 30 min prior to a repeated sprint ability (RSA) test and repetitions to fatigue (RTF) on bench and leg press. The RSA consisted of ten six-second sprints on a friction-loaded cycle ergometer with 30 s recovery. Brachial artery blood flow and vessel diameter were assessed by ultrasound. Blood flow, vessel diameter, SPO2, HR, and BP were assessed at baseline, 30 min post ingestion, immediately post exercise (IPost), and 30 min post exercise (30minPost). With PE, blood flow significantly increased IPost RSA (mean difference [MD]=18.49 mL·min−1; P
- Published
- 2016
46. Total And Regional Body Composition Of Ncaa Division I Female Soccer Athletes Through Competitive Seasons
- Author
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Christopher W. Bach, April Bockin, Tyler A. Bosch, Jonathan M. Oliver, Erica J. Roelofs, Donald R. Dengel, Aaron F. Carbuhn, and Philip R. Stanforth
- Subjects
Geography ,biology ,Athletes ,Physical Therapy, Sports Therapy and Rehabilitation ,Orthopedics and Sports Medicine ,Regional body composition ,Division (mathematics) ,biology.organism_classification ,Demography - Published
- 2020
47. Expression of growth and differentiation factor 5 during joint repair and osteoarthritis
- Author
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Francesco Dell'Accio, Anna H. K. Riemen, Terence D. Capellini, Karolina Kania, H. Wang, Anke J. Roelofs, Fabio Colella, C. De Bari, Kenneth A. Howard, and Thomas Aigner
- Subjects
Rheumatology ,Expression (architecture) ,business.industry ,Biomedical Engineering ,medicine ,Orthopedics and Sports Medicine ,Osteoarthritis ,medicine.disease ,Bioinformatics ,business ,Joint (geology) - Published
- 2020
48. Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding
- Author
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Ian E. Gonzalez, Henriette Frikke-Schmidt, Wenwen Cheng, James L. Trevaskis, Warren Pan, Christopher J. Rhodes, Jessica M. Adams, Randy J. Seeley, David P. Olson, Jonathan N. Flak, Andrew MacKinnon, Shuangcheng Wu, Darleen A. Sandoval, Desiree Gordian, Clemence Blouet, Simon S. Evers, Anthony H. Tsang, Karen J. Roelofs, So-ichiro Fukada, Ermelinda Ndoka, Martin G. Myers, Basma Khoury, Blouet, Clemence [0000-0002-1752-1270], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,NTS ,Male ,medicine.medical_specialty ,Food intake ,obesity ,Nucleus tractus solitarius ,Physiology ,Hindbrain ,Anorexia ,Biology ,Body weight ,Article ,03 medical and health sciences ,Eating ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,PBN ,calcitonin receptor ,Solitary Nucleus ,Gene silencing ,aversion ,Animals ,Calcitonin receptor ,Molecular Biology ,2. Zero hunger ,Mice, Knockout ,Neurons ,digestive, oral, and skin physiology ,Body Weight ,Cell Biology ,Receptors, Calcitonin ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,nervous system ,anorexia ,Female ,medicine.symptom ,Energy Metabolism ,030217 neurology & neurosurgery - Abstract
Summary To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decreased food intake and body weight but (unlike neighboring CckNTS cells) failed to promote aversion, revealing that CalcrNTS neurons mediate a non-aversive suppression of food intake. While both CalcrNTS and CckNTS neurons decreased feeding via projections to the PBN, CckNTS cells activated aversive CGRPPBN cells while CalcrNTS cells activated distinct non-CGRP PBN cells. Hence, CalcrNTS cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing CalcrNTS cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, CalcrNTS neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems., Graphical Abstract, Highlights • NTS Calcr mediates food intake suppression but not aversive responses to sCT • Activating NTS Calcr neurons non-aversively suppresses feeding • These neurons act via non-CGRP PBN neurons • These neurons control long-term energy balance, not just short-term feeding, While the hindbrain is often postulated to control only short-term parameters of feeding via circuits that mediate aversive responses when activated strongly, Cheng et al. have identified a hindbrain system that participates in the physiological control of energy balance and suppresses food intake without activating aversive systems or symptoms.
- Published
- 2020
49. GLP-1 Integrates the Innate Immune System to Glucose Homeostasis
- Author
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Michael Lehrke, Ellen M. Davis, Darleen A. Sandoval, Chelsea R. Hutch, Basma Maerz, Ki-Suk Kim, and Karen J. Roelofs
- Subjects
0301 basic medicine ,Null mice ,medicine.medical_specialty ,030109 nutrition & dietetics ,Innate immune system ,Lipopolysaccharide ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,medicine.disease ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Internal medicine ,Intensive care ,Internal Medicine ,medicine ,Glucose homeostasis ,Pancreas ,business ,Saline - Abstract
Glucagon-like peptide-1 (GLP-1) is a gut peptide that increases post prandially and functions to increase insulin secretion and improve glucose homeostasis. GLP-1 is coded by the preproglucagon gene (Gcg) and is expressed by intestinal and pancreatic cells. Interestingly, GLP-1 is also increased during sepsis, which is the most common cause of death in intensive care units (ICU). The goal of this study was to determine in a preclinical model of sepsis if the increase in GLP-1 was from intestinal or pancreatic cells. In order to model sepsis, we administered lipopolysaccharide (LPS) to Cre-control mice, to mice devoid of Gcg, and thus GLP-1 (Gcg null), to mice with Gcg expression reactivated only in the intestine (GcgRAδIntestine), and to mice with Gcg expression reactivated only in the pancreas (GcgRAδPancreas). LPS significantly increased GLP-1 in the control mice, as well as in the two reactivated genotypes compared to saline. However, the degree of the increase in both GcgRAδIntestine and GcgRAδPancreas mice was about 50% of control animals. LPS first increased, then significantly decreased blood glucose in control, pancreatic and intestinal reactivated mice but was significantly lower across all time points in Gcg null mice. These data suggest that both intestinal and pancreatic sources contribute to the increase in plasma GLP-1 seen in our model of sepsis. However, either pancreatic or intestinal sources of GLP-1 are sufficient to maintain glucose responses to LPS. Disclosure E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. K.J. Roelofs: None. M. Lehrke: Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi, Amgen Inc., Bayer AG, MSD K.K. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC..
- Published
- 2018
50. AB0148 Extracellular vesicle-mediated delivery of ebv small rna (EBER1) activates lupus nephritis related antiviral immunity in tubular epithelial cells via tlr3
- Author
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J. Roelofs, Alexandre E. Voskuyl, N. Groenewegen, K. de Wildt, N. Masoumi, R.J. ten Berge, R. Schiffelers, Sandra A. W. M. Verkuijlen, J. van Weering, K. Jordanova, K. Heutink, Monique A. J. van Eijndhoven, Jaap M. Middeldorp, Michiel Pegtel, M. Tsang a Sjoe, Irene E. M. Bultink, and R. Baglio
- Subjects
Autoimmune disease ,business.industry ,Lupus nephritis ,virus diseases ,Extracellular vesicle ,medicine.disease ,medicine.disease_cause ,Epstein–Barr virus ,Autoimmunity ,Immune system ,Interferon ,medicine ,Cancer research ,Cytokine secretion ,business ,medicine.drug - Abstract
Background In lupus nephritis (LN), genetic and environmental factors drive the chronic activation of antiviral defenses leading to immune complex-mediated glomerular and tubular damage. Increasing evidence suggests the involvement of extracellular vesicles (EVs) in autoimmune disease. Currently a role for EVs in the pathogenesis of lupus nephritis has not been proposed. Objectives To investigate the role of EVs in the pathogenesis of LN. Methods To determine the presence of EVs in kidneys, biopsies from LN patients and IgA- nephropathy and Focal Segmental Glomerulosclerosis control patients were used. Serum samples from SLE patients and from RA patients as controls were used to determine the presence of circulating EVs. Primary renal tubular epithelial cells (TEC) were cultured, and Kidney injury molecule-1 (KIM1) expression was assessed by FACS. Exosomes were analyzed by electron microscopy and western blot. mRNA analysis was performed by qPCR. TLR3 inhibition was performed with TLR3/dsRNA complex inhibitor and with hydroxychloroquine. Results We show that EVs deliver virus-derived small RNA and activate TEC via toll-like receptor 3 (TLR3). Highly specific stem-loop RT-PCRs revealed Epstein Barr Virus (EBV)-encoded small RNAs in LN biopsies while quantitative EBV-DNA PCR, sensitive to a single copy was negative. In situ hybridization failed to detect nuclear EBV-EBER1 (i.e. EBV-infected cells) in LN biopsies. However, we observed atypical EBER signal in the cytoplasm of TECs in LN but not in disease control biopsies, suggestive of uptake of extra-renal EBER. Consistent with this, we detected EBER1 in circulating EVs of SLE sera. The LN tissues express strongly elevated levels of TLR3, Interferon induced transmembrane-1 and -3, and TNFα. Primary TEC cultured in vitro endocytose EBER1-EVs secreted by EBV-infected B cells via phosphatidylserine receptors such as KIM-1. Importantly, EV-EBER1 uptake by TEC triggers antiviral immunity and pro-inflammatory cytokine secretion in a Toll-like receptor 3 (TLR3)-dependent manner. Treatment with hydroxychloroquine (HCQ) or a small molecule inhibitor that blocks TLR3-RNA interactions strongly reduced the pro-inflammatory effects of EBER1. Conclusions We propose that small RNA-loaded EVs exacerbate pre-existing autoimmunity in SLE patients by engaging tubular epithelial TLR3, supporting the rationale for TLR3-blockade as therapeutic strategy in the treatment of lupus nephritis. Disclosure of Interest None declared
- Published
- 2018
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