bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone marrow activation in response to metabolic syndrome and early atherosclerosis
Authors: Devesa Ana , Lobo-González Manuel , Martínez-Milla Juan , Oliva Belén , García-Lunar Inés , Mastrangelo Annalaura , España Samuel , Sanz Javier , Mendiguren José M , Bueno Hector , Fuster Jose J , Andrés Vicente , Fernández-Ortiz Antonio , Sancho David , Fernández-Friera Leticia , Sanchez-Gonzalez Javier , Rossello Xavier , Ibanez Borja , Fuster Valentin 
Published: February 2022

Abstract

Aims
Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis.

Methods and results
Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8–53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3–L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P &lt; 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis—characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts—and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden).

Conclusion
In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.
[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].
Long-Term Trajectories of Frailty and Its Components After Kidney Transplantation
Authors: Chu Nadia M , Ruck Jessica , Chen Xiaomeng , Xue Qian-Li , Norman Silas P , Segev Dorry L , McAdams-DeMarco Mara A 
Published: February 2022

Abstract

Background
Frailty is common and associated with poor outcomes among kidney transplant (KT) recipients. While frailty improves in the first 3 months post-KT with restored kidney function, longer-term trajectories are likely to plateau/decline due to aging and other stressors (eg, immunosuppression). We evaluated longer-term post-KT trajectories of the physical frailty phenotype (PFP) and its components in adult patients at 2 centers.

Methods
PFP components were measured at admission, 1, 3, 6 months, 1 year, and annually thereafter post-KT. We used adjusted mixed-effects models to describe repeated measures of continuous components (weight, gait speed, grip strength, activity) and generalized estimating equations to quantify longitudinal, binomial response patterns (PFP; exhaustion).

Results
Among 1 336 recipients (mean age = 53) followed for a median of 1.9 years (interquartile range [IQR] = 0.1–3.2), likelihood of frailty declined in the first 2.5 years post-KT (adjusted odds ratio [aOR] = 0.96, 95% confidence interval [CI]: 0.95, 0.98), but increased after 2.5 years post-KT (aOR = 1.03, 95% CI: 1.00, 1.05). In the first 2.5 years post-KT, recipients demonstrated increases in weight (0.4 lbs/month, 95% CI: 0.3, 0.5), grip strength (0.2 kg/month, 95% CI: 0.1, 0.2), and activity (23.9 kcal/month, 95% CI: 17.5, 30.2); gait speed remained stable (−0.01 s/month, 95% CI: 0.01, 0.003). Additionally, likelihood of becoming exhausted declined post-KT (OR = 0.99, 95% CI: 0.98, 1.00). After 2.5 years post-KT, recipients demonstrated decreased grip strength (−0.07 kg/month, 95% CI: −0.12, −0.01) and activity (−20 kcal/month, 95% CI: −32.3, −8.2); they had stable weight (−0.003 lbs/month, 95% CI: −0.17, 0.16), gait speed (−0.003 s/month, 95% CI: −0.02, 0.01), and likelihood of becoming exhausted (OR = 1.01, 95% CI: 0.99, 1.02).

Conclusion
Despite frailty improvements in the first 2.5 years, recipients’ frailty worsened after 2.5 years post-KT. Specifically, they experienced gains in strength, activity, and exhaustion in the first 2.5 years post-KT, but declined in strength and activity after 2.5 years post-KT while experiencing persistent slowness. Clinicians should consider monitoring recipients for worsening frailty after 2.5 years despite shorter-term improvements.
The Moho reflectivity of the subduction beneath the Southwestern Alps from ambient seismic noise autocorrelations
Authors: Ashruf T N , Morelli A 
Published: February 2022

SUMMARY
The Western Alps shows a complex crustal organization due to the subduction of the European Plate beneath the Adriatic Plate and exhumation of the mantle wedge. The lithospheric structure of the Western Alps, that may hold significance for understanding orogenic processes and evolution, has been the subject of many geophysical studies, but the Moho profile remains unclear and this has led to controversies about the depth and extent of the European Plate beneath the Adriatic Plate. With the goal of retrieving detailed information on crustal constitution, we use autocorrelation of seismic ambient noise as a tool to map the body wave reflectivity structure at the subduction zone under the southwestern Alps. We use data recorded by the China–Italy–France Alps (CIFALPS) seismic transect, that includes 45 stations located approximately 5–10 km apart along a profile crossing the Alpine continental subduction in the Western Alps. We analyse the data set in four different frequency bands between 0.09 and 2 Hz. We automatically pick the arrival time of the Moho reflection in the second derivative of the envelope of the autocorrelation stack using prior Moho information. The 0.5–1 Hz frequency band mostly gives the best result due to the clear changes in reflectivity along the waveforms of the autocorrelation stacks after the picked arrival times of the Moho reflections. We find spatial coherence between 18 and 23 km depth in the western portion of the profile, indicating relatively homogeneous crustal rocks, and highly reflective structure under the central mountain range, due to the existence of a highly faulted zone. The very thin crust and the underlying mantle wedge known as the Ivrea body show instead high transparency to seismic waves and absence of reflections. The subduction profile of the European Plate shows a steep trend as compared to previous studies. We discuss autocorrelation stacks and Moho depths obtained from the arrival times of the picked reflectivity change in comparison with previous studies to validate the different reflection structures. Stacked ambient noise autocorrelations reliably image varied crustal properties and reflectivity structures in the highly heterogeneous region of the southwestern Alps.
A3 TARGETING PROLINE METABOLISM TO OVERCOME TREATMENT RESISTANCE IN ESOPHAGEAL CANCER
Authors: Douchin J , Nogueira de Almeida L , Gonneaud A , Boisvert F , Dufour A , Giroux V 
Published: February 2022

Abstract

Background
Patients with esophageal malignancy have a 5-year survival rate of only 14% in Canada. This high mortality rate is due to three factors: late diagnosis, difficulty to surgically remove the tumor due to its localization and treatment resistance. Treatment resistance has been ascribed to the presence of cancer stem cells (CSCs) inside the tumor. However, no treatment specifically directed against CSCs is available to patients. Therefore, targeting CSCs is a promising strategy to improve survival of patients with esophageal squamous cell carcinoma (ESCC), the most common type of esophageal cancer worldwide.

Aims
Herein, we developed an unbiased approach to identify new players in chemotherapy and radiotherapy resistance in ESCC.

Methods
We established radioresistant (RR), chemoresistant (CR) and radiochemoresistant (RCR) human ESCC cell lines using weekly radiation and/or continuous treatment with increasing doses of chemotherapeutic agent 5-FU. We validated that the process of resistance acquisition correlates with enrichment in CSCs as revealed by higher ALDH1 expression, and increased proportion of ALDH1high cells and CD24high/CD44high cells in flow cytometry. We then used a proteomic approach to identify new players in treatment resistance.

Results
Interestingly, pathway analysis demonstrated enrichment in energy metabolism as well as amino acid metabolism. Seahorse assays showed a more quiescent metabolism in all three types of resistant cells compared to the control cell line. More precisely, resistant cell lines have a lower respiration rate than control cell line, while glycolysis remains unchanged. Surprisingly, our results show a metabolic rewiring very different from the well-known Warburg effect. To further characterise these metabolic changes, we performed an unbiased metabolomic pilot study and confirmed a decrease in amino acid levels such as proline, in resistant cell lines. Preliminary data show that when cultured in DMEM with proline addition, CD44high/CD24high cell proportion is decreased in control and RR cell lines suggesting that proline is a key regulator of CSC population in ESCC.

Conclusions
To conclude, our results suggest an important role of metabolism in ESCC treatment resistance. This study is a first step towards the identification of new targets to fight treatment resistance in ESCC patients.

Funding Agencies
CAG, CIHRCanada research chair TIER 2
A7 FOXL1+ TELOCYTES IN MOUSE COLON ORCHESTRATE ECM BIODYNAMICS AND WOUND REPAIR RESOLUTION
Authors: Pomerleau V , Reyes-Nicolas V , Jurkovic C , Boisvert F , Perreault N 
Published: February 2022

Abstract

Background
The extracellular matrix (ECM) is a complex assembly of proteins that provide mechanical and biochemical stimuli to the epithelial and mesenchymal cells of the GI mucosa. Deficiencies in ECM assembly, protein production or excessive accumulation can lead to multiples pathologies including fibrosis and cancer. FoxL1+-Telocytes (TCFoxL1+) are subepithelial cells that form a network underneath the epithelium, contributing to the microenvironment that supports epithelial and immune cell homeostasis. We have previously shown that BMPR1A signaling deletion in TCFoxL1+ influences the microenvironment via stromagenesis, immune infiltration and colonic dysplasia in mouse model of GI diseases. However, the precise molecular and mechanical events that contributes to the onset of this state have yet to be elucidated.

Aims
Characterize the modulations in ECM biodynamics induced by BmpR1a-deficient TC FoxL1+ ( BmpR1a△FoxL1+) in mouse colon submucosa.

Methods
Matrisomics was performed to determine the inventory of ECM proteins expressed solely in the GI stromal compartment following tissue deconstruction of control and BmpR1a△FoxL1+ mice colons. Histological and biochemical methods were used to further characterize the collagen network and matrisome-associated modulations. Fluorescence In Situ Hybridization (FISH) was performed to study the bacterial presence in the mucosa.

Results
The set of identified proteins shows an enrichment for proteins involved in collagen network regulation, wound repair homeostasis and immune regulation such as Col1a2, Col3a1, Col6a4 and Coll14a1, as well as SerpinH1, MFAP4, ANXA1 and S100A9. Collagen network is affected with increased deposition and reorganization of fiber alignment. Unfolded collagen content was also increased in dysplastic areas of BmpR1a△FoxL1+ mouse colon with a concomitant increase in the collagen-chaperone SerpinH1. Validations of other targets indicate that BmpR1a△FoxL1+ mice deals with some type of tissue micro-injury and inflammation that is unresolved, creating a unfavorable microenvironment for tissue homeostasis.

Conclusions
Taken together, these results suggest that Bmp-signaling deficient TCFoxL1+ significantly contribute to the collagen network biodynamics through increased collagen deposition, fiber alignment reorganization and regulation of the collagen triple-helix assembly. Other matrisome modulations suggest a state of unresolved wound healing due to tissue injury, that could be the etiology of GI pathology and lead to more severe conditions upon various environmental triggers.

Funding Agencies
CIHR
A11 ISOLATION OF NON-POLAR METABOLITES IN EXCRETORY/SECRETORY PRODUCTS FROM PARASITIC HELMINTHS AND THEIR POTENTIAL AS IMMUNOTHERAPY IN INFLAMMATORY BOWEL DISEASE
Authors: Siciliani E A , Leroux L , Tam M , Arai T , Urban J F , Martin R J , Geary T G , Stevenson M , Lopes F , Jardim A 
Published: February 2022

Abstract

Background
Parasitic helminths are known to modulate host immune responses. This is thought to be mediated by their secretome. We are interested in the excretory/secretory products and mechanisms for modulating immune dysfunction in autoinflammatory diseases.

Aims
This research studies the mechanisms of immune modulation by parasitic helminths in the context of IBD. We aim to describe immunomodulatory helminth-derived metabolites (ESM).

Methods
Helminth-conditioned media was used to isolate ESM, which were further purified using column chromatography.
Bone marrow (BM) derived macrophages (BMDM) from C57BL6 mice, were treated with ESP fractions from Trichuris suis, Ascaris suum, Heligmosomoides polygyrus bakeri or Dirofilaria immitis, stimulated with LPS, and secreted cytokine levels measured. Moreover, BM was cultured with or without ESM throughout differentiation to BMDM.
Colitic mice (3% DSS, 5 days) were treated with A. suum ESM or PBS once daily IP. Colon lengths and TNFα mRNA were measured, and histological preparations were scored to assess pathology.
Bioactive D. immitis ESM were fractionated using preparatory HPLC and assayed for bioactivity. Active fractions were analysed using MS/MS and fragmentation patterns and molecular weights were obtained. The active fractions are currently being studied by NMR to deduce a structure of an active metabolite.

Results
BMDM treated with crude ESM decreased TNFα secretion and increased IL-10. BMDM precursors which were treated with A. suum ESM throughout differentiation had reduced proliferation in a dose dependent manner. These BMDM showed remodeling of BMDM metabolic pathways. Intracellular ROS production was inversely proportional to Alamar blue oxidation.
We found that ESM from A. suum improved DSS-colitis. Specifically, mice with DSS-induced colitis given IP ESM had longer colons, lower histolopathology score, and lower TNFα mRNA expression in gut tissue.
HPLC-fractionated D. immitis ESM used to treat BMDM yielded varying suppression of TNFα with LPS stimulation. MS/MS of TNFα suppressive fractions contained masses with fragmentation patterns which were detected in fractions of several of the above-mentioned parasite species. Preliminary NMR studies will determine if this represents a conserved structure.

Conclusions
Helminth-derived components can immunologically polarize a response in vitro, as well as favour recovery in DSS colitis. Through multiple purification steps, a nearly pure fraction is found to have bioactivity, suggesting a single, bioactive molecule that is conserved across several parasitic helminths. These data are important in understanding the host-parasite interaction modulated by ESM, as well as provide therapeutic potential in IBD.

Funding Agencies
NSERC, FRQNT
A14 THE INTESTINAL MICROBIOTA CONTRIBUTES TO AGE-RELATED MEMORY DECLINE
Authors: Kraimi N , De Palma G , Lu J , Bowdish D , Verdu E , Sibille E , Prevot T , Collins S M , Bercik P 
Published: February 2022

Abstract

Background
Age-related deterioration of cognitive function and memory capacity occur in both humans and rodents. For example, significant memory deficits have been reported in conventionally raised (SPF) old mice compared to conventionally raised young mice submitted to a spatial memory task (Prevot et al., 2019, Mol Neuropsychiatry 5, 84–97). Microbiota-to-brain signaling is now well established in mice and humans, but the extent to which it influences age-associated memory decline is unknown.

Aims
Our study examines whether the intestinal microbiota contributes to age-associated changes in brain function. We address the specific hypothesis that age-associated cognitive decline is attenuated in the absence of the intestinal microbiota.

Methods
We assessed anxiety-like and depressive-like behavior, locomotor activity and spatial memory performance in young germ-free (GF) mice (2–3 months of age, n=24) and senescent GF mice (13–27 months old, n=22) maintained in axenic conditions, and compared them to conventionally raised (SPF) mice of the same age. Anxiety-like behavior, locomotor activity and depressive-like behavior were measured using the light-dark preference, open-field, and tail suspension tests. We also used the Y-maze test based on a spontaneous alternation task to assess cognition, with the alternation rate as a proxy of spatial working memory. The age-associated inflammation was assessed with IL-6 cytokine plasma concentrations measured by ELISA.

Results
Anxiety-like behavior and depressive-like behavior did not change with the age regardless of the microbial status. However, old SPF mice traveled less distance (866.8 cm) than young SPF mice (1375 cm, p &lt; 0.01) in the open-field. Similarly, old GF mice also traveled less distance (458.9 cm) than young GF mice (875.7 cm, p &lt; 0.0001). In contrast to old SPF mice, old GF mice did not show memory impairment in the spatial memory task. Indeed, old SPF mice displayed lower alternation rate of 58.3%, compared to that found in young SPF mice (76.9%, p &lt; 0.05) while both old and young GF mice had an identical alternation rate of 73.3% ( p &gt; 0.05). In addition, IL-6 plasma levels revealed that old GF mice did not show signs of age-associated inflammation that was evident in old SPF mice (3.68 vs. 13.93 pg/ml, p &lt; 0.05).

Conclusions
We conclude that the absence of age-related memory deficit in old germ-free mice is consistent with a role for the microbiota in age-related cognitive decline, likely mediated via the immune system, as suggested by the absence of age-associated inflammation in germ-free mice. We propose that novel microbiota-targeted therapeutic strategies may prevent or delay the cognitive decline of aging.

Funding Agencies
CIHRBalsam Family Foundation
A17 TRP53 REGULATES ESLF-RENEWAL AND CELL DIFFERENTIATION IN KRT15+ INTESTINAL STEM CELLS
Authors: Dubey A , Gonneaud A , Giroux V 
Published: February 2022

Abstract

Background
Different pools of stem cells assure the intestinal epithelium homeostasis and regeneration. We recently reported that Krt15+ intestinal cells harbor self-renewal, multipotent and regenerative capacities, characteristics consistent with a stem cell population. p53 has been associated with the development of various types of cancer, and recent studies suggested it also regulates adult stem cell behavior in some tissues. However, its role in the maintenance of intestinal stem cells has not been explicitly covered. Therefore, we hypothesize that Trp53 loss specifically in Krt15+ intestinal stem cells will perturb the epithelial homeostasis and differentiation.

Aims
Identify the role of Trp53 in the regulation of intestinal stem cell and intestinal homeostasis

Methods
To induce Trp53 loss specifically in Krt15+ cells, we generated Krt15 CrePR1;Trp53fl/fl ( Krt15△Trp53) mice and induced Cre recombination by injecting RU486 (PR agonist). Mice were euthanized after Cre recombination at different time points. Organoid cultures were established from control and experimental mice.

Results
Two-month post Cre recombination, we observed no major morphological changes in the intestinal epithelium. However, we observed that crypts isolated from Krt15△Trp53 mice died rapidly and had difficulties forming organoids. When hyperactivating the Wnt/beta-catenin pathway through CHIR treatment, we observed that budding capacity was maintained in experimental organoids while control organoids formed mainly cysts as expected. We also observed an increased in Paneth cell-specific genes, suggesting an enrichment in Paneth cells. Interestingly, the expression of EpHB2 receptor and its target genes was decreased in organoids derived from Krt15△Trp53 mice. Ephrin signaling plays a crucial role in intestinal homeostasis by regulating cell position and migration, and previous studies suggest that ephrin receptors are a target of p53. Indeed, twelve-month post Cre recombination, altered architecture of crypt and villi was noted in the small intestinal epithelium of Krt15△Trp53 mice. Differentiation towards secretory cell types, specifically Paneth, goblet, and tuft cells, are significantly increased in Krt15△Trp53 mice. Interestingly, we also observed crypt cells expressing both goblet and Paneth cell markers suggesting dysfunction in the cell fate decision. Finally, decreased Notch pathway activation was also observed supporting that Trp53 loss, specifically in Krt15+ cells, leads to a dysregulation of secretory cell fate.

Conclusions
Loss of Trp53 specifically in Krt15+ cells affects the small intestinal homeostasis and secretory cell differentiation. Decreased Notch and ephrin signaling support the possible role of Trp53 in cell fate decision and self-renewal.

Funding Agencies
None