bluuebunny/crossref_metadata_2025_split huggingface dataset:
How Helping You Helps Me: A Longitudinal Analysis of Volunteering and Pathways to Quality of Life Among Older Adults in Singapore
Authors: Ang Shannon , Malhotra Rahul 
Published: February 2024

Abstract

Objectives
Volunteering is known to be associated with well-being among older adults. However, less is known about the psychosocial pathways (e.g., personal mastery, social support) through which this occurs, with past studies tending to rely on cross-sectional data, which are susceptible to selection biases. This study, using longitudinal data, investigates how formal and informal volunteering may affect older adults’ quality of life through personal mastery, perceived social support, and received social support.

Methods
Data are from 2 waves of a nationally representative study of older adults aged 60 years and older in Singapore, conducted between 2016 and 2019 (N = 2,887). We estimate indirect effects using a 2-wave mediation model, relying on bootstrapped confidence intervals for significance testing.

Results
We find indirect effects from volunteering to quality of life through perceived social support and personal mastery, but not through received social support. While any type (formal/informal) and frequency (regular/nonregular) of volunteering promotes quality of life through perceived social support, indirect effects through personal mastery are limited to regular volunteering in formal settings.

Discussion
Results provide longitudinal evidence for perceived social support as a key pathway from volunteering to quality of life. Volunteering may be an effective way to improve quality of life by helping older adults feel more supported, even if it may not affect the actual help that they receive. Further, a structured and sustainable environment may be required for volunteering to promote personal mastery (and through it, quality of life) among older volunteers.
The Association Between Cognitive Reserve and Cognitive Trajectories Among Older Adults
Authors: Khalaila Rabia , Dintica Christina , Yaffe Kristine 
Published: February 2024

Abstract

Background and Objectives
Prior studies on cognitive reserve (CR) and cognitive trajectories are limited and have had conflicting results. Furthermore, most studies have used a single measure of CR that may not reflect a comprehensive exposure. The objective of this study is to determine the impact of individual and composite CR measures on cognitive decline over a 6-year period.

Research Design and Methods
We studied 55,340 participants from 16 European countries, aged 50 and older, who participated in the Survey of Health, Aging, and Retirement in Europe. We used cognitive measures (including immediate memory, delayed memory, verbal fluency, and numeracy) and 3 CR factors (education, occupation, and cognitive activities) collected in 4 waves from 2011 to 2017. Structural equation modeling was used to construct the composite CR score, analyzed as tertile. Linear mixed-effect models were used to examine the study aims.

Results
At baseline, the highest composite CR tertile was associated with a higher cognition score than the middle and lowest CR tertiles (β: −0.28, 95% confidence interval [CI]: −0.29 to −0.26; β: −0.71, 95% CI: −0.72 to −0.70, respectively), as well as for all individual cognitive domains. At longitudinal results, compared with the lowest CR, the highest but not the middle CR tertile demonstrated a slower 6-year decline in global cognition (β: −0.02, 95 % CI: −0.03 to −0.01), as well as in all cognitive domains (p &lt; .05).

Discussion and Implications
A composite CR could be a protective factor for cognitive performance and cognitive decline, and it is more sensitive and inclusive than an individual CR indicator alone.
Molecular cloning, characterisation and molecular modelling of two novel T-synthases from mollusc origin
Authors: Zemkollari Marilica , Oostenbrink Chris , Grabherr Reingard , Staudacher Erika 
Published: February 2024

Abstract
The glycoprotein-N-acetylgalactosamine β1,3-galactosyltransferase, known as T-synthase (EC 2.4.1.122), plays a crucial role in the synthesis of the T-antigen, which is the core 1 O-glycan structure. This enzyme transfers galactose from UDP-Gal to GalNAc-Ser/Thr. The T-antigen has significant functions in animal development, immune response, and recognition processes. Molluscs are a successful group of animals that inhabit various environments, such as freshwater, marine, and terrestrial habitats. They serve important roles in ecosystems as filter feeders and decomposers but can also be pests in agriculture and intermediate hosts for human and cattle parasites. The identification and characterization of novel carbohydrate active enzymes, such as T-synthase, can aid in the understanding of molluscan glycosylation abilities and their adaptation and survival abilities. Here, the T-synthase enzymes from the snail Pomacea canaliculata and the oyster Crassostrea gigas are identified, cloned, expressed, and characterized, with a focus on structural elucidation. The synthesized enzymes display core 1 β1,3-galactosyltransferase activity using pNP-α-GalNAc as substrate and exhibit similar biochemical parameters as previously characterised T-synthases from other species. While the enzyme from C. gigas shares the same structural parameters with the other enzymes characterised so far, the T-synthase from P. canaliculata lacks the consensus sequence CCSD, which was previously considered indispensable.
A2 UVB ON SKIN EXPOSURE MODULATES INTESTINAL HOMEOSTASIS IN MICE
Authors: Jimenez Sanchez M C , Yang H , Dutz J , Sham H , Vallance B 
Published: February 2024

Abstract

Background
Inflammatory diseases, like IBD, are on the rise in Western societies, in concert with changes in the environment, such as reduced sun exposure. Ultraviolet light (UV) B's effects on the skin include upregulating vitamin D and Aryl hydrocarbon receptor (Ahr) signalling, but its potential influence on distant sites, like the gut, are not well-studied. The gut and skin share a strong link, with some GI patients also experiencing skin diseases (O’Neill et al., 2016). We sought to understand how UVB exposure affects gut health, gut microbiota and its metabolic by-products. We hypothesize that UVB will have a significant impact on gut health.

Aims
Test the effect of UVB light using vitamin D deficient (-) and sufficient (+) diets.
Elucidate Ahr activation in the small intestine and colon after UVB exposure.
Explore the gut metabolome after UVB exposure.

Methods
Female C57BL/6 mice were fed vit D (+) or (-) diets, anaesthetized, and then 8 cm2 of their dorsal skin was shaved and exposed to UVB (250 mJ/cm2, 234 sec, 311 nm). One single dose (sample collection after 4 or 10 h) or chronic dosage (9 days every other day). Mice were euthanized to collect serum, cecal content, and stool samples (HILIC negative profile and 16S sequencing). EROD assay was used to test Ahr activation of CYP1A1.

Results
UVB exposure did not cause skin inflammation, but instead induced photoadaptation. When mice with vit D (-) diets were exposed to UVB, their vit D levels rose to match those on vit D (+) diets. Intestinal luminal contents induced a significant 3X increase in Ahr activation at 10 h post-exposure. After chronic UVB exposure, Ahr/CYP1A1 activity increased in Peyer’s patches (p=0.0012) and colon (p=0.01). Serum levels of AhR agonist metabolites post-UVB exposure showed significant increases in kynurenine and indole-3-acetic acid (IAA) at 10 h, while in the feces, Tryptophan levels decreased (p=0.042), but IAA significantly increased (p=0.006). IAA is a known Ahr ligand and produced by gut microbiota when they metabolize Tryptophan, indicating a microbiota response to UVB skin exposure. This was accompanied by an increase in the short chain fatty acids (butyrate, propionate, acetic acid) as well as other metabolites, despite no overt changes in microbiota composition. After 9 days of UVB, significantly increased numbers of goblet cells/crypt in both the ileum and colon.

Conclusions
Our study demonstrates that UVB exposure on the skin leads to increased vitamin D serum levels and Ahr activation along the gastrointestinal tract. It also induces potentially beneficial metabolic changes in the gut microbiota and differentiation of the gut epithelium, highlighting sun exposure's potential intestinal health benefits.

Funding Agencies
CCC, CIHR, None
A4 DNA HYPOMETHYLATION INHIBITS COLITIS-ASSOCIATED CANCER
Authors: Larsen F , Good H , Shin A , Derouet M , Zhang L , Castellani C , Asfaha S 
Published: February 2024

Abstract

Background
Colorectal cancer is the second leading cause of cancer death in Canada. A major risk factor for the development of colorectal cancer is chronic inflammation leading to colitis-associated cancer (CAC). We previously described a CAC mouse model in which tumors arise from DCLK1+ cells following loss of the tumor suppressor adenomatous polyposis coli (APC) and induction of colitis. Interestingly, both colitis and CAC are associated with DNA methylation changes that lead to altered gene expression. Moreover, inhibition of DNA methylation has recently been shown to lead to a viral mimicry response. The effects of DNA methylation on colonic tumorigenesis, however, is not known.

Aims
Thus, we aim to investigate whether inhibition of DNA methylation leads to a viral mimicry response that inhibits colitis-associated tumorigenesis.

Methods
We first examined the effects of DNA hypomethylation on CAC, by crossing Dclk1-CreERT2/Apcf/f mice to Dnmt1f/f mice which allowed for knock-out of the DNA methyltransferase enzyme DNMT1 in DCLK1+ cells. Dclk1/Apcf/f/Dnmt1f/f and Dclk1/Apcf/f (control group) mice were administered three doses of tamoxifen followed by 2.5% dextran sodium sulfate (DSS) for five days to induce colitis. Fourteen weeks later, we assessed colonic tumor number and size. In a separate cohort of Dclk1/Apcf/f mice treated with DSS, we compared colonic tumor number in mice treated with six doses of 5-AZA-2’-deoxycytidine (5-AZA) versus vehicle. The effects of 5-AZA and DSS on DNA methylation were assessed using the Infinium Mouse Methylation BeadChip Array on colonic epithelial cells isolated from mice treated with vehicle versus 5-AZA in the presence or absence of colitis. RNA expression of viral transposable elements and type I interferon response related genes were measured as a readout of a viral mimicry response. Lastly, we investigated the mechanism by which DNA hypomethylation affects tumorigenesis by crossing Dclk1/Apcf/f/Dnmt1f/f mice to MAVS knockout mice and examining tumor number following tamoxifen and DSS administration as above.

Results
Deletion of DNMT1 in DCLK1+ cells or treatment with 5-AZA significantly decreased colonic tumor number and size. Treatment with 5-AZA or DNMT1 loss led to DNA hypomethylation and subsequent upregulation of endogenous retroviral expression. Both 5-AZA treatment and DNMT1 knockout in DCLK1+ cells led to increased expression of type I interferon response genes. Knockout of the type I interferon response related gene, MAVS, reversed the anti-tumor effect observed with DNMT1 loss.

Conclusions
Our findings demonstrate that DNA hypomethylation by 5-AZA or loss of DNMT1 reduces colitis-associated tumorigenesis through activation of a viral mimicry response.

Funding Agencies
CAG, CIHRCancer Research Society, Canada Foundation for Innovation, Lawson Health Research Institute
A8 LUMINAL SHORT CHAIN FATTY ACIDS INCREASE ACTIVITY IN COLONIC MYENTERIC PLEXUS NEURONS IN MICE
Authors: Wongkrasant P , MacNaughton W , Sharkey K 
Published: February 2024

Abstract

Background
The enteric nervous system (ENS) plays a critical role in the control of gastrointestinal functions. Short chain fatty acids (SCFAs) are the products of non-digestible dietary fiber fermentation by gut microbial metabolism and are a primary energy source for enterocytes. However, the impact of SCFAs on the ENS is not well understood.

Aims
We aimed to test whether SCFAs affect enteric neuronal function using a novel intact preparation of the colon.

Methods
Intact segments of the colon from mice expressing a genetically encoded fluorescent calcium (Ca2+) reporter specifically in all enteric neurons (Wnt-1-GCaMP6 mice) or in intrinsic primary afferent neurons (IPANs, Calb1-GCaMP6 mice) were bathed and luminally perfused with Krebs solution. Contractility was inhibited by nicardipine (3 µM) and scopolamine (1 µM). The duration and intensity of neuronal intracellular Ca2+ fluorescence responses to SCFA were visualized by live-cell confocal microscopy and were analyzed using Imaris™ software. The SCFAs were luminally perfused at a constant rate of 10 mL/h for 3 min. NaCl was modified in Krebs solution to correct for the osmolarity of SCFAs.

Results
In the myenteric plexus of Wnt-1-GCaMP6 mice, SCFAs (acetate, 60 mM; propionate, 20 mM or butyrate, 20 mM) caused a rapid and sustained increase in Ca2+ fluorescence (26.8±5.9, 25.8±1.7, and 27.4±5.9 min, respectively). The peak Ca2+ responses were 92.5%± 28.3%, 122.6%±21.5% and 111.7%± 23.0%, respectively. The combination of these three SCFAs increased Ca2+ fluorescence for 20.5±6.3 min and potentiated levels of Ca2+ fluorescence to 125.1%±21.6% above baseline. The percentages of neurons responding to SCFAs were 85.7%, 94.4%, 97.7% and 93.3 % for acetate, propionate, butyrate and a combination of SCFAs, respectively.
In Calb1-GCaMP6 mice, IPANs showed a similar pattern of Ca2+ responses and a proportion of neurons that responded to the SCFAs. Following acetate, propionate, butyrate and combination of SCFAs administration, fluorescence was increased for 13.5±1.2, 20.6±2.7, 24.9±2.2 and 46.1±4.6 min, by a magnitude of 404.3%±153.7%, 129.0%±0.4%, 73.9%±18.8% and 717%±267.0% above baseline and the percentages of neuronal response were 100.0%, 100.0%, 100.0% and 87.5 %, respectively.

Conclusions
We show that SCFAs activate neurons of the myenteric plexus including IPANs. These studies suggest that some of the actions of SCFAs are mediated by the ENS, but further studies are needed to identify the underlying mechanisms of action of SCFAs in the myenteric plexus.

Funding Agencies
CAG, CIHRTRIANGLE Canada
A10 PROLINE METABOLISM AFFECTS CANCER STEM CELLS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Authors: Igouzoul A , Douchin J , Audet-Walsh E , Boisvert F , Giroux V 
Published: February 2024

Abstract

Background
Esophageal squamous cell carcinoma (ESCC) is highly deadly with a 5-year survival rate of only 16%, partly due to treatment resistance. Resistance is associated, among others, with the presence of cancer stem cells (CSC). Previous work in the laboratory has shown that prolonged exposure to anticancer treatments such as radiation and/or 5-FU leads to increased number of CSCs. Interestingly, disruption of amino acid metabolism, especially decreased proline levels, has been observed in treated cells. Proline is a non-essential amino acid that can either be uptake from the environment or synthesized from glutamate or ornithine. However, its role in cancer cells remains poorly understood and controversial.

Aims
Therefore, my project aims at determining the role of proline metabolism in CSC abundance and tumoral properties in ESCC.

Methods
Using ESCC cell lines, TE11 and TE15, we stimulated proline metabolism by adding proline to the media or inhibited its catabolism using L-THFA. L-THFA forces proline accumulation in the cell. We then conducted flow cytometry to quantify CSC proportion, proliferation assay, spheroid formation assay and spheroids included in collagen for migration and invasion assay.

Results
First, the stimulation of proline metabolism decreased the proportion of CSCs in flow cytometry. These results align with our initial observations, where CSC-enriched cells exhibited reduced proline levels. Second, the inhibition of proline catabolism by L-THFA had the opposite effect, namely an increase in the proportion of CSC. Interestingly, these changes in the proportion of CSCs induced by proline or L-THFA translated into changes in clonogenic potential, a capacity typically associated with stem cells. Indeed, limiting dilution spheroids formation assays showed that proline decreased while L-THFA increased the number of formed spheroids. Since spheroids formation is linked to the presence of CSC, this provides new evidence of the impact of proline metabolism on CSC characteristics. Finally, L-THFA treatments drastically increased migratory and invasive abilities in 3D spheroid models compared to untreated or proline-treated conditions.

Conclusions
In conclusion, our results suggest that proline metabolism is implicated in the enrichment of cancer stem cells as well as in their functions.

Funding Agencies
CAG, CIHRinnovation.ca ; Centre de recherche CHUS ; FMSS ; Canada Research Chairs
A14 ABLATION OF THE INTESTINAL EPITHELIAL SIALOME PREDISPOSES TO SPONTANEOUS COLITIS AND COLITIS-ASSOCIATED TUMORIGENESIS VIA MUCUS-DEPENDENT AND -INDEPENDENT MECHANISMS IN MICE
Authors: Bergstrom K S , Shan X , Rathore S , Gao L , Zandberg W , Darrek K , N N , Letef C L , Ghosh S , Xia L 
Published: February 2024

Abstract

Background
Recent work suggests epithelial sialylation (capping of glycoconjugates with the acidic sugar sialic acid) can protect the gut mucosa from inflammatory bowel disease by promoting mucus function. However, these studies are based on partial sialylation knockouts, potentially underestimating the role of glycoconjugate sialylation in mucosal homeostasis.

Aims
We sought to uncover how the complete intestinal epithelial sialome (the total glycan sialylation repetoire) regulates colitis susceptibility in vivo.

Methods
We generated a model of total gut epithelial sialylation deficiency by conditionally and inducibly (via tamoxifen, TM) targeting the CMP-Sia transporter, Slc35a1, in epithelial cells using Cre-Lox technology (Slc35a1f/f; VillinCre(ERT2) or (TM-)IEC Slc35a1-/- mice). We analyzed phenotypes clinically, histologicaly, and via multi-omic apporaches at baseline and in response to challenge.

Results
We confirmed the ablation of mucus sialylation via lectin staining, epithelial Slc35a1 gene expression, and O-glycomics of extracted mucins. In contrast to partial sialylation deficiencies, we found that IEC Slc35a1-/- mice developed mild spontaneous microbiota-dependent chronic colitis that was associated with tumorigenesis in the rectum in 30% of aged mice (&gt;12 mo.). TM-IEC Slc35a1-/- mice developed less severe spontaneous colitis, but were susceptible to acute injury with 1% DSS. Ablation of the gut epithelial sialome led to reduced mucus thickness on fecal sections and within tissues, although the b1/b2 barrier layers were still intact. TM-IEC Slc35a1-/- mice showed altered microbiota composition with an increase in Clostridium spp. at the expense of a global reduction in the abundance of at least 20 unique taxa; however metabolomic analysis did not show any significant differences in short-chain fatty acid levels. IEC Slc35a1-/- Muc2 was more susceptible to fecal protease degradation vs.WT Muc2. While no spontaneous phenotype was observed in the small intestine (SI), treatment with 5-fluorouracil led to worsened SI mucositis and morbidity vs. WT littermates. This was traced to impaired stem cell activities via reduced Lgr5+ cell representation in small intestinal crypts in IEC Slc35a1-/-;Lgr5GFP mice.

Conclusions
Ablation of the intestinal epithelial sialome impacts the mucus-microbiota-stem cell axis with consequences on colonic mucosal homeostasis based on the type of injury. At baseline, loss of sialylation impairs mucus stability and the stem cell niche leading to microbiota-dependent spontaneous colitis and tumorigenesis. However, these same epithelial defects impair epithelial renewal and worsen colitis following acute injury likely due to the cytotoxic environment caused by the chemical agent.

Funding Agencies
CCC
A16 ALTERATIONS TO BOTH INTESTINAL BARRIER INTEGRITY AND THE MICROBIOTA CONSPIRE DURING AGING TO PROMOTE DISEASE PROGRESSION IN A MOUSE MODEL OF MULTIPLE SCLEROSIS
Authors: Hohman L S , Fettig N M , Pu A , Schroeder F , Gommerman J , Osborne L 
Published: February 2024

Abstract

Background
Multiple sclerosis (MS) is a chronic, inflammatory condition impacted by both genetic and environmental factors. Aged individuals have an increased risk of progressive multiple sclerosis (pMS), as well as altered microbiota community composition and elevated levels of circulating gut microbiota-derived metabolites due to compromised gut barrier function. Fecal microbiota transplantation (FMT) studies confirm that an MS-associated microbiome can potentiate disease onset and enhance neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a murine model of MS.

Aims
1) Assess whether an aged microbiota alone is sufficient to promote age-associated progressive-like disease in our mouse model of EAE
2) Determine whether altered intestinal barrier integrity results in central nervous system-specific immune changes and/or disease course during EAE

Methods
To assess the impact of an aged microbiota on EAE outcomes we performed age-disparate human-derived FMT from young vs aged healthy co-habiting, first degree relatives into recipient mice. Then, to further interrogate the role of the gut-brain axis in the association of age and pMS we isolated the compromised intestinal barrier seen in aged individuals as a variable via two methods – Muc2-/- mice, which exhibit a defective mucus barrier, and DSS treated mice.

Results
Following adoptive transfer of young EAE-primed T cells, ‘young’ FMT recipients exhibited disease resolution while an ‘aged’ FMT lead to severe, non-remitting EAE relative to both controls and ‘young’ FMT recipients. This difference in outcomes was not seen in all donor pairs, suggesting that worsened EAE is not a universal feature of the aged microbiota. We collected cecal material, blood, and central nervous system (CNS) tissue from an age-differential FMT mouse pair and performed metabolomic analysis. We found robust differences in the metabolomic profile of young vs aged FMT recipients before and after EAE induction. Further, in both models of altered barrier integrity, we observed altered myeloid cell trafficking to and immune activation in the CNS, suggesting that the intestinal barrier itself plays a critical role in immune activation during EAE.

Conclusions
These findings suggest specific age-related microbiota-derived metabolites, which have increased access to the host system due to a leaky intestinal barrier, may be associated with increased risk of progressive disease and may represent promising therapeutic targets for MS.

Funding Agencies
CIHRMS Canada