bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of Wharton’s jelly-derived stem cells seeded/boron-loaded acellular scaffolds on the healing of full-thickness burn wounds in the rat model
Authors: Nikzad Sadeneh , Same Saeideh , Safiri Saeid , Dolati Sanam , Roushangar Zineh Babak , Meshgi Shahla , Roshangar Leila , Şahin Fikrettin
Published: February 2024

Burn wounds are the most destructive and complicated type of skin or underlying soft tissue injury that are exacerbated by a prolonged inflammatory response. Several cell-based therapeutic systems through the culturing of potent stem cells on modified scaffolds have been developed to direct the burn healing challenges. In this context, a new regenerative platform based on boron (B) enriched-acellular sheep small intestine submucosa (AOSIS) scaffold was designed and used as a carrier for mesenchymal stem cells derived from Wharton’s jelly (WJMSCs) aiming to promote the tissue healing in burn-induced rat models. hWJMSCs have been extracted from human extra-embryonic umbilical cord tissue. Thereafter, 96 third‐degree burned Wistar male rats were divided into 4 groups. The animals that did not receive any treatment were considered as group A (control). Then, group B was treated just by AOSIS scaffold, group C was received cell-seeded AOSIS scaffold (hWJMSCs-AOSIS), and group D was covered by boron enriched-cell-AOSIS scaffold (B/hWJMSCs-AOSIS). Inflammatory factors, histopathological parameters, and the expression levels of epitheliogenic and angiogenic proteins were assessed on 5, 14 and 21 d post-wounding. Application of the B/hWJMSCs-AOSIS on full-thickness skin-burned wounds significantly reduced the volume of neutrophils and lymphocytes at day 21 post-burning, whilst the number of fibroblasts and blood vessels enhanced at this time. In addition, molecular and histological analysis of wounds over time further verified that the addition of boron promoted wound healing, with decreased inflammatory factors, stimulated vascularization, accelerated re-epithelialization, and enhanced expression levels of epitheliogenic genes. In addition, the boron incorporation amplified wound closure via increasing collagen deposition and fibroblast volume and activity. Therefore, this newly fabricated hWJMSCs/B-loaded scaffold can be used as a promising system to accelerate burn wound reconstruction through inflammatory regulation and angiogenesis stimulation.
Spatial Analysis Using Geographically Weighted Ordinary Logistic Regression (GWOLR) Method for Prediction of Particle-Size Fraction in Soil Surface
Authors: Pramoedyo Henny , Ngabu Wigbertus , Riza Sativandi , Iriany Atiek
Published: February 2024

Spatial analysis is a method used to understand the spatial variation of geospatial data. In this study, the Geographically Weighted Ordinary Logistic Regression (GWOLR) method was used in spatial analysis to predict the particle size fraction of the surface soil. The particle size fraction of the surface soil is an important parameter in determining soil productivity and environmental quality. However, the particle size fraction in surface soils can vary spatially and is influenced by geographical factors such as elevation, rainfall, and soil texture. This study will be carried out by collecting particle size fraction data and geospatial data at randomly selected locations. Accurate modelling of soil texture is necessary because it‘s a crucial factor in determining how soil management will go. However, because soil texture is a compositional data set, it is one of the soil attributes that is more challenging to model. The challenge presented by this compositional data set is the imposition of constant quantities, specifically the requirement that the total of the fractions of clay, silt, and sand be 100%. Topographical variability can be derived from DEM data, making it an independent variable or predictor for soil texture prediction. The data will then be analyzed using the GWOLR method to predict the particle size fraction at locations that have not been observed before. The resulting prediction model will then be evaluated using cross-validation to check the accuracy of the model. This study will provide benefits for land management and natural resource management and can improve understanding of the spatial variation of particle size fractions in surface soils and the spatial and geographical factors that influence them. The GWOLR model for predicting particle size fractions in surface soils was carried out with a fixed bi-square weight and a bandwidth of 0.28895. The GWOLR model classification accuracy value is 94 percent, this shows that the GWOLR model for predicting soil particle size is more suitable than the ordinal logistic regression model with a classification accuracy of 90 percent. The aims of this study are to: (1) Establish a soil texture prediction model using the GWOLR method; and (2) Test the reliability of the model in predicting surface soil texture.
Soil Water in Different Management Systems of Coffee-Pine Agroforestry and Its Relation to Coffee Bean Yields
Authors: Ali Yuddin Fitra Ahmad , Oakley Simon , Prayogo Cahyo , Ratna Sari Rika , Dwi Saputra Danny , Maulana Ishaq Rizki , Sigit Wicaksono Kurniawan , Suprayogo Didik
Published: February 2024

Coffee-pine agroforestry is a common land use system in Indonesia, that provides several benefits, including increased soil fertility, biodiversity, and economic returns. However, the management of coffee-pine agroforestry systems can significantly impact on soil water dynamics, affecting coffee bean yields. This study investigated the effects of different management systems on soil water dynamics and coffee bean yields in a coffee-pine agroforestry system in UB Forest, Malang East Java, Indonesia. Five different management systems were evaluated: (i) no management, (ii) pruned coffee with no fertilizer, (iii) pruned coffee with added organic fertilizer, (iv) pruned coffee with added organic-inorganic mix fertilizer, with a planting distance of pine trees of 3 x 2 m, and (v) pruned coffee with added organic-inorganic mix fertilizer under pine trees with a planting distance of 6 x 2 m. The soil water dynamics were measured at depths of 0-0.2 m with a soil moisture sensor and connected with a data logger measured within a year, started in April 2022. Coffee bean yield was measured with 100 coffee plants, then converted to production on ton ha−1. The results showed that the different management systems significantly impacted soil water dynamics and coffee bean yields. The combination of pruning and fertilization is a promising management strategy for increasing coffee bean yields in coffee-pine agroforestry systems. The consequent better growth of coffee plants impacts increasing soil water extraction. This study provides valuable insights for farmers and forest managers who are interested in improving the productivity of coffee-pine agroforestry systems and conserving soil water or sometimes needing water addition through irrigation.
First simultaneous production of a top quark and a photon observed
Authors: Jarman Sam
Published: February 2024

Researchers at the CERN particlephysics lab have observed the simultaneous production of a photon and a top quark for the first time.
Mysterious ultrahigh-energy cosmic ray puzzles astronomers
Authors: Kwan Jacklin
Published: February 2024

One of the most energetic particles ever observed has been spotted by researchers using the Utah-based Telescope Array.Much of the body of Egypt’s Great
Ireland set to join CERN particle-physics lab
Authors: King Anthony
Published: February 2024

The Irish government has finally applied to join the CERN particle-physics laboratory near Geneva as an associate member.
Awards named after male scientists rarely given to women
Authors: Hiscott Laura
Published: February 2024

The gender of the person an award is named after can have a big impact on who is likely to receive it, finds a new study, which notes that men win almost 90% of awards named after male scientists.
Scientists with disabilities suffer $14 000 pay penalty
Authors: Allen Michael
Published: February 2024

Scientists who suffer from a disability that occurred early in their life earn around $14,000 less per year than their colleagues.
Technology triumphs
Authors: McKenzie James
Published: February 2024

James McKenzie celebrates firms in photonics and instrumentation that have won business awards from the Institute of Physics in 2023.
Oppenheimer lessons
Authors: Crease Robert P
Published: February 2024

US authorities celebrated Robert Oppenheimer for developing atomic weapons but sidelined him when he wanted to advise them on their use. It’s an episode that has many lessons for us today, says Robert P Crease.
Oppenheimer: icon of the nuclear age
Authors: Perkowitz Sidney
Published: February 2024

Oppenheimer was the blockbuster movie of 2023 featuring a stellar cast of Hollywood A-listers. But as Sidney Perkowitz reminds us, many other movies, books and stage performances have examined the moral and political implications of the Manhattan Project too.
Coldest: how new quantum states of matter emerged
Authors: Orzel Chad
Published: February 2024

The road to Bose–Einstein condensates and degenerate Fermi gases was paved with ideas that shouldn’t have worked, but did, as Chad Orzel explains in the final segment of his three-part history of laser cooling.
The two faces of Wernher von Braun
Authors: Randall Ian
Published: February 2024

Ian Randall reviews Depravity’s Rainbow by Lewis Bush.
Avoiding barren plateaus in the variational determination of geometric entanglement
Authors: Zambrano L , Muñoz-Moller A D , Muñoz M , Pereira L , Delgado A
Published: February 2024

The barren plateau (BP) phenomenon is one of the main obstacles to implementing variational quantum algorithms in the current generation of quantum processors. Here, we introduce a method capable of avoiding the BP phenomenon in the variational determination of the geometric measure of entanglement for a large number of qubits. The method is based on measuring compatible two-qubit local functions whose optimization allows for achieving a well-suited initial condition from which a global function can be further optimized without encountering a BP. We analytically demonstrate that the local functions can be efficiently estimated and optimized. Numerical simulations up to 18 qubit GHZ and W states demonstrate that the method converges to the exact value. In particular, the method allows for escaping from BPs induced by hardware noise or global functions defined on high-dimensional systems. Numerical simulations with noise agree with experiments carried out on IBM’s quantum processors for seven qubits.
The optimal design of wind-induced vibration energy harvester with microscale and high efficiency
Authors: Chen Siyuan , Bao Guanyu , Guan Yuang , Ma Mingchen , Wang Kejun , Fan Cheng , Wang Qian
Published: February 2024

In order to improve the performance of wind-induced vibration energy harvester (WIV-EH), the bluff body and cantilever beam play a significant role when the energy harvester works. In this paper, a WIV-EH model is designed to explore the factors affecting energy capture efficiency. In the Optimal design of bluff body, five kinds of bluff body is set to analyse the influence of the shape on the lift and lift coefficient by COMSOL Multiphysics 6.0. According to the simulation results, the D-shaped bluff body is optimized by changing the scale ratio and windward surface shape. In the Optimal design of cantilever beam, the result shows that under the same bluff body and wind speed, the shape of cantilever beam will affect the magnitude and distribution of strain. we also designed cantilever beams with different materials and splicing materials, and studied the response voltage output at different wind speeds. According to the above results, a wind tunnel test was designed for verification. The research results may provide new ideas for improving the energy harvesting efficiency of energy harvesters.
A social media intervention for high-intensity drinking among emerging adults: a pilot randomized controlled trial
Authors: Bonar Erin E , Tan Chiu Y , Fernandez Anne C , Goldstick Jason E , Chapman Lyndsay , Florimbio Autumn R , Walton Maureen A
Published: February 2024

Aims

High-intensity drinking (HID) is a pattern of risky drinking defined as at least 8 drinks (for women) or 10 drinks (for men) in a single episode. Individuals engaged in HID may be at greater risk for consequences, necessitating tailored interventions. Herein, we report the feasibility and acceptability of a social media-delivered 8-week intervention for emerging adults with recent HID.

Methods

Using social media advertising, we recruited 102 emerging adults who reported past-month HID. Average age was 20.0 year-olds (SD = 2.0); 51.0% were male. Most identified as White (64.7%; 14.7% Black/African American, 13.7% multiracial) and 26.5% identified as Hispanic/Latinx. Participants were randomized to an 8-week intervention delivered via Snapchat by health coaches (N = 50) or to a control condition (psychoeducational website referral; N = 52). Follow-ups occurred at 2 and 4 months post-baseline.

Results

The intervention was acceptable (85.1% liked it/liked it a lot) and there were high follow-up rates. Participants rated coaches as supportive (91.5%) and respectful (93.6%). Descriptively, helpfulness ratings were higher for non-alcohol-related content (e.g. stress; 59.6% very/extremely helpful) than alcohol-related content (40.4% very/extremely helpful). Regarding engagement, 86.0% engaged approximately weekly and 59.6% indicated they saved intervention snaps. Descriptive data showed reductions over time in several measures of alcohol consumption and consequences as well as cannabis-impaired driving and mental health symptoms.

Conclusions

This 8-week social media intervention for HID was feasible and acceptable among emerging adults, supporting the benefit of future testing in a fully powered trial.
A Bayesian survival treed hazards model using latent Gaussian processes
Authors: Payne Richard D , Guha Nilabja , Mallick Bani K
Published: February 2024

Survival models are used to analyze time-to-event data in a variety of disciplines. Proportional hazard models provide interpretable parameter estimates, but proportional hazard assumptions are not always appropriate. Non-parametric models are more flexible but often lack a clear inferential framework. We propose a Bayesian treed hazards partition model that is both flexible and inferential. Inference is obtained through the posterior tree structure and flexibility is preserved by modeling the log-hazard function in each partition using a latent Gaussian process. An efficient reversible jump Markov chain Monte Carlo algorithm is accomplished by marginalizing the parameters in each partition element via a Laplace approximation. Consistency properties for the estimator are established. The method can be used to help determine subgroups as well as prognostic and/or predictive biomarkers in time-to-event data. The method is compared with some existing methods on simulated data and a liver cirrhosis dataset.
Multiobjective tree-based reinforcement learning for estimating tolerant dynamic treatment regimes
Authors: Song Yao , Wang Lu
Published: February 2024

A dynamic treatment regime (DTR) is a sequence of treatment decision rules that dictate individualized treatments based on evolving treatment and covariate history. It provides a vehicle for optimizing a clinical decision support system and fits well into the broader paradigm of personalized medicine. However, many real-world problems involve multiple competing priorities, and decision rules differ when trade-offs are present. Correspondingly, there may be more than one feasible decision that leads to empirically sufficient optimization. In this paper, we propose a concept of “tolerant regime,” which provides a set of individualized feasible decision rules under a prespecified tolerance rate. A multiobjective tree-based reinforcement learning (MOT-RL) method is developed to directly estimate the tolerant DTR (tDTR) that optimizes multiple objectives in a multistage multitreatment setting. At each stage, MOT-RL constructs an unsupervised decision tree by modeling the counterfactual mean outcome of each objective via semiparametric regression and maximizing a purity measure constructed by the scalarized augmented inverse probability weighted estimators (SAIPWE). The algorithm is implemented in a backward inductive manner through multiple decision stages, and it estimates the optimal DTR and tDTR depending on the decision-maker’s preferences. Multiobjective tree-based reinforcement learning is robust, efficient, easy-to-interpret, and flexible to different settings. We apply MOT-RL to evaluate 2-stage chemotherapy regimes that reduce disease burden and prolong survival for advanced prostate cancer patients using a dataset collected at MD Anderson Cancer Center.
Twenty years of embolization for acute lower gastrointestinal bleeding: a meta-analysis of rebleeding and ischaemia rates
Authors: Yu Qian , Funaki Brian , Ahmed Osman
Published: February 2024

Background

Transarterial embolization (TAE) for acute lower gastrointestinal bleeding (LGIB) can be technically challenging due to the compromise between achieving haemostasis and causing tissue ischaemia. The goal of the present study is to determine its technical success, rebleeding, and post-embolization ischaemia rates through meta-analysis of published literature in the last twenty years.

Methods

PubMed, Embase, and Cochrane Library databases were queried. Technical success, rebleeding, and ischaemia rates were extracted. Baseline characteristics such as author, publication year, region, study design, embolization material, percentage of superselective embolization were retrieved. Subgroup analysis was performed based on publication time and embolization agent.

Results

A total of 66 studies including 2121 patients who underwent embolization for acute LGIB were included. Endoscopic management was attempted in 34.5%. The pooled overall technical success, rebleeding, post-embolization ischaemia rates were 97.0%, 20.7%, and 7.5%, respectively. Studies published after 2010 showed higher technical success rates (97.8% vs 95.2%), lower rebleeding rates (18.6% vs 23.4%), and lower ischaemia rates (7.3% vs 9.7%). Compared to microcoils, NBCA was associated with a lower rebleeding rate (9.3% vs 20.8%) at the expense of a higher post-embolization ischaemia rate (9.7% vs 4.0%). Coagulopathy (P = .034), inotropic use (P = .040), and malignancy (P = .002) were predictors of post-embolization rebleeding. Haemorrhagic shock (P < .001), inotropic use (P = .026), malignancy (P < .001), coagulopathy (P = .002), blood transfusion (P < .001), and enteritis (P = .023) were predictors of mortality. Empiric embolization achieved a similarly durable haemostasis rate compared to targeted embolization (23.6% vs 21.1%) but a higher risk of post-embolization ischaemia (14.3% vs 4.7%).

Conclusion

For LGIB, TAE has a favourable technical success rate and low risk of post-embolization ischaemia. Its safety and efficacy profile has increased over the last decade. Compared to microcoils, NBCA seemed to offer a more durable haemostasis rate at the expense of higher ischaemia risk. Due to the heterogeneity of currently available evidence, future prospective and comparative studies are warranted.

Advances in knowledge

(1) Acute LGIB embolization demonstrate a high technical success rate with acceptable rate of rebleeding and symptomatic ischaemia rates. Most ischaemic stigmata discovered during routine post-embolization colonoscopy were minor. (2) Although NBCA seemed to offer a more durable haemostasis rate, it was also associated with a higher risk of ischaemia compared to microcoils. (3) Coagulopathy, malignant aetiology, and inotropic use were predictors of rebleeding and mortality. (4) Routine post-embolization endoscopy to assess for ischaemia is not indicated.
Social Work and Intractable Conflict: Professional Experiences and Role Perceptions
Authors: Soffer-Elnekave Ruth
Published: February 2024

Social workers worldwide share a common framework and mission: to provide aid to those in need and promote social justice. Yet as an international profession, both global and local realities contribute to the unique ways in which the profession is understood and practised in various locations. This article considers the broad issue of how local and global realities shape social workers’ understanding of the profession using the case of Israeli-Jewish social workers as an exemplar. Narrative and life story methods were used to understand individual life stories within collective political and professional contexts. Sixteen Jewish-Israeli social workers participated in two, individual zoom interviews each in which they described becoming a social worker and practising in the context of an intractable conflict, the Israeli–Palestinian conflict. Three approaches to social work practice emerged, suggesting that social work in Israel has shifted away from applying ecological perspectives, limiting both how social workers understand their roles and how they practise. Recommendations for incorporating a politically aware framework to social work practice, research and education are discussed.
Trauma as the ‘Belief That the World is a Dangerous Place’: The Obfuscation of Systemic Violence in Social Work’s Discourses of Trauma
Authors: Chatterjee Alicia , Park Yoosun
Published: February 2024

The concept of psychological trauma has been taken up widely in popular culture and in diverse academic fields including social work. In this work of poststructuralist discourse analysis, we used methods of close reading to examine a random sample of thirty social work articles on trauma (published 2010–2020). Our aim was not to refute the salience of the concept nor to establish its true meaning and correct usage, but to critically examine its discursive functions; what does ‘trauma’ do in social work? In our analysis, the progressive aims of the discourses of trauma—to counter pathologisation and confer legitimacy to harms that have been marginalised—are unrealised. ‘Trauma’ is deployed in multiple, often contradictory ways and the slippages between intent and function work to construct the trauma-laden as non-normative, damaged subjects, and legitimate objects, thus, of social work scrutiny and intervention. Social work’s discourses of trauma undermine their own efforts to centre a structural analysis. If ‘to perceive the world as a safe place’ is a signifier of normative, non-traumatised functioning, then what does ‘trauma’ do when applied to the racialised, gendered, colonised and marginalised, for whom the world is not a place of safety but of material and psychical violence?
Evolutionary adaptation to climate change
Authors: Edelsparre Allan H , Fitzpatrick Mark J , Saastamoinen Marjo , Teplitsky Céline
Published: February 2024

When the notion of climate change emerged over 200 years ago, few speculated as to the impact of rising atmospheric temperatures on biological life. Tens of decades later, research clearly demonstrates that the impact of climate change on life on Earth is enormous, ongoing, and with foreseen effects lasting well into the next century. Responses to climate change have been widely documented. However, the breadth of phenotypic traits involved with evolutionary adaptation to climate change remains unclear. In addition, it is difficult to identify the genetic and/or epigenetic bases of phenotypes adaptive to climate change, in part because it often is not clear whether this change is plastic, genetic, or some combination of the two. Adaptive responses to climate-driven selection also interact with other processes driving genetic changes in general, including demography as well as selection driven by other factors. In this Special Issue, we explore the factors that will impact the overall outcome of climate change adaptation. Our contributions explain that traits involved in climate change adaptation include not only classic phenomena, such as range shifts and environmentally dependent sex determination, but also often overlooked phenomena such as social and sexual conflicts and the expression of stress hormones. We learn how climate-driven selection can be mediated via both natural and sexual selection, effectively influencing key fitness-related traits such as offspring growth and fertility as well as evolutionary potential. Finally, we explore the limits and opportunities for predicting adaptive responses to climate change. This contribution forms the basis of 10 actions that we believe will improve predictions of when and how organisms may adapt genetically to climate change. We anticipate that this Special Issue will inform novel investigations into how the effects of climate change unfold from phenotypes to genotypes, particularly as methodologies increasingly allow researchers to study selection in field experiments.
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

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

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 < .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

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

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

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

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

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

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 (>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

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