bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAResNet: self-attention residual network for predicting DNA-protein binding
Authors: Shen Long-Chen , Liu Yan , Song Jiangning , Yu Dong-Jun 
Published: March 2021

AbstractKnowledge of the specificity of DNA-protein binding is crucial for understanding the mechanisms of gene expression, regulation and gene therapy. In recent years, deep-learning-based methods for predicting DNA-protein binding from sequence data have achieved significant success. Nevertheless, the current state-of-the-art computational methods have some drawbacks associated with the use of limited datasets with insufficient experimental data. To address this, we propose a novel transfer learning-based method, termed SAResNet, which combines the self-attention mechanism and residual network structure. More specifically, the attention-driven module captures the position information of the sequence, while the residual network structure guarantees that the high-level features of the binding site can be extracted. Meanwhile, the pre-training strategy used by SAResNet improves the learning ability of the network and accelerates the convergence speed of the network during transfer learning. The performance of SAResNet is extensively tested on 690 datasets from the ChIP-seq experiments with an average AUC of 92.0%, which is 4.4% higher than that of the best state-of-the-art method currently available. When tested on smaller datasets, the predictive performance is more clearly improved. Overall, we demonstrate that the superior performance of DNA-protein binding prediction on DNA sequences can be achieved by combining the attention mechanism and residual structure, and a novel pipeline is accordingly developed. The proposed methodology is generally applicable and can be used to address any other sequence classification problems.
Inverses of Matérn covariances on grids
Authors: Guinness Joseph 
Published: March 2021

SummaryWe conduct a study of the aliased spectral densities of Matérn covariance functions on a regular grid of points, elucidating the properties of a popular approximation based on stochastic partial differential equations. While other researchers have shown that this approximation can work well for the covariance function, we find that it assigns too much power at high frequencies and does not provide increasingly accurate approximations to the inverse as the grid spacing goes to zero, except in the one-dimensional exponential covariance case.
Burden of Antimicrobial Resistance: Compared to What?
Authors: de Kraker Marlieke E A , Lipsitch Marc 
Published: March 2021

Abstract
The increased focus on the public health burden of antimicrobial resistance (AMR) raises conceptual challenges, such as determining how much harm multidrug-resistant organisms do compared to what, or how to establish the burden. Here, we present a counterfactual framework and provide guidance to harmonize methodologies and optimize study quality. In AMR-burden studies, 2 counterfactual approaches have been applied: the harm of drug-resistant infections relative to the harm of the same drug-susceptible infections (the susceptible-infection counterfactual); and the total harm of drug-resistant infections relative to a situation where such infections were prevented (the no-infection counterfactual). We propose to use an intervention-based causal approach to determine the most appropriate counterfactual. We show that intervention scenarios, species of interest, and types of infections influence the choice of counterfactual. We recommend using purpose-designed cohort studies to apply this counterfactual framework, whereby the selection of cohorts (patients with drug-resistant, drug-susceptible infections, and those with no infection) should be based on matching on time to infection through exposure density sampling to avoid biased estimates. Application of survival methods is preferred, considering competing events. We conclude by advocating estimation of the burden of AMR by using the no-infection and susceptible-infection counterfactuals. The resulting numbers will provide policy-relevant information about the upper and lower bound of future interventions designed to control AMR. The counterfactuals should be applied in cohort studies, whereby selection of the unexposed cohorts should be based on exposure density sampling, applying methods avoiding time-dependent bias and confounding.
Linking Tooth Shape to Strike Mechanics in theBoa constrictor
Authors: Ryerson William G , Van Valkenburg Tate 
Published: March 2021

SynopsisSnakes, with the obvious exception of the fangs, are considered to lack the regional specialization of tooth shape and function which are exemplified by mammals. Recent work in fishes has suggested that the definition of homodont and heterodont are incomplete without a full understanding of the morphology, mechanics, and behavior of feeding. We investigated this idea further by examining changes in tooth shape along the jaw of Boa constrictor and integrating these data with the strike kinematics of boas feeding on rodent prey. We analyzed the shape of every tooth in the skull, from a combination of anesthetized individuals and CT scanned museum specimens. For strike kinematics, we filmed eight adult boas striking at previously killed rats. We determined the regions of the jaws that made first contact with the prey, and extrapolated the relative positions of those teeth at that moment. We further determined the roles of all the teeth throughout the prey capture process, from the initiation of the strike until constriction began. We found that the teeth in the anterior third of the mandible are the most upright, and that teeth become progressively more curved posteriorly. Teeth on the maxilla are more curved than on the mandible, and the anterior teeth are more linear or recurved than the posterior teeth. In a majority of strikes, boas primarily made contact with the anterior third of the mandible first. The momentum from the strike caused the upper jaws and skull to rotate over the rat. The more curved teeth of the upper jaw slid over the rat unimpeded until the snake began to close its jaws. In the remaining strikes, boas made contact with the posterior third of both jaws simultaneously, driving through the prey and quickly retracting, ensnaring the prey on the curved posterior teeth of both jaws. The curved teeth of the palatine and pterygoid bones assist in the process of swallowing.
An algorithm to identify residential mobility from electronic health-record data
Authors: Meeker Jessica R , Burris Heather , Boland Mary Regina 
Published: March 2021

Abstract

Background
Environmental, social and economic exposures can be inferred from address information recorded in an electronic health record. However, these data often contain administrative errors and misspellings. These issues make it challenging to determine whether a patient has moved, which is integral for accurate exposure assessment. We aim to develop an algorithm to identify residential mobility events and avoid exposure misclassification.

Methods
At Penn Medicine, we obtained a cohort of 12 147 pregnant patients who delivered between 2013 and 2017. From this cohort, we identified 9959 pregnant patients with address information at both time of delivery and one year prior. We developed an algorithm entitled REMAP (Relocation Event Moving Algorithm for Patients) to identify residential mobility during pregnancy and compared it to using ZIP code differences alone. We assigned an area-deprivation exposure score to each address and assessed how residential mobility changed the deprivation scores.

Results
To assess the accuracy of our REMAP algorithm, we manually reviewed 3362 addresses and found that REMAP was 95.7% accurate. In this large urban cohort, 41% of patients moved during pregnancy. REMAP outperformed the comparison of ZIP codes alone (82.9%). If residential mobility had not been taken into account, absolute area deprivation would have misclassified 39% of the patients. When setting a threshold of one quartile for misclassification, 24.4% of patients would have been misclassified.

Conclusions
Our study tackles an important characterization problem for exposures that are assigned based upon residential addresses. We demonstrate that methods using ZIP code alone are not adequate. REMAP allows address information from electronic health records to be used for accurate exposure assessment and the determination of residential mobility, giving researchers and policy makers more reliable information.
Revisiting the Politics of Land Recovery Among White Commercial Farmers in Zimbabwe: Implications for Transitional Justice
Authors: Batisai Kezia , Mudimu George T 
Published: March 2021

Abstract
The land question in postcolonial Africa, particularly in former settler colonies, has an enduring legacy. To illuminate the enduring dimensions of the land question, this article explores various land recovery options adopted by (former) white commercial farmers in Zimbabwe as they renegotiate access, ownership and control of land expropriated via the Fast Track Land Reform Programme. Zimbabwe has been fluid in handling these recovery options as it strives to reposition the economy and score political goals locally and globally. A transitional justice approach ensures that the contemporary land question, rooted in a historical racialized struggle, is resolved on an equality basis that transcends the current politicized productivist land recovery discourse. As the transitional justice approach takes cognisance of longstanding marginalization and embraces robust institutions that withstand political whims and the test of time, it ensures meaningful policy and practical interventions that confront the contentious land question in Zimbabwe and beyond.
Glycine ameliorates mitochondrial dysfunction caused by ABT-199 in porcine oocytes
Authors: Yu Sicong , Gao Lepeng , Song Yang , Ma Xin , Liang Shuang , Lan Hainan , Zheng Xin , Li Suo 
Published: March 2021

Abstract
Mitochondria play an important role in controlling oocyte developmental competence. Our previous studies showed that glycine (Gly) can regulate mitochondrial function and improve oocyte maturation in vitro. However, the mechanisms by which Gly affects mitochondrial function during oocyte maturation in vitro have not been fully investigated. In this study, we induced a mitochondrial damage model in oocytes with the Bcl-2-specific antagonist ABT-199. We investigated whether Gly could reverse the mitochondrial dysfunction caused by ABT-199 exposure and whether it is related to calcium regulation. Our results showed that ABT-199 inhibited cumulus expansion, decreased the oocyte maturation rate and the intracellular glutathione (GSH) level, caused mitochondrial dysfunction, which was confirmed by decreased mitochondrial membrane potential (ΔΨm) and the expression of mitochondrial function-related genes PGC-1α, and increased reactiveoxygenspecies (ROS) levelsand the expression of apoptosis-associated genes Bax, Caspase-3, and Cyto C.More importantly, ABT-199-treated oocytes showed an increase in the intracellular free calcium concentration ([Ca2+]i) and had impaired cortical type 1 inositol 1,4,5-trisphosphate receptors (IP3R1) distribution. Nevertheless, treatment with Gly significantly ameliorated mitochondrial dysfunction, oxidative stress, and apoptosis, and Gly also regulated [Ca2+]i levels and IP3R1 cellular distribution, which further protects oocyte maturation in ABT-199-induced porcine oocytes.Taken together, our results indicate that Gly has a protective action against ABT-199-induced mitochondrial dysfunction in porcine oocytes.
A11 RISK PERCEPTION AND KNOWLEDGE OF COVID-19 IN PATIENTS WITH CELIAC DISEASE
Authors: Zhen J , Stefanolo J , Montoro M , Uscanga L , Day A , Tye-Din J , Ciacci C , Lebwohl B , Pinto-Sanchez M I 
Published: March 2021

Abstract

Background
Celiac disease (CeD) has been associated with an increased risk of respiratory infections, however, we recently demonstrated that the odds of contracting COVID-19 in patients with CeD is similar to that of the general population. Due to this discrepancy, how patients with CeD perceive their risk may differ from their actual risk.

Aims
The aim of this study was to investigate the risk perceptions for contracting COVID-19 in patients with CeD and to determine the factors that may influence their perceptions.

Methods
We distributed a survey throughout 10 countries between March and June 2020 and collected data on demographics, diet, COVID-19 testing, and risk perceptions of COVID-19 in patients with CeD. Participants were recruited through various celiac associations, clinic visits, and social media. Risk perception was assessed by asking individuals whether they believe patients with CeD are at an increased risk of contracting COVID-19 compared to the general population. Logistic regression was used to determine the influencing factors associated with COVID-19 risk perception, such as age, sex, adherence to a gluten-free diet (GFD), and comorbidities such as cardiac/respiratory conditions and diabetes. Data was presented as adjusted odds ratios (aORs).

Results
A total of 10,737 participants with CeD completed the survey. From them, 6,019 (56.1%) patients with CeD perceived they were at a higher risk or were unsure if they were at a higher risk of contracting COVID-19 compared to the non-CeD population. A greater proportion of patients with CeD had high levels of COVID-19 risk perceptions when compared to infections in general (56.1% vs 26.7%; p&lt;0.0001). Consequently, 28.8% reported taking extra COVID-19 precautions as a result of their CeD. Members of celiac associations had lower rates of perceiving an increased risk of COVID-19 when compared to non-members (49.5% vs 57.4%, p&lt;0.0001). Older age (aOR: 0.9; 95% CI: 0.9 to 1, p&lt;0.001), male sex (aOR: 0.85; 95% CI: 0.76 to 0.94, p=0.001), and strict adherence to a GFD (aOR: 0.89; 95% CI 0.82 to 0.97, p=0.007) were associated with a lower perception of COVID-19 risk. Meanwhile, the presence of comorbidities was associated with a higher perception of COVID-19 risk (aOR: 1.34; 95% CI: 1.20 to 1.51, p&lt;0.001).

Conclusions
Overall, a large proportion of patients with CeD, particularly females, those with comorbidities, or those not adhering to a strict GFD, believed they were or were unsure if they were at a higher risk of contracting COVID-19 due to their condition. As high levels of risk perception may increase an individual’s pandemic-related stress and contribute to negative mental health consequences, healthcare providers should maintain consistent communication with the celiac community and provide them with evidence-based recommendations.

Funding Agencies
None
A26 A SYSTEMTIC REVIEW OF MONOGENIC INFLAMMATORY BOWEL DISEASE: CLINICAL PHENOTYPE AND GENOTYPE
Authors: Nambu R , Warner N , Mulder D J , Muise A 
Published: March 2021

Abstract

Background
Advances in genomic technologies have led to an increase in reports of monogenic inflammatory bowel disease (IBD). The majority of the studies on monogenic IBD have focused only on young children aged &lt;6 years. There are no detailed reports containing a comprehensive picture of monogenic IBD with specific numbers on the clinical features, genetic profiles and disease course. Since each gene-specific cause of monogenic IBD is rare, it is difficult to collect cases in a single study even with international cohort studies.

Aims
To elucidate a comprehensive picture of monogenic IBD, we conducted a systematic review of all reported cases of monogenic IBD.

Methods
A systematic review of MEDLINE articles published between January 2000 and December 2019 was conducted. 662 monogenic IBD cases were identified from 273 eligible articles. Data on clinical manifestation, genotype, and management were collected.

Results
The most frequently reported genes causative of monogenic IBD patients were IL10RA, CYBB, IL10RB, and TTC7A (Figure). In total, 64.8% of patients developed IBD before six years old, 15.6% between ages 10 and 17.9 years, and 11.6% at age 18 years or older. Only 32.7% had any history of extra-intestinal manifestation (EIM) before IBD onset. There was substantial difference in the onset age groups and the underlying monogenic disorders. 74.4% developed at least one EIM during their clinical course. The most common EIMs were atypical infection (44.1%), dermatologic abnormality (39.2%), autoimmunity (22.7%) and lymphoid organ abnormality (11.5%). Autosomal recessive (62.8%) was the most common inheritance pattern, and missense-variants (44.3%) were the most identified type of genetic variants. Deletions including CNVs, intronic, synonymous and inversion, which have the possibility to be overlooked by whole exome sequencing were shown in some cases. Bowel surgery, biologics, and hematopoietic stem cell transplantation were performed in 28.3%, 32.8%, and 24.4% of patients, respectively.

Conclusions
Monogenic IBD diagnosis and management is a challenging clinical problem across age groups; the EIMs are more diverse and the management is evidently more difficult compared to non-monogenic IBD. An improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is necessary for effective management.

Funding Agencies
CAG, CIHRUehara Memorial Foundation Fellowship
A27 MSH2 CONTRIBUTES TO SELF-RENEWAL OF ESOPHAGEAL ORGANOIDS
Authors: Rolland M , Gonneaud A , Jean D , Giroux V 
Published: March 2021

Abstract

Background
The esophagus is lined by a stratified epithelium in which basal cells can proliferate and undergo differentiation while migrating towards the lumen. In the basal layer, we also find Krt15+ stem cells that are multipotent, self-renewing and that have regenerative capacity. However, mechanisms that specifically control their functions remain unknown. Interestingly, RNA sequencing and gene set enrichment analysis (GSEA) revealed an enrichment of a gene set associated with DNA repair in Krt15+ cells in comparison to Krt15- cells. We also observed that Msh2 (MutS homolog 2), a gene associated with the DNA mismatch repair (MMR) mechanism, is the most significantly upregulated gene in Krt15+ stem cells.

Aims
To determine the impact of Msh2 loss on self-renewal of esophageal organoids under normal and stress conditions.

Methods
Esophageal epithelial cells were isolated from a wild type mouse and grown as organoids, a 3D culture model that supports stem cell growth and morphologically reproduces the tissue of origin. To determine Msh2 role in esophageal epithelium, this gene was deleted through a CRISPR/Cas9 approach in mouse esophageal organoids. Invalidation was confirmed by Western Blot and immunofluorescence. Impact of Msh2 loss on self-renewal was measured under normal condition and following radiation.

Results
At baseline, loss of Msh2 decreases the organoid formation rate of esophageal organoids. Furthermore, following high-dose radiation, Msh2 deficient cells form less organoids than control cells. These results suggest that self-renewal capacity is reduced when Msh2 is depleted. Interestingly, following radiation, organoids depleted for Msh2 show higher residual levels of p-H2AX, a DNA damage marker, and p-ATM, a key kinase in DNA damage response, suggesting that their capacity to cope with DNA damages is reduced.

Conclusions
Our results suggest that Msh2 contributes to maintaining genomic integrity in esophageal cells and that contributes to maintaining self-renewal capacity of basal cells and possibly esophageal stem cells.

Funding Agencies
Canada Research Chair.
A28 CHARACTERIZING THE ROLE OF NR4A1 IN THE REGULATION OF INTESTINAL SMOOTH MUSCLE CELL PHENOTYPE AND FUNCTION
Authors: Szczepanski H E , Flannigan K L , Mainoli B , Alston L , Lee J , Baruta G M , Venu V P , Shearer J , Dufour A , Hirota S A 
Published: March 2021

Abstract

Background
Intestinal fibrosis and stricture formation are common complications of Crohn’s disease (CD). Recently, smooth muscle hypertrophy/hyperplasia have gained greater recognition as a driver of stricture formation, rather than an increase in fibrosis alone. Despite advances in treatment of CD, current therapies do little to prevent or reverse strictures. NR4A1 is an orphan nuclear receptor that is anti-fibrotic in non-intestinal systems and exhibits anti-proliferative effects in smooth muscle cells (SMCs). NR4A1 gene variants have been associated with increased risk of IBD, however, mechanisms regulating NR4A1 expression and its role in intestinal SMC function have not been investigated.

Aims
To characterize the role of NR4A1 presence and activation in modulating intestinal SMC phenotype.

Methods
Primary intestinal SMCs were isolated from Nr4a1+/+and Nr4a1-/-mice. A commercially sourced human primary intestinal SMC line was also used. Mass spectrometry identified proteomic differences between Nr4a1+/+and Nr4a1-/-SMCs. To assess the role of NR4A1 in regulating SMC growth, basal and platelet-derived growth factor-BB (PDGF-BB)-induced proliferation were quantified. NR4A1 activation was induced by selective agonists, cytosporone B (Csn-B) and 6-mercaptopurine (6-MP). Cellular respirometry was used to determine metabolism in Nr4a1+/+and Nr4a1-/-SMCs. Expression of NR4A1 and phenotypic switching mediators were assessed by qPCR. Immunofluorescence was used to assess contractile markers and cell morphology.

Results
Proteomic analysis revealed increased expression of proteins related to the cell cycle, metabolism, and extracellular matrix synthesis in Nr4a1-/-SMCs. Nr4a1+/+SMCs upregulated proteins involved in smooth muscle contraction and was supported by higher mRNA levels of myocardin and lower Krüppel-like factor 4. Nr4a1-/-cells were more proliferative compared to Nr4a1+/+cells under basal conditions. Treating human intestinal SMCs with Csn-B attenuated proliferation induced by PDGF-BB. Similar effects were observed in Nr4a1+/+SMCs, however, the anti-proliferative effect of Csn-B was absent in Nr4a1-/-cells. Nr4a1-/-SMCs had higher maximal respiration, spare respiratory capacity, and glycolysis. NR4A1 expression was rapidly induced by Csn-B/6-MP and PDGF-BB, the latter suggesting a potential negative feedback mechanism to control mitogen-induced SMC proliferation.

Conclusions
Our results suggest that NR4A1 is a regulator of intestinal SMC proliferation, bioenergetics, and phenotype. Its induction by mitogens may contribute to a negative feedback loop to control smooth muscle growth. These data support targeting NR4A1 to treat excessive smooth muscle hypertrophy/hyperplasia that contributes to tissue remodelling observed in fibrostenotic CD.

Funding Agencies
CCC, CIHR