bluuebunny/crossref_metadata_2025_split huggingface dataset:
A condensed-matter analogue of the false vacuum
Authors: Gibbons Mark 
Published: May 2021

AbstractThrough experimental investigation into the behaviour of a polar dielectric working fluid, an ideal ‘quasi-thermodynamic’ cycle has been established. Particular stages of this cycle are described in terms of a condensed-matter analogue of the false vacuum, when operating under negative pressure. The cycle is established between 37 °C and 15 °C under isochoric conditions. Phase-change work is created in two-directions, positive expansion-work and negative contraction-work. A large proportion of the expansion-work derives from a cooling process where the fluid exhibits negative heat capacity. When heat flux ceases, the fluid becomes unstable and heat capacity switches from negative to positive, displaying a ‘non-equivalence of ensembles’ phase-change. Whilst elements of the fluid behaviour can only be described by the statistical mechanics of non-equilibrium systems, the calculated equations of state for classical thermodynamics are confirmed to be accurate from the experimental investigation. However, the classical thermodynamic calculations for cycle-efficiency do not produce a symmetry of energy conservation. This suggests that an additional form of energy, having long-range interaction and distinct from heat and work input, is involved in the performance of the quasi-thermodynamic cycle. The expansion of a negative pressure fluid that contains inclusion compounds appears responsible for this potential energy interaction as an analogue of the false vacuum potential that can be explained by application of the virial theorem.
Stochasticity helps to navigate rough landscapes: comparing gradient-descent-based algorithms in the phase retrieval problem
Authors: Mignacco Francesca , Urbani Pierfrancesco , Zdeborová Lenka 
Published: May 2021

Abstract
In this paper we investigate how gradient-based algorithms such as gradient descent (GD), (multi-pass) stochastic GD, its persistent variant, and the Langevin algorithm navigate non-convex loss-landscapes and which of them is able to reach the best generalization error at limited sample complexity. We consider the loss landscape of the high-dimensional phase retrieval problem as a prototypical highly non-convex example. We observe that for phase retrieval the stochastic variants of GD are able to reach perfect generalization for regions of control parameters where the GD algorithm is not. We apply dynamical mean-field theory from statistical physics to characterize analytically the full trajectories of these algorithms in their continuous-time limit, with a warm start, and for large system sizes. We further unveil several intriguing properties of the landscape and the algorithms such as that the GD can obtain better generalization properties from less informed initializations.
Development of an antimicrobial stewardship module in an electronic health record: Options to enhance daily antimicrobial stewardship activities
Authors: Dzintars Kathryn , Fabre Valeria M , Avdic Edina , Smith Janessa , Adams-Sommer Victoria , Townsend Jennifer , Jenh Hsu Alice , Cosgrove Sara E 
Published: May 2021

Abstract

Purpose
The purpose of this manuscript is to describe our experience developing an antimicrobial stewardship (AS) module as a clinical decision support tool in the Epic electronic health record (EHR).

Summary
Clinical decision support systems within the EHR can be used to decrease use of broad-spectrum antibiotics, improve antibiotic selection and dosing, decrease adverse effects, reduce antibiotic costs, and reduce the development of antibiotic resistance. The Johns Hopkins Hospital constructed an AS module within Epic. Customized stewardship alerts and scoring systems were developed to triage patients requiring stewardship intervention. This required a multidisciplinary approach with a team comprising AS physicians and pharmacists and Epic information technology personnel, with assistance from clinical microbiology and infection control when necessary. In addition, an intervention database was enhanced with stewardship-specific interventions, and workbench reports were developed specific to AS needs. We herein review the process, advantages, and challenges associated with the development of the Epic AS module.

Conclusion
Customizing an AS module in an EHR requires significant time and expertise in antimicrobials; however, AS modules have the potential to improve the efficiency of AS personnel in performing daily stewardship activities and reporting through a single system.
Aiming off the target: recycling target capture sequencing reads for investigating repetitive DNA
Authors: Costa Lucas , Marques André , Buddenhagen Chris , Thomas William Wayt , Huettel Bruno , Schubert Veit , Dodsworth Steven , Houben Andreas , Souza Gustavo , Pedrosa-Harand Andrea 
Published: May 2021

Abstract

Background and Aims
With the advance of high-throughput sequencing, reduced-representation methods such as target capture sequencing (TCS) emerged as cost-efficient ways of gathering genomic information, particularly from coding regions. As the off-target reads from such sequencing are expected to be similar to genome skimming (GS), we assessed the quality of repeat characterization in plant genomes using these data.

Methods
Repeat composition obtained from TCS datasets of five Rhynchospora (Cyperaceae) species were compared with GS data from the same taxa. In addition, a FISH probe was designed based on the most abundant satellite found in the TCS dataset of Rhynchospora cephalotes. Finally, repeat-based phylogenies of the five Rhynchospora species were constructed based on the GS and TCS datasets and the topologies were compared with a gene-alignment-based phylogenetic tree.

Key Results
All the major repetitive DNA families were identified in TCS, including repeats that showed abundances as low as 0.01 % in the GS data. Rank correlations between GS and TCS repeat abundances were moderately high (r = 0.58–0.85), increasing after filtering out the targeted loci from the raw TCS reads (r = 0.66–0.92). Repeat data obtained by TCS were also reliable in developing a cytogenetic probe of a new variant of the holocentromeric satellite Tyba. Repeat-based phylogenies from TCS data were congruent with those obtained from GS data and the gene-alignment tree.

Conclusions
Our results show that off-target TCS reads can be recycled to identify repeats for cyto- and phylogenomic investigations. Given the growing availability of TCS reads, driven by global phylogenomic projects, our strategy represents a way to recycle genomic data and contribute to a better characterization of plant biodiversity.
From the Strait of Gibraltar to northern Europe: Pleistocene refugia and biogeographic history of heather (Calluna vulgaris, Ericaceae)
Authors: Gil-López Manuel Jesús , Segarra-Moragues José Gabriel , Casimiro-Soriguer Ramón , Ojeda Fernando 
Published: May 2021

AbstractCalluna vulgaris (Ericaceae) is the most widespread and prevalent woody species of the European dry heathland, from the African side of the Strait of Gibraltar to northern Europe. However, previous biogeographic analyses of this species have ignored the western Mediterranean region, despite its preponderant role as a major glacial refugium for European biota. Here, we explore the existence of further Pleistocene glacial refugia for C. vulgaris in the Iberian Peninsula and the Strait of Gibraltar area and provide new insights into the post-glacial colonization of Europe by this emblematic heathland species. We carried out phylogeographical analyses of C. vulgaris samples from 44 locations using four plastid markers (matK, trnH-psbA, trnL-F and rpl16). We built palaeodistribution models using MAXENT to identify possible refugia for C. vulgaris during the mid-Pliocene, Last Interglacial (LIG), Last Glacial Maximum (LGM) and mid-Holocene. Our results identified a genetic lineage exclusive to the Strait of Gibraltar area s.l. (south-western Iberian Peninsula and north-western tip of Africa) as the most probable close to the clade of origin of the species. This lineage also had more private haplotypes than more recent, Eurosiberian clades. The obtained data highlighted two main refugia for C. vulgaris during the LGM, one around the Strait of Gibraltar and another in the north-western Iberian Peninsula. The Strait of Gibraltar area is a major centre of origin or glacial refugium for the heather C. vulgaris. However, the north-western Iberian Peninsula seems to have acted as a secondary glacial refugium for the more recent, Eurosiberian lineage of this species. This study stresses the importance of the Strait of Gibraltar area in the biogeographic history and conservation of the heather and, by extension, the European heathland habitat.
N15 Transition of care programme and treatment adherence in adolescents with Inflammatory Bowel Disease
Authors: Garzia Stafrace N 
Published: May 2021

Abstract

Background
The purpose of this study was to address the grey areas influencing the transition of care (TOC) aspect in adolescents suffering from IBD. In the context of healthcare, the term ‘transition’ refers to a phase of development from one stage to another. ‘TOC’ is defined as the “purposeful planned movement of adolescents and young adults with chronic conditions from child-centred to adult-oriented health care systems” (Blum et al., 1993). The point where the adolescent becomes an adult represents a milestone not only in health care delivery but also in the wider context of knowledge of medication, education, and employment, as well as sexual and psychosocial development amongst others (Greveson et al., 2011). Although this concept of care is still in its early stages, it has found its application in various specialities of medicine, including but not limited to diabetes, juvenile rheumatology, congenital heart diseases (Afzali & Wahbeh, 2017) and gastroenterology conditions, namely inflammatory bowel disease (IBD).

Methods
From this systematic review of literature that discussed TOC, it became evident that this essential process is undervalued and understudied. Transition standards vary between healthcare services and goals. The selected 3 cross-sectional, 1 cohort and 1 multi-site comparison studies published between 2013 and 2018 analysed how IBD treatment compliance in adolescents is affected when going through an established TOC compared to no TOC. While TOC has successfully created clinical targets, identified deficiencies in knowledge, adherence, and transition readiness assessments, there are still few evidence-based tools to assist in the transition process and a relative absence of transition models that have been critically appraised (Bollegala & Nguyen, 2015).

Results
Findings determined that the establishment and attendance of IBD adolescent patients in structured TOC programmes or clinics ensure cohesive treatment adherence. Nevertheless, it was established that further studies must be carried out on the matter at hand.

Conclusion
Recommendations for clinical practice, management, education, and further studies were endorsed. Such suggestions concluded that transition should be delayed until the patient has been assessed for readiness, along with the importance of involving a multidisciplinary team and the development of practical guidelines and skills aimed for optimal, lifelong IBD management.
OP38 Developing a Cost-Effective Genomic Biomarker of Cancer Risk in Patients with Ulcerative Colitis using Low-Pass Whole Genome Sequencing of Unselected Endoscopic Biopsies: A Case-Control Study
Authors: Al Bakir I , Curtius K , Smith K , Kopczynska M , Moorghen M , Hart A , Graham T 
Published: May 2021

Abstract

Background
Patients with ulcerative colitis (UC) are enrolled into surveillance programs for the early detection of colorectal cancer (CRC). However, most patients under surveillance are low-risk and never progress to CRC, while a significant proportion of CRCs in UC form without a preceding confirmed diagnosis of dysplasia. High resolution chromosomal copy-number alteration (CNA) analysis of unselected formalin-fixed paraffin embedded biopsies taken at surveillance colonoscopies using low pass whole genome sequencing (lpWGS) offers an appealing approach to CRC stratification.

Methods
We conducted a retrospective case-control study to compare the CNA burden in four unselected non-neoplastic left-sided colorectal biopsies from patients with E2/E3 UC derived 1–5 years prior to HGD/CRC detection (cases), with that of biopsies from patients who subsequently remained HGD/CRC-free for at least 5 years (controls). The two patient groups were matched by age, gender, duration of IBD and PSC status. lpWGS was performed using a standardised pipeline for epithelial enrichment, DNA extraction, library preparation, next generation sequencing and bioinformatic analysis.

Results
476 biopsies, derived from 42 cases and 77 controls, were analysed. Nearly 80% of patients had a detectable CNA in at least one of their biopsies, with the maximal CNA burden in a typical biopsy involving a median 1.1% of that biopsy’s genome. The CNA burden was significantly greater in the rectum compared to the sigmoid colon and descending colon. The most common CNA events were losses of between 1–30 megabases involving the sub-telomeric regions of chromosomes 5–9 and 22, which were found in similar proportion in both case and control biopsies. However, losses extending beyond sub-telomeric regions, as well as copy number gains, were found more frequently in cases biopsies (p&lt;0.0001). The most discriminating CNA event was the presence of such a loss extending beyond subtelomeric regions in any of the patient’s four biopsies, with a high specificity exceeding 0.95 (see Kaplan-Meier plot). ROC analysis demonstrates that lpWGS output has a fair level of accuracy at predicting future HGD/CRC risk (AUC 0.73).

Conclusion
We identified multiple biopsies, predominantly in cases, with a surprisingly marked CNA burden involving over 10% of the genome, highlighting the fluid phenotype-genotype relationship. Non-dysplastic colitic epithelium can bear a significant burden of CNAs and maintain phenotypic stability for years without neoplastic transformation. Remarkably, by analysing the CNA burden of only four random biopsies, derived from less than 0.05% of the colonic surface area, we can significantly discriminate between case and control cohorts.
P015 Differential expression in colitis-associated cancer compared to Crohn′s disease and ulcerative colitis
Authors: Manna S , Sehn M , Cardoso da Silva D , Elezkurtaj S , Cineus R , Hegazy A , Siegmund B , Weixler B , Hummel M , Gröne J , Schumann M 
Published: May 2021

Abstract

Background
Crohn’s disease (CD) and ulcerative colitis (UC) are autoimmune-mediated conditions of chronic inflammation affecting the intestinal mucosa, that pose a lifelong risk to patients to develop a colitis-associated carcinoma (CAC). Much of current knowledge on mechanisms in CAC development result from murine CAC models, while studies on human CAC carcinogenesis are scarce. Thus, in our present study, we aimed to contribute to the understanding of colitis-associated carcinogenesis by comparative analysis of gene expression in human samples and further validation of these findings in colon organoids.

Methods
RNA isolation was done from microdissected surgical colon specimen from 60 patients that suffered from either UC, CD, UC-CAC, CD-CAC or inflammation-free healthy controls (10 patients per group). Nanostring nCounterTM technology with a gene panel comprising &gt;630 genes was performed to examine genes focusing on mucosal immunology, epithelial barrier/polarity. nSolverTM data analysis software was used for primary data analysis and statistics. Patients were grouped using expression patterns (by heat maps), differential expression and pathway analysis. For organoid cultures, crypts were isolated from mouse colon and cultured using the R-Spondin method. Organoids were subjected to osteopontin treatment. Consecutively, RNA was isolated. This was followed by gene expression analysis of core EMT (epithelial to mesenchymal transition) transcription factors (TFs) focusing on Twist1, Snai1, Snai2 by RT-PCR.

Results
Heat maps generated from the expression data revealed close-to-optimal grouping recapitulating the clinical subgroups. Differential expression comparing CD with CD-CAC and UC with UC-CAC identified 203 and 271 differentially expressed genes, respectively. Genes most significantly upregulated included SPP1/Osteopontin (OPN), GRHL2 and EMT signature gene as fibronectin1 and ZEB1, generating the hypothesis of OPN driving EMT and thereby inducing inflammation-associated carcinogenesis. Furthermore, mouse colon organoids treated with OPN (50ng/µl) revealed an increased expression by 3fold of core the EMT TFs Twist1, Snai1, Snai2.

Conclusion
We provide a comprehensive quantitative gene expression analysis for CAC with comparison of gene expression in CAC to the respective underlying IBD, CD and UC. Identified upregulated or downregulated genes allow to allocate signal transduction pathways important for CAC carcinogenesis. OPN as the most upregulated gene in CAC in our gene panel might be crucial for regulating EMT in CAC carcinogenesis. Thus, our findings uncover the role of OPN in CAC carcinogenesis.
P025 Identification and validation of predictors for tofacitinib through supervised and unbiased approaches in Inflammatory Bowel Disease
Authors: Liu B , Spalinger M , Perez L G , Machicote A , Gagliani N , Scharl M , Huber S 
Published: May 2021

Abstract

Background
Inflammatory Bowel Disease (IBD) is characterized by an overwhelming gut inflammation, where CD4+ effector T cells are main mediators of the inflammatory response. Tofacitinib, a small molecular drug recently used in IBD patients, blocks the JAK/STAT signaling pathway necessary for CD4+ effector T-cell activation. However, clinical data show that a percentage of patients do not respond to the treatment. Our main goal is to identify biomarkers predicting the response of patients to tofacitinib.

Methods
Tofacitinib efficacy was studied in vivo in wild type (WT) and T-cell-specific PTPN2 deficient mice (CD4-Cre;Ptpn2 floxed) in which the JAK/STAT signaling pathway is over activated. WT and PTPN2 deficient mice were gavaged with tofacitinib (50mg/kg, twice daily) or vehicle. Acute DSS-colitis was induced. Colitis development was evaluated by weight loss, colonoscopy and histology. CD4+ T cells were isolated from the colon and analyzed by flow cytometry. To study the effect of tofacitinib on T-cell differentiation, we isolated naïve T cells from mouse spleen and polarized them in vitro to different T-cell subsets with or without tofacitinib. CD4+ T cells differentiation and cytokine production were analyzed by flow cytometry. To evaluate the influence of tofacitinib on human CD4+ T cells, human peripheral blood mononuclear cells (PBMCs) from healthy donors and IBD patients were stimulated in presence of tofacitinib, and analyzed by flow cytometry.

Results
While no protective effect was found after tofacitinib treatment in WT mice, PTPN2 deficient mice were protected from colitis based on less weight loss, lower endoscopic and histological scores. The expression of pro-inflammatory cytokines such as IL-17 and IFN-γ by colonic CD4+ T cells was also decreased by tofacitinib. Consistent with the in vivo observations, in vitro experiments revealed a strong impact of tofacitinib on CD4+ T-cells cytokine production. In PBMCs from IBD patients, IFN-γ and TNF-α expression was strongly impacted. In contrast, in healthy donors, IL-10 was the most impacted cytokine. Finally, tofacitinib decreased the in vitro differentiation of Th1, Th2, Th17, Th22, Treg and Tr1.

Conclusion
In the T-cell-specific PTPN2 deficient mice, tofacitinib exerts a protective effect after DSS-induced colitis. In line with the in vivo findings, in vitro experiments show that tofacitinib has a strong impact on pro-inflammatory cytokine production, especially in the IBD patients. Taken together, these data suggest that tofacitinib might be suitable primarily for IBD patients where the JAK/STAT signaling pathway is over activated.
P040 USP16 regulates p65 activation in macrophages and promotes the inflammatory-carcinoma transformation process in IBD patients
Authors: Zhang Y , Wang C , Yao L , Li M , Jin J , Cao Q 
Published: May 2021

Abstract

Background
Long duration colonic inflammation increases the risk in developing intestinal dysplasia and further tumorigenesis, which is known as colitis-associated cancer (CAC). USP16, a deubiquitinase, is reported to regulate the T cell and macrophage function in acute colitis. But its function in CAC is never been studied.

Methods
We analyzed USP16 expression in tumor tissues and para-tumor tissues from patients with CAC by immunofluorescent staining. Then we established a CAC model in USP16MKO (conditional knock out in macrophage cells) and wild type mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Associated inflammatory cytokines were examined in normal colon and CAC by real-time polymerase chain reaction. And the signaling pathways and molecular mechanisms were studied.

Results
Expression of USP16 was found to be increased in tumor tissues from CAC patients than that in para-tumor controls. USP16MKO mice had fewer and smaller colon tumors than their WT littermates. Various inflammatory cytokines, including Tnf, Il12a, IL12b, Il23a and Il1b, were decreased in the colon tissues of USP16MKO mice. USP16 deficiency leads to the decrease of p65 activation and nucleation in macrophage. Through co-IP and immunofluorescent staining, USP16 was found to have an interaction with p65. And p65 deubiquitination was decreased in USP16 deficient macrophages.

Conclusion
USP16 is increased in colitis-associated cancer and regulates intestinal epithelial carcinogenesis by modulating pro-inflammatory responses in macrophages. USP16 serves as a deubiquitinase of P65 and thus promoting the activation and nucleation. Therefore, USP16 may serve as a novel therapeutic target to block inflammatory-cancer transformation
P045 Oncostatin M induces strong fibrotic and chemokine responses from primary colonic subepithelial myofibroblasts
Authors: Kokkotis G , Tarapatzi G , Drygiannakis I , Filidou E , Kandilogiannakis L , Arvanitidis K , Valatas V , Koutroubakis I , Vradelis S , Kolios G , Bamias G 
Published: May 2021

Abstract

Background
Oncostatin M (OSM) may play an important role in Inflammatory Bowel Disease (IBD) pathogenesis. Specifically, both OSM and its receptor are upregulated in inflamed colonic regions of IBD patients, and high OSM expression has been associated with failure to respond to anti-TNF therapy. Our aim was to investigate the effect of OSM in fibrotic factors and chemokine expression on primary colonic subepithelial myofibroblasts (SEMFs) from healthy individuals (HI).

Methods
Primary SEMFs were isolated from endoscopically-obtained colonic biopsies from HI. SEMFs were stimulated with 1, 10, or 100ng/ml OSM for 6 hours, with or without pre-stimulation with 5ng/ml IL-1α plus 50ng/ml TNF-α for 24h. Total RNA was collected and mRNA transcripts for collagen type I, type III, fibronectin, and the chemokines CCL2, CXCL9, CXCL10 and CXCL11 were measured by reverse transcription quantitative PCR.

Results
Unstimulated SEMFs had a basal expression of collagen type I, III, fibronectin, CCL2, CXCL9, CXCL10 and CXCL11. OSM stimulation augmented chemokine mRNA expression in a dose-dependent manner (Table 1) but had no effect on fibrotic factors expression. Pre-stimulation of myofibroblasts with TNF-α and IL-1α resulted in augmented expression of collagens I and III and fibronectin, in addition to further increases in chemokine expression in response to subsequent stimulation by OSM (Table 2).

Conclusion
Our results show that stimulation with OSM induces fibrotic and chemokine responses by SEMFs. Our findings further support the hypothesis that SEMFs may play a key role in regulating chronic intestinal inflammation and response to biological therapy.