bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human papillomavirus (HPV) DNA methylation changes in HPV-associated head and neck cancer
Authors: Ekanayake Weeramange Chameera , Tang Kai Dun , Irwin Darryl , Hartel Gunter , Langton-Lockton Julian , Ladwa Rahul , Kenny Lizbeth , Taheri Touraj , Whitfield Bernard , Vasani Sarju , Punyadeera Chamindie 
Published: January 2024

AbstractDespite the rising incidence, currently, there are no early detection methods for HPV-driven HNC (HPV-HNC). Cervical cancer studies suggest that HPV DNA methylation changes can be used as a biomarker to discriminate cancer patients from HPV-infected individuals. As such, this study was designed to establish a protocol to evaluate DNA methylation changes in HPV late genes and long control region (LCR) in saliva samples of HPV-HNC patients and HPV-positive controls. Higher methylation levels were detected in HPV late genes (L1 and L2) in both tumour and saliva samples of HPV-HNC patients compared with HPV-positive controls. Moreover, methylation patterns between tumours and corresponding saliva samples were observed to have a strong correlation (Passing-Bablok regression analysis; τ = 0.7483, P &lt; 0.0001). Considering the differences between HNC and controls in methylation levels in late genes, and considering primer amplification efficiencies, 13 CpG sites located at L1 and L2 genes were selected for further evaluation. A total of 18 HNC saliva samples and 10 control saliva samples were assessed for the methylation levels in the selected sites. From the CpG sites evaluated statistically significant differences were identified for CpG sites at L2—CpG 6 (P = 0.0004), L1—CpG 3 (P = 0.0144), L1—CpG 2 (P = 0.0395) and L2—CpG 19 (P = 0.0455). Our pilot data indicate that higher levels of DNA methylation in HPV late genes are indicative of HPV-HNC risk, and it is a potential supplementary biomarker for salivary HPV detection-based HPV-HNC screening.
Functional genetic variants of the disulfidptosis-relatedINF2gene predict survival of hepatitis B virus-related hepatocellular carcinoma
Authors: Wei Junjie , Wen Qiuping , Zhan Shicheng , Cao Ji , Jiang Yanji , Lian Jiawei , Mai Yuejiao , Qiu Moqin , Liu Yingchun , Chen Peiqin , Lin Qiuling , Wei Xiaoxia , Wei Yuying , Huang Qiongguang , Zhang Ruoxin , He Songqing , Yuan Guandou , Wei Qingyi , Zhou Zihan , Yu Hongping 
Published: January 2024

AbstractDisulfidptosis is a novel form of programmed cell death involved in migration and invasion of cancer cells, but few studies investigated the roles of genetic variants in disulfidptosis-related genes in survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We used Cox proportional hazards regression analyses, Kaplan–Meier curves and receiver operating characteristic curves to assess effects of genetic variants in 14 disulfidptosis-related genes on overall survival of 866 HBV-HCC patients. The Bayesian false discovery probability was used for multiple testing corrections. We also investigated biological mechanisms of the significant variants through expression quantitative trait loci analyses using the data from publicly available databases, luciferase reporter assays and differential expression analyses. As a result, we identified two independently functional single nucleotide polymorphisms (SNPs) (INF2 rs4072285 G &gt; A and INF2 rs4444271 A &gt; T) that predicted overall survival of HBV-HCC patients, with adjusted hazard ratios of 1.60 (95% CI = 1.22–2.11, P = 0.001) and 1.50 (95% CI = 1.80–1.90, P &lt; 0.001), respectively, after multiple testing correction. Luciferase reporter assays indicated that both INF2 rs4072285 A and INF2 rs4444271 T alleles increased INF2 mRNA expression levels (P &lt; 0.001) that were also higher in HCC tumor tissues than in adjacent normal tissues (P &lt; 0.001); such elevated INF2 expression levels were associated with a poorer survival of HBV-HCC patients (P &lt; 0.001) in the TCGA database. In summary, this study supported that INF2 rs4072285 and INF2 rs4444271 may be novel biomarkers for survival of HBV-HCC patients.
Three-dimensional structure prediction of [GADS]-proteins as tentative primitive proteins
Authors: Nakayoshi Tomoki , Kato Koichi , Kurimoto Eiji , Oda Akifumi 
Published: January 2024

Abstract
[GADV]-protein is a random peptide constructed from glycine (G), alanine (A), aspartic acid (D), and valine (V), whereas [GADS]-protein is constructed from G, A, D, and serine (S). Both [GADV]- and [GADS]-proteins are candidates of primitive proteins. In this study, the three-dimensional structure formation ability of [GADS]-proteins was compared with that of [GADV]-proteins. Based on the results of molecular dynamics simulations, the secondary structure formation ability and rigid structure formation ability of [GADS]-proteins were inferior to those of [GADV]-proteins.
Understanding the German criticism of Target
Authors: Perotti Roberto 
Published: January 2024

Abstract
Does the accumulation of large Target imbalances threaten the viability of the monetary union? Several German and central European scholars have responded in the affirmative: in the case of a disorderly break-up, debtor countries might have an incentive to default on their Target balances, and this would represent a real loss to Target creditors. Most academics have rejected this argument: in their view, a Target default would be only a paper loss to creditors. I propose a simple and unified framework to study the working of the Target system in response to different shocks. I then argue that the German criticism of the Target system is not so unfounded after all, and should be taken seriously. The underlying problem is the co-existence of separate central banks within the Eurozone; if one wants to preserve this feature, no alternative to the current Target system and its problems seems to be realistically available. In particular, comparisons with the Interdistrict Settlement Account of the US Federal Reserve system are misleading.
On the Role of Personality in Successful Aging: A Scoping Review
Authors: Serrat Rodrigo , Cannella Valentina , Chacur-Kiss Karima , Pons-Vila Joan , Tesch-Römer Clemens 
Published: January 2024

Abstract

Background and Objectives
This study aimed to critically examine current knowledge on the role of personality in successful aging, considering Hooker and McAdams’ 3-level, 6-foci model of personality. The aim was also to pinpoint knowledge gaps that research should address in the future.

Research Design and Methods
We carried out a scoping review of the literature on successful aging and personality, following the 5-step framework proposed by Arksey and O’Malley and further expanded by Levac et al.

Results
Research into the role of personality in successful aging has grown significantly over the last 20 years. However, the increasing number of publications on the topic was primarily accounted for by studies focused on Layer 1 and particularly Layer 2 of McAdams’ model of personality, with Layer 3 being scarcely addressed. Research that included more than 1 layer of personality was rare.

Discussion and Implications
Our study pinpointed gaps that should be considered in future research in this area. These gaps were related to advancing toward agreed-upon definitions of successful aging and personality, broadening the scope of research on this topic, and integrating personality dimensions on research on successful aging.
Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression
Authors: Wong Chao-Jen , Friedman Seth D , Snider Lauren , Bennett Sean R , Jones Takako I , Jones Peter L , Shaw Dennis W W , Blemker Silvia S , Riem Lara , DuCharme Olivia , Lemmers Richard J F L , van der Maarel Silvère M , Wang Leo H , Tawil Rabi , Statland Jeffrey M , Tapscott Stephen J 
Published: January 2024

Abstract
Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.
A NEW APPROACH FOR TREATMENT OF ULCERATIVE COLITIS: A MELANOCORTIN RECEPTOR AGONIST PL8177
Authors: Dhingra Priyanka , Obr Alison , Spana Carl , Dodd John , Kayne Paul 
Published: January 2024

Abstract

INTRODUCTION
The melanocortin system plays an important role in resolving inflammatory processes. The melanocortin 1 receptor (MC1R)–specific agonist PL8177 has demonstrated MC1R binding affinity and functional activity that mirrors that of α-melanocyte–stimulating hormone. The effect of PL8177 on inflammation, cell population composition, and gene and protein expression was investigated in colons from a dextran sulfate sodium (DSS)–induced rat model of colitis.

METHODS
Colitis was induced by 5% DSS in drinking water. Rats received vehicle control (placebo) capsules, oral PL8177 capsules (20, 50, and 100 μg per animal), or mesalazine (positive control). Colons were harvested on day 8. Samples were analyzed for cytokines, and by single nuclei RNA-seq and data-independent acquisition tandem mass spectrometry phosphoproteome profiling. Colitis was assessed by diarrhea and rectal bleeding, colon length shortening, colon weight gain, and histopathology. Total colitis index assessed inflammatory damage.

RESULTS
PL8177 50 μg showed a significant (P&lt;0.05) improvement in colon weight (53% reduction), stool consistency, and fecal occult blood score vs vehicle, and there was significant improvement in the total colitis index for the PL8177 100-μg group vs vehicle. All PL8177 cohorts showed greater improvement in the total colitis index than mesalazine. Mesalazine produced a marked reduction in colon length, but only moderate improvement (35%) in colon weight. Single nuclei RNA-seq showed that in the PL8177 100-μg group, relative cell populations and key gene expression levels were closer to those of healthy controls PL8177 100-μg treatment caused a relative decrease in immune cells and an increase in enterocytes and enteric glial cells compared to vehicle control. Subclustering analysis revealed significant differences between PL8177 100-μg and vehicle populations. Although both showed the presence of macrophages, vehicle-treated colons were primarily M1 macrophages involved in inflammation. In PL8177 100 μg–treated colons, macrophages were primarily pro-resolution M2. Proteomic analysis showed that PL8177-treated colons are more similar to sham colons than to vehicle colons. Also after treatment with PL8177, Smad 2 and 3, proteins known to promote intestinal homeostasis showed expression similar to that seen in the sham group, a result not seen in vehicle-treated colons.

DISCUSSION
Oral PL8177 treatment showed significant improvement in anatomical markers of colitis vs the vehicle and mesalazine control groups, supporting the aim of treating inflammatory bowel disease (IBD). Transcriptomics and proteomics data show that oral PL8177 treatment causes diseased colons to move toward the healthy state and to resolve inflammation. Resolving inflammation—rather than blocking it—provides the possibility of efficacy coupled with safety in treating IBD.
GROUP 3 INNATE LYMPHOID CELLS RELY ON ER STRESS RESPONSE FOR CYTOKINE PRODUCTION IN IBD
Authors: Cao Siyan , Ciorba Matthew , Kaufman Randal , Deepak Parakkal , Colonna Marco 
Published: January 2024

Abstract

BACKGROUNDS
Group 3 innate lymphoid cells (ILC3s) recently emerged as important regulators and potential drug targets for IBD. However, the response of ILC3s to environmental stimuli during intestinal inflammation remains elusive. IRE1a-XBP1 serves as the regulatory hub of the endoplasmic reticulum stress response that plays a vital role in intestinal inflammation.

METHODS
We generated conditional knockout Ire1aflo/flox,Rorc-Cre (Ire1aΔRorc) and Rag-/-Ire1aΔRorc mice with Ire1a deleted in ILC3s. Intestinal infections were induced by Citrobacter rodentium and Clostridium difficile. ILC3s-derived cytokines including IL-22 is crucial for host defense in the acute phase of C. rodentium and C. difficile infection. Dextran sodium sulfate (DSS) was given in drinking water to induce acute colitis. We recruited patients with active Crohn’s disease (CD) and collected ileal biopsies during routine colonoscopy before starting ustekinumab, a non-selective anti-IL-23 antibody. Mucosal ILC3s were isolated for analysis of ILC3s by flow cytometry.

RESULTS
In murine intestinal ILC3s, the activity of IRE1a-XBP1 pathway follows a robust 24h circadian rhythm which parallels that of clock genes and cytokines including IL-22. XBP1s is activated in ILC3s ex vivo by vasoactive intestinal peptide, which was previous shown to orchestrate the circadian expression of IL-22 by ILC3s. IRE1a-XBP1 in intestinal ILC3s is further activated in response to IL-23 and colitis in mice, as well as in inflamed IBD tissues compared to normal tissues from healthy individuals. We further showed that IRE1a-XBP1 activation in stimulated ILC3s requires mitochondrial reactive oxygen species (mtROS) (Fig 1). Using the Ire1aΔRorc mice, we demonstrated that IRE1a-XBP1 is critical for cytokine expression by ILC3s. Ire1aΔRorc mice are highly susceptible to acute C. rodentium and C. difficile infection as well as acute DSS colitis (similar vulnerabilities were found in Rag-/-Ire1aΔRorc mice compared to Rag-/-Ire1aflox/flox littermates). Ire1aΔRorc mice exhibit reduced IL-22 and IL-17A in ILC3s and impaired epithelial barrier function with diminished expression of mucins and antimicrobial peptides. The susceptibilities of Ire1aΔRorc and Rag-/-Ire1aΔRorc mice to colitis were rescued by administration of recombinant IL-22 (Fig 2). Moreover, the frequency of XBP1s+ ILC3s in ileal mucosa from CD patients before initiation of ustekinumab positively correlates with response to therapy.

CONCLUSIONS
We demonstrate that a non-canonical mtROS-IRE1a-XBP1 pathway augments cytokine production by intestinal ILC3s. Loss of IRE1a-XBP1 in ILC3s impairs the optimal and rhythmic expression of protective cytokines and renders the mice more susceptible to intestinal infections and colitis. We also identify XBP1+ ILC3s as a potential biomarker for predicting responsiveness to anti-IL-23 therapies in IBD.
P2Y1 RECEPTOR SIGNALING INFLUENCES EPITHELIAL RESPONSE TO INTESTINAL INFLAMMATION
Authors: Engevik Kristen , Hyser Joseph 
Published: January 2024

Abstract
Purines are among the most influential and ancient biochemical molecules in evolutionary history. In recent years, several studies have identified that nucleotides are released from cells during infection and tissue injury and serve as paracrine signaling molecules that help coordinate host defense and repair responses. These important extracellular signaling molecules activate purinergic receptors, of which there are 19 different purinergic receptor subtypes, which are classified into P1 and P2 receptors. Several studies have revealed crucial roles for P2 purinergic receptors during inflammatory and infectious diseases; however, these studies have largely examined purinergic signaling in immune cells and the enteric nervous system. Yet, while epithelial cells serve as the first barrier against infection and inflammation, the role of purinergic signaling within the gastrointestinal tract remains largely unknown. Our group recently discovered a novel and prominent role for P2Y1 in mediating host responses during rotavirus infection. To extend these studies, we sought to elucidate the P2 purinergic receptor repertoire expressed within gut epithelium and assess their functional role during insult. Using the Human Protein Atlas, we queried single-cell RNA sequencing data for P2 purinergic receptor expression in small intestine, colon, and rectum. In silico analysis revealed high expression of P2Y1, P2Y2, P2Y11 and P2X4 among the purinergic receptors throughout the gastrointestinal tract. Interestingly, P2Y1 showed highest expression in intestinal enterocytes and goblet cells. Further, we compared P2 receptor expression between commonly used, cancer-derived intestinal cell lines (T84, HT29 and Caco2) and crypt-derived human intestinal organoids (HIOs). Both HIOs and T84 and Caco2 cell lines had similar mRNA expressions of P2Y1, P2Y2, P2Y11 and P2X4. However, live calcium imaging studies showed robust responses to P2Y receptor-specific agonists in HIOs, particularly P2Y1 and P2Y2 agonists, but the cancer-derived cell lines failed to respond to these agonists, suggesting these cell lines have defects in P2Y signaling. Functionally, blocking P2Y1, but not P2Y2, significantly delayed wound healing in epithelial scratch assays, indicating a potential role in epithelial injury repair. To delineate the role of epithelial P2Y1 in vivo, we generated VillinCre P2Y1flex/flox mice. At baseline, the knockout animals did not exhibit any overt intestinal defects; however, in the DSS-induced colitis model, the epithelial P2Y1 KO mice had significantly greater weight loss and epithelial damage than their wildtype littermates. These findings confirm that the gastrointestinal tract express P2Y1, P2Y2, P2Y11 and P2X4 purinergic receptors and P2Y1 signaling plays important functional roles in both gastrointestinal epithelial homeostasis and repair of injury.
PERFUSED IN VITRO INTESTINE TISSUE FOR STUDYING INFLAMMATORY BOWEL DISEASE RESPONSE TO DRUG THERAPIES
Authors: Rudolph Sara , Roh Terrence , Longo Brooke , Shokoufandeh Mina , Mumuney Fatimah , Chadha Anushka , Chen Ying , Kaplan David 
Published: January 2024

Abstract
A dynamic perfusion system was designed for cultivation an in vitro model comprising human intestinal colonoids, intestinal myofibroblasts, and monocyte-derived macrophages. The primary aim was to investigate the effect of therapeutic interventions on inflammatory bowel disease (IBD) using this bioengineered system. The approach involved creating a a colonoid epithelial monolayer on a scaffold lumen with myofibroblasts and macrophages in the subepithelial compartment, which was then integrated into a bioreactor enabling controlled perfusion mimicking the dynamic intestinal microenvironment to introduce inflammation and assess responses to traditional and innovative therapies. Inflammation induction in the model resulted in decreased epithelial integrity along with the upregulation of pro-inflammatory cytokines. The addition of myofibroblasts amplified the secretion of pro-inflammatory cytokines GCP-1, GM-CSF, and IL-1α, while concurrently reducing MCP-1 levels. The introduction of myofibroblasts contributed to an enhanced inflammatory response in the tissue. This system is poised to serve as a valuable tool for evaluating potential therapeutic strategies aimed at addressing IBD.
LIQUID-BIOPSY FOR ASSESSING SEVERITY OF INFLAMMATORY BOWEL DISEASE VIA PLASMA MICROBIAL CELL-FREE DNA
Authors: Kale Shiv , Babb Paul , Noll Nicholas , Bercovici Sivan 
Published: January 2024

Abstract
Plasma cell-free DNA (cfDNA) has emerged as a robust biomarker utilized in multiple applications that span cancer screening, diagnosis and monitoring, prenatal testing, and characterization of organ health post-transplantation. Cell-free DNA-based assays leverage the occurrence of processed extracellular DNA that produce unique signatures to discern a variety of biological states, disease manifestations, as well as forms of cell death. Similar to human cells, microbes produce cfDNA when they turnover, providing evident clinical utility in diagnosing and treating deep-seated infections in immunocompromised patients.
Here, we describe the use of plasma microbial cell-free DNA (mcfDNA) as a unique means to assess inflammatory bowel disease type and severity. A total of 392 plasma samples encompassing remission and active (mild, moderate, severe) Crohn’s disease (N=196) and ulcerative colitis (N=196) were provided by the Crohn’s and Colitis Foundation for this study. All samples were derived from patients who had an endoscopic assessment within a 30-day window of plasma collection. Our classifiers, based solely on plasma mcfDNA signatures, are able to discriminate between Crohn’s disease, Ulcerative colitis, or otherwise healthy patient populations with an AUC &gt;0.95. Similarly, a second set of classifiers are able to distinguish between endoscopically validated remission, mild, moderate, and severe disease cases (as determined by Mayo Endoscopic score or Crohn’s disease activity index) with AUCs &gt;0.75. These results correspond to greater than 37% (UC) and 18% (CD) increase in sensitivity in comparison to standard of care measurements via fecal-calprotectin and high sensitivity-C-reactive protein for this cohort. Upon investigation, critical features in our classifiers correspond with well-known signatures from microbes associated with IBD or well-curated from the human microbiome.
The use of mcfDNA for IBD diagnosis and assessment of disease severity may provide clinicians and patients a valuable non-invasive means to gain additional insight into disease progression in a routine manner. Further opportunities to leverage these signatures to predict response to therapy, and validate classifier performance on an independent cohort are currently being explored.
SHORT NONCODING RNAS AS PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT FROM INFLAMMATORY BOWEL DISEASE UNCLASSIFIED TO CROHN’S DISEASE OR ULCERATIVE COLITIS
Authors: James Jaslin , Riis Lene , Sokilde Rolf , Malham Mikkel , Høgdall Estrid , Langholz Ebbe , Nielsen Boye S 
Published: January 2024

Abstract

BACKGROUND
Numerous pathogenic processes are mediated by short noncoding RNAs (ncRNA). Twenty percent of inflammatory bowel disease (IBD) patients are labelled as IBD unclassified (IBDU) at disease onset. Most IBDU patients are reclassified as Crohn's disease (CD) or ulcerative colitis (UC) within few years. Since the therapeutic methods for CD and UC differ, biomarkers that can forecast the categorization of IBDU into CD or UC are highly desired. Here, we investigated whether short ncRNAs can predict CD or UC among IBDU patients.

METHODS
Of 35 IBDU patients initially diagnosed with IBDU, 12, 15, and eight were reclassified into CD(IBDU-CD), UC(IBDU-UC), or remained as IBDU(IBDU-IBDU) respectively. Eight IBD patients, were included as references. Short ncRNA profiling on RNA from mucosal biopsies were performed using Affymetrix miRNA 4.0 array. Selected probe sets were validated using RT-qPCR.

RESULTS
Among all patients and only adults, 306 and 499 probe sets respectively were differentially expressed between IBDU-CD and IBDU-UC. Six of the probe sets were evaluated by RT-qPCR, of which miR-182-5p, miR-451a and ENSG00000239080 (snoU13) together with age and sex resulted in an AUC of 78.6% (95 % CI: 60 - 97) in discriminating IBDU-CD from IBDU-UC.

CONCLUSIONS
Based on the three-short ncRNAs profile it is possible to predict if IBDU patients within 3 years will be reclassified as CD or UC. We showed that the expression profile of IBDU patients differ from that of definite CD or UC, suggesting that a subgroup of IBDU patients may compose a third unique IBD subtype.