bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines
Authors: Fortuno Cristina , Michailidou Kyriaki , Parsons Michael , Dolinsky Jill S , Pesaran Tina , Yussuf Amal , Mester Jessica L , Hruska Kathleen S , Hiraki Susan , O’Connor Robert , Chan Raymond C , Kim Serra , Tavtigian Sean V , Goldgar David , James Paul A , Spurdle Amanda B 
Published: January 2024

Abstract
Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case–control studies, or “proband counting” within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the “PS4 proband counting” criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.
PMAT: an efficient plant mitogenome assembly toolkit using low-coverage HiFi sequencing data
Authors: Bi Changwei , Shen Fei , Han Fuchuan , Qu Yanshu , Hou Jing , Xu Kewang , Xu Li-an , He Wenchuang , Wu Zhiqiang , Yin Tongming 
Published: January 2024

Abstract
Complete mitochondrial genomes (mitogenomes) of plants are valuable resources for nucleocytoplasmic interactions, plant evolution, and plant cytoplasmic male sterile line breeding. However, the complete assembly of plant mitogenomes is challenging due to frequent recombination events and horizontal gene transfers. Previous studies have adopted Illumina, PacBio, and Nanopore sequencing data to assemble plant mitogenomes, but the poor assembly completeness, low sequencing accuracy, and high cost limit the sampling capacity. Here, we present an efficient assembly toolkit (PMAT) for de novo assembly of plant mitogenomes using low-coverage HiFi sequencing data. PMAT has been applied to the de novo assembly of 13 broadly representative plant mitogenomes, outperforming existing organelle genome assemblers in terms of assembly accuracy and completeness. By evaluating the assembly of plant mitogenomes from different sequencing data, it was confirmed that PMAT only requires 1× HiFi sequencing data to obtain a complete plant mitogenome. The source code for PMAT is available at https://github.com/bichangwei/PMAT. The developed PMAT toolkit will indeed accelerate the understanding of evolutionary variation and breeding application of plant mitogenomes.
Allele-specific DNA methylation and gene expression during shoot organogenesis in tissue culture of hybrid poplar
Authors: Guo Ying , Feng Yang-Fan , Yang Gang-Gui , Jia Yan , He Jie , Wu Ze-Yu , Liao Hao-Ran , Wei Qi-Xuan , Xue Liang-Jiao 
Published: January 2024

Abstract
Plant tissue regeneration is critical for genetic transformation and genome editing techniques. During the regeneration process, changes in epigenetic modifications accompany the cell fate transition. However, how allele-specific DNA methylation in two haplotypes contributes to the transcriptional dynamics during regeneration remains elusive. Here we applied an inter-species hybrid poplar (Populus alba × P. glandulosa cv. 84 K) as a system to characterize the DNA methylation landscape during de novo shoot organogenesis at allele level. Both direct and indirect shoot organogenesis showed a reduction in genome-wide DNA methylation. At gene level, non-expressed genes were hypermethylated in comparison with expressed genes. Among the genes exhibiting significant correlations between levels of DNA methylation and gene expression, the expression patterns of 75% of genes were negatively correlated with DNA methylation in the CG context, whereas the correlation patterns in the CHH context were the reverse. The allele-biased DNA methylation was consistent during shoot organogenesis, with fewer than one-thousandth of allele-specific methylation regions shifted. Analysis of allele-specific expression revealed that there were only 1909 genes showing phase-dependent allele-biased expression in the regeneration process, among which the allele pairs with greater differences in transcription factor binding sites at promoter regions exhibited greater differences in allele expression. Our results indicated a relatively independent transcriptional regulation in two subgenomes during shoot organogenesis, which was contributed by cis-acting genomic and epigenomic variations.
Climate Change and the Modern Slavery Conundrum in Africa: Reimagining the Relevance of Human Rights Law
Authors: Ogunniyi Daniel 
Published: January 2024

Abstract
Although climate change is among the main ecological crisis the world is grappling with today, relevant discourses on the subject often focus exclusively on the existential threats it presents ignoring other associated risks, including how it exacerbates modern slavery vulnerabilities. Despite already constituting a major human rights challenge, climate change promises to further exacerbate the modern slavery conundrum in Africa. Thus, in this paper, two interconnected questions are engaged with. Firstly, the climate crisis is interrogated vis-à-vis the way it induces modern slavery vulnerabilities in Africa and undermines human rights. The second aspect assesses the utility of the human rights framework in climate change action and its potential to protect modern slavery victims. While African countries are obligated to implement mitigation and adaptation strategies within their jurisdictions, to effectively address the modern slavery challenge, the paper suggests a stronger focus on global climate action via international cooperation and debt-for-nature swap.
A NOVEL MOUSE MODEL OF CROHN’S DISEASE DRIVEN BY THE INTERACTION OF CD4 T CELLS AND GUT MICROBIOTA-RESPONSIVE γδ T CELLS
Authors: Anderson Nicole , Olson Matthew 
Published: January 2024

Abstract
Inflammatory bowel disease (IBD) is a spectrum of disorders, namely Crohn’s Disease (CD) and Ulcerative Colitis (UC), characterized by distinct patterns of intestinal inflammation, a dysregulated intestinal immune response, and an altered gut microbiota. Given the growing number of new IBD diagnoses (70,000 new cases reported each year) and the inconsistent results of current treatment options, there is a major unmet need to understand IBD pathophysiology to develop more effective treatments. Previous reports indicate that IBD patients have an altered gut microbiota that can influence the development of inflammatory innate and adaptive immune cells that cause intestinal tissue damage and drive IBD pathogenesis. In particular, innate-like γδ T cells have been shown to accumulate within lesional tissue of CD patients and exhibit an inflammatory profile. However, the role of γδ T cells in promoting CD is not well understood, partially due to a lack of mouse models that accurately mimic human γδ T cell phenotypes. Thus, there is a critical need to more deeply understand conventional-γδ cross-talk in the intestine and develop novel animal models that accurately recapitulate these interactions during disease.
We have previously shown that the transcription factors (TFs) STAT3 and BATF play critical roles in pathogenic CD4 T cell differentiation, but their roles in modulating interactions between adaptive and innate-like T cells are less clear. In our preliminary work, we surprisingly found that mice with conventional T cell-specific deletions in STAT3 and BATF, but not each individual TF, developed an aggressive spontaneous colitis with pathology that mimics the intestinal damage seen in Crohn’s disease patients. This spontaneous colitis was hallmarked by elevated numbers of inflammatory (i.e., high IFN-γ producing) γδ T cells in the intestines, which mimic those found in a subset of IBD patients. Importantly, depletion of γδ T cells in this model resulted in diminished disease, implicating these cells as key mediators of CD-like intestinal inflammation. γδ T cells in our model were largely localized between colonic crypts and in close proximity to the gut microbiota, suggesting that they may be influenced by changes in gut microbes. Indeed, we observed that STAT3/BATF-deficient mice exhibited an altered gut microbiota which was required for the dysregulated γδ T cell response. Taken together, our data indicate that STAT3/BATF-expressing conventional CD4 T cells regulate gut microbes that would otherwise drive the generation of inflammatory γδ T cells that contribute to CD-like disease. Therefore, a better understanding of microbe-γδ T cell interactions is imperative for understanding intestinal homeostasis and for defining therapies that may prevent the onset of IBD.

Figure 1 Graphical abstract. This project seeks to identify the interactions between T cells and gut microbiota in driving IBD, more specifically Crohn’s disease.
EVALUATING THE PRE-CLINICAL EFFICACY OF VT1021 (A CLINICAL STAGE DRUG CANDIDATE) IN MULTIPLE EXPERIMENTAL MODELS OF INFLAMMATORY BOWEL DISEASE
Authors: Wang Suming , Clossey Donna , Zota Victor , Li Wendy , Chen Jenny , Cieslewicz Michael , Watnick Randolph , Mahoney Jim , Watnick Jing 
Published: January 2024

Abstract
Inflammatory bowel disease (IBD) is characterized symptomatically by chronic inflammation in the colonic tract. Despite the increased understanding of the physiological symptoms of Crohn’s Disease, and IBD in general, there have been no significant breakthroughs in understanding its etiology or improving treatment. As such, there is an urgent need for efficacious therapies that are aimed specifically at preventing or curing IBD. Bolstering the need for better therapies is the fact that patients with IBD have increased risk of developing intestinal cancers. One of the pathological traits of IBD that heightens the risk of cancer is the increased level of angiogenesis that accompanies the inflammation. As the biological processes of angiogenesis and inflammation are intricately linked, we believe increasing the levels of thrombospondin-1 (TSP-1), an anti-angiogenic and anti-inflammatory protein, can reprogram immune and inflammatory cells to inhibit angiogenesis and induce the resolution of inflammation.
Vigeo has developed VT1021 which stimulates the expression of TSP-1 in inflammatory myeloid derived suppressor cells (MDSCs) systemically. VT1021 achieved proof of concept in a Phase 1/2 clinical trial with multiple cohorts and is currently in Phase 2/3 trials for oncology indications. IBD patients have increased MDSCs in both lesions and peripheral blood. MDSCs are genomically stable and not mutated in IBD patients and thus represent ideal therapeutic targets. Two dextran sulfate sodium (DSS)-induced colitis models were used to evaluate the pre-clinical efficacy of VT1021. In the preventative model, mice were treated with 4% DSS from Day 0 to Day 6 and either saline or VT1021 from Day 0 to Day 8, then sacrificed on Day 8 to collect colon tissue and plasma samples. In the rescue model, mice were treated with 4% DSS from Day 0 to Day 4, then treated with either saline, VT1021 (25, 50, 100 mg/kg) or anti-TNFa from Day 5 to Day 10. Mice were sacrificed on Day 11; colon tissue and plasma samples were collected. In both models, VT1021 treatment significantly prevented the mouse weight loss and bloody stool compared to the saline treatment. VT1021 treatment also decreased the colon inflammation by the measurement of both plasma myeloperoxidase (MPO) level and colon tissue histopathology score. Immunohistochemistry staining of colon tissue samples confirmed that VT1021 treatment stimulated TSP-1 expression in the MDSCs.
Altogether, these findings show that VT1021 treatment has equivalent efficacy to anti-TNFa treatment, while significantly reducing damage to colon tissue. We believe VT1021 will show significantly greater efficacy in patients with longer term use, while avoiding the systemic deleterious side effects common to current approved therapies.
POLYMER-BASED INTERFACE TARGETING INFLAMMATION IN ULCERATIVE COLITIS
Authors: Zhang Sufeng , Jin Amy , Lennerz Jochen , Korzenik Joshua , Traverso Carlo 
Published: January 2024

Abstract
A major hurdle in the treatment of inflammatory bowel disease (IBD) is the lack of effective drug carriers that can precisely deliver the required amount of drug to the sites of inflammation. Available therapies have limited efficacy or severe side effects, largely because of the low concentration of active drugs at the disease sites and non-specific systemic absorption of the administered drugs. Drug delivery targeting the sites of intestinal inflammation offers an approach to maximize therapeutic efficacy while minimizing adverse side effects.
We focus on developing formulations that can provide improved local drug administration in the treatment of ulcerative colitis (UC), one of the two main types of IBD. Targeting sites of inflammation in the gastrointestinal tract can be achieved using drug delivery systems that exploit pathophysiological features of the inflamed intestine. Our previous study showed preferential adhesion of a negatively charged small-molecule-based hydrogel to the inflamed colon in murine models of colitis and biopsies from UC patients; further, a corticosteroid drug delivered by this hydrogel demonstrated an improved efficacy compared to the drug alone. Based on our previous experience, we expanded the small-molecule-based hydrogel to polymer-based hydrogels for enhanced selective targeting. We designed the material so that it has a strong affinity towards ulcers. Through molecular structure design, we functionalized thermo-responsive poly(N-isopropylacrylamide) (PNIPAM)-based polymers to modulate the physicochemical properties of the materials and compared the resultant polymers’ gelation and adhesion to the inflamed colon in dextran sulfate sodium (DSS)-induced colitis in mice. We showed that both the types of chemical modification and polymer molecular weight affected the adhesion of the resultant hydrogels to the inflamed colon. We further quantified the disease parameters of colitis for individual mice and correlated the colitis parameters with polymers’ adhesion. Our study suggests a new strategy for targeting the inflamed colon through harnessing charge-mediated interaction and thermo-responsiveness of PNIPAM-based polymers. By adhering to the inflamed mucosa, our delivery system has the potential to maintain the drug locally at the active ulcer sites where it is needed, thereby minimizing the adverse effects of drugs on the healthy tissue. The examination of these polymeric hydrogels’ mucosal binding provides a further understanding of interactions between the polymers and the biological interface in colitis. These studies were performed in preclinical models of UC that develop colitis similar to human UC, as a prerequisite for future studies.
STERILE NEUTROPHILIA INDUCED VIA CXCR4 ANTAGONISM MITIGATES COLONIC INFLAMMATION BY ENHANCING IMMUNOSUPPRESSIVE REGULATORY T CELLS IN MICE
Authors: Saha Piu , Yeoh Beng San , Vijay-Kumar Matam 
Published: January 2024

Abstract
Sterile neutrophilia (SN) is commonly associated with chronic diseases including inflammatory bowel diseases (IBD), but its defined role is largely unknown. Plerixafor (AMD3100) is a CXCR4 antagonist that promotes neutrophil egress from bone marrow resulting in SN. We first confirmed that C57BL6/J mice administered Plerixafor (10 mg/kg/bw, i.p.,) increased their circulating neutrophils by 50% within 2.5 h. Further, to study the role of SN in IBD, we induced chronic colitis by neutralizing IL-10 signaling via αIL-10R mAb (1.0 mg/mouse, i.p., 4 weekly injections) with or without weekly twice Plerixafor. Control mice were given isotype control mAb. As expected, αIL-10R+Plerixafor-treated mice had increased peripheral and splenic neutrophils. Further, these mice displayed remarkably reduced epithelial damage, hyperplasia, immune cell infiltration, and disease activity index when compared to αIL-10R+vehicle treated mice, which had typical colitis symptoms. To delineate the mechanism for such protection by Plerixafor, we profiled immune cells in circulation, spleen and lamina propria. In circulation αIL-10R+Plerixafor-treated mice had elevated CD3+CD4+ helper T cells (Th) but reduced CD3+CD8+ cytotoxic T (Tc) cells and CD3+CD4+FoxP3+ cells (Tregs) and CD3+CD4+RORγt+ cells (Th17) remained unchanged. While in the spleens of αIL-10R+Plerixafor-treated mice displayed significant increased Tregs, but decreased Th and Tc cells. Interestingly, markedly elevated Tregs, RORγt+ Tregs and tolerogenic IL-10+ Tregs was observed in lamina propria when compared to αIL-10R+ vehicle given mice. Interestingly, the proinflammatory IL-17+ Th cells were decreased in αIL-10R+Plerixafor-treated mice which showed mild colitis. Moreover, to further elucidate the role of Plerixafor in intestinal barrier function in colitic mice, we noticed treatment with Plerixafor increased the expression of occludin and claudins (1, 2), which are the principal transmembrane tight junctions (TJ) proteins; however Plerixafor treatment reduced the expression of zonula occludens (ZO), a peripheral membrane TJ protein. Collectively, our results demonstrate that SN could be an adaptive and beneficial immune response during chronic intestinal inflammation.
HIGH COPY NUMBER POLYMORPHISMS OF ALPHA DEFENSIN 1-3 ARE ASSOCIATED WITH THERAPEUTIC RESPONSIVENESS IN INFLAMMATORY BOWEL DISEASE
Authors: Kanmura Shuji , Morinaga Yuko , Maeda Nobuhisa , Tanaka Akihito , Komaki Yuga , Ido Akio 
Published: January 2024

Abstract

BACKGROUND AND PURPOSE
Prednisolone therapy is the first choice for the treatment of acute severe ulcerative colitis (ASUC), however, the refractory case is sometimes observed. Alpha defensin 1-3 (DEFA1A3) stored in neutrophils acts as an effector factor of innate immunity. It has been reported that the copy number variation of the DEFA1A3 gene is associated with the severity of ulcerative colitis (UC).
However, the impact of DEFA1A3 in response to treatment have not been fully investigated.
Therefore, we aimed to clarify the relationship between the number of DEFA1A3 copies and UC prednisolone treatment response.

SUBJECTS AND METHODS
Patients with UC who had attended our department and related facilities and had the number of DEFA1A3 copies measured were included between 2020 and 2022. The number of DEFA1A3 copies were measured using droplet digital PCR after DNA extraction from peripheral blood mononuclear cells. Mayo score was used to determine the response to prednisolone and severity of UC. ASUC was defined as presence of more than 6 bloody stools/d along with any one of the following: pulse rate&gt; 90 bpm, temperature &gt; 37.8 °C, hemoglobin &lt; 10.5 g/dL, and/or CRP &gt; 30mg/L. Clinical background and various parameters were extracted from medical record information.

RESULTS
The 47 ASUC patients were included in the study. The median DEFA1A3 copy number of the patients was 9, the median DEFA1A3 copy number in ASUC was higher than that in healthy subjects. The DEFA1A3 copy number was significantly higher in the non-remission group than in the remission group after treatment with prednisolone.There were no differences in other parameters such as CRP and WBC between the two groups.

CONCLUSION
DEFA1A3 copy number may be a predictive marker of prednisolone treatment response.
HAND GRIP STRENGTH IS ASSOCIATED WITH CLINICAL SYMPTOM BURDEN IN CROHN'S DISEASE
Authors: Thompson Ashley , Anderson Jenna , Stauffer Patrick , Peress Shira , Sofia M Anthony 
Published: January 2024

Abstract

INTRODUCTION
Inflammatory bowel disease (IBD) is a chronic inflammatory condition that may result in malnutrition and alteration of body composition, such as the development of sarcopenia. Sarcopenia is a known component of frailty, which is a driver of poor health outcomes and a significant independent predictor of mortality in patients with IBD. The purpose of this study was to determine whether grip strength, as a predictor of sarcopenia and frailty, is associated with clinical symptoms, endoscopic disease activity and disease-related disability in patients with IBD.

METHODS
This is a prospective cohort study performed at a single tertiary care center. Outpatient adults aged 18 to 89-years-old with a diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD), were consented and enrolled at the time of an outpatient colonoscopy. Study participants were asked to complete two paper surveys addressing clinical symptoms and IBD Disability Index. Grip strength measurements were obtained using a Jamar dynamometer and adjusted for age and sex by Z-score calculation.

RESULTS
There was a total of 74 patients, with a mean age of 47.06 years, 51.4% male and 48.6% female with a diagnosis of either UC (38%) or CD (62%). The mean disease duration was 15.7 years (0.5-50.7). Mean hand grip Z-score amongst all patients was lower in patients not in clinical remission compared to those in clinical remission (–0.160 vs 0.480, p = 0.025), though in subgroup analysis based on diagnosis, statical significance only maintained in the CD, but not the UC group (-0.230 vs 0.610, p=0.044; 0.020 vs 0.340, p=0.544 respectively). Mean hand grip Z-score was not associated with IBD Disability Index (–0.070 vs 0.250, p= 0.669) or endoscopic disease activity (UC 0.210 vs 0.070, p=0.513; CD –0.108 vs 0.274, p=0.638).

CONCLUSION
Low hand grip strength is associated with clinical disease activity in patients with CD but not UC. Our study does not suggest hand grip strength to be associated with IBD-related disability or endoscopic disease activity in either patients with UC or CD. Data on clinical outcomes at 6-months will be collected.

DISCUSSION
From the findings in our study, hand grip measurements alone may not be the best predictor of disease activity or related disability. There is a lack of validated diagnostic criteria for sarcopenia and frailty in the IBD population and additional diagnostic modalities may be required. While our study suggests that hand grip may be correlated with clinical disease activity in patients with CD, additional studies with a large population size and wider representation of disease severity, such as including hospitalized IBD populations, are needed to further validate these findings.