bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Multiple Roles of Gamma Interferon in Intraepithelial T Cell-Villous Enterocyte Interactions in Active Celiac Disease
Authors: Johnson JE , Agrawal K , Al-Lamki RS , Zhang F , Wang Xi , Liburd S , Tobiasova Z , Rodriguez L , Martins AJ , Sefik E , Flavell RA , Robert ME , Pober JS 
Published: September 2024

AbstractWe identified molecular interactions between duodenal enterocytes and intraepithelial T cells in celiac disease (CeD) vs normal controls. We observed an expected increased ratio of T cells [bearing either T cell receptor (TCR) αβ or γδ and mostly activated cytotoxic T lymphocytes (CTLs) expressing granzyme B, CD45RO, Ki67 and Nur 77 proteins as well as IFNγ mRNA] to villous enterocytes. Few T cells (<5%) express NKG2C or DAP12 proteins. CeD villous enterocytes express an IFNγ signature (by single cell RNA sequencing and nuclear phopho-STAT1 and HLA-DR protein staining). CeD enterocytes express increased IFNγ-inducible chemokines CCL3, CCL4, CXCL10 and CXCL11 mRNA while CeD intraepithelial T cells express reduced levels of CCR5 and CXCR3 chemokine receptors, suggesting ligand-induced downregulation. CeD enterocyte HLA-E mRNA and protein are upregulated whereas HLA-B mRNA but not protein increases. Proximity ligation detected frequent interactions of αβ and γδ TCRs with HLA-E and HLA-B but not with HLA-DR and fewer NKG2C interactions with HLA-E. We suggest that CeD IFNγ-producing TCR αβ and γδ CTLs are recruited into villous epithelium by IFNγ-induced enterocyte production of CCR5 and CXCR3-binding chemokines and kill villous enterocytes primarily by TCR engagement with class I HLA molecules, including HLA-E, likely presenting gluten peptides. The IFN-γ signature of CeD villous enterocytes is a potential biomarker of active disease and a therapeutic target.
Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis
Authors: Luan Yaqi , He Weiwei , Jiang Kunmao , Qiu Shenghui , Jin Lan , Mao Xinrui , Huang Ying , Liu Wentao , Cao Jingyuan , Jin Lai , Wang Rong 
Published: September 2024

AbstractCisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora
Effect of Genotype and Age on a Defined Microbiota in Gnotobiotic SCID Piglets
Authors: Widmer Katherine M. , Rahic-Seggerman Faith , Forster Ahlea , Ahrens-Kress Amanda , Sauer Mary , Mooyottu Shankumar , Vinithakumari Akhil , Dunkerson-Kurzhumov Aaron , Sponseller Brett , Kiupel Matti , Schmitz-Esser Stephan , Tuggle Christopher K. 
Published: September 2024

AbstractSevere combined immunodeficient (SCID) individuals lack functional T and B lymphocytes, leading to a deficient adaptive immune system. SCID pigs are a unique large animal biomedical model as they possess many similarities to humans, allowing for the collection of translatable data in regenerative medicine, cancer, and other biomedical research topics. While many studies suggest early gut microbiota development is necessary for developing the intestinal barrier and immune system, these animals are often cesarian section derived, leaving them uncolonized for normal intestinal microflora. The hypothesis was that an increase in complexity of microbiota inoculum will allow for more stability in the composition of the gut microbiota of SCID piglets. This was tested across multiple litters of SCID piglets with three different defined microbiota consortium (2-strain, 6-strain, 7-strain). All piglets received their designated defined microbiota by oral gavage immediately after birth and again 24 hours later. There was no effect of SCID genotype on the composition of the gut microbiota, but there was a significant effect due to piglet age. Additionally, all three defined microbiota consortia were deemed safe to use in SCID piglets, and the 7-strain microbiota was the most stable over time. Based on these results, the 7-strain defined microbiota will be added to the SCID pig husbandry protocol, allowing for a more reproducible model.
Characterization of Chronotypes Using the Symbolic Aggregate apprXimation (SAX) on Actigraphy Data
Authors: Luo Wen , Androulakis Ioannis P. 
Published: September 2024

AbstractIn this study, we discuss an efficient approach to characterizing chronotypes using Symbolic Aggregate approXimation (SAX) on actigraphy data. Actigraphy, a non-invasive monitoring of human rest/activity cycles, provides valuable insights into sleep-wake behaviors and circadian rhythms. However, the high dimensionality of actigraphy data poses significant challenges in storage, processing, and analysis. To address these challenges, we applied the SAX algorithm to transform continuous time-series actigraphy data into a symbolic representation, enabling dimensionality reduction while preserving essential patterns. We analyzed actigraphy data from the National Health and Nutrition Examination Survey (NHANES) database, covering over 10,000 individuals, and used unsupervised clustering to identify distinct chronotype patterns. The SAX transformation facilitated the application of machine learning techniques, revealing five chronotype clusters characterized by differences in activity onset, resolution, and intensity. Age distribution analysis showed biases towards specific age groups within the clusters, highlighting the relationship between age and chronotype. Key findings include age-related Chronotype variations with younger individuals exhibiting delayed chronotypes with significant differences in sleep onset (SOT) and wake time (WT) compared to older adults, suggesting a phase delay in sleep patterns as age decreases and activity transition dynamics where clusters showed distinct patterns in winding up and winding down periods, providing insights into the dynamics of activity transitions. This study demonstrates the efficiency and effectiveness of SAX in processing large-scale actigraphy data, enabling robust chronotype characterization that can inform personalized healthcare and public health initiatives. Further exploration of SAX integration with other biometric measures could deepen our understanding of human circadian biology and its impact on health and behavior.
Metal sensing properties of the disordered loop from the Arabidopsis metal transceptor IRT1
Authors: Cointry Virginia , Ródenas Reyes , Morellet Nelly , Cotelle Valérie , Neveu Julie , Vert Grégory 
Published: September 2024

AbstractThe plant IRT1 iron transporter is a plasma membrane protein that takes up iron in root upon iron-limited conditions. Besides its primary metal substrate iron, IRT1 also transports other divalent metals that overaccumulate in plants when soil iron is low andIRT1is highly expressed. We previously reported that the intracellular regulatory loop between transmembrane helices TM4 and TM5, comprising IRT1 residues from 144 to 185, is involved in the post-translational regulation of IRT1 by its non-iron metal substrates. Upon excess of zinc, IRT1 (144-185) undergoes phosphorylation by the CIPK23 kinase followed by its ubiquitination by IDF1 to target IRT1 for vacuolar degradation. This zinc-dependent downregulation of IRT1 requires the presence of four histidine (H) residues in IRT1 loop, that directly bind zinc. However, how selective metal binding is achieved and how this allows downstream regulation to take place is largely unknown. Here, we characterized the metal binding properties and structure of IRT1 loop to better understand the molecular basis of non-iron metal sensing and signaling. Using a combination of circular dichroism and NMR, we demonstrate that zinc and manganese bind to IRT1 loop with nanomolar range affinity, and that metal binding does not trigger structuration of the loop. We prove that zinc and manganese binding is mediated by the four H residues and identify aspartic acid (D) residue D173 as helping in metal coordination and participating to metal sensing and metal-dependent degradation of IRT1 in plants. Altogether, our data provide further evidence of how the regulatory loop of IRT1 senses high cytosolic divalent metal concentrations to regulate metal uptake in plants.
Protein secondary structure and remote homology detection
Authors: Al-Fatlawi Ali , Hossen Md. Ballal , El-Hendi Ferras , Schroeder Michael 
Published: September 2024

1AbstractA protein can be represented by its primary, secondary, or tertiary structure. With recent advances in AI, there is now as much tertiary as primary structural data available. Fast and accurate search methods exist for both types of data, with searches over both representations being highly precise. However, primary structure data can sometimes be incomplete. As a result, tertiary structure has become the gold standard for remote homology detection.How does secondary structure perform in remote homology detection? Secondary structure interprets proteins as a sequence using an alphabet representing helices, strands, or loops. It shares its sequential nature with primary structure while retaining topological information similar to tertiary structure.To assess the effectiveness of secondary structure in remote homology detection, we devised a challenging classification task aimed at determining the superfamily membership of very distantly related protein domains. We used benchmarks from the CATH and SCOP databases and evaluated sequence and structure alignment algorithms on primary, secondary, and tertiary structures.As expected, both basic and advanced sequence alignment algorithms applied to primary structure achieved high precision, but their overall area under the curve was lower compared to the gold standard of structural alignment using tertiary structure.Surprisingly, a simple string comparison algorithm applied to secondary structure performed close to the gold standard. This result supports the hypothesis that key structural information is already encoded in secondary structure and suggests that secondary structure may be a promising representation to use when high-confidence structural data is unavailable, such as in cases involving protein flexibility and disorder.
Subtype-specific Patterns of Evolution and Clinically Relevant Genomic Instability in Wilms Tumour
Authors: Cresswell George D. , Chagtai Tasnim , Al-Saadi Reem , Treger Taryn D. , Madhan Gaganjit , Mifsud Borbala , Vujanic Gordan , Williams Richard D. , Luscombe Nicholas M. , Pritchard-Jones Kathy , Mifsud William 
Published: September 2024

AbstractBackgroundUnderstanding cancer evolution is fundamental to predicting cancer progression. However, the evolution of paediatric cancers is still under-researched. Large cohorts of patients are required to determine consistent evolutionary trajectories that shed light on key steps in cancer development and reveal underlying biology, especially in rare cancers. Additionally, well annotated clinical data is necessary for determining if evolutionary biomarkers are predictive of patient outcome.MethodsWe performed detailed evolutionary analysis of 64 paediatric kidney cancers, including 60 Wilms tumours (WT), using DNA microarrays and, in a subset of 30 patients, a WT-specific targeted sequencing assay, to detect copy number alterations (CNA) and mutations, respectively. By analysing multiple tissue samples in the majority of cases we could detect mutation heterogeneity in each tumour. We reconstructed clones across the cohort and described their phylogenetic histories, in addition to detecting mirrored subclonal allelic imbalance.ResultsOur results highlight pervasive evidence of parallel evolution in WTs affecting CNAs, andCTNNB1andTP53mutations. Furthermore, we demonstrate that stromal-type WTs often evolve from a consistent series of events (WT1mutation, 11p uniparental disomy andCTNNB1mutation) and we suggest that 19q uniparental disomy is an important ancestral event in both epithelial and diffuse anaplastic WTs. Finally, we propose the total number of evolutionary CNA events as a prognostic biomarker in WTs for event-free survival, particularly in high-risk WT.ConclusionsOverall, this study sheds light on the evolution of the most common paediatric kidney cancer and links evolutionary analysis to fundamental clinical and biological questions in a large cohort of WTs. We conclude that histological subtypes of WT are often defined by consistent evolutionary sequences. We present evidence that a key marker of evolvability, namely CNA diversity measured phylogenetically across multiple tumour sites, is prognostic of patient outcome and should be considered for clinical use to detect the most aggressive blastemal and diffuse anaplastic type WTs.
A pontine-specific axonal niche supports de novo gliomagenesis
Authors: Xie Zhigang , Pathak Adrija , Bankaitis Vytas A. 
Published: September 2024

AbstractDiffuse intrinsic pontine gliomas (DIPGs), a major type of pediatric high-grade gliomas located in the pons, are the leading cause of death in children with brain cancer. A subset (20-25%) of DIPGs harbor a lysine 27-to-methionine (K27M) mutation inHIST1H3B, which encodes histone H3.1, and an activatingACVR1mutation. The occurrence of this pair of mutations in DIPGs, but not in pediatric gliomas in other anatomical locations, suggests the existence of a pontine-specific niche that favors DIPG gliomagenesis. Unfortunately, the identity of the underlying pontine niche remains elusive as available mouse models fail to recapitulate the anatomic specificity that characterizes DIPGs. Herein we show that the trigeminal root entry zone (TREZ), a pontine structure where several major axon tracts intersect, is enriched with proliferating oligodendrocyte-lineage cells during brainstem development. Introducing bothH3.1K27Mand activatingAcvr1andPik3camutations (which co-occur frequently withH3.1K27Min human DIPGs) into the mouse brain leads to rapid gliomagenesis. This pathology recapitulates the pons specificity of DIPGs as glioma cells proliferate on axon tracts at the TREZ. We further show that a hyaluronan receptor important for cell stemness (HMMR) plays a key role in glioma cell proliferation at the TREZ. We propose thatH3.1K27Mand its co-occurring mutations drive pontine specific gliomagenesis by inducing a proliferative response of oligodendrocyte-lineage cells with enhanced stemness on large TREZ axon tracts.One-Sentence SummaryThe trigeminal root entry zone underlies pontine-specific gliomagenesis driven byH3.1K27Mand its co-occurring mutations.
CD4+Foxp3E2+regulatory T cell frequency predicts breast cancer prognosis and recurrence
Authors: Fusco Clorinda , Rella Francesca Di , Liotti Antonietta , Colamatteo Alessandra , Ferrara Anne Lise , Gigantino Vincenzo , Collina Francesca , Esposito Emanuela , Donzelli Ivana , Porcellini Antonio , Feola Antonia , Micillo Teresa , Perna Francesco , Garziano Federica , Maniscalco Giorgia Teresa , Varricchi Gilda , Mottola Maria , Zuccarelli Bruno , Simone Bruna De , Bonito Maurizio di , Matarese Giuseppe , Accurso Antonello , Pontillo Martina , Russo Daniela , Insabato Luigi , Spaziano Alessandra , Cantone Irene , Pezone Antonio , Rosa Veronica De 
Published: September 2024

AbstractCD4+Foxp3+regulatory T cells (Tregs) are key to maintain peripheralself-tolerance and suppress immune responses to tumors. Their accumulation in the tumor microenvironment (TME) correlates with poor clinical outcome in several human cancers, including breast cancer (BC). However, the properties of intratumoral Tregs remain largely unknown. Here, we found that a functionally distinct subpopulation of tumor-infiltrating Tregs, which express the Foxp3 splicing variant retaining exon 2 (Foxp3E2), is prominent in the TME and peripheral blood of hormone receptor- positive (HR+) BC subjects with poor prognosis. Notably, a comprehensive examination of the Tumor Cell Genome Atlas (TCGA) validated Foxp3E2 as an independent prognostic marker in all other BC subtypes. We found that FOXP3E2 expression underlies BCs with highly immune suppressive landscape, defective mismatch repair and a stem-like signature thus highlighting pathways involved in tumor immune evasion. Finally, we confirmed the higher immunosuppressive capacity of BC patients-derived Foxp3E2+Tregs by functional assays. Our study suggests Foxp3E2+Tregs might be used as an independent biomarker to predict BC prognosis and recurrence, and to develop super-targeted depletion-based immunotherapies.One-sentence summariesFoxp3E2+Treg enrichment reflects an increased tumor-immune suppression and predicts prognosis and recurrence in breast cancer.
Interplay of ferroptotic and apoptotic cell death and its modulation by BH3-mimetics
Authors: Qiu Yun , Hüther Juliana A. , Wank Bianca , Rath Antonia , Tykwe René , Laschat Sabine , Conrad Marcus , Stöhr Daniela , Rehm Markus 
Published: September 2024

AbstractFerroptosis and apoptosis are widely considered to be independent cell death modalities. Ferroptotic cell death is a consequence of insufficient radical detoxification and progressive lipid peroxidation, which is counteracted by glutathione peroxidase 4 (GPX4). Apoptotic cell death can be triggered by a wide variety of stresses, including oxygen radicals, and can be suppressed by anti-apoptotic members of the BCL-2 protein family. Mitochondria are the main interaction site of BCL-2 family members and likewise a major source of oxygen radical stress. We therefore studied if ferroptosis and apoptosis might intersect and possibly interfere with one another. Indeed, cells dying from impaired GPX4 activity displayed hallmarks of both ferroptotic and apoptotic cell death, with the latter including (transient) membrane blebbing, submaximal cytochrome-c release and caspase activation. Targeting BCL-2, MCL-1 or BCL-XL with BH3-mimetics under conditions of moderate ferroptotic stress in many cases synergistically enhanced overall cell death and frequently skewed primarily ferroptotic into apoptotic outcomes. Surprisingly though, in other cases BH3-mimetics, most notably the BCL-XL inhibitor WEHI-539, counter-intuitively suppressed cell death and promoted cell survival following GPX4 inhibition. Further studies revealed that most BH3-mimetics possess previously undescribed antioxidant activities that counteract ferroptotic cell death at commonly employed concentration ranges. Our results therefore show that ferroptosis and apoptosis can intersect. We also show that combining ferroptotic stress with BH3-mimetics, context-dependently can either enhance and convert cell death outcomes between ferroptosis and apoptosis or can also suppress cell death by intrinsic antioxidant activities.
Invasive cancer and spontaneous regression two weeks after papillomavirus infection
Authors: Bilger Andrea , Ward-Shaw Ella T. , Lee Denis L. , King Renee E. , Newton Michael A. , Buehler Darya , Matkowskyj Kristina A. , Sundberg John P. , Hu Rong , Lambert Paul F. 
Published: September 2024

AbstractDevelopment of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans – the throat, anus, and skin – and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression.Summary Graphic
Nanoparticle-Supported, Rapid, and Electronic Detection of SARS-CoV-2 Antibodies and Antigens at Attomolar Level
Authors: Choi Yeji , Mirjalili Seyedsina , Ikbal MD Ashif , McClure Sean , Clemens Scott , Solano Jose , Heggland John , Zuo Jiawei , Wang Chao 
Published: September 2024

AbstractA gold nanoparticle (AuNP)-supported rapid, electronic detection (NasRED) platform is demonstrated with high specificity to differentiate SARS-CoV-2 from human coronaviruses while achieving high sensitivity. Uniquely, active fluidic force is exerted on AuNPs in a microcentrifuge tube, through engineered centrifugation and vortex agitation, to accelerate signal transduction from biochemical protein binding to physical AuNP aggregation and precipitation and finally to electronic signals in a customized, stabilized circuitry. The limits of detection are found <80 aM (12 fg/mL) and ∼700 aM (105 fg/mL) to detect antibodies in human pooled serum and 20% diluted whole blood, and <900 aM (45 fg/mL) and 4.1 fM (200 fg/mL) to detect nucleocapsid proteins in human saliva and nasal fluid, respectively. With a small test volume (6 µL), a rapid turnaround time (as fast as <15 min), low reagent cost (estimated ∼$2), and a small system footprint, this novel digital platform can be utilized for accurate diagnosis and screening of a wide range of infectious and chronic diseases.
A community-oriented, data-driven resource to improve protocol design for cardiac modelling from human pluripotent stem cells
Authors: Chow Chris Siu Yeung , Negi Sumedha , Bao Shaine Chenxin , Fang Chen , Hudson James E. , Shim Woo Jun , Cao Yuanzhao , Palpant Nathan J. 
Published: September 2024

AbstractProtocols for culturing cardiac cells derived from human-induced pluripotent stem cells (hiPSCs) are critical for studying mechanisms of development and disease. This study provides analysis of a community-oriented database to assess parameters used in published cardiac differentiation protocols, including a web-accessible portal for user-guided customisation of protocols. Validation studies support context-dependent roles for media composition in deriving functional maturation of hiPSC-derived cardiomyocytes.