bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequently Together, Among Model Systems Molecular Alterations: Cancer Maintenance Markers with Translational Study Design
Authors: Ylagan Maya , Xu Qi , Kowalski Jeanne 
Published: January 2024

AbstractIn contrast to cancer driver gene alterations, genes with alterations occurring frequently together are unlikely to play a direct role in tumor development, and more likely to contribute to normal cellular functions necessary for the ongoing maintenance and survival of the tumor, with the most robust of these genes preserved across model systems. We introduce two molecular signature-centric methods, RECO (recurring and co-occurring) and Crosstalk, to identify gene sets characterized by molecular alterations that occur frequently together across sample model systems. Our overall approach builds a cancer information exchange among samples systems based on an analysis of gene and sample-level signature pairs using RECO and Crosstalk methods. The results may be used to design translational studies from gene signature discovery in patients to its application in cell lines and patient-derived xenograft models, alongside the discovery of potential cancer maintenance markers. We demonstrate the capabilities of our approach by exploring the discovery of frequently together molecular alterations between patient tumors and cell lines, and between histologically similar tumors with different sites of origin, and their associations with outcomes in several cancers. As understudied, expanded markers, genes with frequently occurring molecular alterations between systems offer potentially new insights into similar cancer etiology and treatment targets outside the norm, in addition to informing on translational study design.Availability and implementation:The method is implemented at:https://github.com/kmlabdms/CIERCE
Transcriptomics effects of per- and polyfluorinated alkyl substances in differentiated neuronal cells
Authors: Running Logan , Cristobal Judith R. , Karageorgiou Charikleia , Camdzic Michelle , Aguilar John Michael , Gokcumen Omer , Aga Diana S. , Atilla-Gokcumen G. Ekin 
Published: January 2024

AbstractPer- and polyfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that bioaccumulate in tissues and pose risks to human health. Increasing evidence links PFAS to neurodegenerative and behavioral disorders, yet the underlying mechanisms of their effects on neuronal function remain largely unexplored. In this study, we utilized SH-SY5Y neuroblastoma cells, differentiated into neuronal-like cells, to investigate the impact of six PFAS compounds— perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), perfluorodecanesulfonic acid (PFDS), 8:2 fluorotelomer sulfonate (8:2 FTS), and 8:2 fluorotelomer alcohol (8:2 FTOH)—on neuronal health. Following a 30 μM exposure for 24 hours, PFAS accumulation ranged from 100–7500 ng/mg of protein. Transcriptomic analysis revealed 721 differentially expressed genes (DEGs) across treatments (padj< 0.05), with 11 DEGs shared among all PFAS exposures, indicating potential biomarkers for neuronal PFAS toxicity. PFOA-treated cells showed downregulation of genes involved in synaptic growth and neural function, while PFOS, PFDS, 8:2 FTS, and 8:2 FTOH exposures resulted in upregulation of genes related to hypoxia response and amino acid metabolism. Lipidomic profiling further demonstrated significant fatty acid upregulation with PFDA, PFDS, and 8:2 FTS, alongside triacylglycerol downregulation with 8:2 FTOH. These findings suggest that the neurotoxic effects of PFAS are structurally dependent, offering insights into the molecular processes that may drive PFAS-induced neuronal dysfunction.SynopsisPer- and poly fluorinated alkyl substances (PFAS) have been shown to bioaccumulate in human tissues and affect health. This study aims to provide insights into the specific biological processes through which PFAS exposure affects neuronal cells.
Proteostatic remodeling of small heat shock chaperones - crystallins by Ran-binding protein 2 and the peptidyl-prolylcis-transisomerase and chaperone activities of its cyclophilin domain
Authors: Patil Hemangi , Cho Kyoung-in , Ferreira Paulo A. 
Published: January 2024

ABSTRACTDisturbances in phase transitions and intracellular partitions of nucleocytoplasmic shuttling substrates promote protein aggregation - a hallmark of neurodegenerative diseases. The modular Ran-binding protein 2 (Ranbp2) is a cytosolic molecular hub for rate-limiting steps of disassembly and phase transitions of Ran-GTP-bound protein ensembles exiting nuclear pores. Chaperones also play central roles in phase transitions and proteostasis by suppressing protein aggregation.Ranbp2haploinsufficiency promotes the age-dependent neuroprotection of the chorioretina against photo-oxidative stress by proteostatic regulations of Ranbp2 substrates and by countering the build-up of poly-ubiquitylated substrates. Further, the peptidyl-prolylcis-transisomerase (PPIase) and chaperone activities of the cyclophilin domain (CY) of Ranbp2 modulate the proteostasis of selective neuroprotective substrates, such as hnRNPA2B1, STAT3, HDAC4 or L/M-opsin, while promoting a decline of ubiquitylated substrates. However, links between CY PPIase activity on client substrates and its effect(s) on ubiquitylated substrates are unclear. Here, proteomics of genetically modified mice with deficits of Ranbp2 uncovered the regulation of the small heat shock chaperones – crystallins by Ranbp2 in the chorioretina. Loss of CY PPIase of Ranbp2 up-regulates αA-crystallin proteostasis, which is repressed in non-lenticular tissues. Conversely, the αA-crystallin’s substrates, γ-crystallins, are down-regulated by impairment of CY‘s C-terminal chaperone activity. These CY-dependent effects cause the age-dependent decline of ubiquitylated substrates without overt chorioretinal morphological changes. A model emerges whereby the Ranbp2 CY-dependent remodeling of crystallins’ proteostasis subdues molecular aging and preordains chorioretinal neuroprotection by augmenting the chaperone buffering capacity and the decline of ubiquitylated substrates against proteostatic impairments. Further, CY’s moonlighting activity holdspan-therapeutic potential against neurodegeneration.
A general platform for targeting MHC-II antigens via a single loop
Authors: Du Haotian , Liu Jingjia , Jude Kevin M. , Yang Xinbo , Li Ying , Bell Braxton , Yang Hongli , Kassardjian Audrey , Mobedi Ali , Parekh Udit , Sperberg R. Andres Parra , Julien Jean-Philippe , Mellins Elizabeth D. , Garcia K. Christopher , Huang Po-Ssu 
Published: January 2024

AbstractClass-II major histocompatibility complexes (MHC-IIs) are central to the communications between CD4+ T cells and antigen presenting cells (APCs), but intrinsic structural features associated with MHC-II make it difficult to develop a general targeting system with high affinity and antigen specificity. Here, we introduce a protein platform, Targeted Recognition of Antigen-MHC Complex Reporter for MHC-II (TRACeR-II), to enable the rapid development of peptide-specific MHC-II binders.TRACeR-IIhas a small helical bundle scaffold and uses an unconventional mechanism to recognize antigens via a single loop. This unique antigen-recognition mechanism renders this platform highly versatile and amenable to direct structural modeling of the interactions with the antigen. We demonstrate thatTRACeR-IIbinders can be rapidly evolved across multiple alleles, while computational protein design can produce specific binding sequences for a SARS-CoV-2 peptide of unknown complex structure.TRACeR-IIsheds light on a simple and straightforward approach to address the MHC peptide targeting challenge, without relying on combinatorial selection on complementarity determining region (CDR) loops. It presents a promising basis for further exploration in immune response modulation as well as a broad range of theragnostic applications.
MicroRNA-145 enhances lung cancer cell progression after exposure to lyophilized fertile hydatid cyst fluid ofEchinococcus granulosussensu stricto
Authors: Mosajakhah Hosein , Shanehbandi Dariush , Ahmadpour Ehsan , Mahami-Oskouei Mahmoud , Janghoor Khadijeh Sadeghi , Spotin Adel 
Published: January 2024

AbstractThere is increasing evidence that the secretory/excretory antigens of the larval stage ofEchinococcus granulosus(hydatid cyst fluid; HCF) can induce both anticancer and oncogenesis effects between parasite-derived metabolites and various cancer lines. The dual role of miR-145 as a tumor suppressor or oncogene has been previously reported in cancers. Nevertheless, it remains unknown, how miR-145 induces apoptosis in HCF-treated lung cancer cells. The fertile HCF was obtained from sheep and subjected to purification and lyophilization. H1299 human lung cancer cells were cultured into two groups: HCF-treated H1299 lung cancer cells and control cells. To evaluate the effects of HCF on the H1299 cells, cell viability was performed by MTT assay. The caspase-3 activity was assessed using fluorometric assay. Furthermore, the mRNA expression of VGEF, Vimentin, caspase-3, miRNA-145, Bax and Bcl-2 genes were characterized by Real-time PCR. A scratch test was done to assess the effects of HCF on cell mobility. MTT assay revealed that there is an increasing slope in the growth of H1299 cells when treated with 60 μg/mL of fertile HCF for 24 h. The fold change of caspase-3, miRNA-145, Bax/Bcl-2 ratio and caspase-3 activity was lower in the HCF-treated H1299 cells than in the control cell. The fold change of VGEF and Vimentin genes in the HCF-treated H1299 cells was higher than that in the control cell. The scratch outcome demonstrated that the mobility of H1299 cells was increased at 24 and 48 hours of scratched time after exposure to HCF. Our results suggest that induction of low expression of miR-145 in patients with hydatid cysts could be a possible oncogenic regulator of lung cancer growth. We conclude that miR-145 may be a promising marker for the diagnosis of lung cancer patients co-infected with pulmonary hydatid cysts. To validate this assumption, further study is needed to assess microRNA profile and potent oncogenesin vivosetting.
Synthetic spider silk forming highly-aligned nanoarchitectures on 2D-material surfaces
Authors: Whittall Dominic R , Kato Ryo , Okimura Akari , Takizawa Rio , Motai Kazunori , Maeda Hiroki , Yamazaki Yui , Yano Taka-aki , Takano Eriko , Hayamizu Yuhei 
Published: January 2024

AbstractThe synergy between silk proteins and nanomaterials can lead to novel materials with improved mechanical and electrical properties. Designed peptides have been previously utilised in the functionalisation of two-dimensional material surfaces in a self-assembly manner, including graphite, to develop highly sensitive electrical biosensors. These studies have predominantly focused on functionalising the surfaces with peptides of less than several kDa in size. In this work, we assessed the capability of a ∼35 kDa synthetic spider silk protein to serve as a candidate biomolecular scaffold on a range of two-dimensional materials: graphite, molybdenum disulphide and boron nitride. The structural properties of the synthetic spider silk protein at the 2D material surface were characterised at the nanoscale for the first time using a multi-analysis approach incorporating atomic force microscopy and fluorescence microscopy, in addition to polarised Raman and tip-enhanced Raman spectroscopy. The synthetic spider silk protein was revealed to self-assemble into stable nanowire structures of monolayer thickness. Our findings have demonstrated the feasibility of functionalising 2D materials with spider silk-based proteins and will unlock new possibilities in the development of next-generation high-performance biosensing devices.
Pancreatic cancer mutationscape: revealing the link between modular restructuring and intervention efficacy amidst common mutations
Authors: Plaugher Daniel , Murrugarra David 
Published: January 2024

AbstractThere is increasing evidence that biological systems are modular in both structure and function. Complex biological signaling networks such as gene regulatory networks (GRNs) are proving to be composed of subcategories that are interconnected and hierarchically ranked. These networks contain highly dynamic processes that ultimately dictate cellular function over time, as well as influence phenotypic fate transitions. In this work, we use a stochastic multicellular signaling network of pancreatic cancer (PC) to show that the variance in topological rankings of the most phenotypically influential modules implies a strong relationship between structure and function. We further show that induction of mutations alters the modular structure, which analogously influences the aggression and controllability of the diseasein silico. We finally present evidence that the impact and location of mutations with respect to PC modular structure directly corresponds to the efficacy of single agent treatmentsin silico, because topologically deep mutations require deep targets for control.
Transcriptomic and epigenetic responses shed light on soybean resistance toPhytophthora sansomeana
Authors: Lee Gwonjin , DiBiase Charlotte N. , Liu Beibei , Li Tong , McCoy Austin G. , Chilvers Martin I. , Sun Lianjun , Wang Dechun , Lin Feng , Zhao Meixia 
Published: January 2024

AbstractPhytophthora root rot caused by oomycete pathogens in the Phytophthora genus poses a significant threat to soybean productivity. While resistance mechanisms againstPhytophthora sojaehave been extensively studied in soybean, the molecular basis underlying immune responses toPhytophthora sansomeanaremains unclear. We investigated transcriptomic and epigenetic responses of two resistant (Colfax and NE2701) and two susceptible (Williams 82 and Senaki) soybean lines at four time points (2, 4, 8, and 16 hours post inoculation, hpi) afterP. sansomeanainoculation. Comparative transcriptomic analyses revealed a greater number of differentially expressed genes (DEGs) upon pathogen inoculation in resistant lines, particularly at 8 and 16 hpi, predominantly associated with ethylene and reactive oxygen species-mediated defense pathways. Moreover, DE transposons were predominantly up-regulated after inoculation and enriched near genes in Colfax. A long non-coding RNA (lncRNA) within the mapped region of the resistance gene exhibited exclusive up-regulation in the resistant lines after inoculation, potentially regulating two flankingLURP-one-relatedgenes. Furthermore, DNA methylation analysis revealed increased CHH methylation levels in lncRNAs after inoculation, with delayed responses in Colfax compared to Williams 82. Overall, our results provide comprehensive insights into soybean responses toP. sansomeana, highlighting potential roles of lncRNAs and epigenetic regulation in plant defense.
Proton pump inhibitors are detrimental to overall survival of patients with glioblastoma multiforme: results from a nationwide real-world evidence database
Authors: Castro Michael P. , Quinn Jameson , Wasserman Asher , Awawda Alaa , Cole Zachariah D. , Shapiro Mark A. , Stuhlmiller Timothy J. , Kesari Santosh 
Published: January 2024

AbstractBackgroundAldehyde dehydrogenase-1A1 (ALDH1A1) is a primary metabolic enzyme impacting outcome of chemotherapy, including temozolomide, the standard-of-care (SOC) for glioblastoma multiforme (GBM). High expression of ALDH1A1 is associated with poor prognosis in multiple cancers. Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity but were recently identified as strong inducers of ALDH1A1, suggesting a negative impact on survival.MethodsReal-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR (NCT03793088). Patients withIDH1/2mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications includingMGMTmethylation status, age, sex, duration of corticosteroid use, extent of resection, starting SOC, and PPI use.ResultsEMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 mo vs. 40.1 mo). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI 1.15-2.44], p=0.007).ConclusionsEvidence from a nationwide cancer registry has suggested PPIs have a strong detrimental effect on OS for GBM patients, particularly those withMGMTpromoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving SOC chemoradiotherapy.Key PointsNationwide glioblastoma study suggests hazardous effect of proton pump inhibitorsDiscretion advised when prescribing proton pump inhibitors to glioblastoma patientsProphylactic proton pump inhibitor use to limit chemo toxicity may increase riskImportance of the StudyRecent molecular evidence suggests off-target activity of proton pump inhibitors (PPIs) may counteract the activity of alkylating chemotherapy in glioblastoma clinical care. Utilizing a time-varying cox proportional hazard model and abstracted clinical data from medical records according to a nationwide observational research protocol, we found PPIs were significantly associated with greater risk of death, independent of corticosteroid use. Importantly, the detrimental effect was most impactful for patients with methylated MGMT promoters who gain the most benefit from standard-of-care temozolomide treatment and experience the best outcomes.
Spectral variation and pigmentary basis of ornamental and mimetic wing colour patches of swallowtail butterflies
Authors: Dharmaraaj Bhavya , Venkatesan Radhika , Kunte Krushnamegh 
Published: January 2024

AbstractColours and colour patterns are extraordinarily diverse traits that are often used as visual signals. To test ecological and evolutionary drivers of these visual signals, a clear understanding of their nature and variation is necessary. Here we characterise variation in wing colouration of Asian mormon swallowtail butterflies (Papilio, subgenusMenelaides). These species exhibit two kinds of colour patches on largely black wings: creamy white/yellow/green patches that are presumably used as sexual ornaments, and pure white patches that are presumably used as mimetic signals. Using reflectance spectrophotometry we quantified spectral properties of black wing background and colour patches between sexes, wing surfaces and mimicry status. We discovered that brightness and saturation of the black background were less variable across sexes, wing surfaces and mimetic/non-mimetic status. However, colour contrast and saturation were higher on dorsal surfaces than on ventral surfaces, and colour contrast between the black background and colour patches was higher in males than in females. Colour patches in non-mimetic butterflies were brighter and more saturated across the whole colour spectrum compared to mimetic butterflies. These patterns of colour variations in relation to their putative functions suggest that: (a) colour patches on dorsal and ventral wing surfaces evolve independently to accommodate differential strengths of natural and sexual selection, (b) sexual ornaments are brighter in non-mimetic males but they also occur in all non-mimetic females, indicating mutual sexual selection on these ornaments, but which is stronger in males, and (c) mimetic male and female butterflies display less sexual contrast in colour patches, indicating relatively similar strength of mimetic selection. Thus, our study characterises colour variation in an extraordinary signal radiation on the wings of swallowtail butterflies, a model clade in ecology, evolution and genetics. Finally, using liquid chromatography-mass spectrometry (LCMS) we identified the pigment papiliochrome-II to be the chemical basis of the presumed sexual ornaments in mormon swallowtails.
Discovery of Oncogenic Mediator Genes in Rectal Cancer Chemotherapy Response using Gene Expression Data from Matched Tumor and Patient-Derived Organoid
Authors: Huang Hanchen , Wu Chao , Colaprico Antonio , Bleu Paulina , Zambare Wini , Alvarez Janet , Kim Min Jung , Bercz Aron , Wang Lily , Paty Philip B. , Romesser Paul B. , Smith J. Joshua , Chen X. Steven 
Published: January 2024

AbstractRectal cancer (RC) presents significant treatment challenges, particularly in the context of chemotherapy resistance. Addressing this, our study pioneers the use of matched RC tumor tissue and patient-derived organoid (PDO) models coupled with the innovative computational tool, Moonlight, to explore the gene expression landscape of RC tumors and their response to chemotherapy. We analyzed 18 tissue samples and 32 matched PDOs, ensuring a high-fidelity representation of the tumor bioloy. Our comprehensive integration strategy involved differential expression analyses (DEAs) and gene regulatory network (GRN) analyses, facilitating the identification of 5,199 genes governing at least one regulon. By using the biological processes (BPs) collected from Moonlight closely related to cancer, we pinpointed 2,118 regulator-regulon groups with potential roles in oncogenic processes. Further, through integration of Moonlight and DEA results identified 334 regulator-regulon groups significantly enriched in both tissue and PDO samples, classifying them as oncogenic mediators (OMs). Among these, four genes (NCKAP1L, LAX1, RAD51AP1, and NAT2) demonstrated an association with drug responsiveness and recurrence-free survival (RFS), offering new insights into the molecular mechanisms of chemotherapy response in RC. Our integrated approach not only underscores the translational fidelity of PDOs, but also harnesses the analytical prowess of Moonlight, setting a new benchmark for targeted therapy research in rectal cancer.