bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective vulnerability and resilience to Alzheimer’s disease tauopathy as a function of genes and the connectome
Authors: Anand Chaitali , Torok Justin , Abdelnour Farras , Maia Pedro D. , Raj Ashish 
Published: March 2024

ABSTRACTBrain regions in Alzheimer’s (AD) exhibit distinct vulnerability to the disease’s hallmark pathology, with the entorhinal cortex and hippocampus succumbing early to tau tangles while others like primary sensory cortices remain resilient. The quest to understand how local/regional genetic factors, pathogenesis, and network-mediated spread of pathology together govern this selective vulnerability (SV) or resilience (SR) is ongoing. Although many risk genes in AD are known from gene association and transgenic studies, it is still not known whether and how their baseline expression signatures confer SV or SR to brain structures. Prior analyses have yielded conflicting results, pointing to a disconnect between the location of genetic risk factors and downstream tau pathology. We hypothesize that a full accounting of genes’ role in mediating SV/SR would require the modeling of network-based vulnerability, whereby tau misfolds, aggregates, and propagates along fiber projections.We therefore employed an extended network diffusion model (eNDM) and tested it on tau pathology PET data from 196 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Thus the fitted eNDM model becomes a reference process from which to assess the role of innate genetic factors. Using the residual (observed–model-predicted) tau as a novel target outcome, we obtained its association with 100 top AD risk-genes, whose baseline spatial transcriptional profiles were obtained from the Allen Human Brain Atlas (AHBA). We found that while many risk genes at baseline showed a strong association with regional tau, many more showed a stronger association with residual tau. This suggests that both direct vulnerability, related to the network, as well as network-independent vulnerability, are conferred by risk genes. We then classified risk genes into four classes: network-related SV (SV-NR), network-independent SV (SV-NI), network-related SR (SR-NR), and network-independent SR (SR-NI). Each class has a distinct spatial signature and associated vulnerability to tau. Remarkably, we found from gene-ontology analyses, that genes in these classes were enriched in distinct functional processes and encompassed different functional networks. These findings offer new insights into the factors governing innate vulnerability or resilience in AD pathophysiology and may prove helpful in identifying potential intervention targets.
Sanctuary: AStarshiptransposon facilitating the movement of the virulence factor ToxA in fungal wheat pathogens
Authors: Bucknell Angus , Wilson Hannah M. , Gonçalves do Santos Karen C. , Simpfendorfer Steven , Milgate Andrew , Germain Hugo , Solomon Peter S. , Bentham Adam , McDonald Megan C. 
Published: March 2024

AbstractThere is increasing evidence that mobile genetic elements can drive the emergence of pathogenic fungal species by moving virulence genes horizontally. The 14 kbpToxhATtransposon has been shown to be moving the necrotrophic effector,ToxA,horizontally between fungal species that infectTriticum aestivum(wheat), namelyParastagonospora nodorum,Pyrenophora tritici-repentis, andBipolaris sorokiniana. All three species utilise the ToxA protein to infect wheat. Previous genomic evidence foundToxhATin distinct chromosomal positions in two isolates ofB. sorokiniana, indicating that the transposon is still active in this species. Here we confirm the movement ofToxhATusing long-read Nanopore MinION sequencing of eight novel and one previously publishedB. sorokinianaisolates. One event of independent transposition ofToxhATwas observed, and target site duplications of “TA” were identified, confirming this was an autonomous movement facilitated by a yet unidentified transposase. Whole genome analysis revealed thatToxhATis a passenger embedded in a much larger, conserved 170–196 kbp mobile genetic element. This element, termedSanctuary, belongs to the newly describedStarshiptransposon superfamily. This classification is based on the presence of short direct repeats, empty insertion sites, a putative tyrosine recombinase gene and other features ofStarshiptransposons. We also show thatToxhAThas been independently captured by two differentStarships,SanctuaryandHorizonwhich share little to no sequenced identity, outside ofToxhAT.This classification makesHorizonandSanctuarypart of a growing number ofStarshipsinvolved in the horizontal gene transfer of adaptive genetic material between fungal species.ImportanceThe work presented here expands our understanding of a novel group of mobile genetic elements calledStarshipsthat facilitate the horizontal exchange of virulence genes in fungal pathogens. Our analysis shows thatSanctuaryandToxhATare likely active and autonomous transposons in theB. sorokinianagenome. We also show that the smallerToxhATtransposon has been independently captured by two differentStarships,viz. SanctuaryinB. sorokinianaandHorizoninP. tritici-repentisandP. nodorum.Outside ofToxhATthese twoStarshipsshare no sequence identity. The capture ofToxhATby two different mobile elements in three different fungal wheat pathogens demonstrates how horizontal transposon transfer is driving the evolution of virulence in these important wheat pathogens.
Client recognition differences between PDI and ERp46 to guide oxidative folding
Authors: Saio Tomohide , Ishii Kotone , Matsusaki Motonori , Kumeta Hiroyuki , Kanemura Shingo , Okumura Masaki 
Published: March 2024

SUMMARYEndoplasmic reticulum (ER)-resident protein disulfide isomerase (PDI) family members function not only as disulfide bond-catalysts but also as chaperones for the oxidative folding of client proteins. However, due to the scarcity of structural data, the client recognition mechanism remains poorly understood. We report the distinct recognition mechanisms for PDI/ERp46 proteins to recruit a reduced and denatured bovine pancreatic trypsin inhibitor (BPTI). NMR data demonstrated that PDI recognizes a broad region consisting of ∼30 amino acid residues in unfolded BPTI in order to function as a chaperone, while ERp46 interacts nonspecifically and weakly with unfolded BPTI to promiscuously and rapidly introduce disulfide bonds. These two distinct client recognition modes are likely important for the functional modulation of the disulfide-catalyst and chaperone against client proteins. Client recognition differences between PDI family proteins likely contribute to determining whether disulfide bonds are introduced into the client protein or aggregates are reduced to an unfolded state during the early folding step. Thus, the mammalian ER ensures concerted protein quality control through the differences in the client recognition modes of PDI family proteins, resulting in the production of large quantities of multiple-disulfide bonded proteins.
Glioma-associated fibroblasts promote glioblastoma resistance to temozolomide through CCL2-CCR2 paracrine signaling
Authors: Zuo Mingrong , Zhang Shuxin , Chen Siliang , Xiang Yufan , Yuan Yunbo , Li Tengfei , Yang Wanchun , Wang Zhihao , He Yuze , Li Wenhao , Feng Wentao , Chen Ni , Yang Yuan , Zeng Yunhui , Mao Qing , Chen Mina , Liu Yanhui 
Published: March 2024

AbstractComplicated tumor microenvironment contributes mostly to chemoresistance in glioblastoma. Glioma-associated fibroblasts (GAFs) were recently identified as non-tumor stromal cells in the glioblastoma microenvironment, whereas their function in glioblastoma chemoresistance is unclear. Herein, we interrogated the correlation between GAFs and chemoresistance of glioblastoma by examining a series of patient-derived GAFs and glioblastoma organoids (GBOs), revealing that GAFs could promote temozolomide resistance in glioblastoma. Mechanistically, C-C motif chemokine ligand 2 (CCL2) secreted by GAFs selectively activated the ERK1/2 signaling in glioblastoma cells to potentiate temozolomide resistance. Pharmacologically disrupting the CCL2-CCR2 axis or MEK1/2-ERK1/2 pathway effectively improved the therapeutic efficacy of temozolomide in GBM cells and patient-derived GBOs, and both decreased phospho-ERK1/2 expression. Collectively, our results identified that targeting the GAF-dominated CCL2-ERK1/2 pathway may be an alternative strategy to alleviate the GAF-mediated chemoresistance of glioblastoma.SignificanceComprehensive interpretation of the mutual support between tumor microenvironment and cancer cells is demanded for glioma with poor response rates to chemotherapy. This study demonstrates that GAFs promote the temozolomide resistance of glioblastoma by secreting cytokine CCL2 to activate ERK1/2 pathway, which may serve as a potential druggable candidate.Graphic abstract.Schematic illustration for GAFs mediated chemoresistance of GBMs and underlying mechanisms.We demonstrate that Glioma-associated Fibroblasts (GAFs) grow in gliomas by isolating and identifying a panel of patient-derived GAFs. CCL2 secreted by GAFs stimulates CCR2 in GBM cells, which promotes activation of the ERK1/2 expression to potentiate GBM chemoresistance.
Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling
Authors: Vallentgoed Wies R. , Hoogstrate Youri , van Garderen Karin A. , van Hijfte Levi , van Dijk Erik , Kouwenhoven Mathilde C. M. , Niers Johanna M. , Draaisma Kaspar , Martin Ivonne , de Leng Wendy W. J. , Tesileanu C. Mircea S. , de Heer Iris , Diepeveen Maud , Lavrova Anna , Eijk Paul P. , Bühler Marcel , Wick Wolfgang , Clement Paul M. , Sanson Marc , Franceschi Enrico , Gorlia Thierry , Golfinopoulos Vassilis , Weller Michael , Weiss Tobias , Robe Pierre A. , Kros Johan M. , Smits Marion , van de Wiel Mark , Ylstra Bauke , Verhaak Roel G. W. , van den Bent Martin J. , Westerman Bart A. , Wesseling Pieter , French Pim J. 
Published: March 2024

1AbstractTo study the evolutionary processes that drive malignant progression of IDH-mutant astrocytomas, we performed multi-omics on a large cohort of matched initial and recurrent tumor samples. The overlay of genetic, epigenetic, transcriptomic and proteomic data, combined with single-cell analysis, have identified overlapping features associated with malignant progression. These features are derived from three molecular mechanisms and provide a rationale of the underlying biology of tumor malignancy: cell-cycling, tumor cell (de-)differentiation and remodeling of the extracellular matrix. Specifically, DNA-methylation levels decreased over time, predominantly in tumors with malignant transformation and co-occurred with poor prognostic genetic events. DNA-methylation was lifted from specific loci associated with DNA replication and was associated with an increased RNA and protein expression of cell cycling associated genes. All results were validated on samples of newly diagnosed IDH-mutant astrocytoma patients included the CATNON randomized phase 3 clinical trial. Importantly, malignant progression was hardly affected by radio- or chemotherapy, indicating that treatment does not affect the course of disease. Our results culminate in a DNA-methylation based signature for objective tumor grading.
Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes
Authors: Landon-Brace Natalie , Innes Brendan T. , Latour Simon , Cadavid Jose L. , Co Ileana L. , Tan Cassidy M. , Nowlan Ferris , Drissler Sybil , Notta Faiyaz , Jackson Hartland Warren , Bader Gary D. , McGuigan Alison P. 
Published: March 2024

AbstractPancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the “classical” and “basal-like” transcriptional subtypes which have prognostic value in PDAC; however, it remains unclear how microenvironmental heterogeneity contributes to the expression of these transcriptional signatures. Here, we used single cell transcriptome analysis of the organoid TRACER platform to explore the effect of oxygen and other microenvironmental gradients on PDAC organoid cells. We found that the microenvironmental gradients present in TRACER significantly impact the distribution of organoid transcriptional phenotypes and the enrichment of gene sets linked to cancer progression and treatment resistance. More significantly, we found that microenvironmental gradients drive changes in the expression of the classical and basal-like transcriptional subtype gene signatures. This effect is likely dominated by the oxygen gradients in TRACER, as hypoxia alone induced decreases in the expression of classical marker GATA6 at both the gene and protein level in PDAC cells. This work suggests that hypoxia contributes to determining transcriptional subtypes in PDAC and broadly underscores the importance of considering microenvironmental gradients in organoid-based transcriptomic studies of PDAC.
Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP1 signaling in dormant disseminated uveal melanoma
Authors: Kadamb Rama , Anton Melisa Lopez , Purwin Timothy J. , Seeneevassen Lornella , Chua Vivian , Waltrich Francis , Teh Jessica L.F. , Nieto M. Angela , Sato Takami , Terai Mizue , Roman Sergio Roman , De Koning Leanne , Zheng Deyou , Aplin Andrew E , Aguirre-Ghiso Julio A 
Published: March 2024

AbstractUveal melanoma (UM) can remain in clinical dormancy for decades only to later produce lethal metastases. Using Gαq/11mut/BAP1wtUM xenograft models and human metastatic samples, we identified NR2F1 as a key inducer of UM disseminated cancer cell (DCC) dormancy. Dormant UM DCCs upregulate NR2F1, neural crest genes and, along with suppression of proliferation programs, NR2F1 silences YAP1/TEAD1 transcription by altering histone H3 activation marks. YAP1 can reciprocally repress NR2F1, but inhibiting Gαq/11 signaling or activating NR2F1 can arrest UM growth. NR2F1 knockout led to dormant DCC awakening and liver metastatic growth. NR2F1 and YAP1 inverse expression was confirmed in human livers carrying UM solitary, small DCC clusters as well as large metastases. Intriguingly, RNA-seq and Cut&Run analysis revealed that NR2F1 short-circuits oncogene signaling by repressing multiple G-protein signaling components. Our work provides previously unrecognized mechanistic insight into UM DCC dormancy and potential pathways for interception.Statement of significanceNR2F1 epigenetically suppresses genes associated with G-protein signaling, cell cycle, and YAP1/TEAD1 pathways, inducing dormancy in uveal melanoma (UM) disseminated cancer cells. This study unveils novel markers for UM dormancy and reactivation, positioning NR2F1 as a promising target for intercepting residual and UM metastatic disease.
Associations of Systemic Inflammation and Senescent Cell Biomarkers with Clinical Outcomes in Older Adults with Schizophrenia
Authors: Chui M.K. Kirsten , Schneider Kevin , Miclau Katherine , LaHue Sara C , Furman David , Leutwyler Heather , Newman John C 
Published: March 2024

AbstractIndividuals with schizophrenia suffer from higher morbidity and mortality throughout life partly due to acceleration of aging-related diseases and conditions. Systemic inflammation is a hallmark of aging and is also observed in schizophrenia. An improved understanding of how inflammation and accelerated aging contribute to long-term health outcomes in schizophrenia could provide more effective treatments to preserve long-term cognitive and physical function. In this pilot cross-sectional study, 24 older adults (≥55 years old) with schizophrenia were assessed on symptoms (Positive and Negative Syndrome Scale), neurocognition (Matrics Consensus Cognitive Battery), mobility (Timed Get Up and Go), and general health (SF-12). Serum levels of 112 different cytokines were measured, from which we derived estimated senescence-associated secretory phenotype (SASP) scores for each participant. Two-tailed Pearson’s bivariate correlations were computed to test the associations between schizophrenia clinical outcomes with individual cytokines, and SASP. Higher levels of eotaxin, IL-1α, IL-1β, and IFNα are associated with both worse PANSS negative and depressive symptoms scores. IL-1α and IL-1β negatively associated with general physical health whereas eotaxin negatively associated with mobility and global cognition. Overall, we found that specific inflammatory cytokines, but not composite measurements of SASP, are associated with clinical outcomes in older adults with schizophrenia.
The segmented flavivirus Alongshan virus reduces mitochondrial mass via degrading STAT2 to suppress innate immune response
Authors: Zhao Yinghua , Sui Liyan , Pan Mingming , Jin Fangyu , Huang Yuan , Fang Shu , Wang Mengmeng , Che Lihe , Xu Wenbo , Liu Ning , Liu Nan , Gao Haicheng , Hou Zhijun , Du Fang , Wei Zhengkai , Zhao Jixue , Zhang Kaiyu , Zhao Yicheng , Wang Ze-Dong , Liu Quan 
Published: March 2024

AbstractAlongshan virus (ALSV) is a newly discovered pathogen of theFlaviviridaefamily, characterized by a multi-segmented genome distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of the emerging segmented flavivirus is crucial for the development of intervention strategies. Here we show that ALSV can infect multiple mammalian cells and induces the expression of antiviral genes. Moreover, ALSV is sensitive to IFN-β and possesses the ability to counteract type I IFN response. Mechanistically, ALSV’s nonstructural protein NSP1 binds to and degrades human STAT2 through an autophagy pathway in a species-dependent manner, resulting in direct inhibition of the expression of interferon-stimulated genes (ISGs). Specifically, NSP1 methyltransferase domain binds to the key sites of F175/R176 located in coiled-coil domain of STAT2. Moreover, NSP1-mediated degradation of STAT2 results in a reduction in mitochondrial mass by disrupting mitochondrial dynamics to induce mitophagy and inhibiting mitochondrial biogenesis, thereby suppressing the innate immune response. Interestingly, inhibiting mitophagy using 3-Methyladenine and enhancing mitochondrial biogenesis using the PPARγ agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass presents an effective antiviral strategy. Our findings elucidate the intricate regulatory crosstalk between ALSV and the host’s innate immune response, providing valuable insights into the pathogenesis and intervention strategy of emerging segmented flavivirus.
Efficient and multiplexed somatic genome editing with Cas12a mice
Authors: Hebert Jess D. , Xu Haiqing , Tang Yuning J. , Ruiz Paloma A. , Detrick Colin R. , Wang Jing , Hughes Nicholas W. , Donosa Oscar , Andrejka Laura , Karmakar Saswati , Aboiralor Irenosen , Tang Rui , Sage Julien , Cong Le , Petrov Dmitri A. , Winslow Monte M. 
Published: March 2024

ABSTRACTSomatic genome editing in mouse models has increased our understanding of thein vivoeffects of genetic alterations in areas ranging from neuroscience to cancer biology and beyond. However, existing models are limited in their ability to create multiple targeted edits. Thus, our understanding of the complex genetic interactions that underlie development, homeostasis, and disease remains incomplete. Cas12a is an RNA-guided endonuclease with unique attributes that enable simple targeting of multiple genes with crRNA arrays containing tandem guides. To accelerate and expand the generation of complex genotypes in somatic cells, we generated transgenic mice with Cre-regulated and constitutive expression of enhancedAcidaminococcus sp.Cas12a (enAsCas12a). In these mice, enAsCas12a-mediated somatic genome editing robustly generated compound genotypes, as exemplified by the initiation of diverse cancer types driven by homozygous inactivation of trios of tumor suppressor genes. We further integrated these modular crRNA arrays with clonal barcoding to quantify the size and number of tumors with each array, as well as the efficiency of each crRNA. These Cas12a alleles will enable the rapid generation of disease models and broadly facilitate the high-throughput investigation of coincident genomic alterations in somatic cellsin vivo.
Computation or Weight Adaptation? Rethinking the Role of Plasticity in Learning
Authors: Lior Gili , Shalev Yuval , Stanovsky Gabriel , Goldstein Ariel 
Published: March 2024

AbstractThe human brain is an adaptive learning system that can generalize to new tasks and unfamiliar environments. The traditional view is that such adaptive behavior requires a structural change of the learning system (e.g., via neural plasticity). In this work, we use artificial neural networks, specifically large language models (LLMs), to challenge the traditional view about the role of plasticity in learning and suggest that such an adaptive behavior can be achieved solely through computation if the learning system is suffciently trained. We focus on statistical learning paradigms. These require identifying underlying regularities in seemingly arbitrary word sequences and are largely considered to require neural plasticity. LLMs can capture arbitrary structures without weight adaptation despite the divergence from their natural language training data. Our work provides novel insights into the role of plasticity in learning, showing that suffciently trained learning systems are highly flexible, adapting to new tasks and environments solely through computation, much more than previously acknowledged. Furthermore, our work opens the door for future research to use deep learning models to conjure hypotheses about the brain.
Dynamic Adaptation in Extant Porins Facilitates Antibiotic Tolerance in EnergeticEscherichia coli
Authors: Mukhopadhyay Sayak , Bishayi Romit , Shaji Aakansha , Lee Annie H. , Gupta Rachit , Mohajeri Mohammad , Katiyar Aditya , McKee Brendan , Schmitz Isabella R. , Shin Rachel , Lele Tanmay P. , Lele Pushkar P. 
Published: March 2024

AbstractBacteria can tolerate antibiotics despite lacking the genetic components for resistance. The prevailing notion is that tolerance results from depleted cellular energy or cell dormancy. In contrast to this view, many cells in the tolerant population of Escherichia coli can exhibit motility – a phenomenon that requires cellular energy, specifically, the proton-motive force (PMF). As these motile-tolerant cells are challenging to isolate from the heterogeneous tolerant population, their survival mechanism is unknown. Here, we discovered that motile bacteria segregate themselves from the tolerant population under micro-confinement, owing to their unique ability to penetrate micron-sized channels. Single-cell measurements on the motile-tolerant population showed that the cells retained a high PMF, but they did not survive through active efflux alone. By utilizing growth assays, single-cell fluorescence studies, and chemotaxis assays, we showed that the cells survived by dynamically inhibiting the function of existing porins in the outer membrane. A drug transport model for porin-mediated intake and efflux pump-mediated expulsion suggested that energetic tolerant cells withstand antibiotics by constricting their porins. The novel porin adaptation we have uncovered is independent of gene expression changes and may involve electrostatic modifications within individual porins to prevent extracellular ligand entry.