bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrinsically linked lineage-specificity of transposable elements and lncRNAs reshapes transcriptional regulation species- and tissue-specifically
Authors: Lin Jie , Wu Yijin , He Sha , Xiong Wei , Pontarotti Pierre , Zhu Hao
Published: March 2024

Lineage-specificity of transcriptional regulation by lncRNAs critically determines whether mouse models reliably mimic human diseases. To address this question, we identified human/mouse-specific lncRNAs from GENCODE-annotated human and mouse lncRNAs, predicted their DNA binding domains (DBDs) and binding sites (DBSs), analysed transposable elements (TEs) in DBDs and DBSs, and analysed functional enrichment of target genes. 84%/98% of human/mouse-specific lncRNAs, 61%/95% of their DBDs, and 46%/73% of their DBSs contain TEs almost exclusively originated from simians/rodents, indicating intrinsically linked lineage-specificity of TEs, lncRNAs, and lncRNAs’ DBSs. We then revealed how transcriptional regulation is lineage-specifically rewired by co-opted lncRNAs and DBSs by analysing distributions of target genes in signalling pathways and expression of target genes in multiple tissues in humans and mice. Transcriptional regulation is greatly rewired species-specifically and tissue-specifically. We further analysed transcriptomic data of Alzheimer’s disease and tumours from human patients and mouse models, with results supporting the above conclusions. Our results reveal the intrinsically linked lineage-specificity of transposable elements, lncRNAs, and transcriptional regulation, provide data and tool for analysing and differentiating transcriptional regulation in humans and mice, and suggest that many evolutionary novelties may be destined to be lineage-specific.
A theoretical basis for cell deaths
Authors: Himeoka Yusuke , Horiguchi Shuhei A. , Kobayashi Tetsuya J.
Published: March 2024

Understanding deaths and life-death boundaries of cells is a fundamental challenge in biological sciences. In this study, we present a theoretical framework for investigating cell death. We conceptualize cell death as a controllability problem within dynamical systems, and compute the life-death boundary through the development of “stoichiometric rays”. This method utilizes enzyme activity as control parameters, exploiting the inherent property of enzymes to enhance reaction rates without affecting thermodynamic potentials. This approach facilitates the efficient evaluation of the global controllability of models. We demonstrate the utility of our framework using its application to a toy metabolic model, where we delineate the life-death boundary. The formulation of cell death through mathematical principles provides a foundation for the theoretical study of cellular mortality.

SIGNIFICANCE STATEMENT

What is death? This fundamental question in biology lacks a clear theoretical framework despite numerous experimental studies. In this study, we present a new way to understand cell death by looking at how cells can or cannot control their states. We define a “dead state” as a state from which a cell cannot return to being alive. Our method, called “Stoichiometric Rays”, helps determine if a cell’s state is dead based on enzymatic reactions. By using this method, we can quantify the life-death boundary in metabolic models. The present framework provides a theoretical basis and a tool for understanding cell death.
Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) secreted by triple-negative breast cancer promotes tumor microenvironment fibrosis
Authors: Verma Surbhi , Giagnocavo Stephanie Dudics , Curtin Meghan C. , Arumugam Menusha , Osburn-Staker Sandra M. , Wang Guoying , Atkinson Aaron , Nix David A. , Lum David H. , Cox James E. , Hilgendorf Keren I.
Published: March 2024

Obesity is a predisposition factor for breast cancer, suggesting a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of ten human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells (ASPC). The screen identified a key adipogenic modulator, Zinc Alpha-2-Glycoprotein (ZAG/AZGP1), secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG in TNBC patients, but not other clinical subtypes of breast cancer, is linked to poor prognosis. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of ASPCs into cancer-associated fibroblasts to support tumorigenesis.
Persistent Behavioral and Physiological Effects of Dietary Protein Restriction
Authors: Soto Paul L. , Morrison Christopher D.
Published: March 2024

Protein provides essential amino acids critical for survival. Recent research has identified that dietary protein restriction induces physiological and behavioral adaptations and that those adaptations are mediated by liver-produced fibroblast growth factor 21 (FGF21) that acts in the brain. Most of the research on adaptations to dietary protein restriction and the biological factors that mediate those adaptations carries an implicit assumption that the effects of dietary protein restriction are reversible. Rarely is the assumption of reversibility directly examined by varying dietary protein content within animals. Recently collected data on preference for protein versus carbohydrate solutions indicates that when mice are placed on a low (5%) protein diet, preference for protein is rapidly increased. However, when mice are switched from a low to normal (20%) protein diet, relative consumption of protein decreases but preference for protein persists. Re-analysis of published data suggests, similarly, that preference for protein-rich food sources remains elevated following exposure to dietary protein restriction and that calcium influx in the ventral tegmental area of the brain in response to protein consumption also remains persistently elevated following dietary protein restriction. Together, the data suggest that prior protein restriction can exert long-lasting effects on protein preference and on brain activity associated with protein consumption. The finding that the effects of protein restriction do not rapidly reverse implies that protein choice may be a function, not only of current nutritional state, but of historical nutritional conditions. Further, these results suggest that a full understanding of the environmental and biological determinants of protein choice requires studies in which dietary protein intake is varied within subjects.
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

Brain 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

There 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.

Importance

The 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

Endoplasmic 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

Complicated 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.

Significance

Comprehensive 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

1

To 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

Pancreatic 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.
Antigenic determinants of HAstV-VA1 neutralization and their relevance in the human immune response
Authors: Ramírez-Bello Inci , López Tomás , Espinosa Rafaela , Ghosh Anisa , Green Kassidy , Riaño-Umbarila Lidia , Gaspar-Castillo Carlos , Alpuche-Aranda Celia M. , López Susana , DuBois Rebecca M. , Arias Carlos F.
Published: March 2024

Astroviruses are highly divergent and infect a wide variety of animal hosts. In 2009, a genetically divergent human astrovirus (HAstV) strain VA1 was first identified in an outbreak of acute gastroenteritis. This strain has also been associated with fatal central nervous system disease. In this work, we report the isolation of three high-affinity neutralizing monoclonal antibodies (Nt-MAbs) targeting the capsid spike domain of HAstV-VA1. These antibodies (7C8, 2A2, 3D8) were used to select individual HAstV-VA1 mutants resistant to their neutralizing activity and also select a HAstV-VA1 triple mutant that escapes neutralization from all three Nt-MAbs. Sequencing of the virus genome capsid region revealed escape mutations that map to the surface of the capsid spike domain, define three potentially independent neutralization epitopes, and help delineate four antigenic sites in rotaviruses. Notably, two of the escape mutations were found to be present in the spike sequence of the HAstV-VA1-PS strain isolated from an immunodeficient patient with encephalitis, suggesting that those mutations arose as a result of the immune pressure generated by the patient’s immunotherapy. In accordance with this observation, human serum samples exhibiting strong neutralization activity against wild-type HAstV-VA1 had a 2.6-fold reduction in neutralization titer when evaluated against the triple-escape HAstV-VA1 mutant, indicating shared neutralization epitopes between the mouse and human antibody response. The isolated Nt-MAbs reported in this work will help characterize the functional sites of the virus during cell entry and have the potential for developing a specific antibody therapy for the neurological disease associated with HAstV-VA1.

Importance

Human astroviruses (HAstVs) have been historically associated with acute gastroenteritis. However, the genetically divergent HAstV-VA1 strain has been associated with central nervous system disease. This work isolated high-affinity neutralizing monoclonal antibodies directed to HAstV-VA1. The proposed binding sites for these antibodies, together with previously reported sites for neutralizing antibodies against classical HAstVs, suggest the existence of at least four neutralization sites on the capsid spike of astroviruses. Our data show that natural infection with human astrovirus VA1 elicits a robust humoral immune response that targets the same antigenic sites recognized by the mouse monoclonal antibodies and strongly suggests the emergence of a variant HAstV-VA1 virus in an immunodeficient patient with prolonged astrovirus infection. The isolated Nt-MAb reported in this work will be helpful in defining the functional sites of the virus involved in cell entry and hold promise for developing a specific antibody therapy for the neurological disease associated with HAstV-VA1.
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

Uveal 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 significance

NR2F1 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.
Predicting drug outcome of population via clinical knowledge graph
Authors: Brbić Maria , Yasunaga Michihiro , Agarwal Prabhat , Leskovec Jure
Published: March 2024

Optimal treatments depend on numerous factors such as drug chemical properties, disease biology, and patient characteristics to which the treatment is applied. To realize the promise of AI in healthcare, there is a need for designing systems that can capture patient heterogeneity and relevant biomedical knowledge. Here we present PlaNet, a geometric deep learning framework that reasons over population variability, disease biology, and drug chemistry by representing knowledge in the form of a massive clinical knowledge graph that can be enhanced by language models. Our framework is applicable to any sub-population, any drug as well drug combinations, any disease, and a wide range of pharmacological tasks. We apply the PlaNet framework to reason about outcomes of clinical trials: PlaNet predicts drug efficacy and adverse events, even for experimental drugs and their combinations that have never been seen by the model. Furthermore, PlaNet can estimate the effect of changing population on trial outcomes with direct implications for patient stratification in clinical trials. PlaNet takes fundamental steps towards AI-guided clinical trials design, offering valuable guidance for realizing the vision of precision medicine using AI.
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

Individuals 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.
A male-essential microRNA is key for avian sex chromosome dosage compensation
Authors: Fallahshahroudi Amir , Rodríguez-Montes Leticia , Taemeh Sara Yousefi , Trost Nils , Tellez Memo , Ballantyne Maeve , Idoko-Akoh Alewo , Taylor Lorna , Sherman Adrian , Sorato Enrico , Johnsson Martin , Moreira Margarida Cardoso , McGrew Mike J. , Kaessmann Henrik
Published: March 2024

Birds have a sex chromosome system in which females are heterogametic (ZW) and males are homogametic (ZZ). The differentiation of avian sex chromosomes from ancestral autosomes entailed the loss of most genes from the W chromosome during evolution. However, to what extent mechanisms evolved that counterbalance the consequences of this extensive gene dosage reduction in female birds has remained unclear. Here we report functional in vivo and evolutionary analyses of a Z-chromosome-linked microRNA (miR-2954) with strongly male-biased expression that was previously proposed to play a key role in sex chromosome dosage compensation1. We knocked out miR-2954 in chicken, which resulted in early embryonic lethality of homozygous knockout males, likely due to the highly specific upregulation of dosage-sensitive Z-linked target genes of miR-2954. Our evolutionary gene expression analyses further revealed that these dosage-sensitive target genes have become upregulated on the single Z in female birds during evolution. Altogether, our work unveils a scenario where evolutionary pressures on females following W gene loss led to the evolution of transcriptional upregulation of dosage-sensitive genes on the Z not only in female but also in male birds. The resulting overabundance of transcripts in males resulting from the combined activity of two dosage-sensitive Z gene copies was in turn offset by the emergence of a highly targeted miR-2954-mediated transcript degradation mechanism during avian evolution. Our findings demonstrate that birds have evolved a unique sex chromosome dosage compensation system in which a microRNA has become essential for male survival.
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

Alongshan 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.
De novo detection of somatic variants in high-quality long-read single-cell RNA sequencing data
Authors: Dondi Arthur , Borgsmüller Nico , Ferreira Pedro F. , Haas Brian J. , Jacob Francis , Heinzelmann-Schwarz Viola ,   Tumor Profiler Consortium, Beerenwinkel Niko
Published: March 2024

In cancer, genetic and transcriptomic variations generate clonal heterogeneity, leading to treatment resistance. Long-read single-cell RNA sequencing (LR scRNA-seq) has the potential to detect genetic and transcriptomic variations simultaneously. Here, we present LongSom, a computational workflow leveraging high-quality LR scRNA-seq data to call de novo somatic single-nucleotide variants (SNVs), including in mitochondria (mtSNVs), copy-number alterations (CNAs), and gene fusions, to reconstruct the tumor clonal heterogeneity. Before somatic variants calling, LongSom re-annotates marker gene based cell types using cell mutational profiles. LongSom distinguishes somatic SNVs from noise and germline polymorphisms by applying an extensive set of hard filters and statistical tests. Applying LongSom to human ovarian cancer samples, we detected clinically relevant somatic SNVs that were validated against matched DNA samples. Leveraging somatic SNVs and fusions, LongSom found subclones with different predicted treatment outcomes. In summary, LongSom enables de novo variant detection without the need for normal samples, facilitating the study of cancer evolution, clonal heterogeneity, and treatment resistance.
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

Somatic 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

The 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

Bacteria 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.
De NovoTANGLED1 Recruitment to Aberrant Cell Plate Fusion Sites in Maize
Authors: Uyehara Aimee N. , Diep Beatrice N. , Allsman Lindy A. , Gayer Sarah G. , Martinez Stephanie E. , Kim Janice J. , Agarwal Shreya , Rasmussen Carolyn G.
Published: March 2024

Division plane positioning is critical for proper growth and development in many organisms. In plants, the division plane is established before mitosis, by accumulation of a cytoskeletal structure called the preprophase band (PPB). The PPB is thought to be essential for recruitment of division site localized proteins, which remain at the division site after the PPB disassembles. Here, we show that a division site localized protein, TANGLED1 (TAN1), is recruited independently of the PPB to the cell cortex at sites, by the plant cytokinetic machinery, the phragmoplast. TAN1 recruitment to de novo sites on the cortex is partially dependent on intact actin filaments and the myosin XI motor protein OPAQUE1 (O1). These data imply a yet unknown role for TAN1 and possibly other division site localized proteins during the last stages of cell division when the phragmoplast touches the cell cortex to complete cytokinesis.

Summary Statement

The plant division site protein TANGLED1 is recruited tode novocell plate insertion sites independently of the preprophase band.
Combinatorialin vivogenome editing identifies widespread epistasis during lung tumorigenesis
Authors: Hebert Jess D. , Tang Yuning J. , Andrejka Laura , Lopez Steven S. , Petrov Dmitri A. , Boross Gábor , Winslow Monte M.
Published: March 2024

Lung adenocarcinoma, the most common subtype of lung cancer, is genomically complex, with tumors containing tens to hundreds of non-synonymous mutations. However, little is understood about how genes interact with each other to enable tumorigenesisin vivo, largely due to a lack of methods for investigating genetic interactions in a high-throughput and multiplexed manner. Here, we employed a novel platform to generate tumors with all pairwise inactivation of ten tumor suppressor genes within an autochthonous mouse model of oncogenic KRAS-driven lung cancer. By quantifying the fitness of tumors with every single and double mutant genotype, we show that most tumor suppressor genetic interactions exhibited negative epistasis, with diminishing returns on tumor fitness. In contrast,Apcinactivation showed positive epistasis with the inactivation of several other genes, including dramatically synergistic effects on tumor fitness in combination withLkb1orNf1inactivation. This approach has the potential to expand the scope of genetic interactions that may be functionally characterizedin vivo, which could lead to a better understanding of how complex tumor genotypes impact each step of carcinogenesis.
Comprehensive constraints on heavy sterile neutrinos from core-collapse supernovae
Authors: Carenza Pierluca , Lucente Giuseppe , Mastrototaro Leonardo , Mirizzi Alessandro , Serpico Pasquale Dario
Published: March 2024

Sterile neutrinos with masses up to O(100)  MeV can be copiously produced in a supernova (SN) core through the mixing with active neutrinos. In this regard, the SN 1987A detection of neutrino events has been used to put constraints on active-sterile neutrino mixing, exploiting the well-known SN cooling argument. We refine the calculation of this limit including neutral current interactions with nucleons, which constitute the dominant channel for sterile neutrino production. We also include, for the first time, the charged current interactions between sterile neutrinos and muons, relevant for the production of sterile neutrinos mixed with muon neutrinos in the SN core. Using the recent modified luminosity criterion, we extend the bounds to the case where sterile states are trapped in the stellar core. Additionally, we study the decays of heavy sterile neutrinos, affecting the SN explosion energy and possibly producing a gamma-ray signal. We also illustrate the complementarity of our new bounds with cosmological bounds and laboratory searches.

Published by the American Physical Society
2024
Twin sterile neutrino dark matter
Authors: Holst Ian , Hooper Dan , Krnjaic Gordan , Song Deheng
Published: March 2024

We propose that the dark matter of our Universe could be sterile neutrinos which reside within the twin sector of a mirror twin Higgs model. In our scenario, these particles are produced through a version of the Dodelson-Widrow mechanism that takes place entirely within the twin sector, yielding a dark matter candidate that is consistent with x-ray and gamma-ray line constraints. Furthermore, this scenario can naturally avoid the cosmological problems that are typically encountered in mirror twin Higgs models. In particular, if the sterile neutrinos in the Standard Model sector decay out of equilibrium, they can heat the Standard Model bath and reduce the contributions of the twin particles to Neff. Such decays also reduce the effective temperature of the dark matter, thereby relaxing constraints from large-scale structure. The sterile neutrinos included in this model are compatible with the seesaw mechanism for generating Standard Model neutrino masses.

Published by the American Physical Society
2024
Local and Global Variability in Developing Human T-Cell Repertoires
Authors: Isacchini Giulio , Quiniou Valentin , Barennes Pierre , Mhanna Vanessa , Vantomme Hélène , Stys Paul , Mariotti-Ferrandiz Encarnita , Klatzmann David , Walczak Aleksandra M. , Mora Thierry , Nourmohammad Armita
Published: March 2024

The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T-cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T-cell maturation in the thymus. Characterizing TCR repertoires across individuals and T-cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T-cell maturation and differentiation. The interindividual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T-cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types.

Published by the American Physical Society
2024
E-commerce for a sustainable future: integrating trust, green supply chain management and online shopping satisfaction
Authors: Jalil Fazila , Yang Jianhua , Al-Okaily Manaf , Rehman Shafique Ur
Published: March 2024

Purpose

This study embarks on a comprehensive investigation into the intricate relationship between consumer trust in e-commerce platforms and the adoption of Green Supply Chain Management (GSCM). It delves into a multifaceted analysis of how these dynamics influence the landscape of online shopping, with a specific focus on four critical dimensions: the efficiency of online purchasing processes, the fulfillment of product delivery commitments, the convenience associated with e-platform utilization, and the safeguarding of consumers' personal information.

Design/methodology/approach

This research employs sophisticated Structural Equation Modeling (SEM) techniques, facilitated by SPSS and SmartPLS software, to meticulously analyze the amassed data and subject the formulated hypotheses to rigorous testing. The empirical foundation of this study draws from a sample of 377 randomly selected online shoppers, providing a robust basis for its insights.

Findings

At its core, this research is squarely focused on unraveling the dynamics of consumer trust within e-commerce platforms and highlighting the pivotal role played by GSCM in making online shopping more ecologically responsible and sustainable. Of paramount importance is the novel dimension introduced by this study the integration of trust in e-commerce platforms, GSCM practices, and the multifarious dimensions of online shopping all within a unified conceptual framework. Trust on e-commerce platforms leads to GSCM. GSCM determines online shopping satisfaction, i.e. efficiency, fulfillment, convenience, and privacy. Finally, GSCM mediates between trust on e-commerce platforms and online shopping satisfaction.

Practical implications

This holistic approach represents a ground-breaking contribution to the existing body of literature. It presents a fresh perspective on the intricate interactions that define the contemporary e-commerce landscape.

Originality/value

This initial research integrates trust in e-commerce platforms, GSCM, and online shopping in a single framework through UTAUT2.
Benchmarking for organisational competitiveness: a resource-based view perspective
Authors: Malhotra Gunjan , Dandotiya Gunjan , Shaiwalini Shipra , Khan Adnan , Homechaudhuri Shreya
Published: March 2024

Purpose

The paper tries to investigate the impact of applications of the resource-based view (RBV) theory in the management field to improve the firm’s profitability. Global firms are innovating and adopting new technology, paving the way to improve their performance.

Design/methodology/approach

We have adopted RBV in management practices such as marketing, strategy, finance, and human resources.

Findings

RBV has gained researchers' attention with the growing competitive world and new challenges to retaining customers and achieving their pre-defined targets. We attempt to identify the issues related to the usage of RBV in management.

Originality/value

Using RBV in management may help researchers create a competitive mindset and be prepared for uncertain challenges in the business world.