bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deposited footprints let cells switch between confined, oscillatory, and exploratory migration
Authors: Ipiña Emiliano Perez , d’Alessandro Joseph , Ladoux Benoît , Camley Brian A. 
Published: September 2023

For eukaryotic cells to heal wounds, respond to immune signals, or metastasize, they must migrate, often by adhering to extracellular matrix. Cells may also deposit extracellular matrix components, leaving behind a footprint that influences their crawling. Recent experiments showed that some epithelial cells on micropatterned adhesive stripes move persistently in regions they have previously crawled over, where footprints have been formed, but barely advance into unexplored regions, creating an oscillatory migration of increasing amplitude. Here, we explore through mathematical modeling how footprint deposition and cell responses to footprint combine to allow cells to develop oscillation and other complex migratory motions. We simulate cell crawling with a phase field model coupled to a biochemical model of cell polarity, assuming local contact with the deposited footprint activates Rac1, a protein that establishes the cell’s front. Depending on footprint deposition rate and response to the footprint, cells on micropatterned lines can display many types of motility, including confined, oscillatory, and persistent motion. On two-dimensional substrates, we predict a transition between cells undergoing circular motion and cells developing an exploratory phenotype. Small quantitative changes in a cell’s interaction with its footprint can completely alter exploration, allowing cells to tightly regulate their motion, leading to different motility phenotypes (confined vs exploratory) in different cells when deposition or sensing is variable from cell to cell. Consistent with our computational predictions, we find in earlier experimental data evidence of cells undergoing both circular and exploratory motion.Significance StatementRecent experiments showed that epithelial cells modify and sense their local environment, creating a footprint that guides their own motion. Here, we explore how these deposited footprints regulate cell motility. We can recapitulate earlier experimental results with a model that assumes the footprint activates proteins that establish the cell front. We find that cells can use their footprints to change how they explore their surroundings, and that small changes in sensing or depositing footprint can switch the cell from being trapped to being able to explore new environments easily. We find both behaviors in experimental data, suggesting that cells can exhibit multiple crawling behaviors depending on how they deposit and respond to their foot-print.
The impact of gestational diabetes on functional capacity of the infant gut microbiome is modest and transient
Authors: Chieu Ryan V. , Hamilton Katharine , Ryan Paul M. , Copeland Julia , Wang Pauline W. , Retnakaran Ravi , Guttman David S. , Parkinson John , Hamilton Jill 
Published: September 2023

ABSTRACTGestational diabetes mellitus (GDM) is a metabolic complication that manifests as hyperglycemia during the later stages of pregnancy. In high resource settings, careful management of GDM limits risk to the pregnancy, and hyperglycemia typically resolves after birth. At the same time, previous studies have revealed that the gut microbiome of infants born to mothers who experienced GDM exhibit reduced diversity and reduction in the abundance of several key taxa, includingLactobacillus. What is not known is what the functional consequences of these changes might be. In this case control study, we applied 16S rRNA sequence surveys and metatranscriptomics to profile the gut microbiome of 30 twelve-month old infants to examine the impact of GDM during pregnancy. Relative to mode of delivery and sex of the infant, maternal GDM status had only a limited impact on the structure and function of the developing microbiome. While GDM samples were associated with a decrease in alpha diversity, we observed no effect on beta diversity and no differentially abundant taxa. Further, while mode of delivery and sex of infant affected the expression of multiple bacterial pathways, most of the impact of GDM status on the function of the infant microbiome appears to be lost by twelve months of age. These data serve to reassure parents and paediatricians that, at least in high resource settings, while mode of delivery appears to impact function and diversity for longer than anticipated, GDM may not have persistent effects on the function nor composition of the infant gut microbiome.
Pharmacological control of CAR T cells through CRISPR-driven rapamycin resistance
Authors: Levesque Sébastien , Carleton Gillian , Duque Victoria , Goupil Claudia , Fiset Jean-Philippe , Villeneuve Sarah , Normandeau Eric , Morin Geneviève , Dumont Nellie , Nelson Brad H. , Laganière Josée , Boyle Brian , Lum Julian J. , Doyon Yannick 
Published: September 2023

ABSTRACTChimeric antigen receptors (CARs) reprogram T cells to recognize and target cancer cells. Despite remarkable responses observed with CAR-T cell therapy in patients with hematological malignancies, CAR-T cell engineering still relies mostly on randomly integrating vectors, limiting the possibilities of fine-tuning T cell function. Here, we designed a CRISPR-based marker-free selection strategy to simultaneously target a therapeutic transgene and a gain-of-function mutation to theMTORlocus to enrich cells resistant to rapamycin, a clinically used immunosuppressant. We readily engineered rapamycin-resistant (RapaR) CAR-T cells by targeting CAR expression cassettes to theMTORlocus. Usingin vitrocytotoxicity assays, and a humanized mouse model of acute lymphoblastic leukemia, we show that RapaR-CAR-T cells can efficiently target CD19+leukemia cells in presence of immunosuppressing doses of rapamycin. Furthermore, our strategy allows multiplexed targeting of rapamycin-regulated immunoreceptors complexes (DARICs) to theMTORandTRACloci to pharmacologically control CAR-T cells’ activity. We foresee that our approach could both facilitate the enrichment of CRISPR-engineered CAR-T cellsex vivoandin vivowhile improving tumor eradication.
Multiomic single-cell analysis identifies von Willebrand factor and TIM3-expressingBCR-ABL1+CML stem cells
Authors: Nilsson Malin S. , Komic Hana , Gustafsson Johan , Sheybani Zahra , Paul Sanchari , Rolfson Ola , Hellstrand Kristoffer , Wennström Lovisa , Martner Anna , Thorén Fredrik B. 
Published: September 2023

AbstractTyrosine kinase inhibitors (TKI) only rarely eradicate leukemic stem cells (LSC) in chronic myeloid leukemia (CML) which commonly necessitates life-long therapy and monitoring of patients. Understanding details of leukemic hematopoiesis in CML may identify targetable pathways for sustained LSC elimination. This study utilized multiomic single-cell characterization of the CD14-CD34+hematopoietic stem and progenitor cell (HSPC) compartment in CML. Combined proteo-transcriptomic profiling of 597 genes and 51 proteins (CITE-seq) was performed along with parallel detection ofBCR-ABL1transcripts in 70,000 HSPC from 16 chronic phase patients and five healthy controls. CD14-CD34+HSPC from diagnosis samples displayed distinct myeloid cell bias with cells mainly annotated as LSC, lympho-myeloid progenitors (LMP)-II, erythrocyte and megakaryocyte progenitors, while few hematopoietic stem cells (HSC), LMP-I, dendritic cell or B cell progenitors were detected. In-depth analysis of the immature CD14-CD34+CD38-/lowcompartment revealed two distinct populations ofBCR-ABL1-expressing CML LSC (denoted LSC-I and LSC-II), where LSC-I showed features of quiescence and CD45RA-cKIT-CD26+TKI therapy-resistant phenotype. These subtypes of immature LSC showed high surface expression of TIM3 and transcription of the von Willebrand factor gene (VWF). Our findings imply that expression ofVWFand TIM3 distinguish LSC from HSC and may be linked to aberrant myeloid-biased hematopoiesis in CML. Additionally, the results identify TIM3 as a conceivable target for sustained elimination of immature LSC in CML.Key pointsWe present a method to detectBCR-ABL1expression at the single-cell level that is compatible with high-throughput CITE-seqThe most immatureBCR-ABL1-expressing LSC population in primary CML shows enhanced expression of von Willebrand factor and TIM3
OmicsPharLeuDB: an integrative database for mining pharmacogenomic data in acute lymphoblastic leukemia
Authors: Peng Yu Zhong 
Published: September 2023

AbstractLeukemia is one of the most common hematological malignancies in children. Recent cancer pharmacogenomic studies profiled large panels of cell lines against hundreds of approved drugs and experimental chemical compounds. However, until now, no comprehensive databases have been specifically designed for leukemia. Therefore, we have developed OmicsPharLeuDB (mugpeng.shinyapps.io/leu_web_english_peng_v2/), a database that includes the largest published studies investigating the viability response of human leukemia cell lines to chemical compound treatment, and the association between drug sensitivity and multi-omics, and also provides a user-friendly interactive website allowing the user to assess drug sensitivity data from a different platform and find the potential relationship between drugs and omics.
Multimodal profiling of chordoma immunity reveals distinct immune contextures
Authors: van Oost S. , Meijer D.M. , IJsselsteijn M.E. , Roelands J. , van den Akker B. , van der Breggen R. , Briaire-de Bruijn I.H. , van der Ploeg M. , Wijers-Koster P.M. , Polak S.B. , Peul W.C. , van der Wal R.J.P. , de Miranda N.F.C.C. , Bovee J.V.M.G. 
Published: September 2023

AbstractChordomas are cancers from the axial skeleton presenting immunological hallmarks of unknown significance. In recent years, some clinical trials demonstrated that chordomas can respond to immunotherapy. We present a comprehensive characterisation of immunological features of 76 chordomas through application of a multimodal approach comprising transcriptional profiling, multidimensional immunophenotyping and TCR profiling. Chordomas generally presented an immune “hot” microenvironment in comparison to other sarcomas, as indicated by the immunologic constant of rejection transcriptional signature. We identified two distinct groups of chordomas based on T cell infiltration. The highly infiltrated group was further characterised by high dendritic cell infiltration and the presence of multicellular immune aggregates in tumours, whereas low T cell infiltration was associated with lower overall cell densities of immune and stromal cells. Interestingly, patients with higher T cell infiltration displayed a more pronounced clonal enrichment of the T cell receptor repertoire compared to those with low T cell counts. Furthermore, we observed that the majority of chordomas maintained HLA class I expression. Our findings shed light on the natural immunity against chordomas. Understanding their immune landscape could guide the development and application of immunotherapies in a tailored manner, ultimately leading to an improved clinical outcome for chordoma patients.
BET inhibition rescues ciliogenesis and ameliorates pancreatitis-driven phenotypic changes in mice with Par3 loss
Authors: Shields Mario A. , Metropulos Anastasia E. , Spaulding Christina , Hirose Tomonori , Ohno Shigeo , Pham Thao N.D. , Munshi Hidayatullah G. 
Published: September 2023

ABSTRACTThe apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas tissue homeostasis are poorly understood. Here, we evaluate the role of Par3 in acinar pancreas injury and homeostasis. While Par3 loss in the mouse pancreas disrupts tight junctions, Par3 loss is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss also exacerbates pancreatitis-induced acinar cell loss, resulting in pronounced pancreatic lipomatosis and failure to regenerate. Moreover, Par3 loss in mice harboring mutant Kras causes extensive pancreatic intraepithelial neoplastic (PanIN) lesions and large pancreatic cysts. We also show that Par3 loss restricts injury-induced primary ciliogenesis. Significantly, targeting BET proteins enhances primary ciliogenesis during pancreatitis-induced injury and, in mice with Par3 loss, limits pancreatitis-induced acinar loss and facilitates acinar cell regeneration. Combined, this study demonstrates how Par3 restrains pancreatitis- and Kras-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate pancreas tissue regeneration.
Loss of EIF4G2 Mediates Aggressiveness in Distinct Human Endometrial Cancer Subpopulations with Poorer Survival Outcome in Patients
Authors: Meril Sara , Avni Maya Muhlbauer , Lior Chen , Bahlsen Marcela , Olender Tsviya , Savidor Alon , Krausz Judit , Peled Hila Belhanes , Birisi Hila , David Nofar , Bialik Shani , Scherz-Shouval Ruth , David Yehuda Ben , Kimchi Adi 
Published: September 2023

AbstractThe non-canonical translation initiation factor EIF4G2 plays essential roles in embryonic development and differentiation, and contributes to the cellular stress response via translation of selective mRNA cohorts. Currently there is limited and conflicting information regarding the potential involvement of EIF4G2 in cancer development and progression. Endometrial cancer (EC) is the most pervasive gynecological cancer in the developed world, with increasing incidence every year. High grade ECs are largely refractory to conventional treatments, presenting poor survival rates and lacking suitable prognostic markers. Here we assayed a cohort of 280 EC patients across different types, grades, and stages, and found that low EIF4G2 expression highly correlated with poor overall and recurrence free survival in Grade 2 EC patients, monitored over a period of up to 12 years. To establish a causative connection between low EIF4G2 expression and cancer progression, we analyzed in parallel two independent human EC cell lines and demonstrated that stable EIF4G2 knock-down resulted in increased resistance to conventional therapies. Depletion of EIF4G2 also increased the prevalence of molecular markers for aggressive cell subsets, and altered their transcriptional and proteomic landscapes. Prominent among the proteins with decreased abundance were Kinesin-1 motor proteins KIF5B and KLC1, 2, 3. Multiplexed imaging of the tumors from this EC patient cohort showed a correlation between decreased protein expression of either KIF5B or KLC1, and poor survival in patients of certain grades and stages. The findings herein reveal potential novel biomarkers for Grade 2 EC with potential ramifications for patient stratification and therapeutic interventions.SignificanceDecreased EIF4G2 protein results in increased drug resistance of aggressive sub-populations of endometrial cancer cells, is associated with poor patient survival, and may serve as a novel prognosis marker for endometrial cancer.
Biased Signaling in Mutated Variants ofβ2-Adrenergic Receptor: Insights from Molecular Dynamics Simulations
Authors: Madhu Midhun K. , Shewani Kunal , Murarka Rajesh K. 
Published: September 2023

AbstractThe molecular basis of receptor bias in G protein-coupled receptors (GPCRs) caused by mutations that preferentially activate specific intracellular transducers over others remains poorly understood. Two experimentally identified biased variants ofβ2-adrenergic receptors (β2AR), a prototypical GPCR, are a triple mutant (T68F, Y132A, and Y219A) and a single mutant (Y219A); the former bias the receptor towards theβ-arrestin pathway by disfavoring G protein engagement, while the latter induces G protein signaling explicitly due to selection against GPCR kinases (GRKs) that phosphorylate the receptor as a prerequisite ofβ-arrestin binding. Though rigorous characterizations have revealed functional implications of these mutations, the atomistic origin of the observed transducer selectivity is not clear. In this study, we investigate the allosteric mechanism of receptor bias inβ2AR using microseconds of all-atom Gaussian accelerated molecular dynamics (GaMD) simulations. Our observations reveal distinct rearrangements in transmembrane helices, intracellular loop 3, and critical residues R1313.50and Y3267.53in the conserved motifs D(E)RY and NPxxY for the mutant receptors, leading to their specific transducer interactions. The reorganization of allosteric communications from the extracellular agonist BI-167107 to the intracellular receptor-transducer interfaces drives the conformational rearrangements responsible for receptor bias in the single and triple mutants. The molecular insights into receptor bias ofβ2AR presented here could improve the understanding of biased signaling in GPCRs, potentially opening new avenues for designing novel therapeutics with fewer side effects and superior efficacy.
When paleontology meets genomics: complete mitochondrial genomes of two saber-toothed cats’ species (Felidae: Machairodontinae)
Authors: Rodrigues-Oliveira Igor Henrique , da Silva Iuri Batista , Rocha Renan Rodrigues , Silva Soares Rafael Augusto , Menegídio Fabiano Bezerra , Garcia Caroline , Pasa Rubens , Kavalco Karine Frehner 
Published: September 2023

AbstractWithin the Machairodontinae subfamily, commonly referred as saber-toothed cats, it is worth noting that only two species, namelyHomotherium latidens, recognized as the scimitar-toothed cat, andSmilodon populator, renowned as the saber-toothed tiger, possess partial mitochondrial genomes accessible in the NCBI database. These sequences, however, do not include the mitogenome control region (D-loop) and have several gaps in their genes, including protein-coding genes (PCGs) that are widely used in phylogenetic analysis. In this study, we aimed to obtain a complete assembly of the mitogenomes of these two species from next-generation sequencing data available at NCBI’s SRA. Thede novoassemblies showed complete mitogenomes with 17,323bp (H. latidens) and 16,769 bp (S. populator), both with 13 PCGs, 22tRNAs, two rRNAs and the D-loop (Control region), with all genes following the standard order and position of most vertebrate mitogenomes. Our phylogeny and molecular dating, despite being generally very similar to previous studies, reveals an earliest divergence between North American and North SeaH. latidensspecimens which may be related to an Early Pleistocene migration across Beringia.
A HEV ORF2 protein-mediated mechanism of hepatitis E-associated kidney disease
Authors: Helmchen Birgit , Leblond Anne-Laure , Lenggenhager Daniela , Jetzer Jasna , Ankavay Maliki , Helmchen Fritjof , Yurtsever Hueseyin , Parrotta Rossella , Healy Marc E. , Pöschel Amiskwia , Markkanen Enni , Semmo Nasser , Ferrié Martin , Cocquerel Laurence , Seeger Harald , Hopfer Helmut , Müllhaupt Beat , Gouttenoire Jérôme , Moradpour Darius , Gaspert Ariana , Weber Achim 
Published: September 2023

AbstractHepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of ade novoimmune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN developed in parallel with increasing glomerular deposition of a noninfectious form of HEV open reading frame 2 (ORF2, capsid) protein secreted in excess. HEV particles or RNA, however, were not detectable. Patients with acute hepatitis E displayed similar but less pronounced deposits. Our results elucidate an immunologic mechanism by which this hepatotropic virus causes variable renal manifestations and establish a link between the HEV ORF2 protein and hepatitis E-associated GN. They directly provide a tool for etiology-based diagnosis of HEV-associated GN as a distinct entity and suggest therapeutic implications.
Generating Novel Leads for Drug Discovery using LLMs with Logical Feedback
Authors: Brahmavar Shreyas Bhat , Srinivasan Ashwin , Dash Tirtharaj , Krishnan Sowmya R , Vig Lovekesh , Roy Arijit , Aduri Raviprasad 
Published: September 2023

AbstractLarge Language Models (LLMs) can be used as repositories of biological and chemical information to generate pharmacological lead compounds. However, for LLMs to focus on specific drug targets typically require experimentation with progressively more refined prompts. Results thus become dependent not just on what is known about the target, but also on what is known about the prompt-engineering. In this paper, we separate the prompt into domain-constraints that can be written in a standard logical form, and a simple text-based query. We investigate whether LLMs can be guided, not by refining prompts manually, but by refining the the logical component automatically, keeping the query unchanged. We describe an iterative procedure LMLF (“Language Models with Logical Feedback”) in which the constraints are progressively refined using a logical notion of generalisation. On any iteration, newly generated instances are verified against the constraint, providing “logical-feedback” for the next iteration’s refinement of the constraints. We evaluate LMLF using two well-known targets (inhibition of the Janus Kinase 2; and Dopamine Receptor D2); and two different LLMs (GPT-3 and PaLM). We show that LMLF, starting with the same logical constraints and query text, can guide both LLMs to generate potential leads. We find: (a) Binding affinities of LMLF-generated molecules are skewed towards higher binding affinities than those from existing baselines; LMLF results in generating molecules that are skewed towards higher binding affinities than without logical feedback; (c) Assessment by a computational chemist suggests that LMLF generated compounds may be novel inhibitors. These findings suggest that LLMs with logical feedback may provide a mechanism for generating new leads without requiring the domain-specialist to acquire sophisticated skills in prompt-engineering.
Joint modelling of whole genome sequence data for human height via approximate message passing
Authors: Depope Al , Bajzik Jakub , Mondelli Marco , Robinson Matthew R. 
Published: September 2023

AbstractHuman height is a model for the genetic analysis of complex traits, and recent studies suggest the presence of thousands of common genetic variant associations and hundreds of low-frequency/rare variants. Here, we show that existing variable selection methods may fail to either select the correct genomic regions, or the appropriate genetic variants due to the complex and potentially long-distance correlation structure of whole genome sequence (WGS) data. To address this, we develop a new algorithmic paradigm based on approximate message passing, gVAMP, which we show accurately localizes associations to variants with the correct frequency and position in the DNA. We apply gVAMP to jointly model the relationship of tens of millions of WGS variants with human height in hundred of thousands of UK Biobank individuals. We find a power relationship of effect size and frequency of −1.1 ± 0.2, identify 59 rare variants and gene burden scores alongside many hundreds of DNA regions containing common variant associations, and show that understanding the genetic basis of complex traits will require the joint analysis of hundreds of millions of variables measured on millions of people. The polygenic risk scores obtained from gVAMP have high accuracy (including a prediction accuracy of ∼ 46% for human height) and outperform current methods for downstream tasks such as mixed linear model association testing across 13 UK Biobank traits. In conclusion, gVAMP offers a scalable foundation towards a wider range of analyses in WGS data.