bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tbx5 overexpression in embryoid bodies increases TAK1 expression but does not enhance the differentiation of sinoatrial node cardiomyocytes
Authors: Dai Yunkai , Nasehi Fatemeh , Winchester Charles D. , Foley Ann C. 
Published: March 2023

AbstractGenetic studies place Tbx5 at the apex of the sinoatrial node (SAN) transcriptional program. To understand its role in SAN differentiation, clonal embryonic stem (ES) cell lines were made that conditionally overexpress Tbx5, Tbx3, Tbx18, Shox2, Islet-1 and Map3k7/TAK1. and cardiac cells differentiated using embryoid bodies (EBs). EBs overexpressing Tbx5, Islet1, and TAK1 beat faster than cardiac cells differentiated from control ES cell lines suggesting possible roles in SAN differentiation. Tbx5 overexpressing EBs showed increased expression of TAK1, but cardiomyocytes did not differentiate as SAN cells. They showed no increase in the expression of Shox2, or Islet1 and decreased expression of HCN4. EBs constitutively overexpressing TAK1 direct cardiac differentiation to the SAN fate, but also have decreased phosphorylation of its targets, p38, and Jnk. This opens the possibility that blocking the phosphorylation of TAK1 targets may have the same impact as forced overexpression. To test this, we treated EBs with 5z-7-Oxozeanol (OXO), an inhibitor of TAK1 phosphorylation. Like TAK1 overexpressing cardiac cells, cardiomyocytes differentiated in the presence of OXO beat faster and showed increased expression of SAN genes (Shox2, HCN4, and Islet1). This suggests that activation of the SAN transcriptional network can be accomplished by blocking the phosphorylation of TAK1.
Tuning the stator subunit of the flagellar motor with coiled-coil engineering
Authors: Ridone Pietro , Winter Daniel L. , Baker Matthew A. B. 
Published: March 2023

AbstractMany bacteria swim driven by an extracellular filament rotated by the bacterial flagellar motor. This motor is powered by the stator complex, MotA5MotB2, a heterodimeric complex which forms an ion channel which couples energy from the ion motive force to torque generation. Recent structural work revealed that stator complex consists of a ring of five MotA subunits which rotate around a central dimer of MotB subunits. Transmembrane (TM) domains TM3 and TM4 from MotA combine with the single TM domain from MotB to form two separate ion channels within this complex. Much is known about the ion binding site and ion specificity; however, to date, no modelling has been undertaken to explore the MotB-MotB dimer stability and the role of MotB conformational dynamics during rotation. Here, we modelled the central MotB dimer using coiled-coil engineering and modelling principles and calculated free energies to identify stable states in the operating cycle of the stator. We found 3 stable coiled-coil states with dimer interface angles of 28°, 56° and 64°. We tested the effect of strategic mutagenesis on the comparative energy of the states and correlated motility with a specific hierarchy of stability between the three states. In general, our results indicate agreement with existing models describing a 36° rotation step of the MotA pentameric ring during the power stroke and provide an energetic basis for the coordinated rotation of the central MotB dimer based on coiled-coil modelling.
Blood-based genome-wide DNA methylation correlations across body fat and adiposity-related biochemical traits
Authors: Hatton Alesha A , Hillary Robert F , Bernabeu Elena , McCartney Daniel L , Marioni Riccardo E , McRae Allan F 
Published: March 2023

AbstractThe recent increase in obesity levels across many countries is likely to be driven by nongenetic factors. The epigenetic modification DNA methylation (DNAm) may help to explore this as it is sensitive to both genetic and environmental exposures. While the relationship between DNAm and body fat traits has been extensively studied [1–9], there is limited literature on the shared associations of DNAm variation across such traits. Akin to genetic correlation estimates, which measure the degree of common genetic control between two traits, here we introduce an approach to evaluate the similarities in DNAm associations between traits, DNAm correlations. As DNAm can be both a cause and consequence of complex traits [5, 10, 11], DNAm correlations have the potential to provide novel insights into trait relationships above that currently obtained from genetic and phenotypic correlations. Utilising 7,519 unrelated individuals from Generation Scotland (GS), we calculated DNAm correlations using the bivariate OREML framework in the OSCA software [12] to investigate the shared associations of DNAm variation between traits. For each trait we also estimated the shared contribution of DNAm between sexes. We identified strong, positive DNAm correlations between each of the body fat traits (BMI, body fat % and waist to hip ratio; ranging from 0.96 to 1.00), finding larger associations than those identified by genetic and phenotypic correlations. We identified a significant deviation from 1 in the rDNAmfor BMI between males and females, with sex-specific DNAm changes associated with BMI identified at eight DNAm probes. Employing genome-wide DNAm correlations to evaluate the similarities in the associations of DNAm with complex traits has provided novel insight into obesity related traits beyond that provided by genetic correlations.
MoveFormer: a Transformer-based model for step-selection animal movement modelling
Authors: Cífka Ondřej , Chamaillé-Jammes Simon , Liutkus Antoine 
Published: March 2023

AbstractThe movement of animals is a central component of their behavioural strategies. Statistical tools for movement data analysis, however, have long been limited, and in particular, unable to account for past movement information except in a very simplified way. In this work, we propose MoveFormer, a new step-based model of movement capable of learning directly from full animal trajectories. While inspired by the classical step-selection framework and previous work on the quantification of uncertainty in movement predictions, MoveFormer also builds upon recent developments in deep learning, such as the Transformer architecture, allowing it to incorporate long temporal contexts. The model predicts an animal’s next movement step given its past movement history, including not only purely positional and temporal information, but also any available environmental covariates such as land cover or temperature. We apply our model to a diverse dataset made up of over 1550 trajectories from over 100 studies, and show how it can be used to gain insights about the importance of the provided context features, including the extent of past movement history. Our software, along with the trained model weights, is released as open source.
High performance imputation of structural and single nucleotide variants in Atlantic salmon using low-coverage whole genome sequencing
Authors: Gundappa Manu Kumar , Robledo Diego , Hamilton Alastair , Houston Ross D. , Prendergast James G. D. , Macqueen Daniel J. 
Published: March 2023

AbstractWhole genome sequencing (WGS), despite its advantages, is yet to replace alternative methods for genotyping single nucleotide variants (SNVs). Structural variants (SVs) have larger effects on traits than SNVs, but are more challenging to accurately genotype. Using low-coverage WGS with genotype imputation offers a cost-effective strategy to achieve genome-wide variant coverage, but is yet to be tested for SVs. Here, we investigate combined SNV and SV imputation with low-coverage WGS data in Atlantic salmon (Salmo salar). As the reference panel, we used genotypes for high-confidence SVs and SNVs for n=445 wild individuals sampled from diverse populations. We also generated 15x WGS data (n=20 samples) for a commercial population out-with the reference panel, and called SVs and SNVs with gold-standard approaches. An imputation method (GLIMPSE) was tested at WGS depths of 1x, 2x, 3x and 4x for samples within and out-with the reference panel. SNVs were imputed with high accuracy and recall across all WGS depths, including for samples out-with the reference panel. For SVs, we compared imputation based purely on linkage disequilibrium (LD) with SNVs, to that supplemented with SV genotype likelihoods (GLs) from low-coverage WGS. Including SV GLs increased imputation accuracy, but as a trade-off with recall, requiring 3-4x coverage for best performance. Combining strategies allowed us to capture 84% of the reference panel deletions with 87% accuracy at 1x WGS. This study highlights the promise of reference panel imputation using low-coverage WGS, including novel opportunities to enhance the resolution of genome-wide association studies by capturing SVs.
Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Authors: Yabo Yahaya A. , Moreno-Sanchez Pilar M. , Pires-Afonso Yolanda , Kaoma Tony , Nosirov Bakhtiyor , Scafidi Andrea , Ermini Luca , Lipsa Anuja , Oudin Anaïs , Kyriakis Dimitrios , Grzyb Kamil , Poovathingal Suresh K. , Poli Aurélie , Muller Arnaud , Toth Reka , Klink Barbara , Berchem Guy , Berthold Christophe , Hertel Frank , Mittelbronn Michel , Heiland Dieter H. , Skupin Alexander , Nazarov Petr V. , Niclou Simone P. , Michelucci Alessandro , Golebiewska Anna 
Published: March 2023

ABSTRACTBackgroundA major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials.MethodsHere, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA-sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors.ResultsWe show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood-brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components.ConclusionOur data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment.
Antibiotic Resistance Gene Variant Sequencing is Necessary to Reveal the Complex Dynamics of Immigration from Sewers to Activated Sludge
Authors: Gibson Claire , Kraemer Susanne A. , Klimova Natalia , Guo Bing , Frigon Dominic 
Published: March 2023

AbstractMicrobial community composition has increasingly emerged as a key determinant of antibiotic resistance gene (ARG) content. However, in activated sludge wastewater treatment plants (AS-WWTPs), a comprehensive understanding of the microbial community assembly process and its impact on the persistence of antimicrobial resistance (AMR) remains elusive. An important part of this process is the immigration dynamics (or community coalescence) between the influent and activated sludge. While the influent wastewater contains a plethora of ARGs, the persistence of a given ARG depends initially on the immigration success of the carrying population, and the possible horizontal transfer to indigenously resident populations of the WWTP.The current study utilised controlled manipulative experiments that decoupled the influent wastewater composition from the influent microbial populations to reveal the fundamental mechanisms involved in ARG immigration between sewers and AS-WWTP. A novel multiplexed amplicon sequencing approach was used to track different ARG sequence variants across the immigration interface, and droplet digital PCR was used to quantify the impact of immigration on the abundance of the targeted ARGs. Immigration caused an increase in the abundance of over 70 % of the quantified ARGs. However, monitoring of ARG sequence variants at the immigration interface revealed various immigration patterns such as (i) suppression of the indigenous mixed liquor variant by the immigrant, or conversely (ii) complete immigration failure of the influent variant. These immigration profiles are reported for the first time here and highlight the crucial information that can be gained using our novel multiplex amplicon sequencing techniques. Future studies aiming to reduce AMR in WWTPs should consider the impact of influent immigration in process optimisation and design.
Development and applications of chimera platforms for tyrosine phosphorylation
Authors: Pergu Rajaiah , Shoba Veronika M. , Chaudhary Santosh K. , Munkanatta Godage Dhanushka N. P. , Deb Arghya , Singha Santanu , Dhawa Uttam , Anokhina Viktoriya , Singh Sameek , Siriwardena Sachini U. , Choudhary Amit 
Published: March 2023

ABSTRACTChimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it in proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical PTM, tyrosine phosphorylation. Furthermore, the contemporary design paradigm of chimeric molecules, formed by joining a non-inhibitory binder of the PTM-inducing enzyme with the binder of the target protein, prohibits the recruitment of most PTM-inducing enzymes as their non-inhibitory binders are unavailable. Here, we report two platforms to generate phosphorylation-inducing chimeric small molecules (PHICS) for tyrosine phosphorylation. We generate PHICS from both non-inhibitory binders (scantily available, platform 1) and kinase inhibitors (abundantly available, platform 2) using cysteine-based group transfer chemistry. PHICS triggered phosphorylation on tyrosine residues in diverse sequence contexts and target proteins (e.g., membrane-associated, cytosolic) and displayed multiple bioactivities, including initiation of a growth receptor signaling cascade and death of drug-resistant cancer cells. These studies provide an approach to induce biologically relevant PTM and lay the foundation for pharmacologic PTM editing (i.e., induction or removal) on target proteins using abundantly available inhibitors of PTM-inducing or erasing enzymes.TOC
The influence of early life exposures on the infant gut virome
Authors: Zhang Yichang , Castro-Mejía Josué L. , Deng Ling , Shah Shiraz A. , Thorsen Jonathan , Rodríguez Cristina Leal , Jessen Leon E. , Dion Moïra B. , Chawes Bo , Bønnelykke Klaus , Sørensen Søren J. , Bisgaard Hans , Moineau Sylvain , Petit Marie-Agnès , Stokholm Jakob , Nielsen Dennis S. 
Published: March 2023

SummaryLarge cohort studies have contributed significantly to our understanding of the factors that influence the development of the bacterial component of the gut microbiome (GM) during the first years of life. However, the factors that shape the colonization by other important GM members such as the viral fraction remain more elusive. Most gut viruses are bacteriophages (phages), i.e., viruses attacking bacteria in a host specific manner, and to a lesser extent, but also widely present, eukaryotic viruses, including viruses attacking human cells. Here, we utilize the deeply phenotyped COPSAC2010 birth cohort consisting of 700 infants to investigate how social, pre-, peri- and postnatal factors may influence the gut virome composition at one year of age, where fecal virome data was available from 645 infants.Among the different exposures studied, having older siblings and living in an urban vs. rural area had the strongest impact on gut virome composition. Differential abundance analysis from a total of 16,118 viral operational taxonomic units (vOTUs) (mainly phages, but also 6.1% eukaryotic viruses) identified 2,105 vOTUs varying with environmental exposures, of which 5.9% were eukaryotic viruses and the rest was phages. Bacterial hosts for these phages were mainly predicted to be within theBacteroidaceae, Prevotellaceae, andRuminococcaceaefamilies, as determined by CRISPR spacer matches. Spearman correlation coefficients indicated strong co-abundance trends of vOTUs and their targeted bacterial host, which underlined the predicted phage-host connections. Further, our findings show that some gut viruses encode important metabolic functions and how the abundance of genes encoding these functions is influenced by environmental exposures. Genes that were significantly associated with early life exposures were found in a total of 42 vOTUs. 18 of these vOTUs had their life styles predicted, with 17 of them having a temperate lifestyle. These 42 vOTUs carried genes coding for enzymes involved in alanine, aspartate and glutamate metabolism, glycolysis-gluconeogenesis, as well as fatty acid biosynthesis. The latter implies that these phages could be involved in the utilization and degradation of major dietary components and affect infant health by influencing the metabolic capacity of their bacterial host.Given the importance of the GM in early life for maturation of the immune system and maintenance of metabolic health, these findings provide a valuable source of information for understanding early life factors that predispose for autoimmune and metabolic disorders.
Distinct roles of the orbitofrontal cortex, ventral striatum, and dopamine neurons in counterfactual thinking of decision outcomes
Authors: Yun Mengxi , Nejime Masafumi , Kawai Takashi , Kunimatsu Jun , Yamada Hiroshi , Kim HyungGoo R. , Matsumoto Masayuki 
Published: March 2023

AbstractIndividuals often assess past decisions by comparing what was gained with what would have been gained had they acted differently. Thoughts of past alternatives that counter what actually happened are called “counterfactuals”. Recent theories emphasize the role of the prefrontal cortex in processing counterfactual outcomes in decision-making, although how subcortical regions contribute to this process remains to be elucidated. Here we report a clear distinction among the roles of the orbitofrontal cortex, ventral striatum and midbrain dopamine neurons in processing counterfactual outcomes in monkeys. Our findings suggest that actually-gained and counterfactual outcome signals are both processed in the cortico-subcortical network constituted by these regions but in distinct manners, and integrated only in the orbitofrontal cortex in a way to compare these outcomes. This study extends the prefrontal theory of counterfactual thinking and provides key insights regarding how the prefrontal cortex cooperates with subcortical regions to make decisions using counterfactual information.TeaserCortical and subcortical systems both contribute to counterfactual thinking of decision outcomes but in distinct manners.
GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer
Authors: Yang Jung-In , Habowski Amber , Deschênes Astrid , Belleau Pascal , Ha Taehoon , Zhou Edward , Tzanavaris Chris , Boyd Jeff , Hollweg Christopher , Zhu Xinhua , Tuveson David , King Daniel A. 
Published: March 2023

AbstractBackgroundMolecular profiling of pancreatic adenocarcinoma (PDAC) demonstrates that genomic and transcriptomic features are associated with prognosis and chemosensitivity. We evaluated treatment outcomes by genetic alterations inTP53andGATA6to determine the prognostic and predictive impact of co-mutations, among patients with pancreatic cancer in New York’s largest healthcare system.MethodsRetrospective analysis was performed of patients at Northwell Health diagnosed with PDAC between 2014 to 2022. Surgical status was used to segregate patients into two groups: resected and unresected.TP53genotype andGATA6amplification status were compared for overall survival (OS) as measured from time of diagnosis. Additionally, patient survival by chemotherapy regimen administered was evaluated. The Kaplan–Meier method was used to determine overall survival (OS) and the Wilcoxon test was used to compare survival curves. Previously established and published patient-derived organoids [1] were used to investigateGATA6expression, genetic status, and chemotherapy drug sensitivity.ResultsTumor mutation status was available for 128 patients.TP53mutations were found in 104 patients (81.3%),GATA6amplifications were found in 18 patients (14.0%), and 16 (12.5%) patients had mutations in both genes. Patients withTP53mutations had worse OS compared to the wild-typeTP53population (n = 22) (median OS 22.4 months, 95% CI 12.5 to 41.1, vs. 44.3 months, 95% CI 24.0 to 82.0, HR 2.03, p = 0.038). Among patients with aTP53mutation, a survival advantage was observed in those who had aGATA6amplification (n=16) compared to those who did not (n=86) (median OS 25.5 months vs. 19.4 months, HR 1.82, p = 0.027). Among patients with unresected PDAC who wereTP53-mutant, the presence ofGATA6amplification (n=11) was associated with a substantial survival advantage compared toGATA6wildtype (n=52) (median OS 25.5 months, vs. 10.1 months, HR 0.35, p = 0.004). In theTP53mutation group, among 33 patients who received gemcitabine and nab-paclitaxel as the first-line palliative chemotherapy, patients withGATA6amplification (n = 8) had significantly improved survival compared to those withoutGATA6amplification (n = 25) (mean OS 23.1 months vs 9.4 months, HR 0.52, p = 0.017). However, pancreatic cancer organoids withTP53mutation (n=34) did not exhibit increased drug sensitivity to GnP withGATA6amplification.ConclusionsGenetic mutations inTP53were associated with shorter OS than wild-typeTP53. We found thatGATA6amplification appeared to attenuate poor prognosis observed inTP53-mutant patients regardless of type of standard chemotherapy received.