bluuebunny/crossref_metadata_2025 huggingface dataset:
Graphlet-based hyperbolic embeddings capture evolutionary dynamics in genetic networks
Authors: Velasco Daniel Tello , Windels Sam F. L. , Rotkevich Mikhail , Malod-Dognin Noël , Pržulj Nataša
Published: November 2023

Motivation

Spatial Analysis of Functional Enrichment (SAFE) is a popular tool for biologists to investigate the functional organisation of biological networks via highly intuitive 2D functional maps. To create these maps, SAFE uses Spring embedding to project a given network into a 2D space in which nodes connected in the network are near each other in space. However, many biological networks are scale-free, containing highly connected hub nodes. Because Spring embedding fails to separate hub nodes, it provides uninformative embeddings that resemble a “hairball”. In addition, Spring embedding only captures direct node connectivity in the network and does not consider higher-order node wiring patterns, which are best captured by graphlets, small, connected, non-isomorphic, induced subgraphs. The scale-free structure of biological networks is hypothesised to stem from an underlying low-dimensional hyperbolic geometry, which novel hyperbolic embedding methods try to uncover. These include coalescent embedding, which projects a network onto a 2D disk.

Results

To better capture the functional organisation of scale-free biological networks, whilst also going beyond simple direct connectivity patterns, we introduce Graphlet Coalescent (GraCoal) embedding, which embeds nodes nearby on a hyperbolic disk if they tend to touch a given graphlet together. We use GraCoal embedding to extend SAFE. Through SAFE-enabled enrichment analysis, we show that GraCoal embeddings captures the functional organisation of the genetic interaction networks of fruit fly, budding yeast, fission yeast andE. colibetter than graphlet-based Spring embedding. We show that depending on the underlying graphlet, GraCoal embeddings capture different topology-function relationships. We show that triangle-based GraCoal embedding captures functional redundancy between paralogous genes.

Availability

https://gitlab.bsc.es/dtello/graphlet-based-SAFE

Contact

natasha@bsc.as

Supplementary information

Supplementary data are available atBioinformaticsonline.
Frequent transitions from night-to-day activity after mass extinctions
Authors: Shafer Maxwell E.R. , Nichols Annika L.A. , Schier Alexander F. , Salzburger Walter
Published: November 2023

Why certain species survive large-scale extinction events while others do not is poorly understood. While the fossil record can provide insights into morphological adaptations that increase survival probabilities, it provides limited information regarding behavioural traits. Here we integrate behavioural data with phylogenetic comparative models to study the evolution of day-night activity patterns (nocturnality and diurnality) in bony fishes, which have persisted through the last four mass extinction events. Our findings in fish, combined with data across all other clades of vertebrates, provide four lines of evidence that nocturnality conferred an evolutionary advantage during mass extinctions, and that frequent nocturnal-to-diurnal transitions facilitated post-extinction diversification: First, phylogenetic reconstruction indicates that the last common ancestors of all vertebrates and of clades of bony vertebrates were nocturnal. Second, in the lineage of bony fishes, which contains over half of all vertebrate species, twice as many transitions between nocturnal and diurnal activity patterns have occurred compared to tetrapods. Third, within a specific ecological niche, different species exhibit distinct temporal activity patterns, suggesting widespread temporal niche partitioning. Fourth, independent bursts in night-to-day transitions followed large-scale extinction events during the last two geological eras in all four major bony vertebrate groups. These observations suggest that ancestral nocturnality and frequent transitions to diurnality helped vertebrates survive and diversify in the face of extinction events, such as those expected during the current “6th mass extinction” event caused by anthropogenic climate change.
Mining Mass Spectra for Peptide Facts
Authors: Zumer Jeremie , Lemieux Sebastien
Published: November 2023

The current mainstream software for peptide-centric tandem mass spectrometry data analysis can be categorized as either database-driven, which rely on a library of mass spectra to identify the peptide associated with novel query spectra, or de novo sequencing-based, which aim to find the entire peptide sequence by relying only on the query mass spectrum. While the first paradigm currently produces state-of-the-art results in peptide identification tasks, it does not inherently make use of information present in the query mass spectrum itself to refine identifications. Meanwhile, de novo approaches attempt to solve a complex problem in one go, without any search space constraints in the general case, leading to comparatively poor results. In this paper, we decompose the de novo problem into putatively easier subproblems, and we show that peptide identification rates of database-driven methods may be improved in terms of peptide identification rate by solving one such subsproblem without requiring a solution for the complete de novo task. We demonstrate this using a de novo peptide length prediction task as the chosen subproblem. As a first prototype, we show that a deep learning-based length prediction model increases peptide identification rates in the ProteomeTools dataset as part of an Pepid-based identification pipeline. Using the predicted information to better rank the candidates, we show that combining ideas from the two paradigms produces clear benefits in this setting. We propose that the next generation of peptide-centric tandem mass spectrometry identification methods should combine elements of these paradigms by mining facts “de novo; about the peptide represented in a spectrum, while simultaneously limiting the search space with a peptide candidates database.
Insights into Molecular Diversity within the FET Family: Unraveling Phase Separation of the N-Terminal Low Complexity Domain from RNA-Binding Protein EWS
Authors: Johnson Courtney N. , Sojitra Kandarp A. , Sohn Erich J. , Moreno-Romero Alma K. , Baudin Antoine , Xu Xiaoping , Mittal Jeetain , Libich David S.
Published: November 2023

The FET family proteins, which includes FUS, EWS, and TAF15, are RNA chaperones instrumental in processes such as mRNA maturation, transcriptional regulation, and the DNA damage response. These proteins have clinical significance: chromosomal rearrangements in FET proteins are implicated in Ewing family tumors and related sarcomas. Furthermore, point mutations in FUS and TAF15 are associated with neurodegenerative conditions like amyotrophic lateral sclerosis and frontotemporal lobar dementia. The fusion protein EWS::FLI1, the causative mutation of Ewing sarcoma, arises from a genomic translocation that fuses the low-complexity domain (LCD) of EWS (EWSLCD) with the DNA binding domain of the ETS transcription factor FLI1. This fusion not only alters transcriptional programs but also hinders native EWS functions like splicing. However, the precise function of the intrinsically disordered EWSLCDis still a topic of active investigation. Due to its flexible nature, EWSLCDcan form transient interactions with itself and other biomolecules, leading to the formation of biomolecular condensates through phase separation – a mechanism thought to be central to the oncogenicity of EWS::FLI1.

In our study, we used paramagnetic relaxation enhancement NMR, analytical ultracentrifugation, light microscopy, and all-atom molecular dynamics (MD) simulations to better understand the self-association and phase separation tendencies of EWSLCD. Our aim was to elucidate the molecular events that underpin EWSLCD-mediated biomolecular condensation. Our NMR data suggest tyrosine residues primarily drive the interactions vital for EWSLCDphase separation. Moreover, a higher density and proximity of tyrosine residues amplify the likelihood of condensate formation. Atomistic MD simulations and hydrodynamic experiments revealed that the tyrosine-rich N and C-termini tend to populate compact conformations, establishing unique contact networks, that are connected by a predominantly extended, tyrosine-depleted, linker region. MD simulations provide critical input on the relationship between contacts formed within a single molecule (intramolecular) and inside the condensed phase (intermolecular), and changes in protein conformations upon condensation. These results offer deeper insights into the condensate-forming abilities of the FET proteins and highlights unique structural and functional nuances between EWS and its counterparts, FUS and TAF15.
Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Authors: Ramirez Christel FA , Taranto Daniel , Ando-Kuri Masami , de Groot Marnix HP , Tsouri Efi , Huang Zhijie , de Groot Daniel , Kluin Roelof JC , Kloosterman Daan J , Verheij Joanne , Xu Jing , Vegna Serena , Akkari Leila
Published: November 2023

Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, we generated somatic HCC mouse models bearing clinically-relevant oncogenic driver combinations and subsequent pathway activation that faithfully recapitulated different human HCC subclasses. We identified cancer genetics’ specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. These models ranged from T cell-rich, more indolent HCC to aggressive tumors exhibiting heightened myeloid cell infiltration. Interestingly, MAPK-activated,NrasG12D-driven tumors presented a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME, contrasting withNrasG12VHCC, enriched in adaptive immune cells. Mechanistically, we identified aNrasG12Dcancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clowcells. GM-CSF blockade curbed the accumulation of this myeloid cell subset, reduced inflammation, induced cancer cell death and prolonged animal survival. Furthermore, the anti-tumor effect of GM-CSF neutralization synergized with the clinically-approved inhibition of the vascular endothelial growth factor (VEGF) to inhibit HCC outgrowth. These findings underscore the striking alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.
Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles
Authors: Xiong Hejian , Wilson Blake A. , Ge Xiaoqian , Gao Xiaofei , Cai Qi , Xu Xueqi , Bachoo Robert , Qin Zhenpeng
Published: November 2023

Glioblastoma (GBM) is the most complex and lethal adult primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that the tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.
Formation of hemiclonal reproduction and hybridogenesis inPelophylax waterfrogs studied with species-specific cytogenomic probes
Authors: Lukáš Choleva , Marie Doležálková-Kaštánková , Veronika Labajová , Alexandr Sember , Marie Altmanová , Karolína Lukšíková , Anna Chung Voleníková , Martina Dalíková , Petr Nguyen , Eleonora Pustovalova , Anna Fedorova , Dedukh Dmitrij
Published: November 2023

Meiosis is a conservative process in all sexual organisms which ensures fertility and is central for producing genetic diversity by recombination and random segregation of parental chromosomes. Yet unexplored mechanisms may disrupt it and cause ‘loss of sex’ followed by the emergence of clonal modes of reproduction. Interspecific hybridization is the primary trigger for this process, but mechanistic basis of the transition to asexuality remains still unknown for most vertebrate animals. To study these processes in water frogs, we performed reciprocal mating between two sexual species,Pelophylax ridibundusandP. lessonae, and produced vital F1 progeny (P. esculentus). The RepeatExplorer2 analysis of low-coverage genomic data of the two parental species identified theP. lessonae-specific minisatellite markerPlesSat01-48(44 bp), which hybridized to (peri)centromeric regions of two chromosome pairs inP. lessonae– the acrocentric chromosome 8 and the chromosome 10 (a carrier of nucleolar organizer region; NOR). Chromosomal mapping combining the novel hybridization probe with the previously designed marker forP. ridibundus-specific centromeric satellite DNA showed that theP. esculentusprogeny do not reproduce sexually. Instead, the F1 generation ofP. esculentusinstantly modified its gametogenesis and established asexual reproduction via hybridogenesis. Gametogenic modifications included premeiotic elimination of one of the parental genomes and clonal propagation of the remaining genome via endoreplication followed by standard meiotic division. The origin of DNA elimination and hybridogenesis in laboratory-produced hybrids supports a hypothesis thatP. esculentusarises recurrently in nature whenever parental species come into reproductive contact. Based on the observed pattern of DNA elimination in the F1 progeny we discuss the origin and evolution of population systems in water frogs and the applicability of a newly designed chromosomal probe for otherPelophylaxtaxa.
JointPRS: A Data-Adaptive Framework for Multi-Population Genetic Risk Prediction Incorporating Genetic Correlation
Authors: Xu Leqi , Zhou Geyu , Jiang Wei , Zhang Haoyu , Dong Yikai , Guan Leying , Zhao Hongyu
Published: November 2023

Genetic prediction accuracy for non-European populations is hindered by the limited sample size of Genome-wide association studies (GWAS) data in these populations. Additionally, it is challenging to tune model parameters with a small tuning dataset for methods that require tuning data, which is often the case for non-European samples. To address these challenges, we propose JointPRS, a novel, data-adaptive framework that simultaneously models multiple populations using GWAS summary statistics. JointPRS incorporates genetic correlation structures into the prediction framework, enabling accurate performance even without individual-level tuning data. Additionally, it uniquely employs a data-adaptive approach, providing a robust solution when only a small tuning dataset is available. Through extensive simulations and real data applications to 22 quantitative traits and four binary traits in five continental populations (European (EUR); East Asian (EAS); African (AFR); South Asian (SAS); and Admixed American (AMR)) evaluated using the UK Biobank (UKBB) and All of Us (AoU), we demonstrate that JointPRS outperforms six other state-of-art methods across three different data scenarios (no tuning data, tuning and testing data from the same cohort, and tuning and testing data from different cohorts) for most traits in non-European populations, while maintaining model simplicity and computational efficiency.
A comprehensive review of South Australia’s Great Artesian Basin spring and discharge wetlands biota
Authors: Beasley-Hall P. G. , Hedges B. A. , Cooper S. J. B. , Austin A. D. , Guzik M. T.
Published: November 2023

Context

The Great Artesian Basin (GAB) feeds thousands of springs in Australia’s arid centre, supporting relictual species not found elsewhere on Earth. Springs are considerably threatened by ongoing water abstraction by industry. Robust management plans are needed to prevent further extirpations of GAB taxa, but fundamental biodiversity knowledge is lacking.

Aims

We aimed to characterise major organismal groups in South Australian GAB springs and surrounding wetlands, their conservation and taxonomic status, and potential biodiversity hotspots and connectivity of spring ecosystems.

Methods

Focusing on South Australia as a case study, we conducted a comprehensive review of GAB spring biota based on the published scientific and grey literature.

Key results

Almost 500 taxa have been recorded from GAB springs, the majority being invertebrates. Community composition is highly heterogeneous among spring clusters and the true extent of spring biodiversity is far greater than currently known.

Conclusions

GAB springs have intrinsic value as refugia for both endemics and cosmopolitan taxa. GAB invertebrates are poorly conserved and largely lacking in taxonomic knowledge. We highlight several potential biodiversity hotspots that have been overlooked in the literature.

Implications

Fundamental biodiversity information on the GAB is crucial for decision-making in conservation management, for industry, and for Traditional Custodians.

Lay summary

The Great Artesian Basin (GAB) is Australia’s largest freshwater resource. Springs fed by the GAB support many species not found elsewhere on Earth, but conservation is hindered by a lack of fundamental knowledge about the plants, animals, and fungi reliant on these habitats. Using South Australia as a case study, we provide a comprehensive review of GAB biodiversity in that state.
Advancing Cell Therapies: Single-Cell Profiling, Generation, Expansion, and Gene Delivery in Rhesus Macaque Plasma B Cells
Authors: Cheng Rene Yu-Hong , Kreuser Shannon , Dahl Noelle , Honaker Yuchi , Soligalla Rupa , Lopez Christina , Rawlings David J. , James Richard G.
Published: November 2023

Engineered long lived plasma cells have the potential to be a new area of cell therapy. A key step in developing this cell therapy is testing in a model with an intact immune system similar to humans. To that end, we have developed methods to purify, expand, and differentiate non-human primate (NHP;rhesus macaque) B cellsex vivo. We consistently achieved 10-fold expansion of NHP B cells using a readily available commercial supplement. After only seven days in culture, large percentages of cells in NHP B cell cultures were differentiated. These cells expressed surface markers found in human antibody secreting cells (CD38 and CD138) and secreted immunoglobulin G. From single cell transcriptome analysis of NHP, we verified the presence of plasma cell markers commonly shared with humans, and have unearthed less recognized markers such asCD59and CD79A. In addition, we identified unique NHP plasma cell markers that are absent in humans including the immune checkpoint moleculeCD274(PD-L1, Programmed Death-Ligand 1). Furthermore, we found that MHC class I molecules were upregulated in NHP plasma cells, in contrast to the pattern observed in humans. Lastly, we also identified the serotypes (AAVD-J) and established the conditions for efficient transduction of NHP B cells with AAV vectors, achieving an editing rate of approximately 60%. We envision that this work will accelerate proof-of-conceptin vivostudies using engineered protein-secreting B cells in the NHP model.
Cold, but not for long enough: first insights into the tolerance to subzero temperatures of the invasive amphipodDikerogammarus villosus
Authors: Mucciolo Serena , Podwysocki Krzysztof , Desiderato Andrea
Published: November 2023

Dikerogammarus villosusis an invasive Ponto-Caspian amphipod, known to have colonized most of the major European freshwater bodies in the last few decades. Several studies assessing its tolerance related to higher temperatures have been performed; however, no records are present about its response to subzero temperatures. Therefore, in this study, we wanted to experimentally assess for the first time the tolerance ofD. villosusto temperatures below 0°C. The animals were exposed to 0°C, -8°C, and room temperature for 2 and 24 hours, tracking their possible movements during the ice melting. Only long exposures at -8°C appeared to be fatal. These results provide new insights for more accurate predictive models regarding the future expansion of this invader.
Deciphering histone mark-specific fine-scale chromatin organization at high resolution with Micro-C-ChIP
Authors: Metelova Mariia , Krietenstein Nils
Published: November 2023

The regulation of cell-type-specific transcription programs is a highly controlled and complex process that needs to be fully understood. The gene regulation is often influenced by distal regulatory elements and their interactions with promoters in three-dimensional space. Although proximity ligation techniques like Hi-C have revolutionized our understanding of genome organization, the genomic resolution for many of these methods is limited by both experimental and financial constraints. Here, we introduce Micro-C-ChIP to provide extremely high-resolution views of chromosome architecture at genomic loci marked by specific covalent histone modifications. This is achieved by chromatin immunoprecipitation of specific chromatin states to target chromosome folding libraries to focus on chromatin domains (regulatory elements, heterochromatin, etc.) of interest, yielding extremely high sequencing depth at these loci. We applied Micro-C-ChIP to mouse embryonic stem cells (mESC) and hTERT-immortalized human retinal epithelial cells (hTERT-RPE1), revealing architectural features of genome organization with comparable or higher resolution than Micro-C datasets sequenced with higher depth. We discovered extensive promoter-promoter networks in both cell types and characterized the specific architecture of bivalently marked promoters in mESC. Together, these data highlight Micro-C-ChIP as a cost-effective approach to exploring the landscape of genome folding at extraordinarily high resolution.
Loss of Nkd1 is epistatic to loss of Axin2 in regulating Wnt signaling
Authors: Bell Ian , Khan Haider , Stutt Nathan , Horn Matthew , Hydzik Teesha , Lum Whitney , Rea Victoria , Clapham Emma , Hoeg Lisa , Van Raay Terence J.
Published: November 2023

Wnt signaling is a crucial developmental pathway involved in early development as well as stem cell maintenance in adults and its misregulation leads to numerous diseases. Thus, understanding the regulation of this pathway becomes vitally important. Axin2 and Nkd1 are widely utilized negative feedback regulators in Wnt signaling where Axin2 functions to destabilize cytoplasmic β-catenin, and Nkd1 functions to inhibit the nuclear localization of β-catenin. Here, we set out to further understand how Axin2 and Nkd1 regulate Wnt signaling by creatingaxin2-/-,nkd1-/-single mutants andaxin2-/-;nkd1-/-double mutant zebrafish using sgRNA/Cas9. All three Wnt regulator mutants were viable and had impaired heart looping, neuromast migration defects, and behavior abnormalities in common, but there were no signs of synergy in theaxin2-/-;nkd1-/-double mutants. Further, Wnt target gene expression by qRT-PCR, and RNA-seq analysis and protein expression by mass spectrometry demonstrated that the doubleaxin2-/-;nkd1-/-mutant resembled thenkd1-/-phenotype demonstrating that Axin2 functions upstream of Nkd1 and that loss of Nkd1 is epistatic to the loss of Axin2. In support of this, the data further demonstrates that Axin2 uniquely alters the properties of β-catenin-dependent transcription having novel readouts of Wnt activity compared tonkd1-/-or theaxin2-/-;nkd1-/-double mutant. We also tested the sensitivity of the Wnt regulator mutants to exacerbated Wnt signaling, where the single mutants displayed characteristic heightened Wnt sensitivity, resulting in an eyeless phenotype. Surprisingly, this phenotype was rescued in the double mutant, where we speculate that cross-talk between Wnt/β-catenin and Wnt/Planar Cell Polarity pathways could lead to altered Wnt signaling in some scenarios. Collectively, the data emphasizes both the commonality and the complexity in the feedback regulation of Wnt signaling.
Pervasive aggregation and depletion of host and viral proteins in response to cysteine-reactive electrophilic compounds
Authors: Julio Ashley R. , Shikwana Flowreen , Truong Cindy , Burton Nikolas R. , Dominguez Emil , Turmon Alexandra C. , Cao Jian , Backus Keriann
Published: November 2023

Protein homeostasis is tightly regulated, with damaged or misfolded proteins quickly eliminated by the proteasome and autophagosome pathways. By co-opting these processes, targeted protein degradation technologies enable pharmacological manipulation of protein abundance. Recently, cysteine-reactive molecules have been added to the degrader toolbox, which offer the benefit of unlocking the therapeutic potential of ‘undruggable’ protein targets. The proteome-wide impact of these molecules remains to be fully understood and given the general reactivity of many classes of cysteine-reactive electrophiles, on- and off-target effects are likely. Using chemical proteomics, we identified a cysteine-reactive small molecule degrader of the SARS-CoV-2 non- structural protein 14 (nsp14), which effects degradation through direct modification of cysteines in both nsp14 and in host chaperones together with activation of global cell stress response pathways. We find that cysteine-reactive electrophiles increase global protein ubiquitylation, trigger proteasome activation, and result in widespread aggregation and depletion of host proteins, including components of the nuclear pore complex. Formation of stress granules was also found to be a remarkably ubiquitous cellular response to nearly all cysteine-reactive compounds and degraders. Collectively, our study sheds light on complexities of covalent target protein degradation and highlights untapped opportunities in manipulating and characterizing proteostasis processes via deciphering the cysteine-centric regulation of stress response pathways.
Patient phenotypes and their relation to TNFα signaling and immune cell composition in critical illness and autoimmune disease
Authors: Krishna Vinod , Banie Homayon , Conceição-Neto Nádia , Murata Yoshihiko , Verbrugge Inge , Trifonov Vladimir , Martinez Roxana , Murali Vasumathy , Lee Yu-Chi , May Richard D , Nájera Isabel , Fowler Andrew , Li Chris Ka Fai
Published: November 2023

Rationale

TNFα inhibitors have shown promise in reducing mortality in hospitalized COVID-19 patients; one hypothesis explaining the limited clinical efficacy is patient heterogeneity in the TNFα pathway.

Methods

We evaluated the effect of TNFα inhibitors in a mouse model of LPS-induced acute lung injury. Using machine learning we attempted predictive enrichment of TNFα signaling in patients with either ARDS or sepsis. We examined biological factors that drive heterogeneity in host responses to critical infection and their relation to clinical outcomes.

Results

In mice, LPS induced TNFα–dependent neutrophilia, alveolar permeability and endothelial injury. In humans, TNFα pathway activation was significantly increased in peripheral blood of patients with critical illnesses and associated with the presence of mature neutrophils across critical illnesses and several autoimmune conditions. Machine learning using a gene signature separated patients into 5 phenotypes; one was a hyper-inflammatory, interferon-associated phenotype enriched for increased TNFα pathway activation and conserved across critical illnesses and autoimmune diseases. Cell subset profiles segregated severely ill patients into neutrophil-subset-dependent groups that were enriched for disease severity, demonstrating the importance of neutrophils in the immune response in critical illness.

Conclusions

TNFα signaling and mature neutrophils are associated with a hyper-inflammatory phenotype of patients, shared across critical illness and autoimmune disease. This phenotyping provides a personalized medicine hypothesis to test anti-TNFα therapy in severe respiratory illness.

Graphical abstract
From sequence to molecules: Feature sequence-based genome mining uncovers the hidden diversity of bacterial siderophore pathways
Authors: Gu Shaohua , Shao Yuanzhe , Rehm Karoline , Bigler Laurent , Zhang Di , He Ruolin , Xu Ruichen , Shao Jiqi , Jousset Alexandre , Friman Ville-Petri , Bian Xiaoying , Wei Zhong , Kümmerli Rolf , Li Zhiyuan
Published: November 2023

Microbial secondary metabolites are a rich source for pharmaceutical discoveries and play crucial ecological functions. While tools exist to identify secondary metabolite clusters in genomes, precise sequence-to-function mapping remains challenging because neither function nor substrate specificity of biosynthesis enzymes can accurately be predicted. Here we developed a knowledge-guided bioinformatic pipeline to solve these issues. We analyzed 1928 genomes ofPseudomonasbacteria and focused on iron-scavenging pyoverdines as model metabolites. Our pipeline predicted 188 chemically different pyoverdines with nearly 100% structural accuracy and the presence of 94 distinct receptor groups required for the uptake of iron-loaded pyoverdines. Our pipeline unveils an enormous yet overlooked diversity of siderophores (151 new structures) and receptors (91 new groups). Our approach, combining feature sequence with phylogenetic approaches, is extendable to other metabolites and microbial genera, and thus emerges as powerful tool to reconstruct bacterial secondary metabolism pathways based on sequence data.

Abstract Figure
Understanding the dynamics of complexin-situenzyme-catalyzed reactions undergoing mechanical stress
Authors: Tikader Baishakhi , Kar Sandip
Published: November 2023

Understanding the diversity in the enzymatic mechanism have utmost importance as it can temporally control the catalytic efficiency. Recent literature suggests that by influencing mechanical properties of hybrid materials, the catalytic efficiency of the enzymatic reactions can be altered significantly. Here, taking a computational and experimental approach, we have dig out the fate of the kinetics of enzyme reaction systems exhibiting relatively complex mechanism than usual Michaelis Menten kinetics involving multiple substrate/enzyme/enzyme-substrate complex. We have developed a numerical recipe improvising stochastic reaction-diffusion approach to explore the role of mechanical stress like compression-decompression cycle (C-D) on modulating the output of enzymatic reaction. The proposed methodology can be used as a theoretical tool to understand how to enhance the catalytic activity and setup appropriate reaction conditions by efficiently using the catalytic cycles. Hence, our methodology will be crucial to identify the most effective strategy to efficiently convert substrate into product in this type of mechanoresponsive materials, which will enable future development of cost-effective biomaterials. In future, the insights gained from this work may find enormous application in drug delivery, tissue engineering, bio-sensing and bio-catalysis.
Breast cancer risk SNPs converge on estrogen receptor binding sites commonly shared between breast tumors to locally alter estrogen signalling output
Authors: Joosten Stacey EP. , Gregoricchio Sebastian , Stelloo Suzan , Yapıcı Elif , Huang Chia-Chi Flora , Collier Maria Donaldson , Morova Tunc , Altintas Berkay , Kim Yongsoo , Canisius Sander , Korkmaz Gozde , Lack Nathan , Vermeulen Michiel , Linn Sabine C. , Zwart Wilbert
Published: November 2023

Estrogen Receptor alpha (ERα) is the main driver and prime drug target in luminal breast. ERα chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ERα chromatin action, along with its biological implications.

Here, we use a large set of ERα ChIP-seq data from 70 ERα+ breast cancers to explore inter-patient heterogeneity in ERα DNA binding, to reveal a striking inter-tumor heterogeneity of ERα action. Interestingly, commonly-shared ERα sites showed the highest estrogen-driven enhancer activity and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ERα-occupied enhancers were enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ERα and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ERα-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ERα landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
Attenuating amyloid-beta pathology in mice with in situ programmed astrocytes
Authors: Zhang Lun , Lu Shuai , Jia Ying-bo , Hou Sheng-jie , Zhu Jie , Liu Xiao-ge , Sun Xiao-ying , Huang Ya-ru , Zhao Yu-xuan , Ren Hongan , Liu Chun-yu , Cui Fang , Liu Dong-qun , Du Xiao-yu , Niu Xiao-yun , Li Ling-jie , Wang Ke , Liang Shi-yu , Yang Jin-ju , Ji Shao-yang , Sun Le , Zhou Wei-wei , Xie Xi-xiu , Yu Xiao-lin , Wang Xiaoqun , Liu Rui-tian
Published: November 2023

Astrocytes are abundant cells in the central nervous system that provide trophic support for neurons and clear detrimental factors, such as Aβ oligomers (AβOs). However, in the brains of Alzheimer’s disease (AD) patients, astrocytes lose these physiological functions. Here, we genetically engineered astrocytes with an anti-AβO chimeric antigen receptor (CAR), constructed by replacing the antigen-binding domain of MerTK with an AβO-specific single-chain variable fragment, to direct their phagocytic activity against AβOs. CAR-engineered astrocytes (CAR-As) showed significantly enhanced phagocytosis of AβOs due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased release of pro-inflammatory cytokines due to inhibition of the NF-κB and cytokine receptor signalling pathways. Consistently, in situ CAR-As markedly ameliorated the cognitive deficits of APP/PS1 transgenic mice possibly by clearing AβOs and creating a non-inflammatory microenvironment for neuronal survival and the restoration of microglia to a healthy phenotype. Our present study is the first to introduce a CAR-A-based therapy, validate its feasibility and effectiveness, and highlight its potential application for the treatment of AD and other brain disorders.
Enabling population protein dynamics through Bayesian modeling
Authors: Lehmann Sylvain , Vialaret Jérôme , Gabelle Audrey , Bauchet Luc , Villemin Jean-Philippe , Hirtz Christophe , Colinge Jacques
Published: November 2023

The knowledge of protein dynamics or turnover in patients provides invaluable information related to certain diseases, drug efficacy, or biological processes. A great corpus of experimental and computational methods has been developed, including by us, in the case of human patients followedin vivo. Moving one step further, we propose here a new modeling approach to capture the highly relevant notion of population protein dynamics. Using two data sets, we show that models inspired by population pharmacokinetics can accurately capture protein turnover within a cohort of individuals, even in presence of substantial inter-individual variability. Such models pave the way for comparative studies searching for altered dynamics or biomarkers in diseases.
Moderate Diversity of activation thresholds promotes cooperation in the Threshold Public Good Games
Authors: Boza Gergely , Számadó Szabolcs
Published: November 2023

Societies face various collective actions which posits social dilemmas, in which a certain number of group members must act cooperatively in order to reach a collective goal. Such social dilemmas are often modelled as Threshold Public Good Games, in which the collective goal is reached successfully if the number of cooperative decisions reaches a threshold. Because cooperation is often a costly act, to coordinate such actions actors can attempt to communicate, to ensure that cooperative decisions are only made once the chances of reaching the goal, thus meeting the threshold is secured. Here we focus on the distribution of activation thresholds in societies, which captures the dynamics of peer pressure and the interaction between different levels of selfish and cooperative behaviours. Here we show that moderate diversity of activation thresholds favours cooperation under wide range of parameters.
POU5F1Bis a human-restricted ROCK inhibitor-sensitive oncoprotein that restructures membrane nanodomains to increase cell adhesion
Authors: Simó-Riudalbas Laia , Offner Sandra , Abrami Laurence , Unterauer Eduard M , Duc Julien , Planet Evarist , Jungmann Ralf , van der Goot Gisou , Trono Didier
Published: November 2023

Evolution confers new species with distinctive biological features, which can translate in purely mechanistic speciation or in novel phenotypic traits.POU5F1Barose by retrotransposition ofPOU5F1/OCT4in the last common ancestor of modern Hominoidae. Its human product is endowed with oncogenic properties, notably promoting gastrointestinal cancer growth and metastasis. Here, we reveal that the oncogenic action of POU5F1B requires ubiquitination of lysine residues found only in the human protein. This post-translational modification is essential for POU5F1B to localize to the cytoplasm and become acylated by the DHHC17 palmitoyltransferase. This leads to POU5F1B association with detergent-resistant membrane subdomains, where it triggers the accumulation of integrins and signaling molecules, and to a stimulation of cell focal adhesion. Finally, we determined that POU5F1B stability is critically dependent on ROCK, a crucial regulator of cytoskeletal dynamics and cell motility.
AssessingArthrospira platensisGrowth Rates in three Jeju Local Medium, Including Jeju Magma Seawater
Authors: Jang Huey
Published: November 2023

Jeju Magma Seawater (JMS), naturally formed beneath the bedrocks of Jeju island, consists of high micronutrient concentrations such as Zinc (Z, 0.019 mg/L), Iron (F, 0.015 mg/L), Manganese (M, 0.008 mg/L), Vanadium (V, 0.015 mg/L), Selenium (S, 0.013 mg/L) and Germanium (G, 0.002 mg/L). Despite the extensive research conducted upon the conventional Zarrouk medium used in Arthrospira platensis culture industry, the commercial potential of JMS on the growth of Arthrospira platensis has been poorly investigated. With respect to growth rate and cost efficiency, the purpose of the study is to discern and compare the growth of Arthrospira platensis in JMS with other accessible mediums on Jeju island. This study investigated the effects of three different growth mediums: Jeju Magma Seawater (JMS), Jeju seawater (JS), and Artificial seawater (AS) to assess their impact on the growth of Arthrospira platensis measured by biomass concentration (g L-1). The ANOVA results showed that JMS exhibited higher growth levels compared to JS ((p = 0.001) < 0.05) and AS (p=0.001). The results of the t-test revealed a statistically significant disparity between mean mass growth in JMS micronutrient-present environment and JMS micronutrient-absent environment (T = 7.94, p (= 4.57e-05) < 0.05). However, based on the growth rate over this experiment, it is estimated that the cost of cultivation required to obtain the same amount of mass is more than seven times higher in JMS compared to conventional Zarrouk medium. Therefore, it is believed that there are limitations to immediate commercialization.
Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer
Authors: Veghini Lisa , Pasini Davide , Delfino Pietro , Fang Rui , Filippini Dea , Neander Christian , Vicentini Caterina , Fiorini Elena , Lupo Francesca , D’Agosto Sabrina L. , Carbone Carmine , Bevere Michele , Behrens Diana , Luchini Claudio , Lawlor Rita T. , Scarpa Aldo , Biffi Giulia , Cheung Phyllis F. , Siveke Jens T. , Corbo Vincenzo
Published: November 2023

Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping out fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in the definition of PDAC CAF phenotypes. We identify the myCAF transcriptional phenotype as uniquely dependent on proficient MAPK signalling. In addition, CAFs displaying elevated MAPK activity are specifically anchored to basal-like/squamous PDAC cells and define tumour subdomains with reduced frequency of CD8+ T cells. We characterize the single-cell transcriptome of mouse PDAC tumours in response to MAPK inhibition and identify gene expression signatures of MAPKhighCAFs, which suggest immunoregulatory functions. Accordingly, a gene expression signature of MAPKhighCAFs correlates with poor prognosis in several human cancer conditions, including PDAC, and with reduced response to immune checkpoint inhibition in immune-reactive solid tumours. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a new strategy for targeting of myofibroblastic CAFsin vivo.
A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies
Authors: Li Xihao , Chen Han , Selvaraj Margaret Sunitha , Van Buren Eric , Zhou Hufeng , Wang Yuxuan , Sun Ryan , McCaw Zachary R. , Yu Zhi , Arnett Donna K. , Bis Joshua C. , Blangero John , Boerwinkle Eric , Bowden Donald W. , Brody Jennifer A. , Cade Brian E. , Carson April P. , Carlson Jenna C. , Chami Nathalie , Chen Yii-Der Ida , Curran Joanne E. , de Vries Paul S. , Fornage Myriam , Franceschini Nora , Freedman Barry I. , Gu Charles , Heard-Costa Nancy L. , He Jiang , Hou Lifang , Hung Yi-Jen , Irvin Marguerite R. , Kaplan Robert C. , Kardia Sharon L.R. , Kelly Tanika , Konigsberg Iain , Kooperberg Charles , Kral Brian G. , Li Changwei , Loos Ruth J.F. , Mahaney Michael C. , Martin Lisa W. , Mathias Rasika A. , Minster Ryan L. , Mitchell Braxton D. , Montasser May E. , Morrison Alanna C. , Palmer Nicholette D. , Peyser Patricia A. , Psaty Bruce M. , Raffield Laura M. , Redline Susan , Reiner Alexander P. , Rich Stephen S. , Sitlani Colleen M. , Smith Jennifer A. , Taylor Kent D. , Tiwari Hemant , Vasan Ramachandran S. , Wang Zhe , Yanek Lisa R. , Yu Bing ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Rice Kenneth M. , Rotter Jerome I. , Peloso Gina M. , Natarajan Pradeep , Li Zilin , Liu Zhonghua , Lin Xihong
Published: November 2023

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer ofNIPSNAP3Aand an intergenic region on chromosome 1.
Hidradenitis Suppurativa Patients Exhibit a Distinctive and Highly Individualized Skin Virome
Authors: Jansen Daan , Bens Lene , Wagemans Jeroen , Green Sabrina I. , Hillary Tom , Vanhoutvin Tine , Laethem An Van , Vermeire Séverine , Sabino João , Lavigne Rob , Matthijnssens Jelle
Published: November 2023

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by recurring painful skin lesions. Despite ongoing research, the exact cause underlying the initiation and progression of disease remains unknown. While prior research has linked the skin microbiota to HS pathology, the role of viruses has remained unexplored. To investigate the skin virota, metagenomic sequencing of viral particles was performed on 144 skin samples from 57 individuals (39 HS patients and 18 controls). It was found that the virome is not only linked to BMI, but also to the presence and severity of HS, marking a diverging viral profile in the progression of disease. Despite no differences in alpha-diversity, HS patients exhibited a significantly higher beta-diversity compared to healthy controls, indicating a more personalized virome with reduced viral sharing among patients. We identified distinct groups of commonly shared phages, referred to as the core phageome, associated with either healthy controls or patients. Healthy controls displayed a higher abundance of two coreCaudoviricetesphages predicted to infectCorynebacteriumandStaphylococcus, comprising normal skin commensals. In contrast, HS patients carried previously uncharacterized phages that were more prevalent in advanced stages of the disease, which likely infectPeptoniphilusandFinegoldia, known HS-associated pathogens. Interestingly, genes involved in superinfection exclusion and antibiotic resistance could be found in phage genomes of healthy controls and HS patients, respectively. In conclusion, we report the existence of distinct core phages that may have clinical relevance in HS pathology by influencing skin bacteria through mechanisms such as superinfection exclusion and antibiotic resistance.