bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemokine Receptor 1 and its associated immune pathway are downregulated in SF3B1MT blood and non-blood cancers
Authors: Dastpak Mahtab , Kim Hyunmin , Paraggio Christina L. , Leonard Claudia E. , Yin Shanye , Chi Binkai , Nassar Kelsey W. , Rowe R. Grant , Hou Zhonggang , Zhang Jiuchun , Cohn Erin F. , Yang Na , Marion William , Zhang Yosra , Daley George Q. , Reed Robin 
Published: April 2022

AbstractMutation of the essential splicing factor SF3B1 is primarily associated with hematological cancers but also occurs in solid tumors. We edited the most common mutation, K700E, into human embryonic stem (ES) cells to determine the effects of this mutation alone in an undifferentiated/non-cancer background. Unexpectedly, >20% of the significantly upregulated genes in the SF3B1K700E ES lines have immune functions. Thus, SF3B1 may have an additional role in proper expression of immune genes in appropriate cell types. In striking contrast, we found that published RNA-seq data from SF3B1 blood (MDS, CLL, AML) and non-blood (BRCA, UVM) cancers exhibited the opposite, downregulation of a multitude of immune pathways with 7 of the pathways shared among all 5 of the SF3B1 cancers. One of these pathways, “leukocyte migration”, is the 1st reported pathway shared among all splicing factor cancers, including the 5 SF3B1 cancers and MDS associated with U2AF1, SRSF2 and ZRSR2. Importantly, we identified CCR1, which is in the leukocyte migration pathway as the only shared downregulated gene in the 5 SF3B1 cancers and in U2AF1MT MDS. We conclude that downregulation of CCR1 and its associated immune pathway may play a key role in pathogenesis of these splicing factor cancers and are thus potential therapeutic targets.
PanGu Drug Model: Learn a Molecule Like a Human
Authors: Lin Xinyuan , Xu Chi , Xiong Zhaoping , Zhang Xinfeng , Ni Ningxi , Ni Bolin , Chang Jianlong , Pan Ruiqing , Wang Zidong , Yu Fan , Tian Qi , Jiang Hualiang , Zheng Mingyue , Qiao Nan 
Published: April 2022

AbstractRecent achievements in large-scale pre-trained models like GPT-3 and PanGu-α showed amazing performances in many downstream tasks, which makes AI friendlier toward industrial users. Deep learning has been recognized as the most promising technology for pharmaceuticals, a powerful molecule pre-trained model could save researchers tons of time. In chemistry classes, the students learn two molecule representations, the molecular formula and the structure formula, and learn to translate them from one way to the other. Inspired by this, we developed a novel deep learning architecture using a graph-to-sequence asymmetric conditional variational autoencoders, called PanGu Drug Model, which can appropriately characterize the molecule from both representations and improve the performance of downstream drug discovery tasks. After pretrained with 1.7 billion small molecules, our proposed model achieved the state-of-the-art results in 20 drug discovery tasks, such as molecule property prediction (predict ADMET properties, compound-target interactions, drug-drug interactions and chemical reaction productivity), molecule generation and molecule optimization. A new drug screening library of 100 million drug-like small molecules with 99.68% novelty was generated by PanGu molecule generator, which could efficiently produce novel compounds with similar physiochemical properties to given distribution, this library could be used to supplement existing compound databases. In addition, PanGu molecule optimizer could optimize the chemical structures of starting molecule with improved molecular property of interest. An automatic multi-objective optimization web application implemented by PanGu Drug Model is available at http://www.pangu-drug.com/.
Quantitative crosslinking and mass spectrometry determine binding interfaces and affinities mediating kinetochore stabilization
Authors: Hagemann Goetz , Solis-Mezarino Victor , Singh Sylvia , Potocnjak Mia , Kumar Chandni , Herzog Franz 
Published: April 2022

AbstractCrosslinking and mass spectrometry (XLMS) are used in integrative structural biology to acquire spatial restraints. We found a dependency between crosslink distances and intensities and developed a quantitative workflow to simultaneously estimate apparent dissociation constants (KD) of contacts within multi-subunit complexes and to aid interface prediction. Quantitative XLMS was applied to study the assembly of the macromolecular kinetochore complex, which is built on centromeric chromatin and establishes a stable link to spindle microtubules in order to segregate chromosomes during cell division. Inter-protein crosslink intensities facilitated determination of phosphorylation-induced binding interfaces and affinity changes. Phosphorylation of outer and inner kinetochore proteins mediated cooperative kinetochore stabilization and decreased the KD values of its interactions to the centromeric nucleosome by ~200-fold, which was essential for cell viability. This work demonstrates the potential of quantitative XLMS for characterizing mechanistic effects on protein assemblies upon post-translational modifications or cofactor interaction and for biological modeling.
A chromosome-length assembly of the Hawaiian Monk seal (Neomonarchus schauinslandi) confirms genomic stability in the Pinnipeds and a prolonged history of “genetic purging”
Authors: Mohr David W. , Gaughran Stephen J. , Paschall Justin , Naguib Ahmed , Chun Pang Andy Wing , Dudchenko Olga , Aiden Erez Lieberman , Church Deanna M. , Scott Alan F. 
Published: April 2022

AbstractThe Hawaiian monk seal (HMS) is the single extant species of tropical earless seals of the genus Neomonachus. The species survived a severe bottleneck in the late 19th century and experienced subsequent population declines until becoming the subject of a NOAA-led species recovery effort beginning in 1976 when the population was fewer than 1000 animals. Like other recovering species, the Hawaiian monk seal has been reported to have reduced genetic heterogeneity due to the bottleneck and subsequent inbreeding. Here we report a chromosomal reference assembly for a male animal produced using a variety of methods including linked-read sequencing, Hi-C contiguity mapping, optical genome mapping, and nanopore long read sequencing. The final assembly consisted of 16 autosomes, an X and portions of the Y chromosomes. We compared variants in the reference animals to nine other HMS and to the human reference NA12878 confirming a low level of variation within the species and one-eighth that of the human reference. A lack of variation in several MHC genes was documented suggesting that this species may be at risk for infectious disease. Lastly, the HMS chromosomal assembly confirmed significant synteny with other pinnipeds. This reference should be a useful tool for long-term management of HMS and evolutionary studies of other carnivorans.
Frontal Cortex Gates Distractor Stimulus Encoding in Sensory Cortex
Authors: Zhang Zhaoran , Zagha Edward 
Published: April 2022

AbstractFrontal cortex suppresses behavioral responses to distractor stimuli. One possible mechanism by which this occurs is by modulating sensory responses in sensory cortex. However, it is currently unknown how frontal cortex modulations of sensory cortex contribute to distractor response suppression. We trained mice to respond to target stimuli in one whisker field and ignore distractor stimuli in the opposite whisker field. During expert task performance, optogenetic inhibition of frontal cortex increased behavioral responses to distractor stimuli. During expert task performance, within sensory cortex we observed expanded propagation of target stimulus responses and contracted propagation of distractor stimulus responses. In contrast to current models of frontal cortex function, frontal cortex did not substantially modulate the response amplitude of preferred stimuli. Rather, frontal cortex specifically suppressed the propagation of distractor stimulus responses, thereby preventing target-preferring neurons from being activated by distractor stimuli. Single unit analyses revealed that wMC decorrelates target and distractor stimulus encoding in target-preferring S1 neurons, which likely improves selective target stimulus detection by downstream readers. Moreover, we observed proactive top-down modulation from frontal to sensory cortex, through the preferential activation of GABAergic neurons. Overall, our study provides important mechanistic details about how frontal cortex gates sensory propagation in sensory cortex to prevent behavioral responses to distractor stimuli.HighlightsPairing of frontal cortex optogenetic inhibition with sensory cortex recordings during a target-distractor Go/NoGo task.During expert task performance, we observed target stimulus response expansion and distractor stimulus response contraction.Optogenetic inhibition of frontal cortex increased false alarm rates and selectively increased the propagation of distractor evoked responses into target-aligned sensory cortex.Even before stimulus onset, frontal cortex preferentially drives GABAergic neurons in distractor-aligned sensory cortex.
The genome sequence of the scarce swallowtail, Iphiclides podalirius
Authors: Mackintosh Alexander , Laetsch Dominik R. , Baril Tobias , Ebdon Sam , Jay Paul , Vila Roger , Hayward Alex , Lohse Konrad 
Published: April 2022

AbstractThe scarce swallowtail, Iphiclides podalirius (Linnaeus, 1758), is a species of butterfly in the family Papilionidae. Here we present a chromosome-level genome assembly for I. podalirius as well as gene and transposable element annotations. We estimate heterozygosity within different partitions of the genome and find a negative correlation between chromosome length and heterozygosity at fourfold-degenerate sites. This high quality genome assembly, the first for any species in the tribe Leptocircini, will be a valuable resource for population genomics in the genus Iphiclides and comparative genomics more generally.
CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis
Authors: Zhang Shengbo , Rautela Jai , Bediaga Naiara G , Kolesnik Tatiana B , You Yue , Dagley Laura F , Bedo Justin , Wang Hanqing , Sun Li , Sutherland Robyn , Surgenor Elliot , Iannarella Nadia , Allan Rhys , Souza-Fonseca-Guimaraes Fernando , Xie Yi , Wang Qike , Zhang Yuxia , Xu Yuekang , Nutt Stephen L , Lew Andrew M , Huntington Nicholas D , Nicholson Sandra E , Chopin Michaël , Zhan Yifan 
Published: April 2022

AbstractThe cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the ability to differentiate macrophages (MØs) with opposing functions, namely proinflammatory M1-like and immunosuppressive M2-like. Despite the importance and opposing functional outcomes of these processes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here we show that GM-CSF induced MØs polarisation resulted in the expression of the Cytokine-inducible SH2-containing protein (CIS), and that CIS deficiency diverted differentiation of monocytes into immunosuppressive M2-like MØs expression. CIS deficiency resulted in the hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting the downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss and gain of function approaches highlighted IRF8 as a critical instructor of the M1-like polarisation program. In vivo, CIS deficiency led to skewing to M2-like macrophages, which induced strong Th2 immune responses characterised by the development of severe experimental asthma. Collectively, we reveal a CIS-censored mechanism interpreting the opposing actions of GM-CSF in MØ differentiation and uncovering its role in controlling allergic inflammation.
Integrated single-cell (phospho-)protein and RNA detection uncovers phenotypic characteristics of human antibody secreting cells
Authors: van Buijtenen Erik , Janssen Wout , Vink Paul , Habraken Maurice J.M. , Wingens Laura J. A. , van Elsas Andrea , Huck Wilhelm T.S. , van Buggenum Jessie A.G.L. , van Eenennaam Hans 
Published: April 2022

AbstractAntibody-secreting cells (ASCs) secrete IgM, IgA, or IgG antibodies and are key components of humoral immunity; however, little is known about unique characteristics of the Ig-classes due to limited availability of material and challenges to quantify many intracellular molecular modalities at a single-cell resolution. We combined a method to in vitro differentiate peripheral B-cells into ASCs with integrated multi-omic single-cell sequencing technologies to quantify subclass-specific hallmark surface markers, transcriptional profiles and signaling transduction pathway components. Our approach detected differential expression of plasmablast and plasma cell markers, homing receptors and IL-2, IL-6, JAK/STAT and mTOR signaling activity across Ig-subclasses. Taken together, our integrated multi-omics approach allowed high-resolution phenotypic characterization of single cells in a complex sample of in vitro differentiated human ASCs. Our strategy is expected to further our understanding of human ASCs in healthy and diseased samples and provide a valuable tool to identify novel biomarkers and potential drug targets.TeaserIntegrated single-cell analysis allows tri-modal phenotypic analysis of in-vitro generated human antibody-secreting cells.
Predicting catchment suitability for biodiversity at national scales
Authors: Dobson Barnaby , Barry Saoirse , Maes-Prior Robin , Mijic Ana , Woodward Guy , Pearse William D. 
Published: April 2022

AbstractBiomonitoring of water quality and catchment management are often disconnected, due to mismatching scales. Great effort and money is spent each year on routine reach-scale surveying across many sites, particularly in the UK, and typically with a focus on pre-defined indicators of organic pollution to compare observed vs expected subsets of common macroinvertebrate indicator species. Threatened species are often ignored due to their rarity as are many invasive species, which are seen as undesirable even though they are increasingly common in freshwaters, especially in urban ecosystems. However, these taxa are monitored separately for reasons related to biodiversity concerns rather than for gauging water quality. Repurposing such monitoring data could therefore provide important new biomonitoring tools that can help catchment managers to directly link the water quality that they aim to control with the biodiversity that they are trying to protect. Here we used the England Non-Native and Rare/Protected species records that track these two groups of species as a proof-of-concept for linking catchment scale management of freshwater ecosystems and biodiversity to a range of potential drivers across England. We used national land use (Centre for Ecology and Hydrology land cover map) and water quality indicator (Environment Agency water quality data archive) datasets to predict the presence or absence of 48 focal threatened or invasive species of concern routinely sampled by the English Environment Agency at catchment scale, with a median accuracy of 0.81 area under the receiver operating characteristic curve. A variety of water quality indicators and land-use types were useful in predictions, highlighting that future biomonitoring schemes could use such complementary measures to capture a wider spectrum of drivers and responses. In particular, the percentage of a catchment covered by freshwater was the single most important metric, reinforcing the need for space/habitat to support biodiversity. We show how our method could inform new catchment management approaches, by highlighting how key relationships can be identified and how to understand, visualise and prioritise catchments that are most suitable for restorations or water quality interventions. The scale of this work, in terms of number of species, drivers and locations, represents a step towards a new approach to catchment management that enables managers to link drivers they can control (water quality and land use) to the biota they are trying to protect (biodiversity).
Bladder cancer organoids as a functional system to model different disease stages and therapy response
Authors: Minoli Martina , Cantore Thomas , Kiener Mirjam , Fedrizzi Tarcisio , Manna Federico La , Karkampouna Sofia , Genitisch Vera , Rodriguez Antonio , Klima Irena , Gasperini Paola , Kiss Bernhard , Seiler-Blarer Roland , Demichelis Francesca , Thalmann George N. , Julio Marianna Kruithof-de 
Published: April 2022

AbstractBladder Cancer (BLCa) inter-patient heterogeneity is considered the primary cause of tumor reoccurrence and treatment failure, suggesting that BLCa patients could benefit from a more personalized treatment approach. Patient-derived organoids (PDOs) have been successfully used as a functional model for predicting drug response in different cancer types. In our study, we established BLCa PDO cultures from different BLCa stages. BLCa PDOs preserve the histological and molecular heterogeneity of the parental tumors, including their multiclonal genetic landscapes. BLCa PDOs consistently share key genetic alterations detected in parental tumors, mirroring tumor evolution in longitudinal sampling. Our drug screening pipeline was implemented using BLCa PDOs, testing both standard-of-care and additional FDA-approved compounds for other solid tumors. Integrative analysis of drug response profiles with matched PDO genomic analysis was used to determine enrichment thresholds for candidate markers of therapy resistance and sensitivity. By assessing the clinical history of longitudinally sampled cases, the clonal evolution of the disease could be determined and matched with drug response profiles. In conclusion, we have developed a clinically relevant pipeline for drug response profile assessment and discovery of candidate markers of therapy resistance.
Sialophorin is an essential host element for vaccine immunity against pulmonary fungal infections
Authors: Mudalagiriyappa Srinivasu , Deepe George S , Nanjappa Som Gowda 
Published: April 2022

AbstractThe global burden of fungal infections is alarming, primarily due to the increasing immune-compromised population. The immuno-preventive/therapeutic measures, including vaccines, are necessary to prevent or control fungal diseases. Identifying a protective host element as a functional phenotypic marker is immensely valuable. We identified a host element, sialophorin, preferentially associated with antifungal memory T cells. We investigated its role in vaccine immunity using a mouse model of pulmonary fungal infection. We found that sialophorin was essential to bolster CD8+T-cell responses to the vaccine by enhancing their differentiation and expanding cytokine-producing cells required for immunity. Using a gain-of-function approach, activating sialophorin using mAb augmented the CD8+T cell responses, and sialophorin-sufficient CD8+T cells were competitively superior in differentiation and expansion to the deficient cells. Sialophorin-mediated vaccine immunity was independent of the T cell trafficking effect. Finally, we show that sialophorin is a potential functional phenotypic marker of fungal vaccine-potency and immunity. Our study revealed that sialophorin is an essential host-target element to bolster vaccine responses and serves as apotential biomarkerof fungal immunity.Author SummaryFungal infections have been rising in recent years due to increased immunocompromised individuals. Vaccination ofat-riskindividuals helps counter the infections. Thus, suitable vaccine platforms are needed with apt adjuvants, and a phenotypic marker of vaccine immunity will bolster the efforts. We identified a phenotypic marker, sialophorin, associated with T cell vaccine immunity to fungal infection. Our findings show an essential role of sialophorin for fungal immunity, as a target of adjuvanticity, and as a potential biomarker of vaccine immunity against many fungal infections.
GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity
Authors: Ribeiro Marcelo Lima , Profitós-Pelejà Núria , Santos Juliana Carvalho , Blecua Pedro , Garau Diana Reyes , Armengol Marc , Fernández-Serrano Miranda , Miskin Hari P. , Bosch Francesc , Esteller Manel , Normant Emmanuel , Roué Gael 
Published: April 2022

AbstractTargeted therapies have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decade; however, most subtypes remain incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory B-NHL patients either as a single-agent or in combination with ublituximab, a CD20 antibody, which is also being combined with the PI3Kδ/CK1e inhibitor, umbralisib (“U2”-regimen). In this study, we demonstrated that TG-1801 potentiates ublituximab-mediated antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP), leading to an additive anti-tumour effect of the TG-1801/U2 combination in B-NHL co-cultures. Accordingly, in a B-NHL xenotransplant model, the triplet achieved a 93% tumour growth inhibition, with 40% of the animals remaining tumour-free 35 days after the last dosing. Transcriptomic analysis further uncovered the upregulation of the G protein-coupled receptor, GPR183, as a crucial event associated with TG-1801/U2 synergism, while pharmacological blockade or genetic depletion of this factor impaired ADCP initiation, as well as cytoskeleton remodelling and cell migration, in B-NHL cultures exposed to the drug combination. Thus, our results set the preclinical rationale and support a combination strategy of TG-1801 with PI3Kδ- and CD20-targeting agents in patients with B-NHL.
Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle
Authors: D’Ercole Chiara , D’Angelo Paolo , Ruggieri Veronica , Proietti Daisy , Riera Carles Sanchez , Macone Alberto , Bonvissuto Davide , Sette Claudio , Giordani Lorenzo , Madaro Luca 
Published: April 2022

SUMMARYStriated muscle is a highly organized structure composed by well-defined anatomical domains with integrated but distinct assignments. So far, the lack of a direct correlation between tissue architecture and gene expression has limited our understanding of how each unit responds to physio-pathologic contexts.Here, we show how the combined use of spatially resolved transcriptomics and immunofluorescence can bridge this gap by enabling the unbiased identification of such domains and the characterization of their response to external perturbations. Using a spatiotemporal analysis, we followed the changes in the transcriptomics profile of specific domains in muscle in a model of denervation. Furthermore, our approach allowed us to identify the spatial distribution and nerve dependence of atrophic signalling pathway and polyamine metabolism to glycolytic fibers. Indeed, we demonstrate a pronounced alteration of polyamine homeostasis upon denervation. Our dataset will serve as a resource for future studies of the mechanisms underlying skeletal muscle homeostasis and innervation.Graphical Abstract