bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histone deacetylase 1 maintains lineage integrity through histone acetylome refinement during early embryogenesis
Authors: Zhou Jeff Jiajing , Cho Jin Sun , Han Han , Blitz Ira L. , Wang Wenqi , Cho Ken W.Y. 
Published: May 2022

AbstractHistone acetylation is a pivotal epigenetic modification that controls chromatin structure and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confine the utilization of the zygotic genome remain to be elucidated. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from mid blastula and onward. The recruitment of Hdac1 to the genome at blastula is instructed maternally. Cis-regulatory modules (CRMs) bound by Hdac1 possess epigenetic signatures underlying distinct functions. We highlight a dual function model of Hdac1 where Hdac1 not only represses gene expression by sustaining a histone hypoacetylation state on inactive chromatin, but also maintains gene expression through participating in dynamic histone acetylation-deacetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities, both in time and space. Taken together, our study reveals a comprehensive role for Hdac1 during early vertebrate embryogenesis.
GliaMorph: A modular image analysis toolkit to quantify Müller glial cell morphology
Authors: Kugler Elisabeth , Bravo Isabel , Durmishi Xhuljana , Marcotti Stefania , Beqiri Sara , Carrington Alicia , Stramer Brian M. , Mattar Pierre , MacDonald Ryan B. 
Published: May 2022

AbstractCell morphology is critical for all cell functions. This is particularly true for glial cells as they rely on their complex shape to contact and support neurons. However, methods to quantify complex glial cell shape accurately and reproducibly are lacking. To address this gap in quantification approaches, we developed an analysis pipeline called “GliaMorph”. GliaMorph is a modular image analysis toolkit developed to perform (i) image pre-processing, (ii) semi-automatic region-of-interest (ROI) selection, (iii) apicobasal texture analysis, (iv) glia segmentation, and (v) cell feature quantification. Müller Glia (MG) are the principal retinal glial cell type with a stereotypic shape linked to their maturation and physiological status. We here characterized MG on three levels, including (a) global image-level, (b) apicobasal texture, and (c) apicobasal vertical-to-horizontal alignment. Using GliaMorph, we show structural changes occurring in the developing retina. Additionally, we study the loss of cadherin2 in the zebrafish retina, as well as a glaucoma mouse disease model. The GliaMorph toolkit enables an in-depth understanding of MG morphology in the developing and diseased retina.Graphical AbstractHighlightsGlial morphology is complex, making it challenging to accurately quantify 3D cell shape.We developed the GliaMorph toolkit for image pre-processing, glial segmentation, and quantification of Müller glial cells.Müller glia elaborate their morphology and rearrange subcellular features during embryonic development.GliaMorph accurately identifies subcellular changes in models with disrupted glia cells, including zebrafish cadherin2 loss of function and a mouse glaucoma model.
Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer
Authors: Mello Ashley , Ngodup Tenzin , Lee Yusoo , Donahue Katelyn L. , Li Jinju , Rao Arvind , Carpenter Eileen S. , Crawford Howard C. , di Magliano Marina Pasca , Lee Kyoung Eun 
Published: May 2022

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibroinflammatory stroma and often experiences conditions of insufficient oxygen availability, or hypoxia. Cancer-associated fibroblasts (CAF) are a predominant and heterogeneous population of stromal cells within the pancreatic tumor microenvironment. Here, we uncover a previously unrecognized role for hypoxia in driving an inflammatory phenotype in PDAC CAFs. We identify hypoxia as a strong inducer of tumor IL1α expression, which is required for inflammatory CAF (iCAF) formation. Notably, iCAFs preferentially reside in hypoxic regions of PDAC. Our data implicate hypoxia as a critical regulator of CAF heterogeneity in PDAC.
The microtubule minus end-binding protein CAMSAP2 does not regulate microtubule dynamics in primary pancreatic β-cells but facilitates insulin secretion
Authors: Ho Kung-Hsien , Osipovich Anna B. , Jayathilake Anissa , Magnuson Mark A. , Gu Guoqiang , Kaverina Irina 
Published: May 2022

AbstractGlucose stimulation induces the remodeling of microtubules in Islet β-cells to potentiate glucose-stimulated insulin secretion. CAMSAP2 is a microtubule minus-end binding protein and is reported to stabilize and position microtubules in several non-β-cells, such as human retinal pigment epithelium cells. In immortalized insulinoma MIN6 cells, CAMSAP2 binds to and forms short stretches at microtubule minus ends in the cytoplasm, which is consistent with the reported subcellular localization and functions of CAMSAP2 in non-β-cells. Surprisingly, we found that CAMSAP2 expressed in primary islet β-cells does not form short stretches in the cytoplasm, but instead is localized to the Golgi apparatus. This novel localization is specific to β-but not α-cells in islets and it is independent of MT-binding. Knockdown of CAMSAP2 by shRNA impairs Golgi-ER trafficking, reduces total insulin content, and attenuates GSIS without affecting the MT dynamics or releasability of insulin granules in islet β-cells. Corresponding to these results, we found that primary islets and MIN6 cells express different CAMSAP2 isoforms. We propose that primary islet β cells use a novel CAMSAP2 isoform for a MT-independent non-canonical function, which is to promote Golgi-ER trafficking that supports efficient production of insulin secretory granules.
Novel ACE2 nanoparticles universally block SARS-CoV-2 variants in the human respiratory tract
Authors: Sauvanet Cécile , Lemos Moara , Bezault Armel , de Francisco Borja Rodríguez , Chan Michael CW , Hui Kenrie PY , Ng Ka-chun , Nicholls John M , Volkmann Niels , Hanein Dorit 
Published: May 2022

AbstractThe continual evolution of SARS-CoV-2 has challenged the efficacy of many COVID19 vaccines and treatment options. One strategy that evades viral escape is using the entry receptor, human Angiotensin-Converting Enzyme 2 (hACE2). Soluble hACE2 receptor domains show potential as decoys but genetic modifications are necessary to provide sufficient efficacy. However, these engineered constructs are potentially susceptible to viral escape. We combined native hACE2 with viral vectors to form nanoparticles presenting hACE2 analogous to human cells. Cell-based viral infection assays and cryogenic in-situ tomography show that hACE2 nanoparticles sequester viruses through aggregation, efficiently blocking entry of SARS-CoV-2 and its variants in model cell systems and human respiratory tract explants using native hACE2. Thus, we show that hACE2 nanoparticles have high potential as pan-variant COVID19 therapeutics.
Differential regulation of mRNA stability modulates transcriptional memory and facilitates environmental adaptation
Authors: Li Bingnan , Zeis Patrice , Alekseenko Alisa , Lin Gen , Tekkedil Manu M , Steinmetz Lars M. , Pelechano Vicent 
Published: May 2022

AbstractTranscriptional memory, by which cells respond faster to repeated stimuli, is key for cellular adaptation and organism survival. Factors related to chromatin organization and activation of transcription have been shown to play a role in the faster response of those cells previously exposed to a stimulus (primed). However, the contribution of post-transcriptional regulation is not yet explored. Here, combining flow cytometry and high throughput sequencing, we perform a genome-wide screen to identify novel factors modulating transcriptional memory in S. cerevisiae in response to galactose nutrition sources. In addition to the well-known chromatin factors modulating transcriptional memory, we find that depletion of the nuclear RNA exosome increases GAL1 expression in primed cells. We perform a genome-wide characterisation of this process and show that changes in nuclear surveillance factor association can enhance both gene induction and repression in primed cells. Finally, we show that in addition to nuclear mRNA degradation, differences in cytoplasmic mRNA decay also modulate transcriptional memory and contribute to faster gene expression remodelling in primed cells. Our results demonstrate that mRNA post-transcriptional regulation, and not only transcription regulation, should be considered when investigating gene expression memory.
Probabilistic Tracking of U-fibers on the Superficial White Matter Surface
Authors: Nie Xinyu , Shi Yonggang 
Published: May 2022

AbstractThe short association fibers or U-fibers connect two neighboring gyri and travel in the superficial white matter (SWM) beneath the cortical layer. These U-fibers are essential for the understanding of neurodevelopment and neurodegeneration. However, the complex structures and the high curvature of the U-fibers lead to erroneous streamlines reconstruction of the traditional tractography since the volume-based tractography cannot use the biological characteristic of U-fibers that they tightly beneath the cortical layer. In this work, we proposed a surface-based framework for probabilistic tracking of the U-fibers on the triangular mesh of the SWM. We develop a novel approach to project the fiber orientation distributions (FODs) data onto the tangent space of the SWM surface. With the projected FODs, an advanced probabilistic tracking technique, which regularizes the streamlines based on the intrinsic geometry of the surface, is developed to reconstruct the highly bent U-fibers on the SWM surface. In the experiment, we demonstrate our method based on the high-resolution diffusion imaging data from the Human Connectome Project (HCP). We quantitatively compare the proposed method with state-of-the-art volume-based tractography from MRTrix and another surface-based tractography on the U-fibers of the central sulcus. Moreover, we show the reconstructed U-fibers on the parietal lobe and frontal lobe. The results show that our method outperforms the other two methods and successfully reconstructs the U-fibers on the cortical regions with high intersubject variability.
Promiscuous feeding across multiple honey bee hosts amplifies the vectorial capacity ofVarroa destructor
Authors: Lamas Zachary S. , Solmaz Serhat , Ryabov Eugene V. , Mowery Joseph , Heermann Matthew , Sonenshine Daniel , Evans Jay D. , Hawthorne David J. 
Published: May 2022

AbstractVarroadestructor is a cosmopolitan pest and leading cause of colony loss of the European honey bee. Historically described as a competent vector of honey bee viruses, this arthropod vector is cause for the global pandemic of Deformed wing virus, now endemic in honeybee populations. Our work shows viral spread is driven byVarroaactively switching from one adult bee to another as they feed. Assays using fluorescent microspheres were used to show the movement of fluids in both directions between host and vector whenVarroafeed. Therefore,Varroacould be in either an infectious or naïve state dependent upon the disease status of their host. We tested this and confirm that the relative risk of aVarroafeeding was dependent on the infectiousness of their previous host.Varroaexhibit remarkable heterogeneity in their host switching behavior, with someVarroaswitching infrequently while others switch at least daily. As a result, relatively few of the most activeVarroaparasitize the majority of bees. This multiple feeding behavior has analogs in vectorial capacity models of other systems, where promiscuous feeding by individual vectors is a leading driver of vectorial capacity. We propose that the honeybee-Varroarelationship offers a unique opportunity to apply principles of vectorial capacity to a social organism, as virus transmission is both vectored and occurs through multiple host-to-host routes common to a crowded society.
The PCI domains are “winged” HEAT domains
Authors: Paul Eleanor Elise , Marintchev Assen 
Published: May 2022

AbstractThe HEAT domains are a family of helical hairpin repeat domains, composed of four or more hairpins. HEAT is derived from the names of four family members: huntingtin, eukaryotic translation elongation factor 3 (eEF3), protein phosphatase 2 regulatory A subunit (PP2A), and mechanistic target of rapamycin (mTOR). HEAT domain-containing proteins play roles in a wide range of cellular processes, such as protein synthesis, nuclear transport and metabolism, and cell signaling. The PCI domains are a related group of helical hairpin domains, with a “winged-helix” (WH) subdomain at their C-terminus, which is responsible for multi-subunit complex formation with other PCI domains. The name is derived from the complexes, where these domains are found: the Proteasome “lid” regulatory subcomplex, the COP9 signalosome (CSN), and eukaryotic translation initiation factor 3 (eIF3). We noted that in structure homology searches using HEAT domains, sometimes PCI domains appeared in the search results ahead of other HEAT domains, which indicated that the PCI domains could be members of the HEAT domain family, and not a related but separate group. Here, we report extensive structure homology analysis of HEAT and PCI domains, both within and between the two groups of proteins. We present evidence that the PCI domains as a group have greater structural homology with individual groups of HEAT domains than some of the HEAT domain groups have among each other. Therefore, our results indicate that the PCI domains have evolved from a HEAT domain that acquired a WH subdomain. The WH subdomain in turn mediated selfassociation into a multi-subunit complex, which eventually evolved into the common ancestor of the Proteasome lid/CSN/eIF3.
RORβ modulates a gene program that is protective against articular cartilage damage
Authors: Chang Mi Ra , Griffin Patrick R. 
Published: May 2022

AbstractOsteoarthritis (OA) is the most prevalent chronic joint disease which increases in frequency with age eventually impacting most people over the age of 65. OA is the leading cause of disability and impaired mobility, yet the pathogenesis of OA remains unclear. Treatments have focused mainly on pain relief and reducing joint swelling. Currently there are no effective treatments to slow the progression of the disease and to prevent irreversible loss of cartilage. Here we demonstrate that stable expression of RORβ in cultured cells results in alteration of a gene program that is supportive of chondrogenesis and is protective against development of OA. Specifically, we determined that RORβ regulates the balance of FGFRs signaling on FGFR1/FGFR3 that ERK1/2-MAPK signaling was suppressed by FGFR1(cartilage destruction) and AKT signaling was enhanced by FGFR3 (cartilage protection). These results suggest a critical role for RORβ in chondrogenesis and suggest that identification of mechanisms that control the expression of RORβ in chondrocytes could lead to the development of disease modifying therapies for the treatment of OA.
ORF6 protein of SARS-CoV-2 inhibits TRIM25 mediated RIG-I ubiquitination to mitigate type I IFN induction
Authors: Khatun Oyahida , Sharma Mansi , Narayan Rohan , Tripathi Shashank 
Published: May 2022

AbstractEvasion and antagonism of host cellular immunity upon SARS-CoV-2 infection confers a profound replication advantage on the virus and contributes to COVID-19 pathogenesis. We explored the ability of different SARS-CoV-2 proteins to antagonize the host innate immune system and found that the ORF6 protein mitigated type-I IFN (interferon) induction and downstream IFN signaling. Our findings also corroborated previous reports that ORF6 blocks the nuclear import of IRF3 and STAT1 to inhibit IFN induction and signaling. Here we show that ORF6 directly interacts with RIG-I and blocks downstream type-I IFN induction and signaling by inhibiting K-63 linked ubiquitination of RIG-I by the E3 Ligase TRIM25. This involves ORF6-mediated targeting of TRIM25 for degradation, also observed during SARS-CoV-2 infection. The type-I IFN antagonistic activity of ORF6 was mapped to its C-terminal cytoplasmic tail, specifically to amino acid residues 52-61. Overall, we provide new insights into how the SARS-CoV-2 ORF6 protein inhibits type I-IFN induction and signaling through distinct mechanisms.
Metalation calculators forE. colistrain JM109 (DE3): Aerobic, anaerobic and hydrogen peroxide exposed cells cultured in LB media
Authors: Foster Andrew W. , Clough Sophie E. , Aki Zeynep , Young Tessa R. , Clarke Alison R. , Robinson Nigel J. 
Published: May 2022

AbstractThree web-based calculators, and three analogous spreadsheets, have been generated that predictin vivometal occupancies of proteins based on known metal affinities. The calculations exploit estimates of the availabilities of the labile buffered pools of different metals inside a cell. Here, metal availabilities have been estimated for a strain ofE. colithat is commonly used in molecular biology and biochemistry research, for example in the production of recombinant proteins. Metal availabilities have been examined for cells grown in LB medium aerobically, anaerobically and in response to H2O2by monitoring the abundance of a selected set of metal-responsive transcripts by qPCR. The selected genes are regulated by DNA-binding metal sensors that have been thermodynamically characterised in related bacterial cells enabling gene expression to be read-out as a function of intracellular metal availabilities expressed as free energies for forming metal complexes. The calculators compare these values with the free energies for forming complexes with the protein of interest, derived from metal affinities, to estimate how effectively the protein can compete with exchangeable binding sites in the intracellular milieu. The calculators then inter-compete the different metals, limiting total occupancy of the site to a maximum stoichiometry of 1, to output percentage occupancies with each metal. In addition to making these new and conditional calculators available, an original purpose of this article was to provide a tutorial which discusses constraints of this approach and presents ways in which such calculators might be exploited in basic and applied research, and in next-generation manufacturing.
Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in mice
Authors: Wagner Stefan , Brierley Daniel I. , Leeson-Payne Alasdair , Jiang Wanqing , Chianese Raffaella , Lam Brian Y. H. , Dowsett Georgina K. C. , Cristiano Claudia , Lyons David , Reimann Frank , Gribble Fiona M. , Yeo Giles S.H. , Trapp Stefan , Heisler Lora K. 
Published: May 2022

AbstractOverweight and obesity are rapidly becoming the “new normal” in developed countries, which promotes a widespread negative impact on human health. Amongst recently developed obesity medications are the serotonin 2C receptor (5-HT2CR) agonist lorcaserin and glucagon-like peptide-1 receptor (GLP-1R) agonists, but the brain circuits employed by these medications to produce their therapeutic effects remain to be fully defined. 5-HT2CRs and GLP-1Rs are widely distributed in the brain, including in the key homeostatic region the nucleus of the solitary tract (NTS) where GLP-1 is produced by preproglucagon (PPGNTS) neurons. PPGNTS cells were profiled using histochemistry and single nucleus RNA sequencing (Nuc-Seq) of mouse brainstem. Transcriptomic analyses revealed 5-HT2CR expression was widespread in PPGNTS clusters. Demonstrating the functional significance of this co-expression, lorcaserin required PPGNTS to reduce food intake. Analysis of second order neurons revealed that local GLP1-R neurons within the NTS are necessary for 5-HT2CRNTS food intake suppression. In contrast, GLP-1RNTS were not required for GLP-1R agonist liraglutide and exendin-4’s short term feeding reduction, suggesting scope for lorcaserin and GLP1-R agonist combination therapy. In support of this, lorcaserin+liraglutide and lorcaserin+exendin-4 produced greater reductions in food intake when administered in combination as compared to monotherapies. These data provide insight into the therapeutic mechanisms of lorcaserin and identify a combination strategy to improve the therapeutic profile of lorcaserin and GLP1-R agonists.
Nucleation and stability of branched versus linear Arp2/3-generated actin filaments
Authors: Cao Luyan , Ghasemi Foad , Way Michael , Jégou Antoine , Romet-Lemonne Guillaume 
Published: May 2022

ABSTRACTActivation of the Arp2/3 complex by VCA-domain-bearing NPFs results in the formation of ‘daughter’ actin filaments branching off the sides of pre-existing ‘mother filaments.’ Alternatively, when stimulated by SPIN90, Arp2/3 directly nucleates ‘linear’ actin filaments. Uncovering the similarities and differences of these two activation mechanisms is fundamental to understanding the regulation and function of Arp2/3. Analysis of individual filaments reveals that the catalytic VCA domain of WASP, N-WASP and WASH, accelerate the Arp2/3-mediated nucleation of linear filaments by SPIN90, in addition to their known branch-promoting activity. Unexpectedly, these VCA domains also destabilize existing branches, as well as SPIN90-Arp2/3 at filament pointed ends. Furthermore, cortactin and GMF, which respectively stabilize and destabilize Arp2/3 at branch junctions, have a similar impact on SPIN90-activated Arp2/3. However, unlike branch junctions, SPIN90-Arp2/3 at the pointed end of linear filaments is not destabilized by piconewton forces, and does not become less stable with time. It thus appears that linear and branched Arp2/3-generated filaments respond similarly to regulatory proteins, albeit with quantitative differences, and that they differ greatly in their responses to aging and to mechanical stress. These results indicate that SPIN90- and VCA-activated Arp2/3 complexes adopt similar yet non-identical conformations, and that their turnover in cells may be regulated differently.