bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pseudouridine-free Ribosome Exhibits Distinct Inter-subunit Movements
Authors: Zhao Yu , Rai Jay , Yu Hongguo , Li Hong 
Published: June 2021

AbstractPseudouridine, the most abundant form of RNA modification, is known to play important roles in ribosome function. Mutations in human DKC1, the pseudouridine synthase responsible for catalyzing the ribosome RNA modification, cause translation deficiencies and are associated with a complex cancer predisposition. The structural basis for how pseudouridine impacts ribosome function remains uncharacterized. Here we report electron cryomicroscopy structures of a fully modified and a pseudouridine-free ribosome from Saccharomyces cerevisiae. In the modified ribosome, the rearranged N1 atom of pseudouridine is observed to stabilize key functional motifs by establishing predominately water-mediated close contacts with the phosphate backbone. The pseudouridine-free ribosome, however, is devoid of such interactions and displays conformations reflective of abnormal inter-subunit movements. The erroneous motions of the pseudouridine-free ribosome may explain its observed deficiencies in translation.
The Food Additive Xanthan Gum Drives Adaptation of the Human Gut Microbiota
Authors: Ostrowski Matthew P. , La Rosa Sabina Leanti , Kunath Benoit J. , Robertson Andrew , Pereira Gabriel , Hagen Live H. , Varghese Neha J. , Qiu Ling , Yao Tianming , Flint Gabrielle , Li James , McDonald Sean , Buttner Duna , Pudlo Nicholas A. , Schnizlein Matthew K. , Young Vincent B. , Brumer Harry , Schmidt Thomas , Terrapon Nicolas , Lombard Vincent , Henrissat Bernard , Hamaker Bruce , Eloe-Fadrosh Emiley A , Tripathi Ashootosh , Pope Phillip B. , Martens Eric 
Published: June 2021

SummaryThe diets of industrialized countries reflect the increasing use of processed foods, often with the introduction of novel food additives. Xanthan gum is a complex polysaccharide with unique rheological properties that have established its use as a widespread stabilizer and thickening agent1. However, little is known about its direct interaction with the gut microbiota, which plays a central role in digestion of other, chemically-distinct dietary fiber polysaccharides. Here, we show that the ability to digest xanthan gum is surprisingly common in industrialized human gut microbiomes and appears to be contingent on the activity of a single bacterium that is a member of an uncultured bacterial genus in the familyRuminococcaceae. We used a combination of enrichment culture, multi-omics, and recombinant enzyme studies to identify and characterize a complete pathway in this uncultured bacterium for the degradation of xanthan gum. Our data reveal that this keystone degrader cleaves the xanthan gum backbone with a novel glycoside hydrolase family 5 (GH5) enzyme before processing the released oligosaccharides using additional enzymes. Surprisingly, some individuals harbor aBacteroidesspecies that is capable of consuming oligosaccharide products generated by the keystoneRuminococcaceaeor a purified form of the GH5 enzyme. ThisBacteroidessymbiont is equipped with its own distinct enzymatic pathway to cross-feed on xanthan gum breakdown products, which still harbor the native linkage complexity in xanthan gum, but it cannot directly degrade the high molecular weight polymer. Thus, the introduction of a common food additive into the human diet in the past 50 years has promoted the establishment of a food chain involving at least two members of different phyla of gut bacteria.
Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies
Authors: Fenix Aidan M. , Miyaoka Yuichiro , Bertero Alessandro , Blue Steven , Spindler Matthew J. , Tan Kenneth K. B. , Perez-Bermejo Juan , Chan Amanda H. , Mayer Steven J. , Nguyen Trieu , Russell Caitlin R. , Lizarraga Paweena , Truong Annie , So Po-Lin , Kulkarni Aishwarya , Chetal Kashish , Sathe Shashank , Sniadecki Nathan J. , Yeo Gene W. , Murry Charles E. , Conklin Bruce R. , Salomonis Nathan 
Published: June 2021

ABSTRACTRNA binding motif protein 20 (RBM20) is a key regulator of alternative splicing in the heart, and its mutation leads to malignant dilated cardiomyopathy (DCM). To understand the mechanism of RBM20-associated DCM, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous DCM-associated missense mutations in RBM20 (R636S) as well as RBM20 knockout (KO) iPSCs. iPSC-derived engineered heart tissues made from these cell lines recapitulated contractile dysfunction of RBM20-associated DCM and revealed greater dysfunction with missense mutations than KO. Analysis of RBM20 RNA binding by eCLIP revealed a gain-of-function preference of mutant RBM20 for 3′ UTR sequences that are shared with amyotrophic lateral sclerosis (ALS) and processing-body associated RNA binding proteins (FUS, DDX6). Deep RNA sequencing revealed that the RBM20 R636S mutant has unique gene, splicing, polyadenylation and circular RNA defects that differ from RBM20 KO, impacting distinct cardiac signaling pathways. Splicing defects specific to KO or R636S mutations were supported by data from R636S gene-edited pig hearts and eCLIP. Super-resolution microscopy verified that mutant RBM20 maintains limited nuclear localization potential; rather, the mutant protein associates with cytoplasmic processing bodies (DDX6) under basal conditions, and with stress granules (G3BP1) following acute stress. Taken together, our results highlight a novel pathogenic mechanism in cardiac disease through splicing-dependent and -independent pathways that are likely to mediate differential contractile phenotypes and stress-associated heart pathology.
Nanoparticle fragmentation at solid state under single picosecond laser pulse stimulation
Authors: Kang Peiyuan , Wang Yang , Wilson Blake A. , Randrianalisoa Jaona , Qin Zhenpeng 
Published: June 2021

ABSTRACTUnderstanding the laser-nanomaterials interaction including nanomaterial fragmentation has important implications in nanoparticle manufacturing, energy, and biomedical sciences. So far, three mechanisms of laser-induced fragmentation have been recognized including non-thermal processes and thermomechanical force under femtosecond pulses, and the phase transitions under nanosecond pulses. Here we show that single picosecond (ps) laser pulse stimulation leads to anomalous fragmentation of gold nanoparticles that deviates from these three mechanisms. The ps laser fragmentation was weakly dependent on particle size, and it resulted in a bimodal size distribution. Importantly, ps laser stimulation fragmented particles below the melting point and below the threshold for non-thermal mechanism. This study reveals a previously unknown regime of nanoparticle fragmentation.
COMMIT: Consideration of metabolite leakage and community composition improves microbial community models
Authors: Wendering Philipp , Nikoloski Zoran 
Published: June 2021

AbstractComposition and functions of microbial communities affect important traits in diverse hosts, from crops to humans. Yet, mechanistic understanding of how metabolism of individual microbes is affected by the community composition and metabolite leakage is lacking. Here, we first show that the consensus of automatically generated metabolic models improves the quality of the draft models, measured by the genomic evidence for considered enzymatic reactions. We then devise an approach for gap filling, termed COMMIT, that considers exchangeable metabolites based on their permeability and the composition of the community. By applying COMMIT with two soil communities from the Arabidopsis thaliana culture collection, we could significantly reduce the gap-filling solution in comparison to filling gaps in individual models. Inspection of the metabolic interactions in the soil communities allows us to identify microbes with community roles of helpers and beneficiaries. Therefore, COMMIT offers a versatile automated solution for large-scale modelling of microbial communities for diverse biotechnological applications.
Chromatin enrichment for Proteomics in Plants (ChEP-P) implicates the histone reader ALFIN-LIKE 6 in jasmonate signalling
Authors: Vélez-Bermúdez Isabel Cristina , Schmidt Wolfgang 
Published: June 2021

AbstractCovalent modifications of core histones govern downstream DNA-templated processes such as transcription by altering chromatin structure and function. Previously, we reported that the plant homeodomain protein ALFIN-LIKE 6 (AL6), abona fidehistone reader that preferentially binds trimethylated lysin 4 on histone 3 (H3K4me3), is critical for recalibration of cellular phosphate (Pi) homeostasis and root hair elongation under Pi-deficient conditions. Here, we demonstrate that AL6 is also involved in the response of Arabidopsis seedlings to jasmonic acid (JA) during skotomorphogenesis, possibly by modulating chromatin dynamics that affect the transcriptional regulation of JA-responsive genes. Dark-grownal6seedlings showed a compromised reduction in hypocotyl elongation upon exogenously supplied JA, a response that was calibrated by the availability of Pi in the growth medium. A comparison of protein profiles between wild-type andal6mutant seedlings using a quantitative Chromatin Enrichment for Proteomics (ChEP) approach, that we modified for plant tissue and designated ChEP-P (ChEP in Plants), yielded a comprehensive suite of chromatin-associated proteins and candidates that may be causative for the mutant phenotype. Altered abundance of proteins involved in chromatin organization inal6seedlings suggests a role of AL6 in coordinating the deposition of histone variants upon perception of internal or environmental stimuli.HighlightCataloguing chromatin-associated proteins revealed that the plant homeodomain protein ALFIN-LIKE 6 orchestrates phosphate and jasmonate signaling in etiolated Arabidopsis seedlings through modulation of the chromatin structure.
NLoed: A Python package for nonlinear optimal experimental design in systems biology
Authors: Braniff Nathan , Pearce Taylor , Lu Zixuan , Astwood Michael , Forrest William S. R. , Receno Cody , Ingalls Brian 
Published: June 2021

AbstractMotivationModelling in systems and synthetic biology relies on accurate parameter estimates and predictions. Accurate model calibration relies, in turn, on data, and on how well-suited the available data is to a particular modelling task. Optimal experimental design (OED) techniques can be used to identify experiments and data collection procedures that will most efficiently contribute to a given modelling objective. However, implementation of OED is limited by currently available software tools that are not well-suited for the diversity of nonlinear models and non-normal data commonly encountered in biological research. Moreover, existing OED tools do not make use of the state-of-the-art numerical tools, resulting in inefficient computation.ResultsHere we present the NLoed software package. NLoed is an open-source Python library providing convenient access to OED methods, with particular emphasis on experimental design for systems biology research. NLoed supports a wide variety of nonlinear, multi-input/output, and dynamic models, and facilitates modelling and design of experiments over a wide variety of data types. To support OED investigations, the NLoed package implements maximum likelihood fitting and diagnostic tools, providing a comprehensive modelling workflow. NLoed offers an accessible, modular, and flexible OED tool-set suited to the wide variety of experimental scenarios encountered in systems biology research. We demonstrate NLOED’s capabilities by applying it to experimental design for characterization of a bacterial optogenetic system.AvailabilityNLoed is available via pip from the PyPi repository;https://pypi.org/project/nloed/. Source code, documentation and examples can be found on Github athttps://github.com/ingallslab/NLoed.Contactbingalls@uwaterloo.caSupplementary informationSupplementary materials are available online.
Unique role and vulnerability of EP300 KIX domain in small-cell lung cancer
Authors: Kim Kee-Beom , Kabra Ashish , Kim Dong-Wook , Xue Yongming , Hou Pei-Chi , Zhou Yunpeng , Miranda Leilani , Shi Xiaobing , Bender Timothy P. , Bushweller John H. , Park Kwon-Sik 
Published: June 2021

SummaryEP300 (E1A binding protein p300) is a versatile transcription co-activator important in cell proliferation and differentiation. The gene EP300 is frequently mutated in diverse cancer types, including small-cell lung cancer (SCLC). While it is widely believed that these mutations result in loss of EP300 function, the impact on SCLC pathogenesis remains largely unknown. Here we demonstrate that mutant EP300 variants lacking histone acetyltransferase (HAT) domain accelerate tumor development in autochthonous mouse models of SCLC. However, unexpectedly, complete knockout of Ep300 suppresses tumor development and inhibits proliferation of both human and mouse SCLC cells. Genetic dissection of EP300 domains identifies kinase-inducible domain (KID)-interacting (KIX) domain, specifically its interaction with transcription factors such as CREB1 and MYB, as the determinant of pro-tumorigenic activity. Blockade of the KIX-mediated protein interactions using a small molecule and a recombinant peptide mimicking the KIX-binding sequences of EP300-interacting partners inhibits the growth of SCLC cells. These findings identify domain-specific roles of EP300 in SCLC and unique vulnerability of the EP300 KIX domain to potential therapeutics.
Organic stabilization of extracellular elemental sulfur in aSulfurovum-rich biofilm: a new role for EPS?
Authors: Cron Brandi , Macalady Jennifer L. , Cosmidis Julie 
Published: June 2021

AbstractThis work shines light on the role of extracellular polymeric substances (EPS) in the formation and preservation of elemental sulfur biominerals produced by sulfur-oxidizing bacteria. We characterized elemental sulfur particles produced within aSulfurovum-rich biofilm in the Frasassi Cave System (Italy). The particles adopt spherical and bipyramidal morphologies, and display both stable (α-S8) and metastable (β-S8) crystal structures. Elemental sulfur is embedded within a dense matrix of EPS and the particles are surrounded by organic envelopes rich in amide and carboxylic groups. Organic encapsulation and the presence of metastable crystal structures are consistent with elemental sulfur organomineralization, i.e. the formation and stabilization of elemental sulfur in the presence of organics, a mechanism that has previously been observed in laboratory studies. This research provides new evidence for the important role of microbial EPS in mineral formation in the environment. We hypothesize that extracellular organics are used by sulfur-oxidizing bacteria for the stabilization of elemental sulfur minerals outside of the cell wall as a store of chemical energy. The stabilization of energy sources (in the form of a solid electron acceptor) in biofilms is a potential new role for microbial EPS that requires further investigation.
Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity
Authors: Thery Fabien , Martina Lia , Asselman Caroline , Repo Heidi , Zhang Yifeng , Sedeyn Koen , Moschonas George D. , Bredow Clara , Teo Qi Wen , Zhang Jingshu , Vessely Madeleine , Leandro Kevin , Eggermont Denzel , De Sutter Delphine , Boucher Katie , Hochepied Tino , Festjens Nele , Callewaert Nico , Saelens Xavier , Dermaut Bart , Knobeloch Klaus-Peter , Beling Antje , Sanyal Sumana , Radoshevich Lilliana , Eyckerman Sven , Impens Francis 
Published: June 2021

ABSTRACTISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we used a viral-like particle trapping technology to identify ISG15-binding proteins and discovered Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly-characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We found that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We showed that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1 (HSV-1), human respiratory syncytial virus (RSV) and coxsackievirus B3 (CVB3), and we observed a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide novel molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.
Computational Neuroimaging of Cognition-Emotion Interactions: Affective and Task-similar Interference Differentially Impact Working Memory
Authors: Ji Jie Lisa , Repovs Grega , Yang Genevieve J. , Savic Aleksandar , Murray John D. , Anticevic Alan 
Published: June 2021

ABSTRACTCognition depends on resisting interference and responding to relevant stimuli. Distracting information, however, varies based on content, requiring distinct filtering mechanisms. For instance, affective information captures attention, disrupts performance and attenuates activation along frontal-parietal regions during cognitive engagement, while recruiting bottom-up regions. Conversely, distraction matching task features (i.e. task-similar) increases fronto-parietal activity. Neural mechanisms behind unique effects of different distraction on cognition remain unknown. Using fMRI in 45 adults, we tested whether affective versus task-similar interference show distinct signals during delayed working memory (WM). We found robust differences between distractor types along fronto-parietal versus affective-ventral neural systems. We studied a hypothesized mechanism of this effect via a biophysically-based computational WM model that implements a functional antagonism between affective/cognitive neural ‘modules’. This architecture reproduced experimental effects: task-similar distractors increased, whereas affective distractors attenuated cognitive module activity while increasing affective module signals. The model architecture suggested that task-based connectivity may be altered in affective-ventral vs. fronto-parietal networks depending on distractor type. Empirically, affective interference significantly increased connectivity within the affective-ventral network, but reduced connectivity between affective-ventral and fronto-parietal networks, which predicted WM performance. These findings detail an antagonistic architecture between cognitive and affective systems, capable of flexibly engaging distinct distractions during cognition.
Novel GVHD resistant humanized-PBMC mouse model for preclinical HIV research
Authors: Holguin Leo , Echavarria Liliana , Burnett John C. 
Published: June 2021

AbstractHumanized mouse models are based on the engraftment of human cells in immunodeficient mouse strains, most notably the NSG strain. Most used models have a major limitation in common, the development of graft-versus-host disease (GVHD). GVHD not only introduces variabilities into the research data but also leads to animal welfare concerns. A new mouse strain, B6.129S-Rag2tm1Fwa CD47tm1Fpl Il2rgtm1Wjl/J which lacks Rag1, IL2rg, and CD47 (triple knockout or TKO), is resistant to GVHD development. We transplanted TKO mice with human peripheral blood mononuclear cells (PBMCs) to establish a new humanized PBMC (hu-PBMC) mouse model. A cohort of these mice was infected with HIV-1 and monitored for plasma HIV viremia and CD4+ T cell depletion. The onset and progression of GVHD were monitored by clinical signs. This study demonstrates that TKO mice transplanted with human PBMCs support engraftment of human immune cells in primary and secondary lymphoid tissues, rectum, and brain. Moreover, the TKO hu-PBMC model supports HIV-1 infection via intraperitoneal, rectal, or vaginal routes, as confirmed by robust plasma HIV viremia and CD4+ T cell depletion. Lastly, TKO mice showed a delayed onset of GVHD clinical signs (∼21 days) and exhibited significant decreases in plasma levels of TNFβ. Based on these results, the TKO hu-PBMC mouse model not only supports humanization and HIV-1 infection but is also resistant to GVHD development, making this model a valuable tool in HIV research.ImportanceCurrently, there is no cure or vaccine for HIV infection, thus continued research is needed to end the HIV pandemic. While many animal models are used in HIV research, none is used more than the humanized mouse model. A major limitation with current humanized mouse models is the development of graft-versus-host disease (GVHD). Here, we show a novel humanized mouse model that is resistant to GVHD development and supports and models HIV infection comparable to well-established humanized mouse models.
An exploration of metabolite and gene responses in mouse skeletal muscles responding to acute sedentary hypoxia
Authors: Xue Feng , Huang Gang , Wang Xi , Deng Jie , Pang Lingxia , Gan Zhuohui 
Published: June 2021

AbstractSkeletal muscles are involved in responses to acute hypoxia as the largest organ in the body. However, as a hypoxic-tolerant tissue, responses in skeletal muscles caused by acute sedentary hypoxia are much less studied. We measured metabolites in skeletal muscles from mice exposed to 8% O2 for 0 minute, 15 minutes and 2 hours and studied the potential relationship between metabolite levels and mRNA levels by reconstructing genome-based metabolic networks and meta-analyzing differentially expressed genes acquired in skeletal muscles after 2 hours of 8% O2 exposure. The metabolite measurement indicated a significant increase in glutamine metabolism but not lactate metabolism in mouse skeletal muscles after 2 hours of hypoxia, where the metabolic responses as a whole were moderate. The central-dogma based metabolic flux analysis suggested an involvement of glutamine metabolism, though, as a whole, metabolite changes and gene changes didn’t show a high correlation. Among metaoblites, glutamine metabolism indicated a significant response and a consistent change which could be interpreted by genome-based network analysis. In summary, though this study suggested a moderate metabolic response which has a weak correlation with gene expression change as a whole, glutamine metabolism indicated rapid responses in skeletal muscles responding to acute sedentary hypoxia.