bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia
Authors: zhang Min , Sun Lei , He Dong , Chen Jian , Dong Zhiqiang , Liang Huiting , Cao Yu , Cai Bingcheng , Yang He 
Published: October 2020

AbstractCellular senescence is a stable state of cell cycle arrest elicited by various stresses. Hypoxia modulates senescence, but its consequences and implications in living organisms remains unknown. Here we identified the eIF4E2-GSK3β pathway regulated by hypoxia to maintain p53 proline-directed phosphorylation (S/T-P) to prevent senescence. We previously knew that GSK3β activates p53 translation through phosphorylation of RBM38 Ser195 (-Pro196). Unexpectedly, eIF4E2 directly binds to GSK3β via a conserved motif, mediating Ser195 phosphorylation. Phosphoproteomics revealed that eIF4E2-GSK3β specifically regulates proline-directed phosphorylation. Peptide e2-I or G3-I that disrupts this pathway dephosphorylates p53 at multiple S/T-P, which accelerate senescence by transcriptional suppressing TOPBP1 and TRX1. Consistently, peptides induce liver senescence that is rescued by TOPBP1 expression, and mediate senescence-dependent tumor regression. Furthermore, hypoxia inhibits eIF4E2-GSK3β. Inspiringly, eIF4E2-GSK3β is unique to mammals, which maintains mice viability and prevents liver senescence against physiological hypoxia. Interestingly, this mammalian eIF4E2 protects heart of zebrafish against hypoxia. Together, we identified a mammalian -unique eIF4E2-GSK3β pathway preventing senescence and guarding against hypoxia in vivo.
Droplet printing reveals the importance of micron-scale structure for bacterial ecology
Authors: Kumar Ravinash Krishna , Meiller-Legrand Thomas A. , Alcinesio Alessandro , Gonzalez Diego , Mavridou Despoina A. I. , Meacock Oliver J. , Smith William P. J. , Zhou Linna , Kim Wook , Su Pulcu Gökçe , Bayley Hagan , Foster Kevin R. 
Published: October 2020

AbstractBacteria often live in diverse communities where the spatial arrangement of strains and species is considered critical for their ecology, including whether strains can coexist, which are ecologically dominant, and how productive they are as a community1,2. However, a test of the importance of spatial structure requires manipulation at the fine scales at which this structure naturally occurs3–8. Here we develop a droplet-based printing method to arrange different bacterial genotypes across a sub-millimetre array. We use this to test the importance of fine-scale spatial structure by printing strains of the gut bacteriumEscherichia colithat naturally compete with one another using protein toxins9,10. This reveals that the spatial arrangement of bacterial genotypes is important for ecological outcomes. Toxin-producing strains largely eliminate susceptible non-producers when genotypes are well-mixed. However, printing strains side-by-side creates an ecological refuge such that susceptible strains can coexist with toxin producers, even to the extent that a susceptible strain outnumbers the toxin producer. Head-to-head competitions between toxin producers also reveals strong effects, where spatial structure can make the difference between one strain winning and mutual destruction. Finally, we print different potential barriers between two competing strains to understand why space is so important. This reveals the importance of processes that limit the free diffusion of molecules. Specifically, we show that cells closest to a toxin producer bind to and capture toxin molecules, which creates a refuge for their clonemates. Our work provides a new method to generate customised bacterial communities with defined spatial distributions, and reveals that micron-scale changes in these distributions can drive major shifts in their ecology.
Ribosome exit tunnel electrostatics
Authors: Joiret Marc , Rapino Francesca , Close Pierre , Geris Liesbet 
Published: October 2020

AbstractThe impact of the ribosome exit tunnel electrostatics on the protein elongation rate or on the forces acting upon the nascent polypeptide chain are currently not fully elucidated. In the past, researchers have measured the electrostatic potential inside the ribosome polypeptide exit tunnel at a limited number of spatial points, at least in prokaryotes. Here, we present a basic electrostatic model of the exit tunnel of the ribosome, providing a quantitative physical description of the tunnel interaction with the nascent proteins at all centro-axial points inside the tunnel. We show how the tunnel geometry causes a positive potential difference between the tunnel exit and entry points which impedes positively charged amino acid residues from progressing through the tunnel, affecting the elongation rate in a range of minus 40% to plus 85% when compared to the average elongation rate. The time spent by the ribosome to decode the genetic encrypted message is constrained accordingly. We quantitatively derived, at single residue resolution, the axial forces acting on the nascent peptide from its particular sequence embedded in the tunnel. The model sheds light on how the experimental data point measurements of the potential are linked to the local structural chemistry of the inner wall and the shape and size of the tunnel. The model consistently connects experimental observations coming from different fields in molecular biology, structural and physical chemistry, biomechanics, synthetic and multi-omics biology. Our model should be a valuable tool to gain insight into protein synthesis dynamics, translational control and into the role of the ribosome’s mechanochemistry in the co-translational protein folding.
The domain-within-domain packing of euchromatin can be described as multiplicative cascades
Authors: Noa Amra , Kuan Hui-Shun , Aschmann Vera , Zaburdaev Vasily , Hilbert Lennart 
Published: October 2020

ABSTRACTThe genome is packed into the cell nucleus in the form of chromatin. Biochemical approaches have revealed that chromatin is packed within domains, which group into larger domains, and so forth. Such domain-within-domain packing, also called hierarchical packing, is equally visible in super-resolution microscopy images of large-scale chromatin organization. While previous work has suggested that chromatin is partitioned into distinct domains via microphase separation, it is unclear how these domains organize into a hierarchical packing. A particular challenge is to find an image analysis approach that fully incorporates such hierarchical packing, so that hypothetical governing mechanisms of euchromatin packing can be compared against the results of such an analysis. Here, we obtain 3D STED super-resolution images from pluripotent zebrafish embryos labeled with improved DNA fluorescence stains, and demonstrate how the hierarchical packing of euchromatin in these images can be described as multiplicative cascades. Multiplicative cascades are an established theoretical concept to describe the placement of ever-smaller structures within bigger structures. Importantly, these cascades can generate artificial image data by applying a single rule again and again, and can be fully specified using only four parameters. Here, we show how the typical patterns of euchromatin organization are reflected in the values of these four parameters. In particular, we can pinpoint the values required to mimic a microphase-separated configuration of euchromatin. We suspect that the concept of multiplicative cascades can also be applied to images of other types of chromatin. In particular, cascade parameters could serve as test quantities to assess whether microphase separation or other theoretical models accurately reproduce the hierarchical packing of chromatin.SIGNIFICANCEDNA is stored inside the cell nucleus in the form of chromatin. Chromatin exhibits a striking three-dimensional organization, where small domains group into larger domains, which again group into larger domains, and so forth. While this hierarchical domain-within-domain organization is obvious from microscopy images, it is still not entirely clear how it is established, or how it should be properly characterized. Here, we demonstrate that multiplicative cascades – a concept from theoretical physics used to characterize for example cloud patterns, galaxy locations, or soil patterns – are also ideally suited to describe the domain-within-domain organization of chromatin. This description is rather simple, using only four numbers, and can thus facilitate testing of competing theories for the domain-within-domain organization of chromatin.
Satellite subgenomic particles are key regulators of adeno-associated virus life cycle
Authors: Zhang Junping , Guo Ping , Yu Xiangping , Lee Kiwon , Firrman Jenni , Chrzanowski Matthew , Chen Kuntao , Chen Xiongwen , Pouchnik Derek , Diao Yong , Samulski Richard Jude , Xiao Weidong 
Published: October 2020

AbstractHistorically, AAV defective interfering particles (DI) were known as abnormal virions arising from natural replication and encapsidation errors. Through single virion genome analysis, we revealed that a major category of DI particles contains a double stranded DNA genome in a “snapback” configuration (SBG). The 5’-SBGs include the P5 promoters and partial rep gene sequences. The 3’-SBGs contains the capsid region. The molecular configuration of 5’-SBGs allowed double stranded RNA transcription in their dimer configuration, which in turn regulate AAV rep expression and may improve AAV packaging. In contrast, 3’-SBGs at its dimer configuration increased levels of cap protein. The generation and accumulation of 5’-SBGs and 3’-SBGs appears to be coordinated to balance the viral gene expression level. Therefore, the functions of 5’-SBGs and 3’-SBGs may help maximize the yield of AAV progenies. We postulate that AAV virus population behaved as a colony and utilizes its subgenomic particles to overcome the size limit of viral genome and encodes additional essential functions.
Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice
Authors: Fuentealba Matias , Fabian Daniel K. , Dönertaş Handan Melike , Thornton Janet M. , Partridge Linda 
Published: October 2020

AbstractGenetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, yet the molecular mechanisms behind these opposite phenotypes remain largely unknown. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among whichPpargc1a,Mif,Aldh5a1andIdh1were frequently observed. Based on the gene sets with consistent changes and also the whole transcriptome, we observed that the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes.HighlightsTranscriptomic changes are more similar within mutant mice that show either lengthened or shortened lifespanThe major transcriptomic differences between long- and short-lived mice are in genes controlling mitochondrial metabolismGene expression changes in short-lived, progeroid, mutant mice resemble those seen during normal ageing
Impact of clade specific mutations on structural fidelity of SARS-CoV-2 proteins
Authors: Basu Souradip , Mukhopadhyay Suparba , Das Rajdeep , Mukhopadhyay Sarmishta , Singh Pankaj Kumar , Ganguli Sayak 
Published: October 2020

AbstractThe SARS-CoV-2 is a positive stranded RNA virus with a genome size of ~29.9 kilobase pairs which spans 29 open reading frames. Studies have revealed that the genome encodes about 16 non-structural proteins (nsp), four structural proteins, and six or seven accessory proteins. Based on prevalent knowledge on SARS-CoV and other coronaviruses, functions have been assigned for majority of the proteins. While, researchers across the globe are engrossed in identifying a potential pharmacological intervention to control the viral outbreak, none of the work has come up with new antiviral drugs or vaccines yet. One possible approach that has shown some positive results is by treating infected patients with the plasma collected from convalescent COVID-19 patients. Several vaccines around the world have entered their final trial phase in humans and we expect that these will in time be available for application to worldwide population to combat the disease. In this work we analyse the effect of prevalent mutations in the major pathogenesis related proteins of SARS-COV2 and attempt to pinpoint the effects of those mutations on the structural stability of the proteins. Our observations and analysis direct us to identify that all the major mutations have a negative impact in context of stability of the viral proteins under study and the mutant proteins suffer both structural and functional alterations as a result of the mutations. Our binary scoring scheme identifies L84S mutation in ORF8 as the most disruptive of the mutations under study. We believe that, the virus is under the influence of an evolutionary phenomenon similar to Muller’s ratchet where the continuous accumulation of these mutations is making the virus less virulent which may also explain the reduction in fatality rates worldwide.
Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity
Authors: Bui Linh T. , Winters Nichelle I. , Chung Mei-I , Joseph Chitra , Gutierrez Austin J. , Habermann Arun C. , Adams Taylor S. , Schupp Jonas C. , Poli Sergio , Peter Lance M. , Taylor Chase J. , Blackburn Jessica B. , Richmond Bradley W. , Nicholson Andrew G. , Rassl Doris , Wallace William A. , Rosas Ivan O. , Jenkins R. Gisli , Kaminski Naftali , Kropski Jonathan A. , Banovich Nicholas E. ,   the Human Cell Atlas Lung Biological Network
Published: October 2020

AbstractPatients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyzed the transcriptomes of 605,904 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observed a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD epithelial cells expressed higher levels of genes linked directly to the efficiency of viral replication and innate immune response. Additionally, we identified basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.
Glutamatergic neurons in the preoptic hypothalamus promote wakefulness, destabilize NREM sleep, suppress REM sleep, and regulate cortical dynamics
Authors: Mondino Alejandra , Hambrecht-Wiedbusch Viviane , Li Duan , York A. Kane , Pal Dinesh , González Joaquin , Torterolo Pablo , Mashour George A. , Vanini Giancarlo 
Published: October 2020

ABSTRACTClinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2+) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. Activation of preoptic glutamatergic neurons also causes a high degree of NREM sleep fragmentation, promotes state instability with frequent arousals from sleep, and shifts cortical dynamics (including oscillations, connectivity, and complexity) to a more wake-like state. We conclude that a subset of preoptic glutamatergic neurons may initiate -but not maintain- arousals from sleep, and their inactivation may be required for NREM stability and REM sleep generation. Further, these data provide novel empirical evidence supporting the conclusion that the preoptic area causally contributes to the regulation of both sleep and wakefulness.
Spatial Heterogeneity of Delta-like 4 Within a Multinucleated Niche Cell Maintains Muscle Stem Cell Diversity
Authors: Eliazer Susan , Sun Xuefeng , Brack Andrew S. 
Published: October 2020

SummaryThe quiescent muscle stem cell (QSC) pool is heterogeneous and generally characterized by the presence and levels of intrinsic myogenic transcription factors. Whether extrinsic factors maintain the diversity of states across the QSC pool remains unknown. The muscle fiber is a multinucleated syncytium that serves as a niche to QSCs, raising the possibility that the muscle fiber regulates the diversity of states across the QSC pool. Here we show that the muscle fiber maintains a continuum of quiescent states, through a gradient of Notch ligand, Dll4, produced by the fiber and captured by QSCs. The abundance of Dll4 captured by the QSC correlates with levels of the SC identity gene, Pax7. Niche-specific loss of Dll4 decreases QSC diversity and shifts the continuum, towards more proliferative and committed states. We reveal that fiber-derived Mindbomb1 (Mib1), an E3 ubiquitin ligase activates Dll4 and controls the spatial localization of Dll4. In response to injury, with a Dll4-replenished niche, the normal continuum and diversity of SC pool is restored, demonstrating bi-directionality within the SC continuum. Our data shows that a post-translational mechanism controls spatial heterogeneity of Notch ligands in a multinucleated niche cell to maintain a continuum of diverse states within the SC pool during tissue homeostasis.
The prion protein is not required for peripheral nerve repair after crush injury
Authors: Henzi Anna , Aguzzi Adriano 
Published: October 2020

AbstractThe cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve regeneration after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP.
Australian university and medical school life during the 1919 influenza pandemic
Authors: Waghorne James 
Published: October 2020

PurposeThis article examines the impact of the 1919 influenza pandemic on the life and culture of Australian universities, and the curious absence of sustained discussion about the crisis in university magazines. It considers two contexts, from the perspective of the general university population, and from the particular focus of medical students.Design/methodology/approachThe primary source for this analysis is based on detailed reading of university magazines across three universities, as well as other primary and secondary literature. The article was written during the 2020 COVID-19 pandemic, which has limited access to some other magazines held in library collections, but the corpus of material is more than sufficient.FindingsThis article shows that the pandemic further deferred the resumption of university life after a hiatus during the First World War. The failure to identify the causal agent limited technical discussion in medical school magazines.Originality/valueThis is one of the first dedicated studies of the effect of the 1919 influenza pandemic on Australian universities. It joins a growing body of work considering the effect of the influenza on different community groups.
Personal values and SME innovation in a Muslim ethnic group in Indonesia
Authors: Games Donard , Soutar Geoffrey , Sneddon Joanne 
Published: October 2020

PurposeThis study aims to examine the relationship between personal values and small and medium enterprise (SME) innovation in Minangkabau, a Muslim ethnic group in Indonesia.Design/methodology/approachA quantitative approach was used to survey 400 small business owners. Structural models were estimated using WarpPLS.FindingsThe study established that SME owners had mixed values. This highlights the context of entrepreneurship because it provides an understanding of the links between personal values and some innovation-related constructs.Research limitations/implicationsThe study made a little comparison of personal values in other Muslim societies. It is beneficial as a reference for future studies on comparisons between the Minangkabau and other ethnic Muslim groups.Practical implicationsMinangkabau small enterprise entrepreneurs need reflection on their values and business innovation because integrating these two aspects strengthens business identity.Social implicationsThe entrepreneurs may need to balance personal and socio-cultural values to implement both business innovation and social harmony successfully.Originality/valueTo the best of the authors’ knowledge, this is the first study that takes into account the innovation concept. It examines personal values related to some concepts on innovation. It can partly be explained by the high level of religiosity in the Minangkabau ethnic group.
Chemical repertoire and biosynthetic machinery of the Aspergillus flavus secondary metabolome: A review
Authors: Uka Valdet , Cary Jeffrey W. , Lebar Matthew D. , Puel Olivier , De Saeger Sarah , Diana Di Mavungu José 
Published: October 2020

AbstractFilamentous fungi represent a rich source of extrolites, including secondary metabolites (SMs) comprising a great variety of astonishing structures and interesting bioactivities. State‐of‐the‐art techniques in genome mining, genetic manipulation, and secondary metabolomics have enabled the scientific community to better elucidate and more deeply appreciate the genetic and biosynthetic chemical arsenal of these microorganisms. Aspergillus flavus is best known as a contaminant of food and feed commodities and a producer of the carcinogenic family of SMs, aflatoxins. This fungus produces many SMs including polyketides, ribosomal and nonribosomal peptides, terpenoids, and other hybrid molecules. This review will discuss the chemical diversity, biosynthetic pathways, and biological/ecological role of A. flavus SMs, as well as their significance concerning food safety and security.