bluuebunny/crossref_metadata_2025_split huggingface dataset:
From local resynchronization to global pattern recovery in the zebrafish segmentation clock
Authors: Uriu Koichiro , Liao Bo-Kai , Oates Andrew C. , Morelli Luis G. 
Published: June 2020

ABSTRACTRhythmic spatial gene expression patterns termed the segmentation clock regulate vertebrate body axis segmentation during embryogenesis. The integrity of these patterns requires local synchronization between neighboring cells by Delta-Notch signaling and its inhibition results in defective segment boundaries. The oscillating tissue deforms substantially throughout development, but whether such tissue-scale morphogenesis complements local synchronization during pattern generation and segment formation is not understood. Here, we investigate pattern recovery in the zebrafish segmentation clock by washing out a Notch inhibitor, allowing resynchronization at different developmental stages, and analyzing the recovery of normal segments. Although from previous work no defects are expected after recovery, we find that washing out at early stages causes a distinctive intermingling of normal and defective segments, suggesting unexpectedly large fluctuations of synchrony before complete recovery. To investigate this recovery behavior, we develop a new model of the segmentation clock combining key ingredients motivated by prior experimental observations: coupling between neighboring oscillators, a frequency profile, a gradient of cell mixing, tissue length change, and cell advection pattern. This model captures the experimental observation of intermingled normal and defective segments through the formation of persistent phase vortices of the genetic oscillators. Experimentally observed recovery patterns at different developmental stages are predicted by temporal changes of tissue-level properties, such as tissue length and cell advection pattern in the model. These results suggest that segmental pattern recovery occurs at two scales: local pattern formation and transport of these patterns through tissue morphogenesis, highlighting a generic mechanism of pattern dynamics within developing tissues.SIGNIFICANCEInteracting genetic oscillators can generate a coherent rhythm and a tissue-level pattern from an initially desynchronized state. Using experiment and theory we study resynchronization and pattern recovery of the zebrafish segmentation clock, which makes the embryonic body segments. Experimental perturbation of intercellular signaling with an inhibitor results in intermingled normal and defective segments. According to theory, this behavior may be caused by persistent local vortices scattered in the tissue during pattern recovery. Full pattern recovery follows dynamic global properties, such as tissue length and advection pattern, in contrast to other genetic oscillators in a static tissue such as circadian clocks. Our work highlights how dynamics of tissue level properties may couple to biochemical pattern formation in tissues and developing embryos.
Amino Sugars Reshape Interactions betweenStreptococcus mutansandStreptococcus gordonii
Authors: Chen Lulu , Walker Alejandro R. , Burne Robert A. , Zeng Lin 
Published: June 2020

ABSTRACTAmino sugars, particularly glucosamine (GlcN) and N-acetylglucosamine (GlcNAc), are abundant carbon and nitrogen sources that are continually supplied in host secretions and in the diet to the biofilms colonizing the human oral cavity. Evidence is emerging that these amino sugars provide ecological advantages to beneficial commensals over oral pathogens and pathobionts. Here, we performed transcriptome analysis onStreptococcus mutansandStreptococcus gordoniigrowing in single-species or dual-species cultures with glucose, GlcN or GlcNAc as the primary carbohydrate source. Compared to glucose, GlcN caused drastic transcriptomic shifts in each bacterium when they were cultured alone. Likewise, co-cultivation in the presence of GlcN yielded transcriptomic profiles that were dramatically different than the single-species results from GlcN-grown cells. In contrast, GlcNAc elicited only minor changes in the transcriptome of either organism in single- and dual-species cultures. Interestingly, genes involved in pyruvate metabolism were among the most significantly affected by GlcN in both species, and these changes were consistent with measurements of pyruvate in culture supernates. Differing from a previous report, growth ofS. mutansalone with GlcN inhibited expression of multiple operons required for mutacin production. Co-cultivation withS. gordoniiconsistently increased the expression byS. mutansof two manganese transporter operons (sloandmntH) and decreased expression of mutacin genes. Conversely,S. gordoniiappeared to be less affected by the presence ofS. mutans, but did show increases in genes for biosynthetic processes in the co-cultures. In conclusion, amino sugars profoundly alter the interactions between a pathogenic and commensal streptococcus by reprogramming central metabolism.IMPORTANCECarbohydrate metabolism is central to the development of dental caries. A variety of sugars available to dental microorganisms influence the development of caries by affecting the physiology, ecology, and pathogenic potential of tooth biofilms. Using two well-characterized oral bacteria, one pathogen (Streptococcus mutans) and one commensal (Streptococcus gordonii) in a RNA deep-sequencing analysis, we studied the impact of two abundant amino sugars on bacterial gene expression and interspecies interactions. The results indicated large-scale remodeling of gene expression induced by GlcN in particular, affecting bacterial energy generation, acid production, protein synthesis, and release of antimicrobial molecules. Our study provides novel insights into how amino sugars modify bacterial behavior, information that will be valuable in the design of new technologies to detect and prevent oral infectious diseases.
Epstein-Barr virus tegument protein BGLF2 in exosomes released from virus-producer cells assistsde novoinfection
Authors: Sato Yoshitaka , Yaguchi Masahiro , Okuno Yusuke , Ishimaru Hanako , Ozaki Somi , Suzuki Takeshi , Inagaki Tomoki , Umeda Miki , Watanabe Takahiro , Fujimuro Masahiro , Murata Takayuki , Kimura Hiroshi 
Published: June 2020

SummaryViruses must adapt to the environment of their host cells to establish infection and persist. Diverse mammalian cells, including virus-infected cells, secrete extracellular vesicles such as exosomes containing proteins and miRNAs, and use these vesicles to mediate intercellular communications. However, the roles of exosomes in viral infection remain unclear. Here we screened viral proteins to identify those responsible for the exosome-mediated upregulation of Epstein-Barr virus (EBV) infection. We found BGLF2 protein encapsulated in exosomes, which were released from EBV-infected cells. BGLF2 protein is a tegument protein that exists the space between the envelope and the nucleocapsid, and it is released into the cytoplasm shortly after infection. BGLF2 protein-containing exosomes enhanced viral gene expression and repressed innate immunity, thereby assisting the EBV infection. In summary, the EBV tegument protein BGLF2 is encapsulated not only encapsulated in viral particles, but also in exosomes secreted from infected cells. Therefore, BGLF2 may play a crucial role in establishing EBV latent infection.
A novelEnterococcus faecalisheme transport regulator (FhtR) is a heme sensor in the gastrointestinal tract
Authors: Saillant Vincent , Lipuma Damien , Ostyn Emeline , Joubert Laetitia , Boussac Alain , Guerin Hugo , Brandelet G. , Arnoux P. , Lechardeur Delphine 
Published: June 2020

AbstractEnterococcus faecalisis a commensal Gram-positive pathogen found in the intestines of mammals, and is also a leading cause of severe infections occurring mainly among antibiotic-treated dysbiotic hospitalized patients. Like most intestinal bacteria,E. faecalisdoes not synthesize heme. Nevertheless, environmental heme can improveE. faecalisfitness by activating respiration metabolism and a catalase that limits hydrogen peroxide stress. Since free heme also generates redox toxicity, its intracellular levels need to be strictly controlled. Here, we describe a unique transcriptional regulator, FhtR, (FaecalishemetransportRegulator), which manages heme homeostasis by controlling an HrtBA-like efflux pump (named HrtBAEf). We show that FhtR, by managing intracellular heme concentration, regulates the functional expression of the heme dependent catalase A (KatA), thus participating in heme detoxification. The biochemical features of FhtR binding to DNA, and its interactions with heme that induce efflux, are characterized. The FhtR-HrtBAEfsystem is shown to be relevant in a mouse intestinal model. We further show that FhtR senses heme from blood and hemoglobin but also from crossfeeding byEscherichia coli. These findings bring to light the central role of FhtR heme sensing in response to heme fluctuations within the gastrointestinal tract, which allow this pathogen to limit heme toxicity while ensuring expression of an oxidative defense system.ImportanceEnterococcus faecalis, a normal, harmless colonizer of the human intestinal flora can cause severe infectious diseases in immunocompromised patients, particularly those that have been heavily treated with antibiotics. Therefore, it is important to understand the factors that promote its resistance and its virulence. Here, we report a new mechanism used byE. faecalisto detect the concentration of heme, an essential but toxic metabolite that is present in the intestine.E. faecalisneeds to scavenge this molecule to respire and fight stress generated by oxydants. Heme sensing triggers the synthesis of a heme efflux pump that balances the amount of heme inside the bacteria. With this mechanism,E. faecaliscan use heme without suffering from its toxicity.
Inter-session repeatability of markerless motion capture gait kinematics
Authors: Kanko Robert M. , Laende Elise , Selbie W. Scott , Deluzio Kevin J. 
Published: June 2020

AbstractThe clinical uptake and influence of gait analysis has been hindered by inherent flaws of marker-based motion capture systems, which have long been the standard method for the collection of gait data including kinematics. Markerless motion capture offers an alternative method for the collection of gait kinematics that presents several practical benefits over marker-based systems. This work aimed to determine the reliability of lower limb gait kinematics from video based markerless motion capture using an established experimental protocol for testing reliability. Eight healthy adult participants performed three sessions of five over-ground walking trials in their own self-selected clothing, separated by an average of 8.5 days, while eight synchronized and calibrated cameras recorded video. 3D pose estimates from the video data were used to compute lower limb joint angles. Inter-session variability, inter-trial variability, and the variability ratio were used to assess the reliability of the gait kinematics. Relative to repeatability studies based on marker-based motion capture, inter-trial variability was slightly greater than previously reported for some angles, with an average across all joint angles of 2.2°. Inter-session variability was smaller on average than previously reported, with an average across all joint angles of 2.5°. Variability ratios were all smaller than those previously reported with an average of 1.2, indicating that the multi-session protocol increased the total variability of joint angles by only 20% of the inter-trial variability. These results indicate that gait kinematics measured using markerless tracking were less affected by multi-session protocols compared to marker-based motion capture.
Defining compartmentalized stem and progenitor populations with distinct cell division frequency in the ocular surface epithelium
Authors: Ishii Ryutaro , Yanagisawa Hiromi , Sada Aiko 
Published: June 2020

SummaryAdult tissues contain label-retaining cell (LRC)s, which are relatively slow-cycling and considered to represent a unique property of tissue stem cell (SC)s. In the ocular surface epithelium, LRCs are detected in the limbus, a boundary between cornea and conjunctiva, and the fornix of the conjunctiva; however, the character of LRCs and identity of SCs remain unclear due to lack of appropriate molecular markers. Here we show that the ocular surface epithelium accommodates spatially distinct stem/progenitor populations with different cell division frequency. By combining EdU pulse-chase analysis and lineage tracing with three CreER transgenic mouse lines: Slc1a3CreER, Dlx1CreERand K14CreER, we detect distinct dynamics of epithelial SCs in the cornea and conjunctiva. In the limbus, long-lived SCs are labeled with Slc1a3CreERand they either migrate centripetally toward the central cornea or laterally expand their clones within the limbal region. In the central cornea, cells are mostly non-LRCs, labeled by Dlx1CreERand K14CreER, and the number of clones declines after a short period of time with rare long-lasting clones, suggesting their properties as short-lived progenitor cells. In the conjunctival epithelium, which consists of bulbar, fornix and palpebral conjunctiva, each territory is regenerated by compartmentalized, distinct SC populations without migrating one region to another. The severe damage of the cornea leads to the cancellation of SC compartments, causing conjunctivalization of the eye, whereas milder limbal injury induces a rapid increase of laterally-expanding clones in the limbus. Taken together, our work provides lineage tracing tools of the eye and defines compartmentalized, multiple SC/progenitor populations in homeostasis and their behavioral changes in response to injury.
Monomeric amyloid β-peptide (1-42) significantly populates compact fibril-like conformations
Authors: Barz Bogdan , Buell Alexander K. , Nath Soumav 
Published: June 2020

AbstractThe aggregation of the amyloid β (Aβ) peptide is a major hallmark of Alzheimer’s disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest assembly units, and play an important role in most of the individual processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. The structure of the Aβ monomer has been shown to be very dynamic and mostly disordered, both in experimental and in computational studies, similar to a random coil. This structural state of the monomer contrasts with the very stable and well defined structural core of the amyloid fibrils. An important question is whether the monomer can adopt transient fibril-like conformations in solution and what role such conformations might play in the aggregation process. Here we use enhanced and extensive molecular dynamics simulations to study the Aβ42 monomer structural flexibility with different force fields, water models and salt concentrations. We show that the monomer behaves as a random coil under different simulation conditions. Importantly, we find a conformation with the N-terminal region structured very similarly to that of recent experimentally determined fibril models. This is to the best of our knowledge the first monomeric structural ensemble to show such a similarity with the fibril structure.
Molecular signaling pathways underlying schizophrenia
Authors: Tiihonen Jari , Koskuvi Marja , Lähteenvuo Markku , Trontti Kalevi , Ojansuu Ilkka , Vaurio Olli , Cannon Tyrone D. , Lönnqvist Jouko , Therman Sebastian , Suvisaari Jaana , Cheng Lesley , Tanskanen Antti , Taipale Heidi , Lehtonen Šárka , Koistinaho Jari 
Published: June 2020

AbstractThe molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. Studies using stem cell-derived neurons have investigated differentially expressed genes (DEGs) and GO and KEGG pathways between patients and controls, but not analyzed data-driven causal molecular pathways involved. We used Ingenuity Pathway Analysis (IPA) to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways,ADCYAP1, ADAMTS, andCACNAgenes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. In contrast, no dopamine-specific genes were consistently involved. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of anADCYAP1, ADAMTS, andCACNA-related pathway, compared to those time periods when the same individual did not use the drug. This association was not attributable to general adherence to drug treatments. The results from the two independent datasets suggest that the GP6 signaling pathway, and theADCYAP1, ADAMTS, andCACNA-related purine, oxidative stress, and glutamatergic signaling pathways are primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists – which have shown beneficial effects in an experimentalAdcyap1-/-mouse model for schizophrenia – could be potential treatments before the full manifestation of illness involving dopaminergic abnormalities.
Perturbed DNA methylation by sustained overexpression of Gadd45b induces chromatin disorganization, DNA strand breaks and dopaminergic neuron death in mice
Authors: Ravel-Godreuil Camille , Massiani-Beaudoin Olivia , Mailly Philippe , Prochiantz Alain , Joshi Rajiv L. , Fuchs Julia 
Published: June 2020

AbstractHeterochromatin disorganization is a key hallmark of aging and DNA methylation state is currently the main molecular predictor of chronological age. The most frequent neurodegenerative diseases like Parkinson disease and Alzheimer’s disease are age-related but how the aging process and chromatin alterations are linked to neurodegeneration is unknown. Here, we investigated the consequences of viral overexpression ofGadd45b, a multifactorial protein involved in active DNA demethylation, in the midbrain of wild-type mice.Gadd45boverexpression induces global and stable changes in DNA methylation, particularly on gene bodies of genes related to neuronal functions. DNA methylation changes were accompanied by perturbed H3K9me3-marked heterochromatin and increased DNA damage. ProlongedGadd45bexpression resulted in dopaminergic neuron degeneration accompanied by altered expression of candidate genes related to heterochromatin maintenance, DNA methylation or Parkinson disease.Gadd45boverexpression rendered midbrain dopaminergic neurons more vulnerable to acute oxidative stress. Heterochromatin disorganization and DNA demethylation resulted in derepression of mostly young LINE-1 transposable elements, a potential source of DNA damage, prior toGadd45b-induced neurodegeneration. Our data implicate that alterations in DNA methylation and heterochromatin organization, LINE-1 derepression and DNA damage can represent important contributors in the pathogenic mechanisms of dopaminergic neuron degeneration with potential implications for Parkinson disease.
Hapln1borganizes the ECM to modulatekitsignaling and control developmental hematopoiesis in zebrafish
Authors: Mahony Christopher B. , Pasche Corentin , Braunersreuther Vincent , Savvides Savvas N. , de Agostini Ariane , Bertrand Julien Y. 
Published: June 2020

AbstractDuring early vertebrate development, hematopoietic stem cells (HSCs) are produced from a hemogenic endothelium located in the dorsal aorta, before they migrate to a transient niche where they expand, the fetal liver and the caudal hematopoietic tissue (CHT), in mammals and zebrafish, respectively. In zebrafish, previous studies have shown that the extracellular matrix (ECM) around the aorta needs to be degraded to allow HSCs to leave the aortic floor and reach blood circulation. However, the role of the ECM components in HSC specification has never been addressed. We show here thathapln1b, a key component of the ECM is specifically expressed in hematopoietic sites in the zebrafish embryo. Gain- and loss-of-function experiments all resulted in the absence of HSCs in the early embryo, showing thathapln1bis required, at the correct level, to specify HSCs in the hemogenic endothelium. Furthermore, we show that the expression ofhapln1bis necessary to maintain the integrity of the ECM through its link domain. In addition, by combining functional analyses and computer modelling, we show thatkitlgbinteracts with the ECM, to specify HSCs. Overall, we have demonstrated that the ECM is an integral component of the microenvironment as it mediates specific cytokine signaling that is required for normal HSC specification.
Monoclonal anti-AMP-antibodies reveal broad and diverse AMPylation patterns in cancer cells
Authors: Höpfner Dorothea , Fauser Joel , Kaspers Marietta S. , Pett Christian , Hedberg Christian , Itzen Aymelt 
Published: June 2020

AbstractAMPylation is a post-translational modification that modifies amino acid side chains with adenosine monophosphate (AMP). Recent progress in the field reveals an emerging role of AMPylation as a universal regulatory mechanism in infection and cellular homeostasis, however, generic tools to study AMPylation are required. Here, we describe three monoclonal anti-AMP antibodies (mAbs) from mouse which are capable of protein backbone independent recognition of AMPylation, in denatured (Western Blot) as well as native (ELISA, IP) applications, thereby outperforming previously reported tools. These antibodies are highly sensitive and specific for AMP modifications, highlighting their potential as tools for new target identification, as well as for validation of known targets. Interestingly, applying the anti-AMP mAbs to various cancer cell lines reveals a previously undescribed broad and diverse AMPylation pattern. In conclusion, the anti-AMP mABs will aid the advancement of understanding AMPylation and the spectrum of modified targets.
Defining the lineage of thermogenic perivascular adipose tissue
Authors: Angueira Anthony R. , Sakers Alexander P. , Cheng Lan , Shrestha Rojesh , Okada Chihiro , Batmanov Kirill , Susztak Katalin , Seale Patrick 
Published: June 2020

SummaryBrown adipose tissue can expend large amounts of energy and thus increasing its amount or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood. Here, we applied single cell transcriptomic analyses,ex vivoadipogenesis assays, and genetic fate mappingin vivoto determine the identity of perivascular adipocyte progenitors. We found that thoracic PVAT initially develops from a fibroblastic lineage, comprising progenitor cells (Pdgfra+;Ly6a+;Pparg−) and preadipocytes (Pdgfra+;Ly6a−;Pparg+). Progenitors and preadipocytes in PVAT shared transcriptional similarity with analogous cell types in white adipose tissue, pointing towards a conserved adipose cell lineage hierarchy. Interestingly, the aortic adventitia of adult animals contained a novel population of adipogenic smooth muscle cells (Myh11+;Pdgfra−;Pparg+) possessing the capacity to generate adipocytesin vitroandin vivo. Taken together, these studies define distinct populations of fibroblastic and smooth muscle progenitor cells for thermogenic PVAT, providing a crucial foundation for developing strategies to augment brown fat activity.