bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimentally-Determined Strengths of Atom-Atom (C, N, O) Interactions Responsible for Protein Self-Assembly in Water: Applications to Folding and Other Protein Processes
Authors: Cheng Xian , Shkel Irina A. , O’Connor Kevin , Record M. Thomas 
Published: May 2020

AbstractFolding and other protein self-assembly processes are driven by favorable interactions between O, N, and C unified atoms of the polypeptide backbone and sidechains. These processes are perturbed by solutes that interact with these atoms differently than water does. C=O···HN hydrogen bonding and various π-system interactions have been better-characterized structurally or by simulations than experimentally in water, and unfavorable interactions are relatively uncharacterized. To address this situation, we previously quantified interactions of alkylureas with amide and aromatic compounds, relative to interactions with water. Analysis yielded strengths of interaction of each alkylurea with unit areas of different hybridization states of unified O, N, C atoms of amide and aromatic compounds. Here, by osmometry, we quantify interactions of ten pairs of amides selected to complete this dataset. A novel analysis yields intrinsic strengths of six favorable and four unfavorable atom-atom interactions, expressed per unit area of each atom and relative to interactions with water. The most favorable interactions are sp2O - sp2C (lone pair-π, presumably n-π*), sp2C - sp2C (π-π and/or hydrophobic), sp2O-sp2N (hydrogen bonding) and sp3C-sp2C (CH-π and/or hydrophobic). Interactions of sp3C with itself (hydrophobic) and with sp2N are modestly favorable, while sp2N interactions with sp2N and with amide/aromatic sp2C are modestly unfavorable. Amide sp2O-sp2O interactions and sp2O-sp3C interactions are more unfavorable, indicating the preference of amide sp2O to interact with water. These intrinsic interaction strengths are used to predict interactions of amides with proteins and chemical effects of amides (including urea, N-ethylpyrrolidone (NEP), and polyvinyl-pyrrolidone (PVP)) on protein stability.SignificanceQuantitative information about strengths of amide nitrogen-amide oxygen hydrogen bonds and π-system and hydrophobic interactions involving amide-context sp2and/or sp3carbons is needed to assess their contributions to specificity and stability of protein folds and assemblies in water, as well as to predict or interpret how urea and other amides interact with proteins and affect protein processes. Here we obtain this information from thermodynamic measurements of interactions between small amide molecules in water and a novel analysis that determines intrinsic strengths of atom-atom interactions, relative to water and per unit area of each atom-type present in amide compounds. These findings allow prediction or interpretation of effects of any amide on protein processes from structure, and may be useful to analyze protein interfaces.
Biologically excretable AIE dots for visualizing through the marmosets intravitally: horizons in future clinical nanomedicine
Authors: Feng Zhe , Bai Siyi , Qi Ji , Sun Chaowei , Zhang Yuhuang , Yu Xiaoming , Ni Huwei , Wu Di , Fan Xiaoxiao , Xue Dingwei , Liu Shunjie , Chen Ming , Gong Junyi , Wei Peifa , He Mubin , Lam Jacky W. Y. , Li Xinjian , Tang Ben Zhong , Gao Lixia , Qian Jun 
Published: May 2020

AbstractSuperb reliability and biocompatibility equip aggregation-induced emission (AIE) dots with tremendous potential for fluorescence bioimaging. However, there is still a chronic lack of design instructions of excretable and bright AIE emitters. Here, we designed a kind of PEGylated AIE (OTPA-BBT) dots with strong absorption and extremely high NIR-II PLQY as 13.6%, and proposed the long-aliphatic-chain design blueprint contributing to their excretion from animal body. Assisted by the OTPA-BBT dots with bright fluorescence beyond 1100 nm and even 1500 nm (NIR-IIb), large-depth cerebral vasculature (beyond 600 μm) as well as real-time blood flowing were monitored through-thinned-skull, and noninvasive NIR-IIb imaging with rich high-spatial-frequency information gave a precise presentation of gastrointestinal tract in marmosets. Importantly, after intravenous or oral administration, the definite excretion of OTPA-BBT dots from the body was demonstrated, which showed an influential evidence of bio-safety.
Anophelesmosquitoes revealed new principles of 3D genome organization in insects
Authors: Lukyanchikova Varvara , Nuriddinov Miroslav , Belokopytova Polina , Liang Jiangtao , Reijnders Maarten J.M.F. , Ruzzante Livio , Waterhouse Robert M. , Tu Zhijian , Sharakhov Igor V. , Fishman Veniamin 
Published: May 2020

AbstractChromosomes are hierarchically folded within cell nuclei into territories, domains and subdomains, but the functional importance and evolutionary dynamics of these hierarchies are poorly defined. Here, we comprehensively profiled genome organizations of fiveAnophelesmosquito species and showed how different levels of chromatin architecture influence contacts between genomic loci. Patterns observed on Hi-C maps are associated with known cytological structures, epigenetic profiles, and gene expression levels. At the level of individual loci, we identified specific, extremely long-ranged looping interactions, conserved for ~100 million years. We showed that the mechanisms underlying these looping contacts differ from previously described Polycomb-dependent interactions and clustering of active chromatin.
The TUTase URT1 connects decapping activators and prevents the accumulation of excessively deadenylated mRNAs to avoid siRNA biogenesis
Authors: Scheer Hélène , de Almeida Caroline , Ferrier Emilie , Simonnot Quentin , Poirier Laure , Pflieger David , Sement François M. , Koechler Sandrine , Piermaria Christina , Krawczyk Paweł , Mroczek Seweryn , Chicher Johana , Kuhn Lauriane , Dziembowski Andrzej , Hammann Philippe , Zuber Hélène , Gagliardi Dominique 
Published: May 2020

AbstractUridylation is a widespread modification destabilizing eukaryotic mRNAs. Yet, molecular mechanisms underlying TUTase-mediated mRNA degradation remain mostly unresolved. Here, we report that theArabidopsisTUTase URT1 participates in a molecular network connecting several translational repressors/decapping activators. URT1 directly interacts with DECAPPING 5 (DCP5), theArabidopsisortholog of human LSM14 and yeast Scd6, and this interaction connects URT1 to additional decay factors like DDX6/Dhh1-like RNA helicases. Nanopore direct RNA sequencing reveals a global role of URT1 in shaping poly(A) tail length, notably by preventing the accumulation of excessively deadenylated mRNAs. Based onin vitroandin plantadata, we propose a model that explains how URT1 could reduce the accumulation of oligo(A)-tailed mRNAs both by favoring their degradation and because 3’ terminal uridines intrinsically hinder deadenylation. Importantly, preventing the accumulation of excessively deadenylated mRNAs avoids the biogenesis of illegitimate siRNAs that silence endogenous mRNAs and perturbArabidopsisgrowth and development.
Multi-contrast Anatomical Subcortical Structures Parcellation
Authors: Bazin Pierre-Louis , Alkemade Anneke , Mulder Martijn J. , Henry Amanda G. , Forstmann Birte U. 
Published: May 2020

AbstractThe human subcortex is comprised of more than 450 individual nuclei which lie deep in the brain. Due to their small size and close proximity, up until now only 7% have been depicted in standard MRI atlases. Thus, the human subcortex can largely be considered as terra incognita. Here we present a new open source parcellation algorithm to automatically map the subcortex. The new algorithm has been tested on 17 prominent subcortical structures based on a large quantitative MRI dataset at 7 Tesla. It has been carefully validated against expert human raters and previous methods, and can easily be extended to other subcortical structures and applied to any quantitative MRI dataset. In sum, we hope this novel parcellation algorithm will facilitate functional and structural neuroimaging research into small subcortical nuclei and help to chart terra incognita.
Reprogramming of serine metabolism is an actionable vulnerability inFLT3-ITDdriven acute myeloid leukaemia
Authors: Bjelosevic Stefan , Gruber Emily , Newbold Andrea , Kats Lev M. , Shembrey Carolyn , Abrehart Thomas C. , Todorovski Izabela , Pomilio Giovanna , Wei Andrew H. , Gregory Gareth P. , Vervoort Stephin J. , Brown Kristin K. , Johnstone Ricky W. 
Published: May 2020

AbstractActivating FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The limited clinical efficacy of FLT3 inhibitor monotherapy has highlighted the need for alternative therapeutic targets and treatments for FLT3-mutant AML. Using human and murine models of MLL-rearranged AML harbouring FLT3 internal tandem duplication (FLT3-ITD) and primary patient samples, we have demonstrated that FLT3-ITD promotes serine uptake and serine synthesis via transcriptional regulation of neutral amino acid transporters (SLC1A4andSLC1A5) and genes in thede novoserine synthesis pathway (PHGDHandPSAT1). Mechanistically, dysregulation of serine metabolism in FLT3-mutant AML is dependent on the mTORC1-ATF4 axis, that drives RNA-Pol II occupancy atPHGDH, PSAT1, SLC1A4andSLC1A5. Genetic or pharmacological inhibition of thede novoserine synthesis pathway selectively inhibited the proliferation of FLT3-ITD AML cells, and this was potentiated by withdrawal of exogenous serine. Purine supplementation effectively rescued the antiproliferative effect of inhibitingde novoserine synthesis, consistent with the idea that serine fuels purine nucleotide synthesis in FLT3-mutant AML. Pharmacological inhibition of the de novo serine synthesis pathway, using the PHGDH inhibitor WQ-2101, sensitises FLT3-mutant AML cells to the standard of care chemotherapy agent cytarabine via exacerbation of DNA damage. Collectively, these data reveal new insights as to how FLT3 mutations reprogram metabolism in AML, and reveal a combination therapy strategy to improve the treatment of FLT3-mutant AML.Statement of SignificanceFLT3 mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine metabolism, thereby rendering FLT3-ITD leukemias dependent on serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-mutant AML to chemotherapy.
DNA polymerase epsilon is a central coordinator of heterochromatin structure and function in Arabidopsis
Authors: Bourguet Pierre , López-González Leticia , Gómez-Zambrano Ángeles , Pélissier Thierry , Hesketh Amy , Potok Magdalena E. , Pouch-Pélissier Marie-Noëlle , Perez Magali , Da Ines Olivier , Latrasse David , White Charles I. , Jacobsen Steven E. , Benhamed Moussa , Mathieu Olivier 
Published: May 2020

AbstractBackgroundChromatin organizes the DNA molecule and regulates its transcriptional activity through epigenetic modifications. Heterochromatic regions of the genome are generally transcriptionally silent while euchromatin is more prone to transcription. During DNA replication, both genetic information and chromatin modifications must be faithfully passed on to daughter strands. There is evidence that DNA polymerases play a role in transcriptional silencing, but the extent of their contribution and how it relates to heterochromatin maintenance is unclear.ResultsWe isolate a strong hypomorphic Arabidopsis thaliana mutant of the POL2A catalytic subunit of DNA polymerase epsilon and show that POL2A is required to stabilize heterochromatin silencing genome wide, likely by preventing replicative stress. We reveal that POL2A inhibits DNA methylation and histone H3 lysine 9 methylation. Hence, release of heterochromatin silencing in POL2A deficient mutants paradoxically occurs in a chromatin context of increased level of these two repressive epigenetic marks. At the nuclear level, POL2A defect is associated with fragmentation of heterochromatin.ConclusionThese results indicate that POL2A is critical to secure both heterochromatin structure and function. We also reveal that unhindered replisome progression is required for the faithful propagation of DNA methylation through the cell cycle.
A cortico-collicular circuit for accurate orientation to shelter during escape
Authors: Campagner Dario , Vale Ruben , Tan Yu Lin , Iordanidou Panagiota , Pavón Arocas Oriol , Claudi Federico , Stempel A. Vanessa , Keshavarzi Sepiedeh , Petersen Rasmus S. , Margrie Troy W. , Branco Tiago 
Published: May 2020

SUMMARYWhen faced with predatorial threats, escape towards shelter is an adaptive action that offers long-term protection against the attacker. From crustaceans to mammals, animals rely on knowledge of safe locations in the environment to instinctively execute rapid shelter-directed escape actions1,2. While previous work has identified neural mechanisms of escape initiation3–5, it is not known how the escape circuit incorporates spatial information to execute rapid flights along the most efficient route to shelter. Here we show that mouse retrosplenial cortex (RSP) and superior colliculus (SC) form a circuit that encodes shelter direction vector and is specifically required for accurately orienting to shelter during escape. Shelter direction is encoded in RSP and SC neurons in egocentric coordinates and SC shelter-direction tuning depends on RSP activity. Inactivation of the RSP-SC pathway disrupts orientation to shelter and causes escapes away from the optimal shelter-directed route, but does not lead to generic deficits in orientation or spatial navigation. We find that the RSP and SC are monosynaptically connected and form a feedforward lateral inhibition microcircuit that strongly drives the inhibitory collicular network due to higher RSP input convergence and synaptic integration efficiency in inhibitory SC neurons. This results in broad shelter direction tuning in inhibitory SC neurons and sharply tuned excitatory SC neurons. These findings are recapitulated by a biologically-constrained spiking network model where RSP input to the local SC recurrent ring architecture generates a circular shelter-direction map. We propose that this RSP-SC circuit might be specialized for generating collicular representations of memorized spatial goals that are readily accessible to the motor system during escape, or more broadly, during navigation when the goal must be reached as fast as possible.
Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity
Authors: Li Chushu , Yao Han , Wang Huanbin , Fang Jing-Yuan , Xu Jie 
Published: May 2020

SummaryCancer cell expression of PD-L1 leads to T cells exhaustion by transducing co-inhibitory signal, and further understanding the regulation of PD-L1 in cancer cells may provide additional therapeutic strategies. Here by drug repurposing screen we identified amlodipine as a potent inhibitor of PD-L1 expression in cancer cells. Further survey of calcium-associated pathways revealed calpains-dependent stabilization of the PD-L1 protein. Intracellular calcium delivered an operational signal to calpain-dependent Beclin-1 cleavage, blocking autophagic degradation of PD-L1 accumulated on recycling endosome (RE). Blocking calcium flux by amlodipine depleted PD-L1 expression and increased CD8+ T cell infiltration in tumor tissues but not in myocardium, causing dose-dependent tumor suppressionin vivo. Rescuing PD-L1 expression eliminated the effects of amlodipine, suggesting the PD-L1 dependent effect of amlodipine. These results reveal a calcium-dependent mechanism controlling PD-L1 degradation, and highlight calcium flux blockade as a potential strategy for combinatorial immunotherapy.
No evidence of phago-mixotropy in Micromonas polaris, the dominant picophytoplankton species in the Arctic
Authors: Jimenez Valeria , Burns John A. , Le Gall Florence , Not Fabrice , Vaulot Daniel 
Published: May 2020

ABSTRACTIn the Arctic Ocean, the small green alga Micromonas polaris dominates pico-phytoplankton during the summer months. It has been previously hypothesized to be phago-mixotrophic (capable of bacteria ingestion) based on laboratory and field experiments. Prey uptake was analysed in several M. polaris strains isolated from different regions and depths of the Arctic Ocean. Using both fluorescent beads and fluorescently labelled bacteria as prey, we found no evidence of phago-mixotrophy in any M. polaris strain by flow cytometric measurement of prey ingestion. In addition, in silico predictions reveal that members of the genus Micromonas lack a genetic signature of phagocytotic capacity.
Influenza C and D viral load in cattle correlates with bovine respiratory disease (BRD): Emerging role of orthomyxoviruses in the pathogenesis of BRD
Authors: Nissly Ruth H. , Zaman Noriza , Ibrahim Puteri Ainaa S. , McDaniel Kaitlin , Lim Levina , Kiser Jennifer N. , Bird Ian , Chothe Shubhada K. , Bhushan Gitanjali L. , Vandegrift Kurt , Neibergs Holly J. , Kuchipudi Suresh V. 
Published: May 2020

AbstractBovine respiratory disease (BRD) is the costliest disease affecting the cattle industry globally. Despite decades of research, the pathophysiology of BRD is not yet fully understood. It is widely believed that viruses predispose cattle to bacterial infection by causing direct damage to the respiratory tract and interfering with the immune system, leading to bacterial pneumonia. BRD remains a major challenge despite extensive vaccination against all major viral pathogens associated with the disease. Orthomyxoviruses (Influenza C & D viruses), have recently been found to infect cattle throughout the United States and are implicated to play a role in BRD. Here, we use the largest cohort study to date to investigate the association of influenza viruses in cattle with BRD. Cattle (n=599) from 3 locations were individually observed and scored for respiratory symptoms using the McGuirk scoring system. Deep pharyngeal and mid-nasal swabs were collected from each animal and were tested quantitatively for bovine viral diarrhea virus, bovine herpesvirus 1, bovine respiratory syncytial virus, bovine coronavirus, influenza C virus (ICV) and influenza D virus (IDV) by real-time PCR. Cattle that have higher viral loads of IDV and ICV also have greater numbers of co-infecting viruses than controls. More strikingly, in BRD-symptomatic cattle, the geometric mean of detectable IDV viral RNA was nearly 2 logs higher in co-infected animals (1.30×104) than those singly infected with IDV (2.19×102). This is strong evidence that viral coinfections can lead to higher replication of IDV. Our results strongly suggest that orthomyxoviruses may be significant contributors to BRD.
Towards the Target: Tilorone, Quinacrine and Pyronaridine Bind to Ebola Virus Glycoprotein
Authors: Lane Thomas R. , Ekins Sean 
Published: May 2020

AbstractPyronaridine, tilorone and quinacrine were recently identified by a machine learning model and demonstratedin vitroandin vivoactivity against Ebola virus (EBOV) and represent viable candidates for drug repurposing. These drugs were docked into the crystal structure of the ebola glycoprotein and then experimentally validatedin vitroto generate Kd values for tilorone (0.73 μM) pyronaridine (7.34 μM), and quinacrine (7.55 μM). These are more potent than the previously reported toremifene (16 μM).
Phenotypic changes of bacteria through opportunity and global methylation leads to antibiotic resistance
Authors: Neerathilingam Muniasamy , Mysore Sumukh , Bairy Sneha , Chandola Chetan , Varadharajan Venkadeshwari , Rajasekharan Ram 
Published: May 2020

AbstractThe antibiotic stress on bacteria leads to initiation of adaptive mechanisms, including exploiting the available opportunity, if any, for cell survival. In order to use the opportunity for survival while under threat, the microbe undergoes various mechanisms which are not completely known e.g. homologous recombination, horizontal gene transfer etc. Our aim is to understand the adaptive mechanism for cell survival during stress, especially antibiotic stress, inE. coliin the presence of opportunity. Understanding this mechanism in bacteria that gained resistance will help in identifying alternative survival pathways. By subjecting a recombination deficient (ΔRecA) strain of bacteria to antibiotic stress, we expected cell death, due to its inability to repair DNA damage (1, 2). Here we show that providing an opportunity in the form of an antibiotic resistance gene with homologous ends aids bacterial survival. There was 3-fold increase in cell envelope thickness along with 2.5-fold increase in phosphatidylethanolamine (PE) content, and enhanced antibiotic resistance to >4000µg/mL (Kan). We observed genome-wide alteration of methylation pattern that lead to changes in transcriptome, proteome, lipidome, and metabolite level, thus, leading to morphological and physiological changes. We prove that global methylation helps in survival of bacteria under stress that changes essential pathways like energy, cell envelope, lipids, amino acids acid, etc. leading to over production of cell wall components including synthesis of PE. By inhibiting the activity of methyltransferase, it is noticed that there is reduction in PE synthesis in agreement with demethylation. This proves that the phenotypic changes are caused due to the global methylation, and also demonstrates that demethylation could be used as a strategy to prevent antibiotic resistance in microbes.One Sentence SummaryGlobal methylation determines the survival of bacteria to gain the antimicrobial resistance with an opportunity
Comparative analysis of macrophage post-translational modifications during intracellular bacterial pathogen infection
Authors: Johnson Jeffrey R. , Parry Trevor , Repasy Teresa , Geiger Kristina M. , Verschueren Erik , Budzik Jonathan M. , Jimenez-Morales David , Newton Billy W. , Powell Emma , Coscoy Laurent , Portnoy Daniel A. , Krogan Nevan J. , Cox Jeffery S. 
Published: May 2020

SUMMARYMacrophages activate robust antimicrobial functions upon engulfing virulent bacteria, yet a wide array of pathogens paradoxically thrive within these innate immune cells. To probe the pathogen-macrophage interface, we used proteomics to comprehensively quantify changes in post-translational modifications (PTMs) of host proteins during infection with three evolutionarily diverse intracellular pathogens:Mycobacterium tuberculosis, Salmonella entericaserovar Typhimurium, andListeria monocytogenes. Comparing global phosphorylation and ubiquitylation patterns identified extensive reprogramming of cellular pathways during infection, with ubiquitylation patterns revealing unique pathogen-specific molecular response signatures undetectable by transcriptional profiling. Differential PTM changes during infection with attenuatedM. tuberculosiscells lacking the ESX-1 virulence determinant revealed extensive modification of phagosome dynamics and antiviral type I interferon activation. We found thatM. tuberculosis-mediated activation of the antiviral OASL1-IRF7 pathway promotes bacterial replication, uncovering a new mechanism of virus-bacterial synergy. Our data reveals remarkable specificity in innate cellular responses to complex stimuli and provides a resource for deeper understanding of host-pathogen interactions.