bluuebunny/crossref_metadata_2025_split huggingface dataset:
HSV Tegument Protein pUL51 Interacts with Host Dynactin for Viral Spread
Authors: White Shaowen , Tran My , Roller Richard J. 
Published: March 2022

AbstractDynein motors are microtubule associated protein complexes that mediate multiple essential cellular processes, such as long-distance cargo trafficking and stabilization of the microtubule organization center. Most of these functions and their regulations depend on the dynein motor subunit dynactin. By using an infection-inducible system, we disrupted dynein motor function after HSV entry by overexpressing a dominant-negative inhibitor of dynein, resulting in a 5-fold growth defect in Vero cells and 1000-fold growth defect in CAD neuronal cells. Also, we found that in infected CAD cells, the dynein complex was recruited to viral assembly sites regardless of microtubule polymerization. Based on these observations, we then identified a novel interaction between conserved HSV-1 tegument protein pUL51 and p150Glued. pUL51 is a palmitoylated Golgi membrane-associated protein that is required for efficient virus assembly and spread. Overexpression of pUL51 alone was sufficient to recruit p150Glued to Golgi membranes. Sequences that are important and sufficient for pUL51-p150Glued interaction were mapped to residues 90 to 124 in pUL51 and residues 548 to 911 in p150Glued. Deletion of a.a 90-124 in pUL51 resulted in a moderate viral growth defect, a profound spread defect, and failure to accumulate both dynactin and the viral spread factor glycoprotein E (gE) at cell-cell junctions. A synthetic peptide that contains pUL51 a.a 90-125 could also inhibit viral growth and spread in pUL51-dependent manner. Taken together, our results suggest that the proper function of pUL51 in efficient viral assembly and spread depends on its interaction with p150Glued.Author SummaryDuring their life-long infections, herpesviruses can spread within the human body in spite of a powerful immune response that includes antibodies that inactivate the virus. The virus accomplishes this by targeting its newly made infectious particles to junctions where infected cells meet their uninfected neighbors. Junctional targeting of virus particles requires that the virus hijack normal cellular machinery used for moving large cargoes within the cell, a process that is only partially understood. In this study, we have discovered a critical interaction between a virus protein that is present in all herpesviruses and a host cell cargo-moving protein that is required for virus spread between cells and shown that this interaction is common to several medically important human herpesviruses. We have also identified a short piece of this virus protein that is responsible for the interaction and shown that this short piece can be used to interrupt the interaction and prevent spread of herpes simplex virus (HSV) in cultured cells. Our study provides prove-of-concept evidence that the spread pathway of HSV, and possibly other herpesviruses, can be targeted for therapeutic purposes.
Toxoplasma gondii ROP1 subverts murine and human innate immune restriction
Authors: Butterworth Simon , Torelli Francesca , Lockyer Eloise J. , Wagener Jeanette , Song Ok-Ryul , Broncel Malgorzata , Russell Matt R. G. , Young Joanna C. , Treeck Moritz 
Published: March 2022

ABSTRACTToxoplasma gondii is an intracellular parasite that can infect many different host species and is a cause of significant human morbidity worldwide. T. gondii secretes a diverse array of effector proteins into the host cell which are critical for infection; however, the vast majority of these secreted proteins are uncharacterised. Here, we carried out a pooled CRISPR knockout screen in the T. gondii Prugniaud strain in vivo to identify secreted proteins that contribute to parasite immune evasion in the host. We identify 22 putative virulence factors and demonstrate that ROP1, the first-identified rhoptry protein of T. gondii, has a previously unrecognised role in parasite resistance to interferon gamma-mediated innate immune restriction. This function is conserved in the highly virulent RH strain of T. gondii and contributes to parasite growth in both murine and human macrophages. While ROP1 affects the morphology of rhoptries, from where the protein is secreted, it does not affect rhoptry secretion. ROP1 interacts with the host cell protein C1QBP, which appears to facilitate parasite immune evasion. In summary, we identify 22 secreted proteins which contribute to parasite growth in vivo and show that ROP1 is an important and previously overlooked effector in counteracting both murine and human innate immunity.
Phase separation of hnRNP A1 upon specific RNA-binding observed by magnetic resonance
Authors: Ritsch Irina , Lehmann Elisabeth , Emmanouilidis Leonidas , Yulikov Maxim , Allain Frédéric , Jeschke Gunnar 
Published: March 2022

AbstractInteraction of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) with specific single-stranded RNA and its relation to liquid-liquid phase separation were investigated in vitro by magnetic resonance based on site-directed spin labelling. An ensemble model of free hnRNP A1 in the absence of RNA was derived from distance distributions between spin labelled sites and small angle X-ray scattering. This model revealed a compact state of the low-complexity domain and interaction of this domain with the RNA recognition motifs. Paramagnetic relaxation enhancement NMR spectroscopy confirmed this interaction. The addition of RNA to dispersed solutions of hnRNP A1 induced phase separation, observed by formation of liquid droplets. The phase separation depended on the RNA concentration and sequence, with continuous wave EPR spectroscopy showing that local protein dynamics is affected by point mutations in the RNA sequence. We propose that an interplay of sequence-specific RNA binding and phase transition serves as a regulatory mechanism for RNA segregation in the stress response of cells.
Floating Sphere Assay: A rapid qualitative method for microvolume analysis of gelation
Authors: Tay Uma Jingxin , Goh Megan , Hui Jeralyn Ching Wen , Arumugam Prakash 
Published: March 2022

1AbstractA huge, unprecedented demand for gelatin coupled with its implications on global sustainability has resulted in the need to discover novel proteins with gelling attributes for applications in the food industry. Currently used gelation assays require large sample volumes and thus the screening for novel gelling proteins is a formidable technical challenge. In this paper, we report the ‘Floating Sphere Assay’ which is a simple, economical, and miniaturized assay to detect minimum gelling concentration with volumes as low as 50 μl. Results from the Floating Sphere Assay are consistent with currently used methods for gelation tests and accurately estimate the Minimum Gelling Concentrations (MGCs) of gelatin, κ-carrageenan and gellan gum. The assay was also able to differentiate the strengths of strong and weak gellan gum gels prepared at pH 3.5 and pH 7.0 respectively. The Floating Sphere Assay can be utilized in high-throughput screens for gelling proteins and can accelerate the discovery of gelatin substitutes.2HighlightsWe report the Floating Sphere Assay that can be used to assesses minimum gelling concentration of solutions with volumes as low as 50 μl.Observing whether a glass sphere placed on the surface of a test solution floats or sinks is diagnostic of gel formationFloating Sphere Assay can distinguish a strong gel from a weak gelFloating Sphere Assay is a rapid and cost-effective approach to screen for novel plant-based gelatin alternatives.
HDAC6 inhibitor ACY-1083 shows lung epithelial protective features in COPD
Authors: Horndahl Jenny , Svärd Rebecka , Berntsson Pia , Wingren Cecilia , Li Jingjing , Abdillahi Suado M , Ghosh Baishakhi , Capodanno Erin , Chan Justin , Ripa Lena , Åstrand Annika , Sidhaye Venkataramana K. , Collins Mia 
Published: March 2022

AbstractAirway epithelial damage is a common feature in respiratory diseases such as COPD and has been suggested to drive inflammation and progression of disease. These features manifest as remodeling and destruction of lung epithelial characteristics including loss of small airways which contributes to chronic airway inflammation. Histone deacetylase 6 (HDAC6) has been shown to play a role in epithelial function and dysregulation, such as in cilia disassembly, epithelial to mesenchymal transition (EMT) and oxidative stress responses, and has been implicated in several diseases. We thus used ACY-1083, an inhibitor with high selectivity for HDAC6, and characterized its effects on epithelial function including epithelial disruption, cytokine production, remodeling, mucociliary clearance and cell characteristics.Primary lung epithelial air-liquid interface cultures from COPD patients were used and the impacts of TNF, TGF-β, cigarette smoke and bacterial challenges on epithelial function in the presence and absence of ACY-1083 were tested. Each challenge increased the permeability of the epithelial barrier whilst ACY-1083 blocked this effect and even decreased permeability in the absence of challenge. TNF was also shown to increase production of cytokines and mucins, with ACY-1083 reducing the effect. We observed that COPD-relevant stimulations created damage to the epithelium as seen on immunohistochemistry sections and that treatment with ACY-1083 maintained an intact cell layer and preserved mucociliary function. Interestingly, there was no direct effect on ciliary beat frequency or tight junction proteins indicating other mechanisms for the protected epithelium.In summary, ACY-1083 shows protection of the respiratory epithelium during COPD-relevant challenges which indicates a future potential to restore epithelial structure and function to halt disease progression in clinical practice.
A neutrophil - B-cell axis governs disease tolerance during sepsis via Cxcr4
Authors: Gawish Riem , Maier Barbara B. , Obermayer Georg , Watzenböck Martin L. , Gorki Anna-Dorothea , Quattrone Federica , Farhat Asma , Lakovits Karin , Hladik Anastasiya , Korosec Ana , Alimohammadi Arman , Mesteri Ildiko , Oberndorfer Felicitas , Oakley Fiona , Brain John , Boon Louis , Lang Irene , Binder Christoph J. , Knapp Sylvia 
Published: March 2022

AbstractSepsis is a life-threatening condition characterized by uncontrolled systemic inflammation and coagulation, leading to multi-organ failure. Therapeutic options to prevent sepsis-associated immunopathology remain scarce.Here, we established a model of long-lasting disease tolerance during severe sepsis, manifested by diminished immunothrombosis and organ damage in spite of a high pathogen burden. We found that, both neutrophils and B cells emerged as key regulators of tissue integrity. Enduring changes in the transcriptional profile of neutrophils, included upregulated Cxcr4 expression in protected, tolerant hosts. Neutrophil Cxcr4 upregulation required the presence of B cells, suggesting that B cells promoted tissue tolerance by suppressing tissue damaging properties of neutrophils. Finally, therapeutic administration of a Cxcr4 agonist successfully promoted tissue tolerance and prevented liver damage during sepsis. Our findings highlight the importance of a critical B-cell/neutrophil interaction during sepsis and establish neutrophil Cxcr4 activation as a potential means to promote disease tolerance during sepsis.SummaryWe show that a B cell/neutrophil interaction in the bone marrow facilitates tissue tolerance during severe sepsis. By affecting neutrophil Cxcr4 expression, B cells can impact neutrophil effector functions. Finally, therapeutic activation of Cxcr4 successfully promoted tissue tolerance and prevented liver damage during sepsis.
Deep learning models for RNA secondary structure prediction (probably) do not generalise across families
Authors: Szikszai Marcell , Wise Michael , Datta Amitava , Ward Max , Mathews David H. 
Published: March 2022

AbstractMotivationThe secondary structure of RNA is of importance to its function. Over the last few years, several papers attempted to use machine learning to improve de novo RNA secondary structure prediction. Many of these papers report impressive results for intra-family predictions, but seldom address the much more difficult (and practical) inter-family problem.ResultsWe demonstrate it is nearly trivial with convolutional neural networks to generate pseudo-free energy changes, modeled after structure mapping data, that improve the accuracy of structure prediction for intra-family cases. We propose a more rigorous method for inter-family cross-validation that can be used to assess the performance of learning-based models. Using this method, we further demonstrate that intra-family performance is insufficient proof of generalisation despite the widespread assumption in the literature, and provide strong evidence that many existing learning-based models have not generalised inter-family.AvailabilitySource code and data is available at https://github.com/marcellszi/dl-rna.
Systematic analysis of YFP gene traps reveals common discordance between mRNA and protein across the nervous system
Authors: Titlow Joshua S , Kiourlappou Maria , Palanca Ana , Lee Jeffrey Y , Gala Dalia S , Ennis Darragh , Yu Joyce J S , Young Florence L , Susano Pinto David Miguel , Garforth Sam , Francis Helena S , Strivens Finn , Mulvey Hugh , Dallman-Porter Alex , Thornton Staci , Arman Diana , Järvelin Aino I , Thompson Mary Kay , Kounatidis Ilias , Parton Richard M , Taylor Stephen , Davis Ilan 
Published: March 2022

SummaryWhile post-transcriptional control is thought to be required at the periphery of neurons and glia, its extent is unclear. Here, we investigate systematically the spatial distribution and expression of mRNA at single molecule sensitivity and their corresponding proteins of 200 YFP trap protein trap lines across the intact Drosophila nervous system. 98% of the genes studied showed discordance between the distribution of mRNA and the proteins they encode in at least one region of the nervous system. These data suggest that post-transcriptional regulation is very common, helping to explain the complexity of the nervous system. We also discovered that 68.5% of these genes have transcripts present at the periphery of neurons, with 9.5% at the glial periphery. Peripheral transcripts include many potential new regulators of neurons, glia and their interactions. Our approach is applicable to most genes and tissues and includes powerful novel data annotation and visualisation tools for post-transcriptional regulation.Brief outlineA novel high resolution and sensitive approach to systematically co-visualise the distribution of mRNAs and proteins in the intact nervous system reveals that post-transcriptional regulation of gene expression is very common. The rich data landscape is provided as a browsable resource (link), using Zegami, a cloud-based data exploration platform (link). Our solution provides a paradigm for the characterisation of post-transcriptional regulation of most genes and model systems.Highlights196/200 (98%) Drosophila genes show discordant RNA and protein expression in at least one nervous system region137/200 (68.5%) mRNAs are present in at least one synaptic compartmentNovel localised mRNA and protein discovered in periphery of glial processesNew paradigm for analysis of post-transcriptional regulation and data exploration
Molecular drivers of insecticide resistance in the Sahelo-Sudanian populations of a major malaria vectorAnopheles coluzzii
Authors: Ibrahim Sulaiman S. , Muhammad Abdullahi , Hearn Jack , Weedall Gareth D. , Nagi Sanjay C. , Mukhtar Muhammad M. , Fadel Amen N. , Mugenzi Leon J. , Patterson Edward I. , Irving Helen , Wondji Charles S. 
Published: March 2022

AbstractInformation on common markers of metabolic resistance in malaria vectors from countries sharing similar eco-climatic characteristics can facilitate coordination of malaria control. Here, we characterized populations of the major malaria vectorAnopheles coluzziifrom Sahel region, spanning four sub-Saharan African countries: Nigeria, Niger, Chad and Cameroon. Genome-wide transcriptional analysis identified major genes previously implicated in pyrethroid and/or cross resistance to other insecticides, overexpressed across the Sahel, including CYP450s, glutathione S-transferases, carboxylesterases, and cuticular proteins. Several, well-known markers of insecticide resistance were found in high frequencies - including in the voltage-gated sodium channel (V402L, I940T, L995F, I1527T and N1570Y), theacetylcholinesterase-1 gene (G280S) and theCYP4J5-L43F (fixed). High frequencies of the epidemiologically important chromosomal inversions, 2La, 2Rb and 2Rc were observed (∼80% for 2Rb and 2Rc). The 2La alternative arrangement is fixed across the Sahel. Low frequencies of these inversions (<10%) were observed in the fully insecticide susceptible laboratory colony ofAn. coluzzii(Ngoussou). Several of the most commonly overexpressed metabolic resistance genes sit in these three inversions. Two commonly overexpressed genes,GSTe2andCYP6Z2were functionally validated. TransgenicDrosophila melanogasterexpressingGSTe2exhibited extremely high DDT and permethrin resistance (mortalities < 10% in 24 h). Serial deletion of the 5’ intergenic region, to identify putative nucleotide(s) associated withGSTe2overexpression, revealed that simultaneous insertion of adenine nucleotide and a transition (T->C), between Fork-head box L1 and c-EST putative binding sites were responsible for the high overexpression ofGSTe2in the resistant mosquitoes. Transgenic flies expressingCYP6Z2exhibited marginal resistance towards 3-phenoxybenzylalcohol (a primary product of pyrethroid hydrolysis by carboxylesterases) and a type II pyrethroid, α-cypermethrin. However, significantly higher mortalities were observed inCYP6Z2transgenic flies compared with controls, on exposure to the neonicotinoid, clothianidin. This suggests a possible bioactivation of clothianidin into a toxic intermediate, which if true make it an ideal insecticide against populations ofAn. coluzziioverexpressing this P450. These findings will facilitate regional collaborations within the Sahel region, and refine implementation strategies through re-focusing interventions, improving evidence-based, cross-border policy towards local and regional malaria pre-elimination.
Personality variation is eroded by simple social behaviours in collective foragers
Authors: Rands Sean A. , Ioannou Christos C. 
Published: March 2022

ABSTRACTThe movement of groups can be heavily influenced by ‘leader’ individuals who differ from the others in some way. A major source of differences between individuals is the repeatability and consistency of their behaviour, commonly considered as their ‘personality’, which can influence both position within a group as well as the tendency to lead. However, links between personality and behaviour may also depend upon the immediate social environment of the individual; individuals who behave consistently in one way when alone may not express the same behaviour socially, when they may be conforming with the behaviour of others. Experimental evidence shows that personality differences can be eroded in social situations, but there is currently a lack of theory to identify the conditions where we would expect personality to be suppressed. Here, we develop a simple individual-based framework considering a small group of individuals with differing tendencies to perform risky behaviours when travelling away from a safe home site towards a foraging site, and compare the group behaviours when the individuals follow differing rules for aggregation behaviour determining how much attention they pay to the actions of their fellow group-members. We find that if individuals pay attention to the other members of the group, the group will tend to remain at the safe site for longer, but then travel faster towards the foraging site. This demonstrates that simple social behaviours can result in the repression of consistent inter-individual differences in behaviour, giving the first theoretical consideration of the social mechanisms behind personality suppression.
Multisensory integration in neurons of the medial pulvinar of macaque monkey
Authors: Vittek Anne-Laure , Juan Cécile , Nowak Lionel G. , Girard Pascal , Cappe Céline 
Published: March 2022

SummaryThe pulvinar is a heterogeneous thalamic nucleus, which is well developed in primates. One of its subdivisions, the medial pulvinar, is connected to many cortical areas, including the visual, auditory and somatosensory cortices, as well as with multisensory areas and premotor areas. However, except for the visual modality, little is known about its sensory functions. A hypothesis is that, as a region of convergence of information from different sensory modalities, the medial pulvinar plays a role in multisensory integration. To test this hypothesis, two macaque monkeys were trained to a fixation task and the responses of single-units to visual, auditory and auditory-visual stimuli were examined. Analysis revealed auditory, visual and multisensory neurons in the medial pulvinar. It also revealed multisensory integration in this structure, mainly subadditive and suppressive. These findings show that the medial pulvinar is involved in multisensory integration.
Sleep Deprivation Induces Acute Dissociation via Altered EEG Rhythms Expression and Connectivity
Authors: Menicucci Danilo , Cesari Valentina , Cipriani Enrico , Piarulli Andrea , Gemignani Angelo 
Published: March 2022

AbstractThe fragmented sleep, fragmented mind hypothesis has associated sleep disturbances and dissociative states in subjects with dissociative traits, as supported by neurophysiological theories of consciousness stating that altered states might result from an altered functional interaction among brain modules due to inefficient sleep processes.Irrespective of dissociative traits, it is conceivable that a labile sleep-wake cycle might fuel dissociative states such as derealization, depersonalization, and dissociative amnesia.To verify whether acute sleep loss can prompt dissociative states and to identify possible psychophysiological correlates, we evaluated dissociative experiences (by means of Phenomenology of Consciousness Inventory and Clinician Administered Dissociative State Scale) and resting state EEG features (band-wise spectral content and phase synchronization) after total sleep deprivation.After deprivation, participants reported increased perception of altered state of consciousness and dissociative experiences, and a decreased perception of cognitive control. Analyzing the psychophysiological correlates of dissociative states following deprivation, we observed the following results: the higher the prefrontal theta spectral content, the higher the depersonalization state and the lower the self-awareness; the higher the intensity of the dissociative experiences, the higher the synchronization increase in alpha, beta, and gamma bands; the higher the decrease of higher-order functions, the higher the synchronization in the aforementioned bands.Thus, acute sleep deprivation appears to fuel dissociative experiences by establishing a state of consciousness promoted by a higher large-scale synchronization at high frequencies.