bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted V1 comodulation supports task-adaptive sensory decisions
Authors: Haimerl Caroline , Ruff Douglas A. , Cohen Marlene R. , Savin Cristina , Simoncelli Eero P. 
Published: February 2021

AbstractSensory-guided behavior requires reliable encoding of stimulus information in neural populations, and task-specific readout through a selective combination of these responses. The former has been the topic of extensive study, but the means by which the brain achieves the latter remain poorly understood, especially when adapting to changing task demands. Here we introduce a novel theory for adaptive sensory processing based on functionally-targeted stochastic modulation. We find that responses of neurons in area V1 of monkeys performing a visual orientation discrimination task exhibit low-dimensional, rapidly fluctuating gain modulation, which is stronger in neurons that are most informative for the current behavioral task. We propose that this modulation serves as a label that supports adaptive downstream readout. Our theoretical and experimental results show that V1 modulation can be used to decode from neural activity after only a small number of training trials, consistent with observed behavior. In a hierarchical visual neural network model, the modulator-induced labels are learned quickly and accompany task information across several processing stages to finally guide decisions. Consistent with this model, we find that the V1 modulatory signal is also present in the activity of simultaneously recorded MT units, and that its label of task information is preserved. Our findings provide evidence for a novel mechanism for task-adaptive information routing in the brain, through targeted co-modulation.
Single-cell sequencing characterizes intratumoral profile of immune cells in old mice
Authors: Zhang Cangang , Lei Lei , Yang Xiaofeng , Zheng Huiqiang , Su Yanhong , Jiao Anjun , Wang Xin , Liu Haiyan , Zou Yujing , Shi Lin , Zhou Xiaobo , Sun Chenming , Zhang Lianjun , Hou Yuzhu , Xiao Zhengtao , Zhang Baojun 
Published: February 2021

AbstractIt has long been thought that aging is a major risk factor for cancer incidence. However, accumulating evidence indicates increased resistance of old animals to tumor growth. A systematic understanding of how old individuals defend against tumor invasion is currently lacking. Here we investigated the differences of age-associated alterations in tumor-infiltrating immune cells between young and old mice using single-cell RNA analysis. Our results showed that a higher proportion of cytotoxic CD8+T cells, nTregs, cDC, and M1-type macrophages, while a higher percentage of exhausted CD8+T cells, iTregs, pDC, and M2-type macrophages were found in young mice. Importantly, TCR diversity analysis showed top 10 TCR clones consisted primarily of exhausted CD8+T cells in young mice whereas tip clones were predominantly cytotoxic CD8+T cells in old mice. Consistently, trajectory inference demonstrated that CD8+T cells preferentially differentiated into cytotoxic cells in old mice in contrast to exhausted cells in young mice. Meanwhile, we confirmed the main distinctions between young and old mice by flow cytometry. Collectively, our data revealed that a significantly higher proportion of effector immune cells in old mice defend against tumor progression, providing a framework for the immunotherapy of elderly patients with tumors.
Clinical Phage Microbiology: A suggestedin-vitroframework for phage therapy
Authors: Gelman Daniel , Yerushalmy Ortal , Ben-Porat Shira , Rakov Chani , Alkalay-Oren Sivan , Adler Karen , Khalifa Leron , Abdalrhman Mohanad , Coppenhagen-Glazer Shunit , Aslam Saima , Schooley Robert T , Nir-Paz Ran , Hazan Ronen 
Published: February 2021

AbstractPersonalized-phage-therapy is a promising solution for the emerging crisis of bacterial infections that fail to be eradicated by conventional antibiotics.One of the most crucial elements of personalized-phage-therapy is the proper matching of phages and antibiotics to the target bacteria in a given clinical setting. However, to date, there is no consensus guideline for laboratory procedures that enablein vitroevaluation of phages intended for treatment.In this work, we suggest a framework and strategies identify appropriate phages and combine them with antibiotics in clinical microbiology laboratories. This framework, which we term here “Clinical Phage Microbiology” is based on our experience and other previously reported cases of both, successful and failed phage treatments.Additionally, we discuss troubleshooting methodologies for possible pitfalls and special cases that may need to be assessed before treatment including interactions with the host immune system, biofilms, and polymicrobial infections.We believe that the “Clinical Phage Microbiology” pipeline presented here should serve as the basis for standardization of laboratory protocols to match phages for personalized therapy.
p16-3MR: a novel model to study cellular senescence in cigarette smoke-induced lung injuries during aging
Authors: Kaur Gagandeep , Sundar Isaac K. , Rahman Irfan 
Published: February 2021

ABSTRACTCellular senescence and lung aging are associated with the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to study cellular senescence in relation to age-related lung pathologies is the lack of a suitablein vivomodel. In view of this, we provide evidence that supports the suitability of p16-3MR mice to study cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice has a trimodal reporter fused to the promoter of p16INK4agene that enables detection, isolation and selective elimination of senescent cells, thus making it a suitable model to study cellular senescence. To determine its suitability in CS-mediated lung pathologies, we exposed young (12-14 months) and old (17-20 months) p16-3MR mice to 30-day CS exposure and studied the expression of senescent genes (p16, p21 and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-challenged young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-challenged young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed age-dependent alteration in the (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-challenged young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model to study cellular senescence in age-related pathologies and could help understand the pathobiology of cellular senescence in lung conditions like COPD and fibrosis.
Chaperones Skp and SurA dynamically expand unfolded outer membrane protein X and synergistically disassemble oligomeric aggregates
Authors: Chamachi Neharika , Hartmann Andreas , Ma Mai Quynh , Krainer Georg , Schlierf Michael 
Published: February 2021

AbstractPeriplasmic chaperones Skp and SurA are essential players in outer membrane protein (OMP) biogenesis. They prevent unfolded OMPs from misfolding during their passage through the periplasmic space and aid in the disassembly of OMP aggregates under cellular stress conditions. However, functionally important links between interaction mechanisms, structural dynamics, and energetics that underpin both Skp and SurA association with OMPs have remained largely unresolved. Here, using single-molecule fluorescence spectroscopy, we dissect the conformational dynamics and thermodynamics of Skp and SurA binding to unfolded OmpX, and explore their disaggregase activities. We show that both chaperones expand unfolded OmpX distinctly and induce microsecond chain reconfigurations in the client OMP structure. We further reveal that Skp and SurA bind their substrate in a fine-tuned thermodynamic process via enthalpy–entropy compensation. Finally, we observed synergistic activity of both chaperones in the disaggregation of oligomeric OmpX aggregates. Our findings provide an intimate view into the multi-faceted functionalities of Skp and SurA and the fine-tuned balance between conformational flexibility and underlying energetics in aiding chaperone action during OMP biogenesis.
A more accurate method for colocalisation analysis allowing for multiple causal variants
Authors: Wallace Chris 
Published: February 2021

AbstractIn genome-wide association studies (GWAS) it is now common to search for, and find, multiple causal variants located in close proximity. It has also become standard to ask whether different traits share the same causal variants, but one of the popular methods to answer this question, coloc, makes the simplifying assumption that only a single causal variant exists for any given trait in any genomic region. Here, we examine the potential of the recently proposed Sum of Single Effects (SuSiE) regression framework, which can be used for fine-mapping genetic signals, for use with coloc. SuSiE is a novel approach that allows evidence for association at multiple causal variants to be evaluated simultaneously, whilst separating the statistical support for each variant conditional on the causal signal being considered. We show this results in more accurate coloc inference than other proposals to adapt coloc for multiple causal variants based on conditioning. We therefore recommend that coloc be used in combination with SuSiE to optimise accuracy of colocalisation analyses when multiple causal variants exist.
Adult zebrafish anaesthesia: a study of efficacy and behavioural recovery of different anaesthetics
Authors: Jorge Sara , Ferreira Jorge M , Olsson I Anna S , Valentim Ana M 
Published: February 2021

AbstractThe use of proper anaesthesia in zebrafish research is essential to ensure fish welfare and data reliability. However, anaesthesia long-term side effects remain poorly understood. The purpose of this study was to assess anaesthesia quality and recovery in adult zebrafish using different anaesthetic protocols and to determine possible long-term effects on the fish activity and anxiety-like behaviours after anaesthesia.Mixed sex adult AB zebrafish were randomly assigned to 5 different groups (control, 175mg/L MS222, 45 mg/L clove oil, 2 mg/L etomidate and 5mg/L propofol combined with 150mg/L lidocaine) and placed in the respective anaesthetic bath. Time to lose the equilibrium, response to touch and to tail pinch stimuli, and recovery after anaesthesia administration were evaluated. In addition, after stopping anaesthesia, respiratory rate, activity and anxiety-like behaviours in the novel tank test were studied.Overall, all protocols proved to be adequate for zebrafish anaesthesia research as they showed full recovery at 1h, and only etomidate had minor effects on fish behaviour in the novel tank, a validated test for anxiety.
The periodic axon membrane skeleton leads to high-density sodium nanodomains but does not impact action potentials
Authors: Chai Zhaojie , Tzingonunis Anastasios V. , Lykotrafitis George 
Published: February 2021

ABSTRACTRecent work has established that axons have a periodic skeleton structure comprising of azimuthal actin rings connected via longitudinal spectrin tetramer filaments. This structure endows the axon with structural integrity and mechanical stability. Additionally, voltage-gated sodium channels follow the periodicity of the active-spectrin arrangement, spaced ∼190 nm segments apart. The impact of this periodic sodium channel arrangement on the generation and propagation of action potentials is unknown. To address this question, we simulated an action potential using the Hodgkin-Huxley formalism in a cylindrical compartment but instead of using a homogeneous distribution of voltage-gated sodium channels in the membrane, we applied the experimentally determined periodic arrangement. We found that the periodic distribution of voltage-gated sodium channels does not significantly affect the generation or propagation of action potentials, but instead leads to high-density sodium channel nanodomains. This work provides a foundation for future studies investigating the role of the voltage-gated sodium channel periodic arrangement in the axon.
Protocol for mapping the spatial variability in cell wall mechanical bending behavior in living leaf pavement cells
Authors: Li Wenlong , Keynia Sedighe , Belteton Samuel A. , Afshar-Hatam Faezeh , Szymanski Daniel B. , Turner Joseph A. 
Published: February 2021

AbstractAn integrated, experimental-computational approach is presented to analyze the variation of elastic bending behavior in the primary cell wall of livingArabidopsis thalianapavement cells and to measure turgor pressure in the cells quantitatively under different osmotic conditions. Mechanical properties, size and geometry of cells and internal turgor pressure greatly influence their morphogenesis. Computational models of plant morphogenesis require values for wall elastic modulus and turgor pressure but very few experiments were designed to validate the results using measurements that deform the entire thickness of the cell wall. Because new wall material is deposited from inside the cell, full-thickness deformations are needed to quantify relevant changes associated with cell development. The approach here uses laser scanning confocal microscopy to measure the three-dimensional geometry of a single pavement cell, and indentation experiments equipped with high magnification objective lens to probe the local mechanical responses across the same cell wall. These experimental results are matched iteratively using a finite element model of the experiment to determine the local mechanical properties, turgor pressure, and cell height. The resulting modulus distribution along the periclinal wall is shown to be nonuniform. These results are consistent with the characteristics of plant cell walls which have a heterogeneous organization. This research and the resulting model will provide a reference for future work associated with the heterogeneity and anisotropy of mechanical properties of plant cell walls in order to understand morphogenesis of the primary cell walls during growth and to predict quantitatively the magnitudes/directions of cell wall forces.One sentence summaryThe distribution of elastic modulus of the periclinal cell walls of livingArabidopsisepidermis is nonuniform as measured by bending the entire thickness of the wall.HighlightsExperimental characterization of the spatial distribution of elastic bending behavior across the periclinal wallQuantification of the turgor pressure of the living plant epidermal cells validated with osmotic treatmentsQuantification of the effect of cell geometry on the measured mechanical responseGraphical abstract
A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis
Authors: de Cevins Camille , Luka Marine , Smith Nikaïa , Meynier Sonia , Magérus Aude , Carbone Francesco , García-Paredes Víctor , Barnabei Laura , Batignes Maxime , Boullé Alexandre , Stolzenberg Marie-Claude , Pérot Brieuc P. , Charbit Bruno , Fali Tinhinane , Pirabarakan Vithura , Sorin Boris , Riller Quentin , Abdessalem Ghaith , Beretta Maxime , Grzelak Ludivine , Goncalves Pedro , Di Santo James P. , Mouquet Hugo , Schwartz Olivier , Zarhrate Mohammed , Parisot Mélanie , Bole-Feysot Christine , Masson Cécile , Cagnard Nicolas , Corneau Aurélien , Bruneau Camille , Zhang Shen-Ying , Casanova Jean-Laurent , Meunier Brigitte Bader , Haroche Julien , Melki Isabelle , Lorrot Mathie , Oualha Mehdi , Moulin Florence , Bonnet Damien , Belhadjer Zahra , Leruez Marianne , Allali Slimane , Leguen Christèle Gras , de Pontual Loïc ,   Pediatric-Biocovid Study Group, Fischer Alain , Duffy Darragh , Laucat Fredéric Rieux- , Toubiana Julie , Ménager Mickaël M. 
Published: February 2021

AbstractSARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κB activity, TNF-α signaling, associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology.
Deletion ofFibroblast growth factor 9globally and in skeletal muscle results in enlarged tuberosities at sites of deltoid tendon attachments
Authors: Leek Connor C. , Soulas Jaclyn M. , Bhattacharya Iman , Ganji Elahe , Locke Ryan C. , Smith Megan C. , Bhavsar Jaysheel D. , Polson Shawn W. , Ornitz David M. , Killian Megan L. 
Published: February 2021

AbstractThe growth of most bony tuberosities, like the deltoid tuberosity (DT), rely on the transmission of muscle forces at the tendon-bone attachment during skeletal growth. Tuberosities distribute muscle forces and provide mechanical leverage at attachment sites for joint stability and mobility. The genetic factors that regulate tuberosity growth remain largely unknown. In mouse embryos with global deletion offibroblast growth factor 9(Fgf9), the DT size is notably enlarged. In this study, we explored the tissue-specific regulation of DT size using both global and targeted deletion ofFgf9. We showed that cell hypertrophy and mineralization dynamics of the DT, as well as transcriptional signatures from skeletal muscle but not bone, were influenced by the global loss ofFgf9. Loss ofFgf9during embryonic growth led to increased chondrocyte hypertrophy and reduced cell proliferation at the DT attachment site. This endured hypertrophy and limited proliferation may explain the abnormal mineralization patterns and locally dysregulated expression of markers of endochondral development inFgf9nullattachments. We then showed that targeted deletion ofFgf9in skeletal muscle leads to postnatal enlargement of the DT. Taken together, we discovered thatFgf9may play an influential role in muscle-bone crosstalk during embryonic and postnatal development.
3D viscoelastic drag forces contribute to cell shape changes during organogenesis in the zebrafish embryo
Authors: Sanematsu Paula C. , Erdemci-Tandogan Gonca , Patel Himani , Retzlaff Emma M. , Amack Jeffrey D. , Lisa Manning M. 
Published: February 2021

AbstractThe left-right organizer in zebrafish embryos, Kupffer’s Vesicle (KV), is a simple organ that undergoes programmed asymmetric cell shape changes that are necessary to establish the left-right axis of the embryo. We use simulations and experiments to investigate whether 3D mechanical drag forces generated by the posteriorly-directed motion of the KV through the tailbud tissue are sufficient to drive such shape changes. We develop a fully 3D vertex-like (Voronoi) model for the tissue architecture, and demonstrate that the tissue can generate drag forces and drive cell shape changes. Furthermore, we find that tailbud tissue presents a shear-thinning, viscoelastic behavior consistent with those observed in published experiments. We then perform live imaging experiments and particle image velocimetry analysis to quantify the precise tissue velocity gradients around KV as a function of developmental time. We observe robust velocity gradients around the KV, indicating that mechanical drag forces must be exerted on the KV by the tailbud tissue. We demonstrate that experimentally observed velocity fields are consistent with the viscoelastic response seen in simulations. This work also suggests that 3D viscoelastic drag forces could be a generic mechanism for cell shape change in other biological processes.Highlightsnew physics-based simulation method allows study of dynamic tissue structures in 3Dmovement of an organ through tissue generates viscoelastic drag forces on the organthese drag forces can generate precisely the cell shape changes seen in experimentPIV analysis of experimental data matches simulations and probes tissue mechanicsGraphical abstract
“Contra omnes et singulos a via domini aberrantes”: accounting for confession and pastoral power during the Roman Inquisition (1550–1572)
Authors: Bigoni Michele , Antonelli Valerio , Funnell Warwick , Cafaro Emanuela Mattia 
Published: February 2021

PurposeThe study investigates the use of accounting information in the form of a confession as a tool for telling the truth about oneself and reinforcing power relations in the context of the Roman Inquisition.Design/methodology/approachThe study adopts Foucault's understanding of pastoral power, confession and truth-telling to analyse the accounting practices of the Tribunal of the Inquisition in the 16th century Dukedom of Ferrara.FindingsDetailed accounting books were not simply a means for pursuing an efficient use of resources, but a tool to force the Inquisitor to open his conscience and provide an account of his actions to his superiors. Accounting practices were an identifying and subjectifying practice which helped the Inquisitor to shape his Christian identity and internalise self-discipline. This in turn reinforced the centralisation of the power of the Church at a time of great crisis.Research limitations/implicationsThe use of accounting for forcing individuals to tell the truth about themselves can inform investigations into the use of accounting records as confessional tools in different contexts, especially when a religious institution seeks to reinforce its power.Social implicationsThe study documents the important but less discernible contributions of accounting to the formation of Western subjectivity at a time which Foucault considers critical in the development of modern governmental practices.Originality/valueThe study considers a critical but unexplored episode in Western religious history. It offers an investigation of the macro impact of religion on accounting practices. It also adds to the literature recognising the confessional properties of written information by explicitly focusing on the use of financial information as a form of confession that has profound power implications.