bluuebunny/crossref_metadata_2025_split huggingface dataset:
Asymptotic analysis of optimal vaccination policies
Authors: Penn Matthew J. , Donnelly Christl A. 
Published: June 2022

AbstractTargeted vaccination policies can have a significant impact on the number of infections and deaths in an epidemic. However, optimising such policies is complicated and the resultant solution may be difficult to explain to policy-makers and to the public. The key novelty of this paper is a derivation of the leading order optimal vaccination policy under multi-group SIR (Susceptible-Infected-Recovered) dynamics in two different cases. Firstly, it considers the case of a small vulnerable subgroup in a population and shows that (in the asymptotic limit) it is optimal to vaccinate this group first, regardless of the properties of the other groups. Then, it considers the case of a small vaccine supply and transforms the optimal vaccination problem into a simple knapsack problem by linearising the final size equations. Both of these cases are then explored further through numerical examples which show that these solutions are also directly useful for realistic parameter values. Moreover, the findings of this paper give some general principles for optimal vaccination policies which will help policy-makers and the public to understand the reasoning behind optimal vaccination programs in more generic cases.Author summaryThe COVID-19 pandemic has illustrated the importance of vaccination programs in preventing infections and deaths from an epidemic. A common feature of vaccination programs across the world has been a prioritisation of different groups within each country’s population, particularly those who are more vulnerable to the disease. Finding the best priority order is crucial, but may be complicated and difficult to justify to policy-makers and the public. In this paper, we consider two extreme cases where the best prioritisation order can be mathematically derived. Firstly, we consider the case of a population with a very small, very vulnerable group and show that this group should always be vaccinated first. Then, we consider the case of a small supply of vaccines and derive an equation which gives the best prioritisation order. Understanding these extreme cases is important, as it highlights general principles of optimal policies which will be useful when understanding the solution in more complicated settings.
Uncovering the spatial landscape of molecular interactions within the tumor microenvironment through latent spaces
Authors: Deshpande Atul , Loth Melanie , Sidiropoulos Dimitrios N. , Zhang Shuming , Yuan Long , Bell Alexander , Zhu Qingfeng , Ho Won Jin , Santa-Maria Cesar , Gilkes Daniele , Williams Stephen R. , Uytingco Cedric R. , Chew Jennifer , Hartnett Andrej , Bent Zachary W. , Favorov Alexander V. , Popel Aleksander S. , Yarchoan Mark , Zheng Lei , Jaffee Elizabeth M. , Anders Robert , Danilova Ludmila , Stein-O’Brien Genevieve , Kagohara Luciane T. , Fertig Elana J. 
Published: June 2022

AbstractRecent advances in spatial transcriptomics (ST) enable gene expression measurements from a tissue sample while retaining its spatial context. This technology enables unprecedented in situ resolution of the regulatory pathways that underlie the heterogeneity in the tumor and its microenvironment (TME). The direct characterization of cellular co-localization with spatial technologies facilities quantification of the molecular changes resulting from direct cell-cell interaction, as occurs in tumor-immune interactions. We present SpaceMarkers, a novel bioinformatics algorithm to infer molecular changes from cell-cell interaction from latent space analysis of ST data. We apply this approach to infer molecular changes from tumor-immune interactions in Visium spatial transcriptomics data of metastasis, invasive and precursor lesions, and immunotherapy treatment. Further transfer learning in matched scRNA-seq data enabled further quantification of the specific cell types in which SpaceMarkers are enriched. Altogether, SpaceMarkers can identify the location and context-specific molecular interactions within the TME from ST data.
Dynamic DNA methylation reveals novel cis-regulatory elements in murine hematopoiesis
Authors: Schönung Maximilian , Hartmann Mark , Krämer Stephen , Stäble Sina , Hakobyan Mariam , Kleinert Emely , Aurich Theo , Cobanoglu Defne , Heidel Florian H. , Fröhling Stefan , Milsom Michael D. , Schlesner Matthias , Lutsik Pavlo , Lipka Daniel B. 
Published: June 2022

ABSTRACTBackgroundThe differentiation of hematopoietic stem and progenitor cells (HSPCs) to terminally differentiated immune cells is accompanied by large-scale remodeling of the DNA methylation landscape. While significant insights into the molecular mechanisms of hematopoietic tissue regeneration were derived from mouse models, profiling of DNA methylation changes has been hampered by high cost or low resolution using the methods available. This problem has been overcome by the recent development of the Infinium Mouse Methylation BeadChip (MMBC) array, facilitating methylation profiling of the mouse genome at single CpG resolution at affordable cost.ResultsWe extended the RnBeads package to provide a computational framework for the analysis of MMBC data. This framework was applied to a newly generated MMBC reference map of mouse hematopoiesis encompassing nine different cell types. The analysis of dynamically regulated CpG sites showed progressive and unidirectional DNA methylation changes from HSPCs to differentiated hematopoietic cells and allowed the identification of lineage- and cell type-specific DNA methylation programs. Comparison to previously published catalogues of cis-regulatory elements (CREs) revealed 12,856 novel putative CREs which were dynamically regulated by DNA methylation (mdCREs). These mdCREs were predominantly associated with patterns of cell type-specific DNA hypomethylation and could be identified as epigenetic control regions regulating the expression of key hematopoietic genes during differentiation.ConclusionsWe established a publicly available analysis pipeline for MMBC datasets and provide a DNA methylation atlas of mouse hematopoiesis. This resource allowed us to identify novel putative CREs involved in hematopoiesis and will serve as a platform to study epigenetic regulation of normal and malignant hematopoiesis.
Lateral Axonal Modulation is Required for Stimulus-Specific Olfactory Conditioning in Drosophila
Authors: Manoim Julia E. , Davidson Andrew M. , Weiss Shirley , Hige Toshihide , Parnas Moshe 
Published: June 2022

SummaryEffective and stimulus-specific learning is essential for animals’ survival. Two major mechanisms are known to aid stimulus-specificity of associative learning. One is accurate stimulus-specific representations in neurons. The second is limited effective temporal window for the reinforcing signals to induce neuromodulation only after sensory stimuli. However, these mechanisms are often imperfect in preventing unspecific associations; different sensory stimuli can be represented by overlapping populations of neurons, and more importantly the reinforcing signals alone can induce neuromodulation even without coincident sensory-evoked neuronal activity. Here, we report a crucial neuromodulatory mechanism that counteracts both limitations and is thereby essential for stimulus specificity of learning. In Drosophila, olfactory signals are sparsely represented by cholinergic Kenyon cells (KCs), which receive dopaminergic reinforcing input. We find that KCs have numerous axo-axonic connections mediated by the muscarinic type-B receptor (mAChR-B). By using functional imaging and optogenetic approaches, we show that these axo-axonic connections suppress both odor-evoked calcium responses and dopamine-evoked cAMP signals in neighboring KCs. Strikingly, behavior experiments demonstrate that mAChR-B knockdown in KCs impairs olfactory learning by inducing undesired changes to the valence of an odor that was not associated with the reinforcer. Thus, this local neuromodulation acts in concert with sparse sensory representations and global dopaminergic modulation to achieve effective and accurate memory formation.HighlightsLateral KC axo-axonic connections are mediated by muscarinic type-B receptorKC connections suppress odor-evoked calcium responses and dopamine-evoked cAMPknockdown of the muscarinic type-B receptor impairs olfactory learningImpaired learning is due to changes to the valence of the unconditioned odor
The reef-building coralGalaxea fascicularis: a new model system for coral symbiosis research
Authors: Puntin Giulia , Craggs Jamie , Hayden Róisín , Engelhardt Kara E. , McIlroy Shelby , Sweet Michael , Baker David M. , Ziegler Maren 
Published: June 2022

AbstractReef-building corals owe their evolutionary success to their symbiosis with unicellular algae (Symbiodiniaceae). However, increasingly frequent heat waves lead to coral mass-bleaching events and pose a serious threat to the survival of reef ecosystems. Despite significant efforts, a mechanistic understanding of coral-algal symbiosis functioning, what leads to its breakdown and what can prevent it, remains incomplete. The main obstacles are low amenability of corals to experimental handling and, owing to its obligatory nature, the difficulties of manipulating the coral-algal association. Indeed, many studies on the symbiotic partnership are conducted on other cnidarian model organisms and their results may therefore not be fully transferable to tropical reef-building corals. Here, we identify the tropical stony coral speciesGalaxea fascicularisas a novel candidate coral model system. Individual polyps of this species can be separated, enabling highly replicated genotype studies, and are well suited to experimental investigation of the symbiosis as they can be easily and effectively rid of their algal symbionts (bleached). We show that bleached adult individuals can reestablish symbiosis with non-native symbionts, and we report the completion of the gametogenic cycleex-situ, with the successful spawning in aquaria over multiple years. These achievements help overcome several of the major limitations to direct research on corals and highlight the potential ofG. fascicularisas an important new model system for investigations of symbiosis functioning and manipulation.
Ion mobility-resolved phosphoproteomics with dia-PASEF and short gradients
Authors: Oliinyk Denys , Meier Florian 
Published: June 2022

AbstractMass spectrometry-based phosphoproteomics has identified >150,000 post-translational phosphorylation sites in the human proteome. To disentangle their functional relevance, complex experimental designs that require increased throughput are now coming into focus. Here, we apply dia-PASEF on a trapped ion mobility (TIMS) mass spectrometer to analyze the phosphoproteome of a human cancer cell line in short liquid chromatography gradients. At low sample amounts equivalent to ∼20 ug protein digest per analysis, we quantified over 12,000 phosphopeptides including ∼8,000 class I phosphosites in one hour without a spectral library. Decreasing the gradient time to 15 min yielded virtually identical coverage of the phosphoproteome, and with 7 min gradients we still quantified about 80% of the class I sites with a median coefficient of variation <10% in quadruplicates. We attribute this in part to the increased peak capacity, which effectively compensates for the higher peptide density per time unit in shorter gradients. Our data shows a five-fold reduction in the number of co-isolated peptides with TIMS. In the most extreme case, these were positional isomers of nearby phosphosites that remained unresolved with fast chromatography. In summary, we demonstrate how key features of dia-PASEF translate to phosphoproteomics, resulting in high throughput and sensitivity.
Bayesian Analysis for 3D combinatorial CRISPR screens
Authors: Madenach Lukas , Lohoff Caroline 
Published: June 2022

AbstractCombinatorial CRISPR screens are a well-established tool for the investigation of genetic interactions in a high-throughput fashion. Currently, advancements from 2D combinatorial CRISPR screens towards 3D combinatorial screens are made, but at the same time an easy-to-use computational method for the analysis of 3D combinatorial screens is missing. Here we propose a Bayesian analysis method for 3D CRISPR screens based on a well-established 2D CRISPR screen analysis protocol. With our tool we hope to provide researchers with an out-of-the-box analysis solution, avoiding the need for time-consuming and resource-intensive development of custom analysis protocols.
Sublytic gasdermin-D pores captured in atomistic molecular simulations
Authors: Schaefer Stefan L. , Hummer Gerhard 
Published: June 2022

AbstractGasdermin-D (GSDMD) is the ultimate effector of pyroptosis, a form of programmed cell death associated with pathogen invasion and inflammation. After proteolytic cleavage by caspases activated by the inflammasome, the GSDMD N-terminal domain (GSDMDNT) assembles on the inner leaflet of the plasma membrane and induces the formation of large membrane pores. We use atomistic molecular dynamics simulations to study GSDMDNT monomers, oligomers, and rings in an asymmetric plasma membrane mimetic. We identify distinct interaction motifs of GSDMDNT with phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and phosphatidylserine (PS) head-groups and describe differential lipid binding between the pore and prepore conformations. Oligomers are stabilized by shared lipid binding sites between neighboring monomers acting akin to double-sided tape. We show that already small GSDMDNT oligomers form stable, water-filled and ion-conducting membrane pores bounded by curled beta-sheets. In large-scale simulations, we resolve the process of pore formation by lipid detachment from GSDMDNT arcs and lipid efflux from partial rings. We find that that high-order GSDMDNT oligomers can crack under the line tension of 86 pN created by an open membrane edge to form the slit pores or closed GSDMDNT rings seen in experiment. Our simulations provide a detailed view of key steps in GSDMDNT-induced plasma membrane pore formation, including sublytic pores that explain nonselective ion flux during early pyroptosis.SignificanceGasdermins execute pyroptotic membrane perforation that is responsible for the release of inflammatory signals and ultimately leads to lytic cell death. They assemble into an approximately 20 nm wide transmembrane β-barrel pore across the plasma membrane. With atomistic molecular simulations of gasdermin-D in a realistic asymmetric plasma membrane mimetic, we show that already small oligomers can form stable water-filled and ionconducting pores. Simulations of larger oligomeric assemblies reveal instabilities in the circular prepore and demonstrate pathways to the formation of slit and ring-shaped pores. Our work gives structural and dynamic insight into how small membrane pores emerge that dissipate the ionic gradient of the cell, but not yet cause cell lysis.
A unique single nucleotide polymorphism in Agouti Signalling Protein (ASIP) gene changes coat colour of Sri Lankan Leopard (Panthera pardus kotiya) to dark black
Authors: Sooriyabandara Meegasthanne Gamaralalage Chandana , Bandaranayake Asitha Udaya , Jayasundara Shyaman , Hathurusinghe Hathurusinghe Arachchilage Bhagya M , Marasighe Marasinghe Sumanasirige Leslie Ranj , Prasad Gajadeera Arachchige Tharaka , Abeywardana Vithana Pathirannehalage Malaka Kas , Pinidiya Manoj Akalanka , Nilanthi Rajapakse Mudiyanselage Renuka , Bandaranayake Pradeepa Chandani Gunathilake 
Published: June 2022

ABSTRACTThe Sri Lankan Leopard (Panthera pardus kotiya) is an endangered subspecies restricted to isolated and fragmented populations in Sri Lanka. Among them, the melanistic leopards have been recorded on rare occasions. The existing literature suggests that melanism evolved several times in the Felidae family, with three separate species revealing distinct mutations. Nevertheless, the mutations in the remaining species, including Sri Lankan black leopard, are unknown. We used reference-based assembled the nuclear genomes of Sri Lankan normal and black leopard and de novo assembled mitogenomes of the same to investigate the genetic basis, adaptive significance, and evolutionary history of the Sri Lankan black leopard. Our data suggested coalescence time of Sri Lankan regular and black leopards at ∼0.5 Million years, sisters to Panthera pardus lineage. Interestingly, in the black leopard, a single nucleotide polymorphism in exon-4 possibly completely ablates Agouti Signaling Protein (ASIP) function. Existing genomic data suggest new a species-specific mutation of the ASIP gene in the Felidae family, contributing to naturally occurring colouration polymorphism. As such, the Sri Lankan black leopard and normal leopard probably evolved from the same ancestor, while the mutation in the ASIP gene resulted in black coat colour. This rare mutation could be adaptable to the environment that back leopards reported, camouflage, with a likelihood of recurrence and transmission to future generations. However, protecting this sensitive environment is critical for the conservation of the existing populations and providing breeding grounds.
Parallelization with Dual-Trap Single-Column Configuration Maximizes Throughput of Proteomic Analysis
Authors: Kreimer Simion , Haghani Ali , Binek Aleksandra , Hauspurg Alisse , Seyedmohammad Saeed , Rivas Alejandro , Momenzadeh Amanda , Meyer Jesse , Raedschelders Koen , Van Eyk Jennifer E. 
Published: June 2022

AbstractProteomic analysis on the scale that captures population and biological heterogeneity over hundreds to thousands of samples requires rapid mass spectrometry methods which maximize instrument utilization (IU) and proteome coverage while maintaining precise and reproducible quantification. To achieve this, a short liquid chromatography gradient paired to rapid mass spectrometry data acquisition can be used to reproducibly profile a moderate set of analytes. High throughput profiling at a limited depth is becoming an increasingly utilized strategy for tackling large sample sets but the time spent on loading the sample, flushing the column(s), and re-equilibrating the system reduces the ratio of meaningful data acquired to total operation time and IU. The dual-trap single-column configuration presented here maximizes IU in rapid analysis (15 min per sample) of blood and cell lysates by parallelizing trap column cleaning and sample loading and desalting with analysis of the previous sample. We achieved 90% IU in low micro-flow (9.5 µL/min) analysis of blood while reproducibly quantifying 300-400 proteins and over 6,000 precursor ions. The same IU was achieved for cell lysates, in which over 4,000 proteins (3,000 at CV below 20%) and 40,000 precursor ions were quantified at a rate of 15 minutes/sample. Thus, deployment of this dual-trap single column configuration enables high throughput epidemiological blood-based biomarker cohort studies and cell-based perturbation screening.
Actin nucleotide state modulates the F-actin structural landscape evoked by bending forces
Authors: Reynolds Matthew J. , Hachicho Carla , Carl Ayala G. , Gong Rui , Alushin Gregory M. 
Published: June 2022

SummaryATP hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation. Force and actin filament (F-actin) nucleotide state in turn modulate the engagement of actin binding proteins (ABPs) to regulate actin dynamics through unknown mechanisms. Here, we show that bending forces evoke structural transitions in F-actin which are modulated by actin nucleotide state. Cryo-electron microscopy (cryo-EM) structures of ADP- and ADP-Pi-F-actin with sufficient resolution to visualize bound solvent reveal inter-subunit interactions primarily bridged by waters which could contribute to lattice flexibility. Despite substantial ordered solvent differences in the nucleotide binding cleft, these structures feature essentially indistinguishable protein backbone conformations which are unlikely to be discriminable by ABPs. We next introduce a machine-learning enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain level detail. Bent F-actin structures reveal major rearrangements at inter-subunit interfaces characterized by striking alterations of helical twist and deformations of individual protomers which are distinct in ADP- and ADP-Pi-F-actin. This suggests phosphate rigidifies actin subunits to alter F-actin’s bending structural landscape. We therefore propose actin nucleotide state serves as a co-regulator of F-actin mechanical regulation, as bending forces evoke nucleotide-state dependent conformational transitions that could be readily detected by ABPs.
Effect of workplace status on employees’ creativity from the perspective of expectation identity: a moderated chain double mediation model
Authors: Liu Yuanyuan , Zhao Li , Liu Pingqing , Yang Zheng 
Published: June 2022

PurposeDrawing upon the creativity interaction theory and expectation-identity perspective, the purpose of this paper is to construct a chain mediation model of the influence of workplace status on individual creativity from the perspective of expectation identity and to explore the moderating effect of prosocial motivation in this model.Design/methodology/approachThis study reached 529 employees from 35 enterprises as the investigation objects and used structural equation model and hierarchical regression for data analysis. Data on workplace status, prosocial motivation, creativity expectations and creativity role identity were collected at Time Point T1, and individual creativity was collected at time point T2 (one month later).FindingsThe results reveal that: workplace status has a significantly positive effect on creativity; creativity performance expectations and creativity role identity have partial mediating effect in the relationship between workplace status and creativity, respectively; creativity performance expectations and creativity role identity play a chain double mediation role in the relationship between workplace status and creativity; and prosocial motivation moderates the relationship between workplace status and creativity and further moderates the chain double mediation effect of creativity performance expectations and creativity role identity.Originality/valueIn existing studies, conclusions about the relationship between workplace status and individual creativity could be divided into three viewpoints: positive, negative and U-shaped. These inconsistent findings on the relationship between workplace status and creativity imply that the relationship is complex and not fully elucidated. This may be attributed to the fact that workplace status is influenced by cultural factors and research objects. This study reinterprets the relationship between workplace status and individual creativity through the lens of creativity interaction theory and demonstrates the significance of employee workplace status in the Chinese context.