bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying the role of naturally- and vaccine-derived neutralizing antibodies as a correlate of protection against COVID-19 variants
Authors: Cohen Jamie A. , Stuart Robyn M. , Rosenfeld Katherine , Lyons Hil , White Michael , Kerr Cliff C. , Klein Daniel J. , Famulare Michael 
Published: June 2021

AbstractThe functional relationship between neutralizing antibodies (NAbs) and protection against SARS-CoV-2 infection and disease remains unclear. We jointly estimated protection against infection and disease progression following natural infection and vaccination from meta-study data. We find that NAbs are strongly correlated with prevention of infection and that any history of NAbs will stimulate immune memory to moderate disease progression. We also find that natural infection provides stronger protection than vaccination for the same level of NAbs, noting that infection itself, unlike vaccination, carries risk of morbidity and mortality, and that our most potent vaccines induce much higher NAb levels than natural infection. These results suggest that while sterilizing immunity may decay, we expect protection against severe disease to be robust over time and in the face of immune-evading variants.
A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia
Authors: Reisman Benjamin J. , Guo Hui , Ramsey Haley E. , Wright Madison T. , Reinfeld Bradley I. , Ferrell P. Brent , Sulikowski Gary A. , Rathmell W. Kimryn , Savona Michael R. , Plate Lars , Rubinstein John L. , Bachmann Brian O. 
Published: June 2021

AbstractCancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. CryoEM of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence define the mechanism of action of apoptolidin family glycomacrolides and establish a path to address OXPHOS-dependent cancers.
Scaling principles of white matter brain connectivity
Authors: Ardesch Dirk Jan , Scholtens Lianne H. , de Lange Siemon C. , Roumazeilles Lea , Khrapitchev Alexandre A. , Preuss Todd M. , Rilling James K. , Mars Rogier B. , van den Heuvel Martijn P. 
Published: June 2021

AbstractBrains come in many shapes and sizes. Nature has endowed big-brained primate species like humans with a proportionally large cerebral cortex. White matter connectivity – the brain’s infrastructure for long-range communication – might not always scale at the same pace as the cortex. We investigated the consequences of this allometric scaling for white matter brain network connectivity. Structural T1 and diffusion MRI data were collated across fourteen primate species, describing a comprehensive 350-fold range in brain volume. We report volumetric scaling relationships that point towards a restriction in macroscale connectivity in larger brains. Building on previous findings, we show cortical surface to outpace white matter volume and the corpus callosum, suggesting the emergence of a white matter ‘bottleneck’ of lower levels of connectedness through the corpus callosum in larger brains. At the network level, we find a potential consequence of this bottleneck in shaping connectivity patterns, with homologous regions in the left and right hemisphere showing more divergent connectivity in larger brains. Our findings show conserved scaling relationships of major brain components and their consequence for macroscale brain circuitry, providing a comparative framework for expected connectivity architecture in larger brains such as the human brain.
3D atlas of the pituitary gland of the model fish medaka
Authors: Royan Muhammad Rahmad , Siddique Khadeeja , Csucs Gergely , Puchades Maja A. , Nourizadeh-Lillabadi Rasoul , Bjaalie Jan G. , Henkel Christiaan V. , Weltzien Finn-Arne , Fontaine Romain 
Published: June 2021

AbstractIn vertebrates, the anterior pituitary plays a crucial role in regulating several essential physiological processes via the secretion of at least seven peptide hormones by different endocrine cell types. Comparative and comprehensive knowledge of the spatial distribution of those endocrine cell types is required to better understand their role during the animal life. Using medaka as the model and several combinations of multi-color fluorescence in situ hybridization, we present the first 3D atlas revealing the gland-wide distribution of seven endocrine cell populations: lactotropes, thyrotropes, Lh and Fsh gonadotropes, somatotropes, and pomca-expressing cells (corticotropes and melanotropes) in the anterior pituitary of a teleost fish. By combining in situ hybridization and immunofluorescence techniques, we deciphered the location of corticotropes and melanotropes within the pomca-expressing cell population. The 3D localization approach reveals sexual dimorphism of tshba- and pomca-expressing cells in the adult medaka pituitary. Finally, we show the existence of bi-hormonal cells co-expressing lhb-fshb, fshb-tshba and lhb-sl using single-cell transcriptomics analysis and in situ hybridization. This study offers a solid basis for future comparative studies of the teleost pituitary and its developmental plasticity.Highlights- We offer the first 3D atlas of a teleost pituitary, which presents a valuable resource to the endocrinology and model fish community.- The atlas reveals the 3D spatial distribution of the seven endocrine cell types and blood vessels in the juvenile/adult male and female pituitary.- Gene expression for tshba and pomca, as well as the population size of cells expressing these genes, displays obvious sexual dimorphism in the adult medaka pituitary.- Multi-color in situ hybridization and single cell RNA-seq reveal the existence of bi-hormonal cells, co-expressing lhb-fshb, fshb-tshba, lhb-sl, and a few multi-hormonal cells.- An online version of the atlas is available at https://www.nmbu.no/go/mpg-atlas.
Accelerated Antibody Discovery Targeting the SARS-CoV-2 Spike Protein for COVID-19 Therapeutic Potential
Authors: Mullen Tracey E. , Abdullah Rashed , Boucher Jacqueline , Brousseau Anna Susi , Dasuri Narayan K. , Ditto Noah T. , Doucette Andrew M. , Emery Chloe , Gabriel Justin , Greamo Brendan , Patil Ketan S. , Rothenberger Kelly , Stolte Justin , Souders Colby A. 
Published: June 2021

AbstractRapid deployment of technologies capable of high-throughput and high-resolution screening is imperative for timely response to viral outbreaks. Risk mitigation in the form of leveraging multiple advanced technologies further increases the likelihood of identifying efficacious treatments in an aggressive timeline. In this study, we describe two parallel, yet distinct, in vivo approaches for accelerated discovery of antibodies targeting the SARS-CoV-2 spike protein. Working with human transgenic Alloy-GK mice, we detail a single B-cell discovery workflow to directly interrogate antibodies secreted from plasma cells for binding specificity and ACE2 receptor blocking activity. Additionally, we describe a concurrent accelerated hybridoma-based workflow utilizing a DiversimAb™ mouse model for increased diversity. The panel of antibodies isolated from both workflows revealed binding to distinct epitopes with both blocking and non-blocking profiles. Sequence analysis of the resulting lead candidates uncovered additional diversity with the opportunity for straightforward engineering and affinity maturation. By combining in vivo models with advanced integration of screening and selection platforms, lead antibody candidates can be sequenced and fully characterized within one to three months.
Neuromodulators generate multiple context-relevant behaviors in a recurrent neural network by shifting activity flows in hyperchannels
Authors: Tsuda Ben , Pate Stefan C. , Tye Kay M. , Siegelmann Hava T. , Sejnowski Terrence J. 
Published: June 2021

AbstractNeuromodulators are critical controllers of neural states, with dysfunctions linked to various neuropsychiatric disorders. Although many biological aspects of neuromodulation have been studied, the computational principles underlying how neuromodulation of distributed neural populations controls brain states remain unclear. Compared with specific contextual inputs, neuromodulation is a single scalar signal that is broadcast broadly to many neurons. We model the modulation of synaptic weight in a recurrent neural network model and show that neuromodulators can dramatically alter the function of a network, even when highly simplified. We find that under structural constraints like those in brains, this provides a fundamental mechanism that can increase the computational capability and flexibility of a neural network. Diffuse synaptic weight modulation enables storage of multiple memories using a common set of synapses that are able to generate diverse, even diametrically opposed, behaviors. Our findings help explain how neuromodulators “unlock” specific behaviors by creating task-specific hyperchannels in the space of neural activities and motivate more flexible, compact and capable machine learning architectures.SignificanceNeuromodulation through the release of molecules like serotonin and dopamine provides a control mechanism that allows brains to shift into distinct behavioral modes. We use an artificial neural network model to show how the action of neuromodulatory molecules acting as a broadcast signal on synaptic connections enables flexible and smooth behavioral shifting. We find that individual networks exhibit idiosyncratic sensitivities to neuromodulation under identical training conditions, highlighting a principle underlying behavioral variability. Network sensitivity is tied to the geometry of network activity dynamics, which provides an explanation for why different types of neuromodulation (molecular vs direct current modulation) have different behavioral effects. Our work suggests experiments to test biological hypotheses and paths forward in the development of flexible artificial intelligence systems.
More than a stick in the mud: Eelgrass leaf and root bacterial communities are distinct from those on physical mimics
Authors: Kardish Melissa R. , Stachowicz John. J. 
Published: June 2021

SummaryWe examine the role of physical structure vs. biotic interactions in structuring host-associated microbial communities on a marine angiosperm, Zostera marina, eelgrass. Across several months and sites, we compared microbiomes on physical mimics of eelgrass roots and leaves to those on intact plants. We find large, consistent differences in the microbiome of mimics and plants, especially on roots, but also on leaves. Key taxa that are more abundant on leaves have been associated with microalgal and macroalgal disease and merit further investigation to determine their role in mediating plant-microalgal-pathogen interactions. Root associated taxa were associated with sulfur and nitrogen cycling, potentially ameliorating environmental stresses for the plant. Our work identifies targets for future work on the functional role of the seagrass microbiome in promoting the success of these angiosperms in the sea.Originality-Significance StatementWe show that eelgrass establishes a distinct microbial community from a physical mimic on both its leaves and roots. This is, to our knowledge, the first comparison of seagrass to a mimicked physical environment. Insights from our study establish bacterial targets for future functional studies of seagrass-microbiome interactions.
CamelliA-based simultaneous imaging of Ca2+ dynamics in subcellular compartments
Authors: Guo Jingzhe , He Jiangman , Dehesh Katayoon , Yang Zhenbiao 
Published: June 2021

AbstractAs a universal second messenger, calcium (Ca2+) transmits specific cellular signals via a spatiotemporal signature generated from its extracellular source and internal stores. Our knowledge of the mechanisms underlying generation of a Ca2+ signature is hampered by limited tools enabling simultaneous monitoring of the dynamics of Ca2+ levels in multiple subcellular compartments. To overcome the limitation and to further improve spatiotemporal resolutions, here we have assembled a molecular toolset (the CamelliA lines) in Arabidopsis that enables simultaneous and high-resolution monitoring of Ca2+ dynamics in multiple subcellular compartments through imaging analyses of different single-colored GECIs (Genetically Encoded Calcium Indicators). Indeed, the uncovering of the previously unrecognized Ca2+ signatures in three types of Arabidopsis cells in response to internal and external cues is a testimony to the wide applicability of the newly generated toolset for elucidating the subcellular sources contributing to the Ca2+signatures in plants.One sentence summaryA toolset for simultaneous imaging of Ca2+ dynamics in subcellular compartments has uncovered unrecognized Ca2+ signatures in Arabidopsis cells in response to developmental and external cues.
Decoding continuous variables from event-related potential (ERP) data with linear support vector regression (SVR) using the Decision Decoding Toolbox (DDTBOX)
Authors: Bode Stefan , Schubert Elektra , Hogendoorn Hinze , Feuerriegel Daniel 
Published: June 2021

AbstractBackgroundMultivariate classification analysis for event-related potential (ERP) data is a powerful tool for predicting cognitive variables. However, classification is often restricted to categorical variables and under-utilises continuous data, such as response times, response force, or subjective ratings. An alternative approach is Support Vector Regression (SVR), which uses single-trial data to predict continuous variables of interest.New MethodIn this tutorial-style paper, we demonstrate how SVR is implemented in the Decision Decoding Toolbox (DDTBOX). To illustrate in more detail how results depend on specific toolbox settings and data features, we report results from two simulation studies resembling real EEG data, and one real ERP-data set, in which we predicted continuous variables across a range of analysis parameters.ResultsAcross all studies, we demonstrate that SVR is effective for analysis windows ranging from 2 ms – 100 ms, and relatively unaffected by temporal averaging. Prediction is still successful when only a small number of channels encode true information, and the analysis is robust to temporal jittering of the relevant information in the signal.Comparison with existing MethodsOur result show that SVR as implemented in DDTBOX can reliably predict continuous, more nuanced variables, which may not be well-captured by classification analysis.ConclusionsIn sum, we demonstrate that linear SVR is a powerful tool for the investigation of single-trial EEG data in relation to continuous variables, and we provide practical guidance for users.
Genetic and chemotherapeutic causes of germline hypermutation
Authors: Kaplanis Joanna , Ide Benjamin , Sanghvi Rashesh , Neville Matthew , Danecek Petr , Coorens Tim , Prigmore Elena , Short Patrick , Gallone Giuseppe , McRae Jeremy , Odhams Chris , Moutsianas Loukas ,   Genomics England Research Consortium, Carmichael Jenny , Barnicoat Angela , Firth Helen , O’Brien Patrick , Rahbari Raheleh , Hurles Matthew 
Published: June 2021

SummaryMutation in the germline is the source of all evolutionary genetic variation and a cause of genetic disease. Previous studies have shown parental age to be the primary determinant of the number of new germline mutations seen in an individual’s genome. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 hypermutated individuals with between two and seven times more de novo single nucleotide variants (dnSNVs) than expected. In most of these families (8/12) the excess mutations could be attributed to the father. We determined that two of these families had genetic drivers of germline hypermutation, with the fathers carrying damaging genetic variation in known DNA repair genes, causing distinctive mutational signatures. For five families, by analysing clinical records and mutational signatures, we determined that paternal exposure to chemotherapeutic agents prior to conception was a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare and relatively modest in degree and that most hypermutated individuals will not have a genetic disease.
Gene Expression Associated with Individual Variability in Intrinsic Functional Connectivity
Authors: Li Liangfang , Wei Yongbin , Zhang Jinbo , Ma Junji , Yi Yangyang , Gu Yue , Li Liman Man Wai , Lin Ying , Dai Zhengjia 
Published: June 2021

AbstractIt has been revealed that intersubject variability (ISV) in intrinsic functional connectivity (FC) is associated with a wide variety of cognitive and behavioral performances. However, the underlying organizational principle of ISV in FC and its related gene transcriptional profiles remain unclear. Using resting-state fMRI data from the Human Connectome Project (299 participants) and microarray gene expression data from the Allen Human Brain Atlas, we conducted a transcription-neuroimaging association study to investigate the spatial configurations of ISV in intrinsic FC and their associations with gene transcriptional profiles. We found that the multimodal association cortices showed the greatest ISV in FC, while the unimodal cortices and subcortical areas showed the least ISV. Importantly, partial least squares regression analysis revealed that the transcriptional profiles of genes associated with human accelerated regions (HARs) could explain 31.29% of the variation in the spatial distribution of ISV in FC. The top-related genes in the transcriptional profiles were enriched for the development of the central nervous system, neurogenesis and the cellular components of synapse. Moreover, we observed that the effect of gene expression profile on the heterogeneous distribution of ISV in FC was significantly mediated by the cerebral blood flow configuration. These findings highlighted the spatial arrangement of ISV in FC and their coupling with variations in transcriptional profiles and cerebral blood flow supply.
Optogenetic stimulation of primate V1 reveals local laminar and large-scale cortical networks related to perceptual phosphenes
Authors: Ortiz-Rios Michael , Agayby Beshoy , Balezeau Fabien , Haag Marcus , Rima Samy , Schmid Michael C. 
Published: June 2021

AbstractDeveloping optogenetics in non-human primates (NHPs) is essential for translating its successful implementation in rodents to clinical applications in humans. However, information about how optogenetics influences the primate cortex remains limited. Here, we evaluate how optogenetic stimulation of the primate primary visual cortex (V1) affects local and large-scale network activation concerned with visual perception. To this end we injected an optogenetic construct (AAV9-hSyn-ChR2-eYFP) into the V1 cortex of four macaque monkeys (macaca mulatta) and measured the effects of optogenetic V1 stimulation using functional magnetic resonance imaging (fMRI), laminar electrophysiology, and behavioural assessment. In three macaques, blood-oxygen-dependent (BOLD) fMRI activity could be reliably elicited with optogenetic stimulation in V1 and several connected extrastriate brain areas, including V2/V3, motion-sensitive area MT and the frontal-eye-fields (FEF), in particular when pulsed stimulation at 40 Hz was applied. BOLD modulation was associated with consistent neural spiking activity measured in V1 of two macaques. More detailed analysis revealed strongest neuronal activation in layer 4B and infragranular layers, which tightly reflected the histological expression pattern of the optogenetic construct in V1. Driving this visual network proved sufficient to elicit a visual percept (‘phosphene’) in one macaque during a perceptual choice task. Taken together, our findings reveal the laminar and large-cortical activation pattern related to visual phosphene generation and emphasize the need for further improving optogenetic methods in NHPs as a step towards applications in humans.
Atomic force microscopy reveals the mechanical properties of breast cancer bone metastases
Authors: Chen Xinyue , Hughes Russell , Mullin Nic , Hawkins Rhoda J. , Holen Ingunn , Brown Nicola J. , Hobbs Jamie K. 
Published: June 2021

ABSTRACTMechanically dependent processes are essential in cancer metastases. However, reliable mechanical characterisation of metastatic cancer remains challenging whilst maintaining the tissue complexity and an intact sample. Using atomic force microscopy, we quantified the micro-mechanical properties of relatively intact metastatic breast tumours and their surrounding bone microenvironment isolated from mice, and compared with other breast cancer models bothex vivoandin vitro. A unique mechanical distribution of extremely low elastic modulus and viscosity was identified on metastatic tumours, which were significantly more compliant than both 2Din vitrocultured cancer cells and subcutaneous tumour explants. The presence of mechanically distinct metastatic tumour did not result in alterations of the mechanical properties of the surrounding microenvironment at meso-scale distances (> 200 µm). These findings demonstrate the utility of atomic force microscopy in studies of complex tissues and provide new insights into the mechanical properties of cancer metastases in bone.
High-throughput discovery of peptide activators of a bacterial sensor kinase
Authors: Brink Kathryn R. , Mu Andrew M. , Hoang Ky V. , Groszman Ken , Gunn John S. , Tabor Jeffrey J. 
Published: June 2021

AbstractBacteria use two-component system (TCS) signaling pathways to sense and respond to peptides involved in host defense, quorum sensing, and inter-bacterial warfare. However, little is known about the peptide-sensing capabilities of these TCSs. Here, we develop a high-throughput E. coli display method to characterize the effects of human antimicrobial peptides (AMPs) on the pathogenesis-regulating TCS PhoPQ of Salmonella Typhimurium. We find that PhoPQ senses AMPs comprising diverse sequences, structures, and biological functions. Using thousands of AMP variants, we identify sub-domains and biophysical features responsible for PhoPQ activation. We show that most of the newfound activators induce PhoPQ in S. Typhimurium, suggesting a role in virulence regulation. Finally, we find that PhoPQ homologs from Klebsiella pneumoniae and extraintestinal pathogenic E. coli, which occupy different in vivo niches, exhibit distinct AMP response profiles. Our high-throughput method enables new insights into the specificities, mechanisms, and evolutionary dynamics of TCS-mediated peptide sensing in bacteria.