bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dementia risk factors modify hubs but leave other connectivity measures unchanged in asymptomatic individuals: a graph theoretical analysis
Authors: Clarke Hannah , Messaritaki Eirini , Dimitriadis Stavros I , Metzler-Baddeley Claudia 
Published: October 2020

AbstractBackgroundAlzheimer’s Disease (AD) is the most common form of dementia with genetic and environmental risk contributing to its development. Graph theoretical analyses of brain networks constructed from structural and functional MRI measurements have identified connectivity changes in AD and individuals with mild cognitive impairment (MCI). However, brain connectivity in asymptomatic individuals at risk of AD remains poorly understood.MethodsWe analysed diffusion-weighted magnetic resonance imaging (dMRI) data from 160 asymptomatic individuals (38-71 years) from the Cardiff Ageing and Risk of Dementia Study (CARDS). We calculated white matter tracts and constructed whole-brain, default-mode-network and visual structural brain networks that incorporate multiple structural metrics as edge weights. We then calculated the relationship of three AD risk factors, namely Apolipoprotein-E ε4 genotype (APOE4), family history (FH) of dementia, and central obesity, on graph theoretical measures and hubs.ResultsWe observed no risk-related differences in clustering coefficients, characteristic path lengths, eccentricity, diameter and radius across the whole-brain, default-mode-network or visual system. However, a hub in the right paracentral lobule was present in all high-risk groups (FH, APOE4, obese) but absent in low-risk groups (no FH, APOE4-ve, healthy weight).DiscussionWe identified no risk-related effects on graph theoretical metrics in the structural brain networks of cognitively healthy individuals. However, high-risk was associated with a hub in the right paracentral lobule, an area with motor and sensory functions related to the lower limb. If this phenotype is shown to predict symptom development in longitudinal studies, it could be used as an early biomarker of AD.Impact StatementAlzheimer’s Disease is a common form of dementia which to date has no cure. Identifying early biomarkers will aid the discovery and development of treatments that may slow AD progression in the future. In this paper we report that asymptomatic individuals at heightened risk of dementia due to their family history, Apolipoprotein-E ε4 genotype and body adiposity have a hub in the right paracentral lobule which is absent in low-risk groups. If this phenotype were to predict the development of symptoms in a longitudinal study of the same cohort, it could provide an early biomarker of disease progression.
Antifragile therapy
Authors: West Jeffrey , Desai Bina , Strobl Maximilian , Pierik Luke , Velde Robert Vander , Armagost Cole , Miles Richard , Robertson-Tessi Mark , Marusyk Andriy , Anderson Alexander R. A. 
Published: October 2020

AbstractAntifragility is a recently coined word used to describe the opposite of fragility. Systems or organisms can be described as antifragile if they derive a benefit from systemic variability, volatility, randomness, or disorder. Herein, we introduce a mathematical framework to quantify the fragility or antifragility of cancer cell lines in response to treatment variability. This framework enables straightforward prediction of the optimal dose treatment schedule for a range of treatment schedules with identical cumulative dose. We apply this framework to non-small-cell lung cancer cell lines with evolved resistance to ten anti-cancer drugs. We show the utility of this antifragile framework when applied to 1) treatment resistance, and 2) collateral sensitivity of sequential monotherapies.
The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density
Authors: Jones Stephanie K. , Rha Jennifer , Kim Sarah , Morris Kevin J. , Omotade Omotola F. , Moberg Kenneth H. , Myers Kenneth R. , Corbett Anita H. 
Published: October 2020

AbstractZC3H14 (Zinc fingerCysCysCysHis domain-containing protein14), an evolutionarily conserved member of a class of tandem zinc finger (CCCH) polyadenosine (polyA) RNA binding proteins, is associated with a form of heritable, nonsyndromic autosomal recessive intellectual disability. Previous studies of a loss of function mouse model,Zc3h14Δex13/Δex13, provide evidence that ZC3H14 is essential for proper brain function, specifically for working memory. To expand on these findings, we analyzed the dendrites and dendritic spines of hippocampal neurons fromZc3h14Δex13/Δex13mice, bothin situandin vitro.These studies reveal that loss of ZC3H14 is associated with a decrease in total spine density in hippocampal neuronsin vitroas well as in the dentate gyrus of 5-month old mice analyzedin situ. This reduction in spine densityin vitroresults from a decrease in the number of mushroom-shaped spines, which is rescued by exogenous expression of ZC3H14. We next performed biochemical analyses of synaptosomes prepared from whole wild-type andZc3h14Δex13/Δex13mouse brains to determine if there are changes in steady state levels of postsynaptic proteins upon loss of ZC3H14. We found that ZC3H14 is present within synaptosomes and that a crucial postsynaptic protein, CaMKIIα, is significantly increased in these synaptosomal fractions upon loss of ZC3H14. Together, these results demonstrate that ZC3H14 is necessary for proper dendritic spine density in cultured hippocampal neurons and in some regions of the mouse brain. These findings provide insight into how a ubiquitously expressed RNA binding protein leads to neuronal-specific defects that result in brain dysfunction.
Phylogenetic evidence of headful packaging strategy in gene transfer agents
Authors: Esterman Emma , Wolf Yuri I. , Kogay Roman , Koonin Eugene V. , Zhaxybayeva Olga 
Published: October 2020

AbstractGene transfer agents (GTAs) are virus-like particles encoded and produced by many bacteria and archaea. Unlike viruses, GTAs package fragments of the host genome instead of the genes that encode the components of the GTA itself. As a result of this non-specific DNA packaging, GTAs can transfer genes within bacterial and archaeal communities. GTAs clearly evolved from viruses and are thought to have been maintained in prokaryotic genomes due to the advantages associated with their DNA transfer capacity. The most-studied GTA is produced by the alphaproteobacteriumRhodobacter capsulatus(RcGTA), which packages random portions of the host genome at a lower DNA density than usually observed in tailed bacterial viruses. How the DNA packaging properties of RcGTA evolved from those of the ancestral virus remains unknown. To address this question, we reconstructed the evolutionary history of the large subunit of the terminase (TerL), a highly conserved enzyme used by viruses and GTAs to package DNA. We found that RcGTA-like TerLs grouped within viruses that employ the headful packaging strategy. Because distinct mechanisms of viral DNA packaging correspond to differences in the TerL amino acid sequence, our finding suggests that RcGTA evolved from a headful packaging virus. Headful packaging is the least sequence-specific mode of DNA packaging, which would facilitate the switch from packaging of the viral genome to packaging random pieces of the host genome during GTA evolution.
EEG signatures of contextual influences on visual search with real scenes
Authors: Meghdadi Amir H. , Giesbrecht Barry , Eckstein Miguel P 
Published: October 2020

AbstractThe use of scene context is a powerful way by which biological organisms guide and facilitate visual search. Although many studies have shown enhancements of target-related electroencephalographic activity (EEG) with synthetic cues, there have been fewer studies demonstrating such enhancements during search with scene context and objects in real world scenes. Here, observers covertly searched for a target in images of real scenes while we used EEG to measure the steady state visual evoked response to objects flickering at different frequencies. The target appeared in its typical contextual location or out of context while we controlled for low-level properties of the image including target saliency against the background and retinal eccentricity. A pattern classifier using EEG activity at the relevant modulated frequencies showed target detection accuracy increased when the target was in a contextually appropriate location. A control condition for which observers searched the same images for a different target orthogonal to the contextual manipulation, resulted in no effects of scene context on classifier performance, confirming that image properties cannot explain the contextual modulations of neural activity. Pattern classifier decisions for individual images was also related to the aggregated observer behavioral decisions for individual images. Together, these findings demonstrate target-related neural responses are modulated by scene context during visual search with real world scenes and can be related to behavioral search decisions.Significance StatementContextual relationships among objects are fundamental for humans to find objects in real world scenes. Although there is a larger literature understanding the brain mechanisms when a target appears at a location indicated by a synthetic cue such as an arrow or box, less is known about how the scene context modulates target-related neural activity. Here we show how neural activity predictive of the presence of a searched object in cluttered real scenes increases when the target object appears at a contextual location and diminishes when it appears at a place that is out of context. The results increase our understanding of how the brain processes real scenes and how context modulates object processing.
Common host variation drives malaria parasite fitness in healthy human red cells
Authors: Ebel Emily R , Kuypers Frans A , Lin Carrie , Petrov Dmitri A , Egan Elizabeth S 
Published: October 2020

SUMMARYThe replication ofPlasmodium falciparumparasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. The influence of host RBC variation on parasite replication is largely uncharted, aside from a handful of deleterious alleles like sickle cell. Here, we integrated analyses of exome sequencing, RBC phenotyping, and parasite fitness assays on blood from 122 individuals, most with African ancestry. In donors lacking alleles for hemoglobinopathies or G6PD deficiency, RBC phenotypes including size, deformability, and hydration status explained 21-38% of the variation in parasite growth rate. With the addition of non-pathogenic polymorphisms in 14 RBC proteins includingSPTA1, PIEZO1, andATP2B4, our model explained 73-82% of the variation in parasite growth rate. Interestingly, we observed little evidence for divergent selection on this variation between Africans and Europeans. These findings suggest a model in which widespread, non-pathogenic variation in a moderate number of genes strongly modulatesP. falciparumfitness in RBCs.
Humans surviving cholera develop antibodies againstVibrio choleraeO-specific polysaccharide that inhibit pathogen motility
Authors: Charles Richelle C. , Kelly Meagan , Tam Jenny M. , Akter Aklima , Hossain Motaher , Islam Kamrul , Biswas Rajib , Kamruzzaman Mohammad , Chowdhury Fahima , Khan Ashraful I. , Leung Daniel T. , Weil Ana , LaRocque Regina C. , Bhuiyan Taufiqur Rahman , Rahman Atiqur , Mayo-Smith Leslie M. , Becker Rachel L. , Vyas Jatin M. , Faherty Christina S. , Nickerson Kourtney P. , Giffen Samantha , Ritter Alaina S. , Waldor Matthew K. , Xu Peng , Kováč Pavol , Calderwood Stephen B. , Kauffman Robert C. , Wrammert Jens , Qadri Firdausi , Harris Jason B. , Ryan Edward T. 
Published: October 2020

ABSTRACTThe mechanism of protection against cholera afforded by previous illness or vaccination is currently unknown. We have recently shown that antibodies targeting O-specific polysaccharide (OSP) ofVibrio choleraecorrelate highly with protection against cholera.V. choleraeis highly motile and possesses a flagellum sheathed in O-specific polysaccharide (OSP), and motility ofV. choleraecorrelates with virulence. Using high speed video microscopy, and building upon previous animal-related work, we demonstrate that sera, polyclonal antibody fractions, and OSP-specific monoclonal antibodies recovered from humans surviving cholera blockV. choleraemotility at both subagglutinating and agglutinating concentrations. This anti-motility effect is reversed by pre-adsorbing sera and polyclonal antibody fractions with purified OSP; and is associated with OSP-specific but not flagellin-specific monoclonal antibodies. F[ab] fragments of OSP-specific polyclonal antibodies do not inhibit motility, suggesting a requirement for antibody-mediated crosslinking in motility inhibition. We show that OSP-specific antibodies do not directly affectV. choleraeviability, but that OSP-specific monoclonal antibody highly protects against death in the murine cholera model. We usedin vivocompetitive index studies to demonstrate that OSP-specific antibodies impede colonization and survival ofV. choleraein intestinal tissues, and that this impact is motility-dependent. Our findings suggest that the impedance of motility by antibodies targetingV. choleraeOSP contributes to protection against cholera.IMPORTANCECholera is a severe dehydrating illness of humans caused byVibrio cholerae. V. choleraeis a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), andV. choleraemotility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, sinceV. choleraeis a non-invasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibitV. choleraemotility and are associated with protection against challenge in a motility-dependent manner.
Face neurons in human visual cortex
Authors: Decramer Thomas , Premereur Elsie , Zhu Qi , Van Paesschen Wim , van Loon Johannes , Vanduffel Wim , Taubert Jessica , Janssen Peter , Theys Tom 
Published: October 2020

AbstractThe exquisite capacity of primates to detect and recognize faces is crucial for social interactions. Although disentangling the neural basis of human face recognition remains a key goal in neuroscience, direct evidence at the single-neuron level is virtually nonexistent. We recorded from face-selective neurons in human visual cortex, in a region characterized by functional magnetic resonance imaging (fMRI) activations for faces compared to objects (i.e. the occipital face area, OFA). The majority of visually responsive neurons in this fMRI activation showed strong selectivity at short latencies for faces compared to objects. Feature scrambled faces and face-like objects could also drive these neurons, suggesting that the OFA is not tightly-tuned to the visual attributes that typically define whole human faces. These single-cell recordings within the human face processing system provide vital experimental evidence linking previous imaging studies in humans and invasive studies in animal models.
Dopamine D1 receptor activation drives plasticity in the songbird auditory pallium
Authors: Macedo-Lima Matheus , Boyd Hannah M. , Remage-Healey Luke 
Published: October 2020

AbstractVocal learning species must form and extensively hone associations between sounds and social contingencies. In songbirds, dopamine signaling guides song motor-production, variability, and motivation, but it is unclear how dopamine regulates fundamental auditory associations for learning new sounds. We hypothesized that dopamine regulates learning in the auditory pallium, in part by interacting with local neuroestradiol signaling. Here, we show that zebra finch auditory neurons frequently coexpress D1 receptor (D1R) protein, neuroestradiol-synthase, GABA, and parvalbumin. Auditory classical conditioning increased neuroplasticity gene induction in D1R-positive neurons.In vitro,D1R pharmacological activation reduced the amplitude of GABAergic and glutamatergic currents, and increased the latter’s frequency.In vivo, D1R activation reduced the firing of putative interneurons, increased the firing of putative excitatory neurons, and made both neuronal types unable to adapt to novel stimuli. Together, these data support the hypothesis that dopamine acting via D1Rs modulates learning and memory in the songbird sensory cortex.
Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-in vivo predictions of hepatic clearance
Authors: Krishnan Preethi , Smith Andrew K. , Ropella Glen E.P. , Dutta Lopamudra , Kennedy Ryan C. , Hunt C. Anthony 
Published: October 2020

AbstractWe explore a virtual experiment strategy to discover plausible mechanism-based explanations for frequently inaccurate predictions of hepatic drug clearance made using established in vitro-in vivo extrapolation methods. We describe a three-protocol plan that uses validated software analogs of real in vitro and in vivo systems constructed using a common set of objects, components, spaces, and methods. Both systems utilize identical quasi-autonomous hepatocyte analogs containing enzyme-like objects. We parameterize concrete mobile objects (virtual compounds) to simulate the referent drug’s disposition and removal characteristics in vitro and in vivo. The goal of Protocol one (Protocol two) is that measures of virtual compound removal using the in vitro analog (in vivo analog) map directly to the measurements used to compute intrinsic clearance (in vivo hepatic clearance). Protocol three, the focus of this work, requires achieving an essential cross-system validation target. For a subset of virtual compounds, measurements of unbound compounds entering hepatocytes (and their subsequent removal) during virtual in vitro experiments will directly predict corresponding measures made during virtual in vivo experiments. We study four highly permeable virtual compounds when their unbound fraction is fixed at one of seven values (0.05-1.0). Results span the range of hepatic extraction ratios. We achieve the cross-system validation target in 15 cases. In the other 13 cases, explanations of the in vitro-in vivo differences in disposition and removal trace to differences in compound-hepatocyte access within the two analogs during execution. The hepato-mimetic structural organization of hepatocytes within the in vivo analog, which is absent within the in vitro analog, is the determining factor. The results taken together support the feasibility of using the three-protocol plan to help explain observed in vitro-in vivo extrapolation discrepancies. We conjecture that, for some cases, the model mechanism-based explanations of discrepancies described herein will have wet-lab counterparts.
Clinical connectome fingerprints of cognitive decline
Authors: Sorrentino Pierpaolo , Rucco Rosaria , Lardone Anna , Liparoti Marianna , Lopez Emahnuel Troisi , Cavaliere Carlo , Soricelli Andrea , Jirsa Viktor , Sorrentino Giuseppe , Amico Enrico 
Published: October 2020

AbstractBrain connectome fingerprinting is rapidly rising as a novel influential field in brain network analysis. Yet, it is still unclear whether connectivity fingerprints could be effectively used for mapping and predicting disease progression from human brain data. We hypothesize that dysregulation of brain activity in disease would reflect in worse subject identification. Hence, we propose a novel framework,Clinical Connectome Fingerprinting, to detect individual connectome features from clinical populations. We show that “clinical fingerprints” can map individual variations between elderly healthy subjects and patients undergoing cognitive decline in functional connectomes extracted from magnetoencephalography data. We find that identifiability is reduced in patients as compared to controls, and show that these connectivity features are predictive of the individual Mini-Mental State Examination (MMSE) score in patients. We hope that the proposed methodology can help in bridging the gap between connectivity features and biomarkers of brain dysfunction in large-scale brain networks.
PIEZO2 mediates ultrasonic hearing via cochlear outer hair cells in mice
Authors: Li Jie , Liu Shuang , Song Chenmeng , Hu Qun , Zhao Zhikai , Deng Tuantuan , Wang Yi , Zhu Tong , Zou Linzhi , Wang Shufeng , Chen Jiaofeng , Liu Lian , Hou Hanqing , Yuan Kexin , Zheng Hairong , Liu Zhiyong , Chen Xiaowei , Sun Wenzhi , Xiao Bailong , Xiong Wei 
Published: October 2020

AbstractUltrasonic hearing is exploited for hunting and navigation as in echolocation by microbats and bottleneck dolphins, and for social communication like ultrasonic vocalization by mice and rats. However, the molecular and cellular basis for ultrasonic hearing is not known yet. Here we show that knockout of the mechanosensitive ion channel PIEZO2 in cochlea disrupts the ultrasonic hearing but not the low-frequency hearing in mice, as shown by audiometry and acoustically-associative freezing behavior. Deletion ofPiezo2in the outer hair cells specifically abolishes the associative learning of the mice upon hearing the ultrasonic frequency.Ex vivocochlear Ca2+imaging revealed that the ultrasonic transduction requires both PIEZO2 and the hair-cell mechanotransduction channel. Together, our study demonstrates that the outer hair cells are the effector cells with PIEZO2 as an essential molecule for ultrasonic hearing in mice.Significance StatementSome animals have evolved an incredible ability for vocalizing and hearing ultrasonic frequencies that is inaudible for humans (> 20 kHz). For many years, it has been considered that animals hear ultrasonic frequencies with their cochlear hair cells, using the identical set of mechanotransduction molecules in the hair bundles for hearing audible frequencies. Here, we show that the mice lacking the mechanosensitive ion channel PIEZO2 hardly hear ultrasonic frequencies, while can still be sensitive to audible frequencies. Thus, animals may use a partially different mechanism for sensing physiological ultrasound.