bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of evolutionary modes for trait-based cascades in mutualistic networks
Authors: Bastazini Vinicius Augusto Galvão , Debastiani Vanderlei , Cappelatti Laura , Guimarães Paulo , Pillar Valério D. 
Published: October 2021

AbstractThe erosion of functional diversity may foster the collapse of ecological systems. Functional diversity is ultimately determined by the distribution of species traits. As species traits are a legacy of species evolutionary history, one might expect that the mode of trait evolution influences community resistance under the loss of functional diversity. In this paper, we investigate the role of trait evolutionary dynamics on the robustness of mutualistic networks undergoing the following scenarios of species loss: i) random extinctions, ii) loss of functional distinctiveness and iii) extinctions biased towards larger sizes. We simulated networks defined by models of single trait complementary and evolutionary modes where traits can arise in recent diversification events with weak phylogenetic signal, in early diversification events with strong phylogenetic signal, or as a random walk through evolutionary time. Our simulations show that mutualistic networks are especially vulnerable to extinctions based on trait distinctiveness and more robust to random extinction dynamics. The networks show an intermediate level of robustness against size-based extinctions. Despite the small range of variation in network robustness, our results show that the mode of trait evolution matters for network robustness in all three scenarios. Networks with low phylogenetic signal are more robust than networks with high phylogenetic signal across all scenarios. As a consequence, our results predict that mutualistic networks based upon current adaptations are more likely to cope with extinction dynamics than those networks that are based upon conserved traits.
Biomarker Candidates for Tumors Identified from Deep-Profiled Plasma Stem Predominantly from the Low Abundant Area
Authors: Tognetti Marco , Sklodowski Kamil , Müller Sebastian , Kamber Dominique , Muntel Jan , Bruderer Roland , Reiter Lukas 
Published: October 2021

AbstractThe plasma proteome has the potential to enable a holistic analysis of the health state of an individual. However, plasma biomarker discovery is difficult due to its high dynamic range and variability. Here, we present a novel automated analytical approach for deep plasma profiling and applied it to a 180-sample cohort of human plasma from lung, breast, colorectal, pancreatic, and prostate cancer.Using a controlled quantitative experiment, we demonstrate a 257% increase in protein identification and a 263% increase in significantly differentially abundant proteins over neat plasma.In the cohort, we identified 2,732 proteins. Using machine learning, we discovered biomarker candidates such as STAT3 in colorectal cancer and developed models that classify the disease state. For pancreatic cancer, a separation by stage was achieved.Importantly, biomarker candidates came predominantly from the low abundance region, demonstrating the necessity to deeply profile because they would have been missed by shallow profiling.
Cryo-EM structure of human Nup155 reveals the biochemical basis for atrial fibrillation linked genetic mutation R391H
Authors: Niranjan Sangeeta , Singh Jyotsana , Chauhan Radha 
Published: October 2021

SummaryHuman nuclear pore complexes are composed of ∼32 distinct nucleoporins to facilitate bidirectional nucleo-cytoplasmic transport. Many of them have been associated with various human diseases such as an inherited mutation (R391H) in Nup155 is shown as the clinical cause of atrial fibrillation and sudden cardiac arrest. Due to the lack of structural knowledge and mechanistic insights, the roles of Nups in NPC assembly and relevance in human diseases are very restricted. Here, we show the cryo-EM structure of human Nup155 at 5.2-5.7. Å resolution deciphered from 3 distinct particle classes: N-terminus (19-863), C-terminus (864-1337), and longer N-terminus (19-1069). It revealed intrinsic plasticity at the middle domain of Nup155 and the role of species-specific loop regions in an atypical 7-bladed β-propeller domain to provide a distinct interface for Nup93 and Nup35. Due to the proximity of these Nups interacting sites near the Arginine-391 position, atrial fibrillation linked genetic mutation (R391H) causes dissociation from NPC in absence of N-terminal 112 residues.HighlightsCryo-EM structure of human Nup155 at 5.2 Å resolutionSeven bladed β-propeller domain at N-terminus of Nup155 exhibited distinct features for interaction with Nup35 and Nup93The middle domain of Nup155 is highly dynamic in natureStructural mapping allows mechanistic interpretation of AF linked R391H mutation
Evidence of individual differences in motives for nicotine seeking in classical nicotine self-administration and associated outcomes of varenicline administration
Authors: Garcia-Rivas Vernon , Fiancette Jean-François , Tostain Jessica , de Maio Giulia , Wiart Jean-François , Gaulier Jean-Michel , Deroche-Gamonet Véronique 
Published: October 2021

AbstractBackgroundSmokers vary in their motives for tobacco seeking, suggesting that they could benefit from personalized treatments. However, these variations have received little attention in animal models for the study of tobacco dependence. In the most classically used model, ie. intravenous self-administration of nicotine in the rat, seeking behaviour is reinforced by the combination of intravenous nicotine with a discrete stimulus (eg. discrete cue light). In both human and animals, two types of psychopharmacological interactions between nicotine and environmental stimuli have been evidenced. Whether these two types of interactions contribute equally to nicotine seeking in all individuals is unknown.MethodsWe combined behavioural pharmacology and clustering analysis. In an outbred male rat population, we tested whether nicotine and the discrete nicotine-associated cue light contributed equally to self-administration in all individuals. Two clusters of rats were identified, in which we further studied the nature of the psychopharmacological interaction between nicotine and the cue, as well as the response to the cessation aid varenicline when nicotine was withdrawn.ResultsNotably, withdrawing nicotine produced drastic opposed effects on seeking behavior in the two identified clusters of rats; a 50% increase vs a 18% decrease, respectively. The first cluster of rats sought for the primary reinforcing effects of nicotine and the discrete cue light that has gained nicotine-like secondary reinforcing properties. The second cluster sought nicotine for its ability to enhance the primary reinforcing effects of the discrete cue light. Critically, the approved cessation aid Varenicline counteracted the absence of nicotine in both, but eventually decreasing seeking in the former but increasing it in the latter.ConclusionsClassical rodent models for the study of the reinforcing and addictive effects of nicotine hide individual variations in the psychopharmacological motives supporting seeking behavior. These variations may be a decisive asset for improving their predictive validity in the perspective of precision medicine for smoking cessation.
Intracellular Delivery of Antibodies for Selective Cell Signaling Interference
Authors: Hershman Rebecca L. , Li Yamin , Ma Feihe , Xu Qioabing , Van Deventer James A. 
Published: October 2021

AbstractMany intracellular signaling events remain poorly characterized due to a general lack of tools to interfere with “undruggable” targets. Antibodies have the potential to elucidate intracellular mechanisms via targeted disruption of cell signaling cascades because of their ability to bind to a target with high specificity and affinity. However, due to their size and chemical composition, antibodies cannot innately cross the cell membrane, and thus access to the cytosol with these macromolecules has been limited. Here, we describe strategies for accessing the intracellular space with recombinant antibodies mediated by cationic lipid nanoparticles to selectively disrupt intracellular signaling events. To enable such investigations, we first produced a series of antibody constructs, known as scFv-Fcs, containing additional, genetically encoded negative charges located at the C-termini of the constructs. Preparing proteins with negatively charged motifs has previously been shown to enhance intracellular protein delivery with cationic lipids, but usually for the purpose of genome editing or targeted cell death. We started by generating derivatives of scFv-Fc17, an antibody construct previously reported to bind specifically to signal transducer and activator of transcription 3 (STAT3) phosphorylated at Tyr705 (pYSTAT3). We screened a small number of lipids from our combinatorial lipid library with flow cytometry and found that PBA-Q76-O16B facilitated the most efficient delivery of scFv-Fcs under the conditions tested. In HepG2 cells, we observed up to 60.5% delivery efficacy, while in a STAT3-luciferase reporter cell line up to 71.5% delivery efficacy was observed. These results demonstrated the feasibility of accessing the intracellular space with scFv-Fcs. However, we also note that no more than modest changes were observed upon changing the numbers of negative charges in these constructs during delivery. Characterization of the cytotoxicity, size, and encapsulation efficiency of scFv-Fcs with PBA-Q76-O16B revealed that the constructs were generally well-behaved, with addition of differing quantities of negative charge resulting in at most modest effects. Importantly, functional assays monitoring transcriptional activity in luciferase reporter cell lines and HepG2 cells demonstrated significant reduction of gene expression downstream of pYSTAT3 following delivery of scFv-Fc17 constructs. Together, our results establish the use of recombinantly produced antibodies to selectively interfere with cell signaling events driven by a single posttranslational modification. Efficient intracellular delivery of engineered antibodies opens up possibilities for modulation of previously “undruggable” targets, including for potential therapeutic applications.
Intrinsic timescales as an organizational principle of neural processing across the whole rhesus macaque brain
Authors: Manea Ana M.G. , Zilverstand Anna , Uğurbil Kâmil , Heilbronner Sarah R. , Zimmermann Jan 
Published: October 2021

AbstractHierarchical temporal dynamics are a fundamental computational property of the brain; however, there are no whole-brain, noninvasive investigations into timescales of neural processing in animal models. To that end, we used the spatial resolution and sensitivity of ultrahigh field fMRI performed at 10.5 Tesla to probe timescales across the whole macaque brain. We uncovered within-species consistency between timescales estimated from fMRI and electrophysiology. Crucially, we extended existing electrophysiological hierarchies to whole brain topographies. Our results validate the complementary use of hemodynamic and electrophysiological intrinsic timescales, establishing a basis for future translational work. Further, with these results in hand, we were able to show that one facet of the high-dimensional functional connectivity topography of any region in the brain is closely related to hierarchical temporal dynamics. We demonstrated that intrinsic timescales are organized along spatial gradients that closely match functional connectivity gradient topographies across the whole brain. We conclude that intrinsic timescales are a unifying organizational principle of neural processing across the whole brain.Declaration of InterestsThe authors declare no competing interests.
SARS-CoV-2 RNA and antibody dynamics in a Dutch household study with dense sampling frame
Authors: Han Wanda G.H. , Swart Arno , Marinovic Axel Bonacic , Eggink Dirk , Reimerink Johan , Wijsman Lisa A. , van der Veer Bas , van den Brink Sharon , van den Brandt Anne-Marie , van Tol Sophie , Godeke Gert-Jan , Brouwer Fion , Hoogerwerf Marieke , Reukers Daphne F.M. , Rots Nynke , Reusken Chantal , Meijer Adam 
Published: October 2021

AbstractThis study investigated the dynamics of SARS-CoV-2 infection and diagnostics in household members of different ages and with different symptom severity after SARS-CoV-2 exposure during the early phase of the pandemic. Households with a SARS-CoV-2 confirmed positive case and at least one child in the Netherlands were followed for 6 weeks. Naso (NP)- and oropharyngeal (OP) swabs, oral fluid and feces specimens were analyzed for SARS-CoV-2 RNA and serum for SARS-CoV-2-specific antibodies. The dynamics of the presence of viral RNA and the serological response was modeled to determine the sampling time-frame and sample type with the highest sensitivity to confirm or reject a SARS-CoV-2 diagnosis. Transmission of SARS-CoV-2 between adults and children within a household was correlated with symptom severity of index cases. In children higher viral loads compared to adults were detected at symptom onset. Early in infection, higher viral loads were detected in NP and OP specimens, while RNA in especially feces were longer detectable. SARS-CoV-2-specific antibodies have a 90% probability of detection from 7 days (total Ig) and 18 days (IgG) since symptom onset. In conclusion this study has shown that on average, children carry higher loads of virus as compared to adults early after infection. For highest probability of detection in SARS-CoV-2 diagnostics early in infection, RT-PCR on NP and OP specimens are more sensitive than on oral fluid and feces. For SARS-CoV-2 diagnostics late after infection, RT-PCR on feces specimens and serology are more valuable.
Estimating the Efficacy of Common Treatments in Children and Young Adults Diagnosed with Cerebral Palsy Using Three Machine Learning Algorithms
Authors: Schwartz Michael H. , Ries Andrew J. , Georgiadis Andrew G. 
Published: October 2021

AbstractBackgroundOrthopedic and neurological deformity are often treated in children and young adults with cerebral palsy (CP). Due to challenges arising from combinatorics, research funding priorities, and medical practicalities, the efficacy of these treatments is not well studied.ObjectivesOur goal was to estimate the efficacy of 13 common orthopedic and neurological treatments at four different levels of outcome in children and young adults diagnosed with CP. The outcome levels considered were anatomy and physiology, gait parameter, overall gait pattern, and function.MethodsWe used three well-establish causal inference approaches (direct matching, virtual twins, and Bayesian causal forests) and a large clinical gait analysis database to estimate the average treatment effect on the treated (ATT). We then examined the efficacy across treatments, methods, and outcome levels.ResultsThe median ATT of 13 common treatments in children and young adults with CP, measured as Cohen’s D, bordered on medium at the anatomy and physiology level (median [IQR] = 0.42 [.05, .60]) and became smaller as we moved along the causal chain through gait parameter (0.21 [.01, .33]), overall gait pattern (0.09 [.03, .19]), and function (−0.01 [-.06, .13]).ConclusionsCurrent treatments have medium effects on anatomy and physiology, but modest to minimal efficacy on gait and function. Further work is needed to understand the source of heterogeneous treatment effects, which are large in this patient population. Replication or refutation of these findings by other centers will be valuable to establish the generalizability of these results and for benchmarking of best practices.
Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions
Authors: Hasan Rahat , Humphrey Jack , Bettencourt Conceição , Lashley Tammaryn , Fratta Pietro , Raj Towfique 
Published: October 2021

AbstractFrontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.
Deep Learning Model for Mortality Prediction of ICU Patients with Paralytic Ileus
Authors: Razo Martha , Pishgar Maryam , Darabi Houshang 
Published: October 2021

AbstractBackgroundParalytic Ileus (PI) patients in the Intensive Care Unit (ICU) are at a significant risk of death. Prediction of at-risk patients for mortality after 24 hours of admission of ICU PI patients is important to increase the life expectancy of PI patients.Methods and ResultsThe proposed framework,DLMP(Deep Learning Model for Mortality Prediction of ICU Patients with PI) is a powerful deep learning model consisting of six total unique clinical lab items and two demographics as inputs to a Neural Network(NN) of only two neuron layers. Using the Medical Information Mart for Intensive Care III (MIMIC-III) dataset of 1,017 ICU PI patients, theDLMPresulted in the best prediction performance with an AUC score of 0.866.ConclusionThe proposed approach is capable of modeling the mortality of ICU patients after 24 hours admission using only six unique total clinical data and two demographics with a simple NN architecture.DLMPframework significantly improves the outcome prediction compared to the process mining and machine learning models. The proposedDLMPhas the potential of allowing clinicians to create targeted interventions that reduce mortality for PI patients in an ICU setting.
Optimizing the live attenuated influenza A vaccine backbone for high-risk patient groups
Authors: Bonifacio João P.P. , Williams Nathalia , Garnier Laure , Hugues Stephanie , Schmolke Mirco , Mazel-Sanchez Beryl 
Published: October 2021

AbstractThe live attenuated influenza vaccine (LAIV) is approved for intranasal spray application in 2-49 year-old patients with safety concerns limiting its use in younger children and immunocompromised patients, mainly from the higher incidence of adverse events and the possibility of uncontrolled replication and reversion to a pathogenic strain, respectively. Further attenuation of the LAIV could generally improve its safety profile, which might come at the cost of reduced immunogenicity. To solve this dilemma, we took advantage of a recently defined mechanism of ER stress induction by modifying IAV non-structural protein 1 (NS1). The modified LAIV (AAmut/PR8) showed stronger ER stress activation in vitro and replicated to lower titers in vivo compared to its parental strain, without affecting protection against homo-subtypic or hetero-subtypic IAV strains. AAmut/PR8 could pose as a suitable strategy to attend the gap to the current LAIV recommendation guidelines in susceptible target populations.
Neutral competition explains the clonal composition of neural organoids
Authors: Pflug Florian G. , Haendeler Simon , Esk Christopher , Lindenhofer Dominik , Knoblich Jürgen A. , von Haeseler Arndt 
Published: October 2021

SummaryCerebral organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progeny arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This exceeds what can be explained by existing stochastic models of corticogenesis, indicating the existence of an additional source of stochasticity. We propose an explanation in terms of the SAN model in which this additional source of stochasticity is the survival time of a lineage within a long-lived population of symmetrically dividing cells under neutral competition. We demonstrate that this model explains the experimentally observed variability of lineage sizes and we derive a formula that captures the quantitative relationship between survival time and lineage size. Finally, we show that our model implies the existence of a regulatory mechanism to keeps the size of the symmetrically dividing cell population constant.
Selective modulation of cell surface proteins during vaccinia infection: implications for immune evasion strategies
Authors: Depierreux Delphine M , Altenburg Arwen F , Soday Lior , Fletcher-Etherington Alice , Anthrobus Robin , Ferguson Brian J , Weekes Michael P , Smith Geoffrey L 
Published: October 2021

AbstractThe interaction between immune cells and virus-infected targets involves multiple plasma membrane (PM) proteins. A systematic study of PM protein modulation by vaccinia virus (VACV), the paradigm of host regulation, has the potential to reveal not only novel viral immune evasion mechanisms, but also novel factors critical in host immunity. Here, >1000 PM proteins were quantified throughout VACV infection, revealing selective downregulation of known T and NK cell ligands including HLA-C, downregulation of cytokine receptors including IFNAR2, IL-6ST and IL-10RB, and rapid inhibition of expression of certain protocadherins and ephrins, candidate activating immune ligands. Downregulation of most PM proteins occurred via a proteasome-independent mechanism. Upregulated proteins included a decoy receptor for TRAIL. Twenty VACV-encoded PM proteins were identified, of which five were not recognised previously as such. Collectively, this dataset constitutes a valuable resource for future studies on antiviral immunity, host-pathogen interaction, poxvirus biology, vector-based vaccine design and oncolytic therapy.