bluuebunny/crossref_metadata_2025 huggingface dataset:
Are disturbances in mentalization ability similar between schizophrenic patients and borderline personality disorder patients? A pilot study
Authors: Bar Tair , Ikshaibon Issam , Abu-Alhiga Muhammad , Peleg Tamar , Awad Yaseen , Plazur Eilam , Golani Idit , Peleg Ido , Shamir Alon
Published: November 2021

There is a growing interest in theory of mind (ToM) performance among individuals with psychiatric disorders, however, the difference and the performance level between different diagnoses is unclear. Here, we compared the ToM abilities of schizophrenia, schizoaffective and borderline personality individuals (BPD) with healthy individuals, and searched for a correlation between ToM ability, social skills, and empathy. Overall, diagnostic groups performed worse in the Reading the Mind in the Eyes test and recognized fewer Faux Pax motifs than healthy individuals recognize. No difference was observed in the ability to perform the eyes test between schizophrenic patients with and without the affective components and BPD patients. Both schizophrenia and BPD patients received a higher score in the autism-spectrum questioner, while all the diagnostic groups scored lower on the empathy quotient scale than healthy individuals. Finally, a correlation was found between ToM ability and empathy, but not with autistic-related traits. Results indicate that both cognitive and affective aspects of ToM are impaired across all the diagnostic groups, challenge the ability to use ToM as a differential diagnostic tool, and strengthens the correlation between decreased empathy and impaired ToM.
A population framework for predicting the proportion of people infected by the far-field airborne transmission of SARS-CoV-2 indoors
Authors: Iddon Christopher , Jones Benjamin , Sharpe Patrick , Cevik Muge , Fitzgerald Shaun
Published: November 2021

The number of occupants in a space influences the risk of far-field airborne transmission of SARS-CoV-2 because the likelihood of having infectious and susceptible people both correlate with the number of occupants. This paper explores the relationship between occupancy and the probability of infection, and how this affects an individual person and a population of people. Mass-balance and dose-response models determine far-field transmission risks for an individual person and a population of people after sub-dividing a large reference space into 10 identical comparator spaces.

For a single infected person, the dose received by an individual person in the comparator space is 10-times higher because the equivalent ventilation rate per infected person is lower when the per capita ventilation rate is preserved.

However, accounting for population dispersion, such as the community prevalence of the virus, the probability of an infected person being present and uncertainty in their viral load, shows the transmission probability increases with occupancy and the reference space has a higher transmission risk. Also, far-field transmission is likely to be a rare event that requires a high emission rate, and there are a set of Goldilocks conditions that are just right when ventilation is effective at mitigating against transmission. These conditions depend on the viral load, because when they are very high or low, ventilation has little effect on transmission risk.

Nevertheless, resilient buildings should deliver the equivalent ventilation rate required by standards as minimum.
Evaluation of new polymer-iodine complexes for the fabrication of medical devices
Authors: López-Álvarez Marina , Ulmer Herb , Klay Nico , van Dijl Jan Maarten
Published: November 2021

Povidone-iodine has been a true success story in the fight against infections by harnessing the antimicrobial and antiviral properties of elemental iodine for water-based applications. However, to date there has been little success in implementing iodine attributes in water-insoluble engineering plastics. Here, we describe the first development of biocidal active polyamide- and polyurethane-iodine complexes at laboratory and commercially relevant scales. These polymer-iodine materials are active against a broad range of microorganisms, including bacteria, yeast and fungi, and can be used as base materials for medical devices. The use of new polymer-iodine complexes for infection prevention in medical devices, such as sutures, catheters and drains, or wound care is expected to have significant positive effects at reducing healthcare-acquired infections. In addition, the materials are expected to find significant applications in other fields, such as air handling with the production of biocidal face masks and air filters to control spread of pathogens.
Number of detected proteins as the function of the sensitivity of proteomic technology in human liver cells
Authors: Vavilov Nikita , Ilgisonis Ekaterina , Lisitsa Andrey , Ponomarenko Elena , Farafonova Tatiana , Tikhonova Olga , Zgoda Victor , Archakov Alexander
Published: November 2021

The main goal of the Russian part of C-HPP is to detect and functionally annotate missing proteins (PE2-PE4) encoded by human chromosome 18. However, identifying such proteins in a complex biological mixture using mass spectrometry (MS)-based methods is difficult due to the insufficient sensitivity of proteomic analysis methods. In this study, we determined the proteomic technology sensitivity using a standard set of UPS1 proteins as an example. The results revealed that 100% of proteins in a mixture could only be identified at a concentration of at least 10−9 M. The decrease in concentration leads to protein losses associated with technology sensitivity, and no UPS1 protein is detected at a concentration of 10−13 M. Therefore, two-dimensional fractionation of samples was applied to improve sensitivity. The human liver tissue was examined by selected reaction monitoring and shotgun methods of MS analysis using one-dimensional and two-dimensional fractionation to identify the proteins encoded by human chromosome 18. A total of 134 proteins were identified. The overlap between proteomic and transcriptomic data in human liver tissue was ~50%. This weak convergence is due to the low sensitivity of proteomic technology compared to transcriptomic approaches. Data is available via ProteomeXchange with identifier PXD026997.
Intact double stranded RNA is mobile and triggers RNAi against viral and fungal plant pathogens
Authors: Brosnan Christopher A. , Sawyer Anne , de Felippes Felipe F. , Carroll Bernard J. , Waterhouse Peter M. , Mitter Neena
Published: November 2021

Topical application of double-stranded RNA (dsRNA) as RNA interference(RNAi) based biopesticides represents a sustainable alternative to traditional transgenic, breeding-based or chemical crop protection strategies. A key feature of RNAi is its ability to act non-cell autonomously, a process that plays a critical role in plant protection. However, the uptake of dsRNA upon topical application, and its ability to move and act non-cell autonomously remains debated and largely unexplored. Here we show that when applied to a leaf, unprocessed full-length dsRNA enters the vasculature and rapidly moves to multiple distal below ground, vegetative and reproductive tissue types in several model plant and crop hosts. Intact unprocessed dsRNA was detected in the apoplast of leaves, roots and flowers after leaf application and maintained in subsequent new growth. Furthermore, we show mobile dsRNA is functional against root infecting fungal and foliar viral pathogens. Our demonstration of the uptake and maintained movement of intact and functional dsRNA stands to add significant benefit to the emerging field of RNAi-based plant protection.
FAMOSS, a conserved 41-aa peptide involved in plant tip growth regulation
Authors: Mamaeva Anna , Kniazev Andrey , Sedlov Ilia , Golub Nina , Kharlampieva Daria , Manuvera Valentin , Rakitin Victor , Nosov Alexander , Fomenkov Artem , Pavlyukov Marat , Kovalchuk Sergey , Ziganshin Rustam , Glushkevich Anna , Lazarev Vassili , Fesenko Igor
Published: November 2021

Recent evidence shows that small open reading frame (smORF; <100 codons)-encoded peptides (SEPs) containing transmembrane domains are preadapted to be progenitors of novel functional genes. A dozen of such SEPs translated from long non-coding RNAs (lncRNAs) are already functionally characterised in animals. However, functional plant lncRNA-smORF-coded peptides are not yet described. Here, we report detailed functional characterization of a 41-aa peptide encoded by lncRNA-smORFs in the moss Physcomitrium patens, which was named “FAst-growing MOSS” (FAMOSS). We found that the FAMOSS interacts with the Rab-type small GTPase proteins and its overexpression leads to faster moss growth rate and more intensive vesicular transport in apical cells, while its knockout results in the opposite effect. The FAMOSS contains a predicted transmembrane domain and possible orthologs from streptophyta algae to flowering plants have a very conserved structure. Thus, the FAMOSS peptide is a previously unknown conserved player of Rab-mediated processes in plants. Our findings are in line with functional studies of transmembrane SEPs in animals and prove the principles of SEPs evolution. This study provides new insights into functions of plant lncRNA-smORFs.
Reducing voltage-dependent potassium channel Kv3.4 levels ameliorates synapse loss in a mouse model of Alzheimer’s disease
Authors: Yeap Jie , Sathyaprakash Chaitra , Toombs Jamie , Tulloch Jane , Scutariu Cristina , Rose Jamie , Burr Karen , Davies Caitlin , Colom-Cadena Marti , Chandran Siddharthan , Large Charles H , Rowan Matthew JM , Gunthorpe Martin J , Spires-Jones Tara L
Published: November 2021

Synapse loss is associated with cognitive decline in Alzheimer’s disease (AD) and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta (Aβ) around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human AD brain tissue, but the mechanisms leading from Aβ to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltagegated potassium channel subtype 3.4 (Kv3.4) may play a role in Aβ-mediated neurotoxicity. Here, we tested whether this channel could also be involved in Aβ synaptotoxicity. Using adeno-associated virus and CRISPR (clustered regularly interspaced short palindromic repeats) technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial AD associated mutations in amyloid precursor protein and presenilin 1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in AD brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human AD and control brain and is associated with synapses in human iPSC-derived cortical neurons. Interestingly, we observe a decrease in Kv3.4 expression in iPSC derived cortical neurons when they are challenged with human Alzheimer’s disease derived brain homogenate. These results suggest that approaches to reduce Kv3.4 expression and/or function could be protective against Aβ-induced synaptic alterations.
Vertebrate extracellular matrix protein hemicentin-1 interacts physically and genetically with basement membrane protein nidogen-2
Authors: Zhang Jin-Li , Richetti Stefania , Ramezani Thomas , Welcker Daniela , Lütke Steffen , Pogoda Hans-Martin , Hatzold Julia , Zaucke Frank , Keene Douglas R. , Bloch Wilhelm , Sengle Gerhard , Hammerschmidt Matthias
Published: November 2021

Hemicentins are large proteins of the extracellular matrix that belong to the fibulin family and play pivotal roles during development and homeostasis of a variety of invertebrate and vertebrate tissues. However, bona fide interaction partners of hemicentins have not been described as yet. Here, applying surface plasmon resonance spectroscopy and co-immunoprecipitation, we identify the basement membrane protein nidogen-2 (NID2) as a binding partner of mouse and zebrafish hemicentin-1 (HMCN1), in line with the formerly described essential role of mouse HMCN1 in basement membrane integrity. We show that HMCN1 binds to the same protein domain of NID2 (G2) as formerly shown for laminins, but with an approximately ten-fold lower affinity and in a competitive manner. Furthermore, immunofluorescence and immunogold labelling revealed that HMCN1/Hmcn1 is localized close to basement membranes and in partial overlap with NID2/Nid2a in different tissues of mouse and zebrafish. Genetic knockout and antisense-mediated knockdown studies in zebrafish further show that loss of Nid2a leads to similar defects in fin fold morphogenesis as the loss of Laminin-α5 (Lama5) or Hmcn1. Finally, combined partial loss-of-function studies indicated that nid2a genetically interacts with both hmcn1 and lama5. Together, these findings suggest that despite their mutually exclusive physical binding, hemicentins, nidogens, and laminins tightly cooperate and support each other during formation, maintenance, and function of basement membranes to confer tissue linkage.
Association between plasma phospho-tau181 and cognitive change from age 73 to 82: Lothian Birth Cohort 1936
Authors: Saunders Tyler S. , Heslegrave Amanda , King Declan , Harris Sarah , Ritchie Craig , Muniz-Terrera Graciela , Deary Ian J. , Cox Simon R. , Zetterberg Henrik , Spires-Jones Tara
Published: November 2021

INTRODUCTION

Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer’s disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we tested whether plasma p-tau181predicts cognitive decline and whether it is present in synapses in human brain.

METHODS

General cognitive ability and plasma p-tau181 concentration were measured in 195 participants at ages 72 and 82. Levels of p-tau181 in total homogenate and synaptic fractions were compared with western blot (n=10-12 per group), and synaptic localisation was examined using array tomography.

RESULTS

Elevated baseline plasma p-tau181 and increasing p-tau181 over time predicted steeper general cognitive decline. We observe p-tau181 in neurites, presynapses, and post-synapses in the brain.

DISCUSSION

Baseline and subsequent change in plasma p-tau181 may represent rare biomarkers of differences in cognitive ageing across the 8th decade of life and may play a role in synaptic function in the brain.
Generation of Infant-dedicated Fine-grained Functional Parcellation Maps of Cerebral Cortex
Authors: Wang Fan , Zhang Han , Wu Zhengwang , Hu Dan , Zhou Zhen , Wang Li , Lin Weili , Li Gang ,   for UNC/UMN Baby Connectome Project Consortium
Published: November 2021

Infancy is a dynamic and immensely important period in human brain development. Studies of infant functional development using resting-state fMRI rely on precisely defined cortical parcellation maps. However, available adult-based functional parcellation maps are not applicable for infants due to their substantial differences in functional organizations. Fine-grained infant-dedicated cortical parcellation maps are highly desired but remain scarce, due to difficulties ranging from acquiring to processing of infant brain MRIs. In this study, leveraging 1,064 high-resolution longitudinal rs-fMRIs from 197 infants from birth to 24 months and advanced infant-dedicated processing tools, we create the first set of infant-specific, fine-grained cortical functional parcellation maps. Besides the conventional folding-based cortical registration, we specifically establish the functional correspondences across individuals using functional gradient densities and generate both age-specific and age-common fine-grained parcellation maps. The first set of comprehensive brain functional developmental maps are accordingly derived, and reveals a complex, hitherto unseen multi-peak fluctuation development pattern in temporal variations of gradient density, network sizes, and local efficiency, with more dynamic changes during the first 9 months than other ages. Our proposed method is applicable in generating fine-grained parcellations for the whole lifespan, and our parcellation maps will be available online to advance the neuroimaging field.
Septin-7 is indispensable for proper skeletal muscle architecture and function
Authors: Gönczi Mónika , Ráduly Zsolt , Szabó László , Fodor János , Telek Andrea , Dobrosi Nóra , Balogh Norbert , Szentesi Péter , Kis Gréta , Antal Miklós , Trencsényi György , Dienes Beatrix , Csernoch László
Published: November 2021

Today septins are considered as the fourth component of the cytoskeleton with the Septin-7 isoform playing a critical role in the formation of higher order structures. While its importance has already been confirmed in several intracellular processes of different organs, very little is known about its role in skeletal muscle. Here, using Septin-7 conditional knock-down mouse model, the C2C12 cell line, and enzymatically isolated adult muscle fibers the organization and localization of septin filaments is revealed, and an ontogenesis-dependent expression of Septin-7 is demonstrated. KD mice displayed a characteristic hunchback phenotype with skeletal deformities, reduction in vivo and in vitro force generation, and disorganized mitochondrial networks. Furthermore, knock-out of Septin-7 in C2C12 cells resulted in complete loss of cell division while KD cells provided evidence that Septin-7 is essential in proper myotube differentiation. These and the transient increase in Septin-7 expression following muscle injury demonstrate its vital contribution to muscle regeneration and development.
Prefrontal, striatal, and VTA subnetwork dynamics during novelty and exploration
Authors: Dede Adam J.O. , Marzban Nader , Mishra Ashutosh , Reichert Robert , Anderson Paul M. , Cohen Michael X
Published: November 2021

Multiple distinct brain areas have been implicated in memory including the prefrontal cortex (PFC), striatum (STR), and ventral tegmental area (VTA). Information-exchange across these widespread networks requires flexible coordination at a fine time-scale. In the present study, we collected high-density recordings from the PFC, STR, and VTA of male rats during baseline, encoding, consolidation, and retrieval stages of memory formation. Novel sub-regional clustering analyses identified patterns of spatially restricted, temporally coherent, and frequency specific signals that were reproducible across days and were modulated by behavioral states. Clustering identified miniscule patches of neural tissue. Generalized eigen decomposition (GED) reduced each cluster to a single time series. Amplitude envelope correlation of the cluster time series was used to assess functional connectivity between clusters. Dense intra- and inter regional functional connectivity characterized the baseline period, with delta oscillations playing an outsized role. There was a dramatic pruning of network connectivity during encoding. Connectivity rebounded during consolidation, but connections in the theta band became stronger, and those in the delta band were weaker. Finally, during retrieval, connections were not as severely reduced as they had been during encoding, and specifically theta and higher-frequency connections were stronger. Underlying these connectivity changes, the anatomical extent of clusters observed in the gamma band in the PFC and in both the gamma and delta bands in the VTA changed markedly across behavioral conditions. These results demonstrate the brain’s ability to reorganize functionally at both the intra- and inter-regional levels during different stages of memory processing.

SIGNIFICANCE STATEMENT

The brain is often thought of as a mosaic of areas each with static functions that activate or deactivate with task demands. Here, we used large-scale recordings (196 simultaneous electrodes) and developed a multivariate analysis approach to analyze data from all our recording locations simultaneously. This analysis revealed that the brain dramatically reorganized itself at both local and long-distance spatial scales during different stages of memory processing. These results demonstrate an extreme degree of flexibility in functional anatomy. Rather than thinking about the brain as a set of static mosaic tiles, it may better be characterized as a quickly moldable piece of clay where each part’s function changes as the whole is reshaped from moment to moment.
Human-in-the-loop optimization of visual prosthetic stimulation
Authors: Fauvel Tristan , Chalk Matthew
Published: November 2021

Abstract

Retinal prostheses are a promising strategy to restore sight to patients with retinal degenerative diseases. These devices compensate for the loss of photoreceptors by electrically stimulating neurons in the retina. Currently, the visual function that can be recovered with such devices is very limited. This is due, in part, to current spread, unintended axonal activation, and the limited resolution of existing devices. Here we show, using a recent model of prosthetic vision, that optimizing how visual stimuli are encoded by the device can help overcome some of these limitations, leading to dramatic improvements in visual perception. We propose a strategy to do this in practice, using patients’ feedback in a visual task. The main challenge of our approach comes from the fact that, typically, one only has access to a limited number of noisy responses from patients. We propose two ways to deal with this: first, we use a model of prosthetic vision to constrain and simplify the optimization; second, we use preferential Bayesian optimization to efficiently learn the encoder using minimal trials. To test our approach, we presented healthy subjects with visual stimuli generated by a recent model of prosthetic vision, to replicate the perceptual experience of patients fitted with an implant. Our optimization procedure led to significant and robust improvements in perceived image quality, that transferred to increased performance in other tasks. Importantly, our strategy is agnostic to the type of prosthesis and thus could readily be implemented in existing implants.
Generalizable approaches for genomic prediction of metabolites in plants
Authors: Brzozowski Lauren J. , Campbell Malachy T. , Hu Haixiao , Caffe Melanie , Gutiérrez Lucía , Smith Kevin P. , Sorrells Mark E. , Gore Michael A. , Jannink Jean-Luc
Published: November 2021

Plant metabolites are important for plant breeders to improve nutrition and agronomic performance, yet integrating selection for metabolomic traits is limited by phenotyping expense and limited genetic characterization, especially of uncommon metabolites. As such, developing biologically-based and generalizable genomic selection methods for metabolites that are transferable across plant populations would benefit plant breeding programs. We tested genomic prediction accuracy for more than 600 metabolites measured by GC-MS and LC-MS in oat (Avena sativa L.) seed. Using a discovery germplasm panel, we conducted metabolite GWAS (mGWAS) and selected loci to use in multi-kernel models that encompassed metabolome-wide mGWAS results, or mGWAS from specific metabolite structures or biosynthetic pathways. Metabolite kernels developed from LC-MS metabolites in the discovery panel improved prediction accuracy of LC-MS metabolite traits in the validation panel, consisting of more advanced breeding lines. No approach, however, improved prediction accuracy for GC-MS metabolites. We tested if similar metabolites had consistent model ranks and found that, while different metrics of ‘similarity’ had different results, using annotation-free methods to group metabolites led to consistent within-group model rankings. Overall, testing biological rationales for developing kernels for genomic prediction across populations, contributes to developing frameworks for plant breeding for metabolite traits.
Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors
Authors: Patoori Sruti , Barnada Samantha M. , Large Christopher , Murray John I. , Trizzino Marco
Published: November 2021

The hippocampus is associated with essential brain functions such as learning and memory. Human hippocampal volume is significantly greater than expected when compared to non-human apes, suggesting a recent expansion. Intermediate progenitors, which are able to undergo multiple rounds of proliferative division before a final neurogenic division, may have played a role in the evolutionary hippocampal expansion. To investigate the evolution of gene regulatory networks underpinning hippocampal neurogenesis in apes, we leveraged the differentiation of human and chimpanzee induced Pluripotent Stem Cells into TBR2-positive hippocampal intermediate progenitors (hpIPCs). We find that the gene networks active in hpIPCs are significantly different between humans and chimpanzees, with ∼2,500 genes differentially expressed. We demonstrate that species-specific transposon-derived enhancers contribute to these transcriptomic differences. Young transposons, predominantly Endogenous Retroviruses (ERVs) and SINE-Vntr-Alus (SVAs), were co-opted as enhancers in a species-specific manner. Human-specific SVAs provided substrates for thousands of novel TBR2 binding sites, and CRISPR-mediated repression of these SVAs attenuates the expression of ∼25% of the genes that are upregulated in human intermediate progenitors relative to the same cell population in the chimpanzee.

Summary statement

Evolution of human and chimpanzee hippocampal development was mediated by co-option of young retrotransposons into species-specific enhancers.
Hyperspectral Counting of Multiplexed Nanoparticle Emitters in Single Cells and Organelles
Authors: Jena Prakrit V. , Gravely Mitchell , Cupo Christian C. , Safaee Mohammad M. , Roxbury Daniel , Heller Daniel A.
Published: November 2021

Nanomaterials are the subject of a range of biomedical, commercial, and environmental investigations involving measurements in living cells and tissues. Accurate quantification of nanomaterials, at the tissue, cell, and organelle levels, is often difficult, however, in part due to their inhomogeneity. Here, we propose a method that uses the diverse optical properties of a nanomaterial preparation in order to improve quantification at the single-cell and organelle level. We developed ‘hyperspectral counting’, which employs diffraction-limited imagingviahyperspectral microscopy of a diverse set of nanomaterial emitters, to estimate nanomaterial counts in live cells and sub-cellular structures. A mathematical model was developed, and Monte Carlo simulations were employed, to improve the accuracy of these estimates, enabling quantification with single-cell and single-endosome resolution. We applied this nanometrology technique to identify an upper-limit of the rate of uptake into cells - approximately 3,000 particles endocytosed within 30 minutes. In contrast, conventional ROI counting results in a 230% undercount. The method identified significant heterogeneity and a broad non-Gaussian distribution of carbon nanotube uptake within cells. For example, while a particular cell contained an average of 1 nanotube per endosome, the heterogenous distribution resulted in over 7 nanotubes localizing within some endosomes, substantially changing the accounting of subcellular nanoparticle concentration distributions. This work presents a method to quantify cellular and subcellular concentrations of a heterogeneous carbon nanotube reference material, with implications for nanotoxicology, drug/gene delivery, and nanosensor fields.
NucPosDB: a database of nucleosome positioning in vivo and nucleosomics of cell-free DNA
Authors: Shtumpf Mariya , Piroeva Kristan V. , Agrawal Shivam P. , Jacob Divya R. , Teif Vladimir B.
Published: November 2021

Nucleosome positioning is involved in many gene regulatory processes happening in the cell and it may change as cells differentiate or respond to the changing microenvironment in a healthy or diseased organism. One important implication of nucleosome positioning in clinical epigenetics is its use in the “nucleosomics” analysis of cell-free DNA (cfDNA) for the purpose of patient diagnostics in liquid biopsies. The rationale for this is that the apoptotic nucleases that digest chromatin of the dying cells mostly cut DNA between nucleosomes. Thus, the short pieces of DNA in body fluids reflect the positions of nucleosomes in the cells of origin. Here we report a systematic nucleosomics database – NucPosDB, curating published nucleosome positioning datasets in vivo as well as datasets of sequenced cell-free DNA (cfDNA) that reflect nucleosome positioning in situ in the cells of origin. Users can select subsets of the database by a number of criteria and then obtain raw or processed data. NucPosDB also reports the originally determined regions with stable nucleosome occupancy across several individuals with a given condition. An additional section provides a catalogue of computational tools for the analysis of nucleosome positioning or cfDNA experiments and theoretical algorithms for the prediction of nucleosome positioning from DNA sequence. We provide an overview of the field, describe the structure of the database in this context and demonstrate data variability using examples of different medical conditions. NucPosDB is useful both for analysis of fundamental gene regulation processes and training computational models for patient diagnostics based on cfDNA. The database currently curates ∼400 publications on nucleosome positioning in cell lines and in situ as well as cfDNA from >10,000 patients and healthy volunteers. For open-access cfDNA datasets as well as key MNase-seq datasets in human cells, NucPosDB allows downloading processed mapped data in addition to the stable-nucleosome regions. NucPosDB is available at https://generegulation.org/nucposdb/.
Systematic Evaluation of Machine Learning Algorithms for Neuroanatomically-Based Age Prediction in Youth
Authors: Modabbernia Amirhossein , Whalley Heather C. , Glahn David C. , Thompson Paul M. , Kahn Rene S. , Frangou Sophia
Published: November 2021

Application of machine learning algorithms to structural magnetic resonance imaging (sMRI) data has yielded behaviorally meaningful estimates of the biological age of the brain (brain-age). The choice of the machine learning approach in estimating brain-age in children and adolescents is important because age-related brain changes in these age-groups are dynamic. However, the comparative performance of the multiple machine learning algorithms available has not been systematically appraised. To address this gap, the present study evaluated the accuracy (Mean Absolute Error; MAE) and computational efficiency of 21 machine learning algorithms using sMRI data from 2,105 typically developing individuals aged 5 to 22 years from five cohorts. The trained models were then tested in two independent holdout datasets, comprising 4,078 pre-adolescents aged 9-10 years and another sample of 594 individuals aged 5-21 years. The algorithms encompassed parametric and nonparametric, Bayesian, linear and nonlinear, tree-based, and kernel-based models. Sensitivity analyses were performed for parcellation scheme, number of neuroimaging input features, number of cross-validation folds, number of extreme outliers, and sample size. The best performing algorithms were Extreme Gradient Boosting (MAE of 1.49), Random Forest Regression (MAE of 1.58) and Support Vector Regression with Radial Basis Function Kernel (MAE of 1.64) which had acceptable and comparable computational efficiency. Findings of the present study could be used as a guide for optimizing methodology when quantifying age-related changes in youth.
Long-Range Electrostatic Interactions Significantly Modulate the Affinity of Dynein for Microtubules
Authors: Pabbathi Ashok , Coleman Lawrence , Godar Subash , Paul Apurba , Garlapati Aman , Spencer Matheu , Eller Jared , Alper Joshua
Published: November 2021

The dynein family of microtubule minus-end directed motor proteins drives diverse functions in eukaryotic cells, including cell division, intracellular transport, and flagellar beating. Motor protein processivity, which characterizes how far a motor walks before detaching from its filament, depends on the interaction between its microtubule-binding domain (MTBD) and the microtubule. Dynein’s MTBD switches between high- and low-binding affinity states as it steps. Significant structural and functional data show that specific salt bridges within the MTBD and between the MTBD and the microtubule govern these affinity state shifts. However, recent computational work suggests that non-specific, long-range electrostatic interactions between the MTBD and the microtubule may also play a significant role in the processivity of dynein. To investigate this hypothesis, we mutated negatively charged amino acids remote from the dynein MTBD-microtubule-binding interface to neutral residues and measured the binding affinity using microscale thermophoresis and optical tweezers. We found a significant increase in the binding affinity of the mutated MTBDs for microtubules. Furthermore, we found that charge screening by free ions in solution differentially affected the binding and unbinding rates of MTBDs to microtubules. Together, these results demonstrate a significant role for long-range electrostatic interactions in regulating dynein-microtubule affinity. Moreover, these results provide insight into the principles that potentially underlie the biophysical differences between molecular motors with various processivities and protein-protein interactions more generally.

Statement of Significance

The dynein family of motor proteins drives the motility of multiple cellular functions by walking toward the minus end of microtubules. The biophysical mechanisms of dynein rely on its ability to change affinity for the microtubule as it steps. Specific short-range electrostatic interactions acting at the microtubule-binding domain (MTBD)-microtubule interface are known to govern binding affinity. This study shows that non-specific longer-range electrostatic interactions due to charged amino acids remote from the binding interface also contribute significantly to the binding affinity mechanisms. Our results suggest that subtle differences in the electrostatic charge distribution within the MTBD significantly affect the molecular biophysical motility mechanisms in the dynein family of motors.
Interaction between theta-phase and spike-timing dependent plasticity simulates theta induced memory effects
Authors: Wang Danying , Parish George , Shapiro Kimron L. , Hanslmayr Simon
Published: November 2021

Rodent studies suggest that spike timing relative to hippocampal theta activity determines whether potentiation or depression of synapses arise. Such changes also depend on spike timing between pre- and post-synaptic neurons, known as spike-timing-dependent plasticity (STDP). STDP, together with theta-phase-dependent learning, has inspired several computational models of learning and memory. However, evidence to elucidate how these mechanisms directly link to human episodic memory is lacking. In a computational model, we modulate long-term potentiation (LTP) and long-term depression (LTD) of STDP, by opposing phases of a simulated theta rhythm. We fit parameters to a hippocampal cell culture study in which LTP and LTD were observed to occur in opposing phases of a theta rhythm. Further, we modulated two inputs by cosine waves with synchronous and asynchronous phase offsets and replicate key findings in human episodic memory. Learning advantage was found for the synchronous condition, as compared to the asynchronous conditions, and was specific to theta modulated inputs. Importantly, simulations with and without each mechanism suggest that both STDP and theta-phase-dependent plasticity are necessary to replicate the findings. Together, the results indicate a role for circuit-level mechanisms, which bridges the gap between slice preparation studies and human memory.

Author Summary

Long-lasting changes in synaptic connectivity between neurons have been suggested to support learning and memory processes at the cellular level in the brain. Such synaptic modifications depend on synchronous activation of neurons, which leads to generate brain oscillations. Human memory studies focus on the relationships between brain oscillations and memory processes. Direct evidence on how the cellular mechanism links to human memory behaviour is lacking. To investigate the direct link between synaptic plasticity mechanisms and human memory formation, we built a computational neural network that implements two synaptic plasticity mechanisms, which are well-established in the rodents’ hippocampus. One mechanism shows that strengthening or weakening in synaptic connectivity depends on the phases of ongoing brain oscillation at theta frequency (4 – 8 Hz), which is a dominant signal in the hippocampus. The other mechanism suggests that synaptic modification depends on the precise timing of action potentials between two neurons. Our model successfully reproduces results from rodents, as well as several human episodic memory studies which demonstrated that human associative memory performance depends on phase synchronisation in theta frequency. These findings suggest a link between specific learning mechanisms at cellular level and human memory behaviour.
Expression of mini-G proteins specifically halt cognate GPCR trafficking and intracellular signalling
Authors: Manchanda Yusman , Ramchunder Zenouska , Shchepinova Maria M , Rutter Guy A , Inoue Asuka , Tate Edward W , Jones Ben , Tomas Alejandra
Published: November 2021

Mini-G proteins are engineered thermostable variants of Gα subunits designed to specifically stabilise G protein-coupled receptors (GPCRs) in their active conformation for structural analyses. Due to their smaller size and ease of use, they have become popular tools in recent years to assess specific GPCR behaviours in cells, both as reporters of receptor coupling to each G protein subtype and for in-cell assays designed to quantify compartmentalised receptor signalling from a range of subcellular locations. Here, we describe a previously unappreciated consequence of the co-expression of mini-G proteins with their cognate GPCRs, namely a profound disruption in GPCR trafficking and intracellular signalling caused by the co-expression of the specific mini-G subtype coupled to the affected receptor. We studied the Gαs-coupled pancreatic beta cell class B GPCR glucagon-like peptide-1 receptor (GLP-1R) as a model to describe in detail the molecular consequences derived from this effect, including a complete halt in β-arrestin-2 recruitment and receptor internalisation, despite near-normal levels of receptor GRK2 recruitment and lipid nanodomain segregation, as well as the disruption of endosomal GLP-1R signalling by mini-Gs co-expression. We also extend our analysis to a range of other prototypical GPCRs covering the spectrum of Gα subtype coupling preferences, to unveil a widely conserved phenomenon of GPCR internalisation blockage by specific mini-G proteins coupled to a particular receptor. Our results have important implications for the design of methods to assess intracellular GPCR signalling. We also present an alternative adapted bystander intracellular signalling assay for the GLP-1R in which we substitute the mini-Gs by a nanobody, Nb37, with specificity for active Gαs:GPCR complexes and no deleterious effect on the capacity for GLP-1R internalisation.
The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms
Authors: Kleinova Renata , Leuchtenberger Alina F. , Giudice Claudio Lo , Tanzer Andrea , Derdak Sophia , Picardi Ernesto , Jantsch Michael F.
Published: November 2021

Adenosine deaminase acting on RNA (ADAR) (also known as ADAR1) promotes A-to-I conversion in double-stranded and highly structured RNAs. ADAR1 has two isoforms transcribed from different promoters: ADAR1p150, which is mainly cytoplasmic and interferon-inducible, and constitutively expressed ADAR1p110 that is primarily localized in the nucleus.

Mutations in ADAR1 cause Aicardi – Goutières syndrome (AGS), a severe autoinflammatory disease in humans associated with aberrant IFN production. In mice, deletion of ADAR1 or selective knockout of the p150 isoform alone leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype can be rescued by concurrent deletion of cytoplasmic dsRNA-sensor MDA5. These findings indicate that the interferon- inducible p150 isoform is indispensable and cannot be rescued by the ADAR1p110 isoform. Nevertheless, editing sites uniquely targeted by ADAR1p150 but also mechanisms of isoform- specificity remain elusive.

Here we combine RIP-seq on human cells expressing ADAR1 isoforms and combine this with analysis of isoform-specific editing patterns in genetically modified mouse cells to extensively investigate ADAR1-isoform binding- and editing characteristics.

Moreover, using mutated ADAR variants, we examine the effect of two unique features of ADAR1p150 on its target specificity: 1) cytoplasmic localization and 2) Z-DNA binding domain α. Our findings indicate that ZBDα contributes only minimally to p150 editing-specificity and that isoform-specific editing is directed mainly by the cytoplasmic localization of the editase.
Spatial charting of single cell transcriptomes in tissues
Authors: Wei Runmin , He Siyuan , Bai Shanshan , Sei Emi , Hu Min , Thompson Alastair , Chen Ken , Krishnamurthy Savitri , Navin Nicholas E.
Published: November 2021

Single cell RNA sequencing (scRNA-seq) methods can profile the transcriptomes of single cells but cannot preserve spatial information. Conversely, spatial transcriptomics (ST) assays can profile spatial regions in tissue sections, but do not have single cell genomic resolution. Here, we developed a computational approach called CellTrek that combines these two datasets to achieve single cell spatial mapping. We benchmarked CellTrek using a simulation study and two in situ datasets. We then applied CellTrek to reconstruct cellular spatial structures in existing datasets from normal mouse brain and kidney tissues. We also performed scRNA-seq and ST experiments on two ductal carcinoma in situ (DCIS) tissues and applied CellTrek to identify tumor subclones that were restricted to different ducts, and specific T cell states adjacent to the tumor areas. Our data shows that CellTrek can accurately map single cells in diverse tissue types to resolve their spatial organization.
T-cell microvilli simulations show operation near packing limit and impact on antigen recognition
Authors: Morgan Jonathan , Pettmann Johannes , Dushek Omer , Lindsay Alan E.
Published: November 2021

T-cells are immune cells that continuously scan for foreign-derived antigens on the surfaces of nearly all cells, termed antigen presenting cells (APCs). They do this by dynamically extending numerous protrusions called microvilli (MV) that contain T-cell receptors (TCRs) towards the APC surface in order to scan for antigens. The number, size, and dynamics of these MV, and the complex multi-scale topography that results, play a yet unknown role in antigen recognition. We develop an anatomically informed model of the T-cell/APC interface to elucidate the role of MV dynamics in antigen sensitivity and discrimination. We find that MV surveillance reduces antigen sensitivity compared to a completely flat interface unless MV are stabilized in an antigen-dependent manner and find that MV have only a modest impact on antigen discrimination. The model highlights that MV contacts optimise the competing demands of fast scanning speeds of the APC surface with antigen sensitivity and that T-cells operate their MV near the interface packing limit. Finally, we find that observed MV contact lifetimes can be largely influenced by conditions in the T-cell/APC interface with these lifetimes often being longer than the simulation or experimental observation period. The work highlights the role of MV in antigen recognition.

Significance Statement

T-cells search for foreign-derived antigens on the surface of antigen presenting cells (APC) by dynamically extending tubular protrusions called microvilli (MV) which form membrane close-contacts. Although known for decades, their role in antigen recognition remains unclear. Guided by recent experiments, we built an anatomically informed stochastic model of MV scanning and compared with a topologically flat interface. We find that MV scanning modestly impacts antigen discrimination, yet it enables T-cells to balance the competing effects of maintaining sensitivity while conducting rapid APC surveillance. The model can reconcile discrepancies in observed MV lifetimes and demonstrates that observed area coverage fractions correspond to geometric packing limits. Our work suggests that MVs promote positive signaling outcomes despite anatomical constraints to close contact formation.
Evolutionary features of a prolific subtype of avian influenza A virus in European waterfowl
Authors: Wille Michelle , Tolf Conny , Latorre-Margalef Neus , Fouchier Ron A. M. , Halpin Rebecca A. , Wentworth David E. , Ragwani Jayna , Pybus Oliver G. , Olsen Björn , Waldenström Jonas
Published: November 2021

Avian influenza A virus (AIV) is ubiquitous in waterfowl, and detected annually at high prevalence in waterfowl during the Northern Hemipshere autumn. Some AIV subtypes are globally common in waterfowl, such as H3N8, H4N6, and H6N2, and are detected in the same populations at high frequency, annually. In order to investigate genetic features associated to the long-term maintenance of common subtypes in migratory ducks, we sequenced 248 H4 viruses isolated across 8 years (2002-2009) from Mallards (Anas platyrhynchos) sampled in southeast Sweden. Phylogenetic analyses showed that both H4 and N6 sequences fell into in three distinct lineages, structured by year of isolation. Specifically, across the eight years of the study, we observed lineage replacement, whereby a different HA lineage circulated in the population each year. Analysis of deduced amino acid sequences of the HA lineages illustrated key differences in regions of the globular head of hemagglutinin that overlap with established antigentic sites in homologous hemagglutinin H3, suggesting the possibility of antigenic differences among these HA lineages. Beyond HA, lineage replacement was common to all segments, such that novel genome constellations were detected across years. A dominant genome constellation would rapidly amplify in the duck population, followed by unlinking of gene segments as a result of reassortment within 2-3 weeks following introduction. These data help reveal the evolutionary dynamics exhibited by AIV on both annual and decadal scales in an important reservoir host.