bluuebunny/crossref_metadata_2025 huggingface dataset:
NanoTox: Development of a parsimoniousin silicomodel for toxicity assessment of metal-oxide nanoparticles using physicochemical features
Authors: AnanthaSubramanian Nilesh , Palaniappan Ashok
Published: February 2021

Metal-oxide nanoparticles find widespread applications in mundane life today, and cost-effective evaluation of their cytotoxicity and ecotoxicity is essential for sustainable progress. Machine learning models use existing experimental data, and learn the relationship of various features to nanoparticle cytotoxicity to generate predictive models. In this work, we adopted a principled approach to this problem by formulating a feature space based on intrinsic and extrinsic physico-chemical properties, but exclusive of anyin vitrocharacteristics such as cell line, cell type, and assay method. A minimal set of features was developed by applying variance inflation analysis to the correlation structure of the feature space. Using a balanced dataset, a mapping was then obtained from the normalized feature space to the toxicity class using various hyperparameter-tuned machine learning models. Evaluation on an unseen test set yielded > 96% balanced accuracy for both the random forest model, and neural network with one hidden layer model. The obtained cytotoxicity models are parsimonious, with intelligible inputs, and include an applicability check. Interpretability investigations of the models yielded the key predictor variables of metal-oxide nanoparticle cytotoxicity. Our models could be applied on new, untested oxides, using a majority-voting ensemble classifier, NanoTox, that incorporates the neural network, random forest, support vector machine, and logistic regression models. NanoTox is the very first predictive nanotoxicology pipeline made freely available under the GNU General Public License (https://github.com/NanoTox).
Partitioning variability in animal behavioral videos using semi-supervised variational autoencoders
Authors: Whiteway Matthew R , Biderman Dan , Friedman Yoni , Dipoppa Mario , Buchanan E Kelly , Wu Anqi , Zhou John , Bonacchi Niccolò , Miska Nathaniel J , Noel Jean-Paul , Rodriguez Erica , Schartner Michael , Socha Karolina , Urai Anne E , Salzman C Daniel ,   The International Brain Laboratory, Cunningham John P , Paninski Liam
Published: February 2021

Recent neuroscience studies demonstrate that a deeper understanding of brain function requires a deeper understanding of behavior. Detailed behavioral measurements are now often collected using video cameras, resulting in an increased need for computer vision algorithms that extract useful information from video data. Here we introduce a new video analysis tool that combines the output of supervised pose estimation algorithms (e.g. DeepLabCut) with unsupervised dimensionality reduction methods to produce interpretable, low-dimensional representations of behavioral videos that extract more information than pose estimates alone. We demonstrate this tool by extracting interpretable behavioral features from videos of three different head-fixed mouse preparations, as well as a freely moving mouse in an open field arena, and show how these interpretable features can facilitate downstream behavioral and neural analyses. We also show how the behavioral features produced by our model improve the precision and interpretation of these downstream analyses compared to using the outputs of either fully supervised or fully unsupervised methods alone.
Tetrameric UvrD helicase is located at theE. colireplisome due to frequent replication blocks
Authors: Wollman Adam J. M , Syeda Aisha H. , Howard Jamieson A. L. , Payne-Dwyer Alex , Leech Andrew , Warecka Dominika , Guy Colin , McGlynn Peter , Hawkins Michelle , Leake Mark C.
Published: February 2021

DNA replication in all organisms must overcome nucleoprotein blocks to complete genome duplication. Accessory replicative helicases inEscherichia coli, Rep and UvrD, help remove these blocks and aid the re-initiation of replication. Mechanistic details of Rep function have emerged from recent live cell studies; however, the division of UvrD functions between its activities in DNA repair and role as an accessory helicase remain unclear in live cells. By integrating super-resolved single-molecule fluorescence microscopy with biochemical analysis, we find that UvrD self-associates into tetrameric assemblies and, unlike Rep, is not recruited to a specific replisome protein despite being found at approximately 80% of replication forks. Instead, its colocation with forks is likely due to the very high frequency of replication blocks composed of DNA-bound proteins, including RNA polymerase and factors involved in repairing DNA damage. Deletingrepand DNA repair factor genesmutSanduvrA, and inhibiting transcription through RNA polymerase mutation and antibiotic inhibition, indicates that the level of UvrD at the fork is dependent on UvrD’s function. Our findings show that UvrD is recruited to sites of nucleoprotein blocks via different mechanisms to Rep and plays a multi-faceted role in ensuring successful DNA replication.
Characterizing gene expression responses to biomechanical strain in anin vitromodel of osteoarthritis
Authors: Hung Anthony , Housman Genevieve , Briscoe Emilie A. , Cuevas Claudia , Gilad Yoav
Published: February 2021

Osteoarthritis (OA) is a common chronic degenerative joint disease affecting articular cartilage and underlying bone. Both genetic and environmental factors appear to contribute to the development of this disease. Specifically, pathological levels of biomechanical stress on joints play a notable role in disease initiation and progression. Population-level gene expression studies of cartilage cells experiencing biomechanical stress may uncover gene-by-environment interactions relevant to OA and human joint health. To build a foundation for such studies, we applied differentiation protocols to develop anin vitrosystem of chondrogenic cell lines (iPSC-chondrocytes). We characterized gene regulatory responses of three human iPSC-chondrocyte lines to cyclic tensile strain treatment. We measured the contribution of biological and technical factors to gene expression variation in this system and, even in this small sample, found several genes that exhibit inter-individual expression differences in response to mechanical strain, including genes previously implicated in OA. Expanding this system to include iPSC-chondrocytes from a larger number of individuals will allow us to characterize and better understand gene-by-environment interactions related to OA and joint health.
Variation in self-compatibility among genotypes and across ontogeny in a self-fertilizing vertebrate
Authors: Gresham Jennifer D , Earley Ryan L , Clark Anna , Keck Chloe M.T. , Longmire Alexis E. , Nelson Abye E. , Quertermous Haylee M. , White Ashley B
Published: February 2021

Mixed mating strategies offer the benefits of both self-fertilizing ones own eggs (selfing) and outcrossing, while limiting the costs of both methods. The economics of mixed mating is further determined by individual self-compatibility. In gynodioecious (hermaphrodites, females) and androdioecious (hermaphrodites, males) species, the level of self-compatibility of the hermaphrodites also acts as a selection pressure on the fitness of the other sex. Mangrove rivulus fish populations are comprised of selfing hermaphrodites and males that result from hermaphrodites changing sex. Although hermaphrodites overwhelmingly reproduce through internal selfing, they occasionally oviposit unfertilized eggs. Males can externally fertilize these eggs. Here, we reveal that fecundity and self-compatibility varies within individuals across ontogeny until about 365 days post hatch, and among individuals derived from lineages that vary in their propensity to change sex. Hermaphrodites from high sex changing lineages were significantly less fecund and self-compatible than hermaphrodites from low sex changing lineages. These differences in self-compatibility and fecundity have the potential to drive evolutionary changes on mating strategy and the fitness of males in populations of the mangrove rivulus. This study also illustrates the importance of including lineage variation when estimating the costs and benefits of mixed mating strategies.
Outbreeding depression as a selective force on mixed mating in the mangrove rivulus fish,Kryptolebias marmoratus
Authors: Gresham Jennifer D. , Lewis Kever A. , Summers Stephanie P. , Gresham Percy E. , Earley Ryan L.
Published: February 2021

Mixed mating, a reproduction strategy utilized by many plants and invertebrates, optimizes the cost to benefit ratio of a labile mating system. One type of mixed mating includes outcrossing with conspecifics and self-fertilizing one’s own eggs. The mangrove rivulus fish (Kryptolebias marmoratus)is one of two vertebrates known to employ both self-fertilization (selfing) and outcrossing. Variation in rates of outcrossing and selfing within and among populations produces individuals with diverse levels of heterozygosity. I designed an experiment to explore the consequences of variable heterozygosity across four ecologically relevant conditions of salinity and water availability (10‰, 25‰, and 40‰ salinity, and twice daily tide changes). I report a significant increase in mortality in the high salinity (40‰) treatment. I also report significant effects on fecundity measures with increasing heterozygosity. The odds of laying eggs decreased with increasing heterozygosity across all treatments, and the number of eggs laid decreased with increasing heterozygosity in the 10‰ and 25‰ treatments. Increasing heterozygosity also was associated with a reduction liver mass and body condition in all treatments. My results highlight the fitness challenges that accompany living in mangrove forests ecosystem and provide the first evidence for outbreeding depression on reproductive and condition-related traits.
DNA reconciles morphology and colouration in the drunk blenny genusScartichthys(Teleostei: Blenniidae) and provides insights into their evolutionary history
Authors: Delrieu–Trottin E. , Salvo H. Hartmann , Agudelo P. Saenz , Landaeta M. F. , Matus A. Perez
Published: February 2021

The blenniids of the genusScartichthysare one of the most common fishes of Central and South American Pacific coastal reefs. This being said, Scartichthys spp. remain difficult to identify in the field, and identification is particularly challenging across the ca. 6000 km where three of the four currently accepted species are known to occur in sympatry. A reason for this is that the main taxonomic characters from traditional taxonomy are indeed elusive. Additionally, At the same time, species can display multiple colour patterns in the field, depending on their ontogenetic stage, habitat association, and reproductive behaviour. Overall, molecular characterization is warranted to help address these issues. Here, we have used a novel approach to revise the genus by combining colouration, morphological, and molecular data of representative specimens of the four currently valid species and seven described colour patterns. From this, we show that only three of the four species should be considered as valid;Scartichthys gigas(Steindachner, 1876),S. variolatus(Valenciennes, 1836), andS. viridis(Valenciennes, 1836); while S. crapulatus Williams 1990 should be synonymized withS. viridis. In the same way, our analyses show that one of the colour patterns attributed so far only toS. gigasis characteristic of the juvenile stages ofS. viridis. Our time-calibrated phylogeny shows that this genus is relatively young and that the estimated time of divergence betweenScartichthys gigasandS. viridisis around 1.71 Ma. In comparison, the Desventuradas and Juan Fernandez Islands endemicS. variolatusdiverged about 1.95 Ma. Our results help to clarify the taxonomy of Scartichthys.

SIGNIFICANCE STATEMENT

The blenniids of the genus Scartichthys are one of the most common fishes of Central and South American Pacific coastal reefs. Here we provide an updated phylogeny of this genus, comparing for the first time morphological, coloration, and molecular data in combination to resolve a 30-year-old discord among ecologists and taxonomists and discuss the potential underlying evolutionary processes that led to their presentday distribution.
High-order interactions maintain or enhance structural robustness of a coffee agroecosystem network
Authors: González González Cecilia , Van Cauwelaert Emilio Mora , Boyer Denis , Perfecto Ivette , Vandermeer John , Benítez Mariana
Published: February 2021

The capacity of highly diverse systems to prevail has proven difficult to explain. In addition to methodological issues, the inherent complexity of ecosystems and issues like multicausality, non-linearity and context-specificity make it hard to establish general and unidirectional explanations. Nevertheless, in recent years, high order interactions have been increasingly discussed as a mechanism that benefits the functioning of highly diverse ecosystems and may add to the mechanisms that explain their persistence. Until now, this idea has been explored by means of hypothetical simulated networks. Here, we test this idea using an updated and empirically documented network for a coffee agroecosystem. We identify potentially key nodes and measure network robustness in the face of node removal with and without incorporation of high order interactions. We find that the system’s robustness is either increased or unaffected by the addition of high order interactions, in contrast with randomized counterparts with similar structural characteristics. We also propose a method for representing networks with high order interactions as ordinary graphs and a method for measuring their robustness.

Highlights

The robustness of a coffee-associated ecological network is either increased or unaffected by the incorporation of high order interactions.

A method is proposed for representing high order interactions in ordinary networks.

A method is proposed to measure the robustness of networks with high order interactions.

High order interactions may promote the persistence of diverse ecosystems.
Loss of FAS1 function reveals rescue of an aberrant intra-S-phase checkpoint by the G2/M checkpoint regulator SOG11[OPEN]
Authors: Eekhout Thomas , Dvorackova Martina , Garcia José Antonio Pedroza , Dadejova Martina Nespor , Kalhorzadeh Pooneh , Van den Daele Hilde , Vercauteren Ilse , Fajkus Jiri , De Veylder Lieven
Published: February 2021

The WEE1 and ATR kinases represent important regulators of the plant intra-S-phase checkpoint, as evidenced by the hypersensitivity ofWEE1KOandATRKOroots to replication inhibitory drugs. Here, we report on the identification of a defective allele of theFASCIATA1(FAS1) subunit of the chromatin assembly factor 1 (CAF-1) complex as a suppressor ofWEE1- or ATR-deficient plants. We demonstrate that lack ofFAS1activity results in the activation of an ATM- and SOG1-mediated G2/M-arrest that makes the ATR and WEE1 checkpoint regulators redundant. This ATM activation accounts for telomere erosion and loss of ribosomal DNA described for thefas1plants. Knocking outSOG1in thefas1 wee1background restores replication stress sensitivity, demonstrating that SOG1 plays a prominent role as secondary checkpoint regulator in plants that fail to activate the intra-S-phase checkpoint.

One-Sentence Summary

Lack of the chromatin assembly factor-1 subunit FAS1 results in a DNA damage response that overrules the need for replication checkpoint activators.
Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome
Authors: Chandra Sunandini , Mannino Philip J. , Thaller David J. , Ader Nicholas R. , King Megan C. , Melia Thomas J. , Lusk C. Patrick
Published: February 2021

Mechanisms that turnover components of the nucleus and inner nuclear membrane (INM) remain to be fully defined. We explore how components of the INM are selected by a cytosolic autophagy apparatus through a transmembrane nuclear envelope-localized cargo adaptor, Atg39. A split-GFP reporter shows that Atg39 localizes to the outer nuclear membrane (ONM) and thus targets the INM across the nuclear envelope lumen. Consistent with this, sequence elements that confer both nuclear envelope localization and a membrane remodeling activity are mapped to the Atg39 lumenal domain; these lumenal motifs are required for the autophagy-mediated degradation of an integral INM protein. Interestingly, correlative light and electron tomography shows that the overexpression of Atg39 leads to the expansion of the ONM and the enclosure of a network of INM-derived vesicles in the nuclear envelope lumen. Thus, we propose an outside-in model of nucleophagy where INM is delivered into vesicles in the nuclear envelope lumen, which can be targeted by the autophagosome.
Sialic acid ligands of CD28 block co-stimulation of T cells
Authors: Edgar Landon J. , Thompson Andrew J. , Vartabedian Vincent F. , Kikuchi Chika , Woehl Jordan L. , Teijaro John R. , Paulson James C.
Published: February 2021

Effector T cells comprise the cellular arm of the adaptive immune system and are essential for mounting immune responses against pathogens and cancer. To reach effector status, co-stimulation through CD28 is required. Here, we report that sialic acid-containing glycans on the surface of both T cells and APCs are alternative ligands of CD28 that compete with binding to its well-documented activatory ligand CD80 on the APC, resulting in attenuated co-stimulation. Removal of sialic acids enhances T cell activation and enhances the activity of effector T cells made hypofunctional via chronic viral infection through a mechanism that is synergistic with antibody blockade of the inhibitory PD-1 axis. These results reveal a previously unrecognized role for sialic acids in attenuation of CD28 mediated co-stimulation of T cells.

One Sentence Summary

Sialic acids attenuate the second signal required for T cell activation.
Sequences in the Human papillomavirus Type 18 (HPV18) Upstream Regulatory Region regulate Viral Genome Replication, Establishment and Persistence
Authors: Coursey Tami L. , Van Doorslaer Koenraad , McBride Alison A.
Published: February 2021

During persistent human papillomavirus infection, the viral genome replicates as an extrachromosomal plasmid that is efficiently partitioned to daughter cells during cell division. We have previously shown that an element which overlaps the HPV18 transcriptional enhancer promotes stable DNA replication of replicons containing the viral replication origin. Here we perform comprehensive analyses to elucidate the function of this maintenance element. We conclude that no unique element or binding site in this region is absolutely required for persistent replication and partitioning, and instead propose that the overall chromatin architecture of this region is important to promote efficient use of the replication origin. These results have important implications on the genome partitioning mechanism of papillomaviruses.
Regulation of large-conductance Ca2+- and voltage-gated K+channels by electrostatic interactions with auxiliary β subunits
Authors: Tian Yutao , Heinemann Stefan H. , Hoshi Toshinori
Published: February 2021

Large-conductance Ca2+- and voltage-gated K+(BK KCa1.1) channel complexes include pore-forming Slo1 α subunits and often auxiliary β subunits, latter of which noticeably modify the channel’s pharmacological and gating characteristics. In the absence of intracellular Ca2+, β1 and β4 modestly shift the overall voltage dependence of the channel to the positive direction by decreasing the probability that the ion conduction gate is open without any allosteric influence from the channel’s voltage or Ca2+sensors. This intrinsic open probability is also critically regulated by the intracellular-facing329RKK331segment of human Slo1 (hSlo1) downstream of the transmembrane segment S6 in association with two negatively charged residues in S6 (E321 and E324) (Tian et al., Proc Natl Acad Sci USA, 116, 8591-8596, 2019). This study examined how β1/β4 and the RKK segment function together to control the channel gate. With select mutations in the RKK segment, inclusions of β1 or β4 can dramatically increase the intrinsic gate opening probability and shift the overall voltage dependence of the channel to the negative direction by up to 200 mV without Ca2+. This remarkable shift is mediated at least in part by electrostatic interactions between the Slo1 RKK and β N-terminal segments as suggested by the results of double-mutant cycle analysis, ionic strength experiments, and molecular modelling. With or without auxiliary β subunits, the Slo1 RKK and E321/E324 segments are thus critical determinants of the intrinsic open probability of the ion conduction gate and changes in the electrostatic environment near the RKK-EE segments are a potential mechanism of pharmacological gating modifiers.
A massive 7T fMRI dataset to bridge cognitive and computational neuroscience
Authors: Allen Emily J. , St-Yves Ghislain , Wu Yihan , Breedlove Jesse L. , Dowdle Logan T. , Caron Brad , Pestilli Franco , Charest Ian , Hutchinson J. Benjamin , Naselaris Thomas , Kay Kendrick
Published: February 2021

Extensive sampling of neural activity during rich cognitive phenomena is critical for robust understanding of brain function. We present the Natural Scenes Dataset (NSD), in which high-resolution fMRI responses to tens of thousands of richly annotated natural scenes are measured while participants perform a continuous recognition task. To optimize data quality, we develop and apply novel estimation and denoising techniques. Simple visual inspections of the NSD data reveal clear representational transformations along the ventral visual pathway. Further exemplifying the inferential power of the dataset, we use NSD to build and train deep neural network models that predict brain activity more accurately than state-of-the-art models from computer vision. NSD also includes substantial resting-state and diffusion data, enabling network neuroscience perspectives to constrain and enhance models of perception and memory. Given its unprecedented scale, quality, and breadth, NSD opens new avenues of inquiry in cognitive and computational neuroscience.
A novel two-generation approach for understanding the population dynamics of gregarious parasitoids
Authors: Samková Alena , Raška Jan , Hadrava Jiří , Skuhrovec Jiří
Published: February 2021

Parasitoids, as important natural enemies, help maintain balance in natural ecosystems. Their population dynamics is generally predicted from the number of individuals. Here, using gregarious parasitoids as models, we show that this traditional approach omits one important parameter: the mother’s manipulation of offspring fertility due to the clutch size–body size– fertility correlation. As a result of this correlation, when females deliberately adjust the number of offspring laid in a host, they determine not only the number but also the body sizes and reproductive potentials of those offspring. For the first time in the model speciesAnaphes flavipes, we determined the parasitoid’s offspring fertility from clutch size. Using this, we experimentally clarified the advantage of specific clutch size combinations and we show that identical fertility in the F1 generation can lead to distinctly different fertility values in the F2 generation. Even with the same number of hosts, lower fertility in the F1 generation can cause higher fertility in the F2 generation. Based on these results, we propose a novel two-generation approach which includes the clutch size–body size–fertility correlation. Our novel approach provides a new perspective for determining the individual fitness levels of gregarious parasitoids with new options for the modelling of parasitoid population dynamics.
Germline activity of the heat shock factor HSF-1 programs the insulin-receptordaf-2inC. elegans
Authors: Das Srijit , Min Sehee , Prahlad Veena
Published: February 2021

The mechanisms by which maternal stress alters offspring phenotypes remain poorly understood. Here we report that the heat shock transcription factor HSF-1, activated in theC. elegansmaternal germline upon stress, epigenetically programs the insulin-like receptordaf-2by increasing repressive H3K9me2 levels throughout thedaf-2gene. This increase occurs by the recruitment of theC. elegansSETDB1 homolog MET-2 by HSF-1. Increased H3K9me2 levels atdaf-2persist in offspring to downregulatedaf-2,activate theC. elegansFOXO ortholog DAF-16 and enhance offspring stress resilience. Thus, HSF-1 activity in the mother promotes the early life programming of the insulin/IGF-1 signaling (IIS) pathway and determines the strategy of stress resilience in progeny.

One Sentence Summary

HSF-1 recruits MET-2 to silencedaf-2and mediate early life programming ofC. elegansupon stress
Ribosomes in RNA granules are stalled on mRNA sequences that are consensus sites for FMRP association
Authors: Anadolu Mina N. , Sun Jingyu , Kailasam Senthilkumar , Simbriger Konstanze , Markova Teodora , Jafarnejad Seyed Mehdi , Lefebvre Francois , Ortega Joaquin , Gkogkas Christos G. , Sossin Wayne S.
Published: February 2021

Local translation in neurons is mediated in part by the reactivation of stalled polysomes. Stalled polysomes may be enriched within the pellet of sucrose gradients used to separate polysomes from monosomes. We find that this fraction, isolated from P5 rat brains of both sexes, is enriched in proteins implicated in stalled polysome function, such as the fragile X mental retardation protein (FMRP) and Up-frameshift mutation 1 homolog (UPF1). Cryo-EM analysis of ribosomes in this fraction indicates they are stalled, mainly in the hybrid state. Ribosome profiling of this fraction showed an abundance of footprint reads derived from mRNAs of cytoskeletal proteins implicated in neuronal development and an enrichment of footprint reads on RNA binding proteins. Compared to those usually found in ribosome profiling studies, the footprint reads were more extended on their 3’end and were found in reproducible peaks in the mRNAs. These peaks were enriched in motifs previously associated with mRNAs cross-linked to FMRP in vivo, independently linking the ribosomes in the sedimented pellet to the ribosomes associated with FMRP in the cell. The data supports a model in which specific sequences in mRNAs act to stall translation elongation in neurons.
A preliminary assessment of allostatic load in male mantled howler monkeys
Authors: Dias Pedro Américo D. , Coyohua-Fuentes Alejandro , Chavira-Ramírez David Roberto , Canales-Espinosa Domingo , Rangel-Negrín Ariadna
Published: February 2021

Allostatic load refers to the wear and tear of the organism associated with the repeated activation of mechanisms that allow for homeostasis. Although allostasis (i.e., maintaining stability through change) is achieved through the orchestration of multiple systems, assessments of allostatic load in wildlife have usually relied on the measurement of single or few physiological mediators. In the present study, we aimed at constructing an allostatic load index (ALI) for male mantled howler monkeys (Alouatta palliata) based on seven physiological mediators (C-peptide, triiodothyronine, glucocorticoids, testosterone, amount of activity, foraging effort, and participation in agonistic interactions). We then examined if variation in this ALI was associated with social, ecological, and abiotic challenges. For five years, we studied ten adult males belonging to two groups. We assessed physiological mediators via behavioral observations (3,364 hours of samplings), and both urine (1,500 assayed samples) and fecal (1,500 assayed samples) sampling. We calculated an ALI based on mediator specific risk scores. Seasonality, encounters with extragroup males, mating, and centrality were positively related with male allostatic load, though only the first two had significant effects on ALI. ALI reflected the physiological and behavioral responses of males to social, ecological, and abiotic challenges. It remains for future research to determine if the observed trends correspond to normal fluctuations in mechanisms that allow male mantled howler monkeys to cope with their environment.
Experimental evidence for enhanced receptor binding by rapidly spreading SARS-CoV-2 variants
Authors: Laffeber Charlie , de Koning Kelly , Kanaar Roland , Lebbink Joyce HG
Published: February 2021

Rapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 9-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation does not significantly influence the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 3-fold weaker than N501Y. The recently emerging double mutant E484K/N501Y binds as tight as N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.
Unexpected false feelings of familiarity about faces are associated with increased pupil dilations
Authors: Ziman Kirsten , Manning Jeremy R.
Published: February 2021

Our subjective sense that something we encounter is familiar to us is reflected by changes in pupil size. Although pupil dilation effects of familiarity have been well documented, familiarity is not the only, or even the strongest, contributing factor to pupil dilation. Changes in pupil dilation also reflect changes in brightness, affective or emotional responses, hormonal release, expected value or utility, and surprise, among others. Because many factors can affect pupil dilation, important questions remain about how pupil dilation changes reflect high-order cognitive processes, like attention and memory. For example, because surprise and familiarity are often difficult to fully distinguish (since new experiences can be surprising or unexpected), it can be difficult to tease apart pupil dilation effects of surprise versus familiarity. To better understand the effects of surprise and familiarity on pupil dilation, we examined pupil responses during a recognition memory task involving photographs of faces and outdoor scenes. When participants rated novel face images as “familiar,” we observed a robust pupil dilation response.
TP-MAP - an Integrated Software Package for the Analysis of 1D and 2D Thermal Profiling Data
Authors: Feyertag Felix , Huber Kilian V.M.
Published: February 2021

Thermal profiling (TP) has emerged as a promising experimental methodology for elucidating the molecular targets of drugs and metabolites on a proteome-wide scale. Here, we present the Thermal Profiling Meltome Analysis Program (TP-MAP) software package for the analysis and ranking of 1D and 2D thermal profiling datasets. TP-MAP provides a user-friendly interface to quickly identify hit candidates and further explore targets of interest via intersection and crosslinking to public databases.
Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8
Authors: Remillard David , Savage Nikolas A. , Kedves Alexia T. , Paulk Joshiawa , Chen Xin , Garcia Francisco J. , Romanowski Michael J. , Horton Patricia A. , Murphy Jason , Schirle Markus , Harrington Edmund M. , Maxwell Matthew B. , Pham Helen Trinh , Maksimovic Igor , Thomas Jason R. , Forrester William C.
Published: February 2021

Bromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state-specific compositions. Recent studies have revealed tumor-specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting the structure and composition of associated complex members. To enable the study of ligand engaged complex assemblies, we established a chemoproteomics approach using a functionalized derivative of the BRD9 ligand BI-9564 as an affinity matrix. Unexpectedly, in addition to known interactions with BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromodomain-containing subunit BRD8. We apply this finding, alongside homology model guided design, to develop chemical biology approaches for the study of BRD8 inhibition, and to arrive at first-in-class selective and cellularly active probes for BRD8. These tools will empower further pharmacological studies of BRD9 and BRD8 within respective BAF and NuA4 complexes.
Frequency of quorum sensing mutations inPseudomonas aeruginosastrains isolated from different environments
Authors: O’Connor Kathleen , Zhao Conan Y. , Mei Madeline , Diggle Stephen P.
Published: February 2021

Pseudomonas aeruginosauses quorum sensing (QS) to coordinate the expression of multiple genes necessary for establishing and maintaining infection. It has previously been shown thatlasRQS mutations frequently arise in cystic fibrosis (CF) lung infections, however, there has been far less emphasis on determining whether other QS system mutations arise during infection or in other environments. To test this, we utilized 852 publicly available sequencedP. aeruginosagenomes from thePseudomonasInternational Consortium Database (IPCD) to studyP. aeruginosaQS mutational signatures. To study isolates by source, we focused on a subset of 654 isolates collected from CF, wounds, and non-infection environmental isolates, where we could clearly identify their source. We also worked a small collection of isolatesin vitroto determine the impact oflasRandpqsmutations on isolate phenotypes. We found thatlasRmutations are common across all environments and are not specific to infection nor a particular infection type. We also found that thepqssystem proteins PqsA, PqsH, PqsL and MexT, a protein of increasing importance to the QS field, are highly variable. Conversely, RsaL, a negative transcriptional regulator of thelassystem, was found to be highly conserved, suggesting selective pressure to represslassystem activity. Overall, our findings suggest that QS mutations inP. aeruginosaare common and not limited to thelassystem; however, LasR is unique in the frequency of putative loss-of-function mutations.
Pulsatile contractions and pattern formation in excitable actomyosin cortex
Authors: Staddon Michael F. , Munro Edwin M. , Banerjee Shiladitya
Published: February 2021

The actin cortex is an active adaptive material, embedded with complex regulatory networks that can sense, generate, and transmit mechanical forces. The cortex exhibits a wide range of dynamic behaviours, from generating pulsatory contractions and travelling waves to forming organised structures. Despite the progress in characterising the biochemical and mechanical components of the actin cortex, the emergent dynamics of this mechanochemical system is poorly understood. Here we develop a reaction-diffusion model for the RhoA signalling network, the upstream regulator for actomyosin assembly and contractility, coupled to an active actomyosin gel, to investigate how the interplay between chemical signalling and mechanical forces regulate stresses and patterns in the cortex. We demonstrate that mechanochemical feedback in the cortex acts to destabilise homogeneous states and robustly generate pulsatile contractions. By tuning active stress in the system, we show that the cortex can generate propagating contraction pulses, form network structures, or exhibit topological turbulence.
Clinically-driven design of synthetic gene regulatory programs in human cells
Authors: Israni Divya V. , Li Hui-Shan , Gagnon Keith A. , Sander Jeffry D. , Roybal Kole T. , Keith Joung J. , Wong Wilson W. , Khalil Ahmad S.
Published: February 2021

Synthetic biology seeks to enable the rational design of regulatory molecules and circuits to reprogram cellular behavior. The application of this approach to human cells could lead to powerful gene and cell-based therapies that provide transformative ways to combat complex diseases. To date, however, synthetic genetic circuits are challenging to implement in clinically-relevant cell types and their components often present translational incompatibilities, greatly limiting the feasibility, efficacy and safety of this approach. Here, using a clinically-driven design process, we developed a toolkit of programmable synthetic transcription regulators that feature a compact human protein-based design, enable precise genome-orthogonal regulation, and can be modulated by FDA-approved small molecules. We demonstrate the toolkit by engineering therapeutic human immune cells with genetic programs that enable titratable production of immunotherapeutics, drug-regulated control of tumor killingin vivoand in 3D spheroid models, and the first multi-channel synthetic switch for independent control of immunotherapeutic genes. Our work establishes a powerful platform for engineering custom gene expression programs in mammalian cells with the potential to accelerate clinical translation of synthetic systems.
Functional modules within a distributed neural network control feeding in a model medusa
Authors: Weissbourd Brandon , Momose Tsuyoshi , Nair Aditya , Kennedy Ann , Hunt Bridgett , Anderson David J.
Published: February 2021

Jellyfish are free-swimming, radially symmetric organisms with complex behaviors that arise from coordinated interactions between distinct, autonomously functioning body parts. This behavioral complexity evolved without a corresponding cephalization of the nervous system. The systems-level neural mechanisms through which such decentralized control is achieved remain unclear. Here, we address this question using the jellyfish,Clytia,and present it as a new neuroscience model. We describe a coordinated, asymmetric behavior in which food is passed from the umbrellar margin to the central mouth via directed margin folding. Using newly developed transgenic jellyfish lines to ablate or image specific neuronal subpopulations, we find, unexpectedly, that margin folding reflects the local activation of neural subnetworks that tile the umbrella. Modeling suggests that this structured ensemble activity emerges from sparse, local connectivity rules. These findings reveal how an organismal behavior can emerge from local interactions between functional modules in the absence of a central brain.
Loss of Muscleblind Splicing Factor ShortensC. elegansLifespan by Reducing the Activity of p38 MAPK/PMK-1 and Transcription Factors ATF-7 and Nrf/SKN-1
Authors: Matilainen Olli , Ribeiro Ana R. S. , Verbeeren Jens , Cetinbas Murat , Sadreyev Ruslan I. , Garcia Susana M. D. A.
Published: February 2021

Muscleblind-like splicing regulators (MBNLs) are alternative splicing factors that have an important role in developmental processes. Dysfunction of these factors is a key contributor of different neuromuscular degenerative disorders, including Myotonic Dystrophy type 1 (DM1). Since DM1 is a multisystemic disease characterized by symptoms resembling accelerated aging, we asked whether MBNLs regulate cellular processes required to maintain normal lifespan. By utilizing the model organismCaenorhabditis elegans, we found that loss of MBL-1 (the sole ortholog of mammalian MBNLs), which is known to be required for normal lifespan, shortens lifespan by decreasing the activity of p38 MAPK/PMK-1 as well as the function of transcription factors ATF-7 and SKN-1. Furthermore, we show that mitochondrial stress caused by knockdown of mitochondrial electron transport chain components promotes the longevity ofmbl-1mutants in a partially PMK-1-dependent manner. Together, the data establish a mechanism of how DM1-associated loss of muscleblind affects lifespan. Furthermore, this study suggests that mitochondrial stress could alleviate symptoms caused by the dysfunction of muscleblind splicing factor, creating a potential approach to investigate for therapy.

Reviewer token for the RNA-seq data (GEO: GSE146801):wvataksittaffcj
Connectome-based individual prediction of cognitive behaviors via the graph propagation network reveals directed brain network topology
Authors: Wu Dongya , Li Xin , Feng Jun
Published: February 2021

The brain connectome supports the information flow underlying human cognitions and should reflect the individual variability in human cognitive behaviors. Various studies have utilized the brain connectome to predict individual differences in human behaviors. However, traditional studies viewed the brain connectome feature as a vector of one dimension, a method which neglects topological structures of the brain connectome. To utilize topological properties of the brain connectome, we proposed that graph neural network which combines graph theory and neural network can be adopted. Different from previous node-driven graph neural networks that parameterize on the node feature transformation, we designed an edge-driven graph neural network named graph propagation network that parameterizes on the information propagation within the brain connectome. We compared various models in predicting the individual total cognition based on the resting-state functional connectome. The edge-driven graph propagation network showed the highest prediction accuracy and outperformed the node-driven graph neural network and traditional partial least square regression. The graph propagation network also revealed a directed network topology encoding the information flow, indicating that the high-level association cortices are responsible for the information integration underlying the total cognition. These results suggest that the edge-driven graph propagation network can better explore the topological structure of the brain connectome and can serve as a new method to associate the brain connectome and human behaviors.
Seven amino acid types suffice to reconstruct the core fold of RNA polymerase
Authors: Yagi Sota , Padhi Aditya K. , Vucinic Jelena , Barbe Sophie , Schiex Thomas , Nakagawa Reiko , Simoncini David , Zhang Kam Y. J. , Tagami Shunsuke
Published: February 2021

Abstract

The extant complex proteins must have evolved from ancient short and simple ancestors. Nevertheless, how such prototype proteins emerged on the primitive earth remains enigmatic. The double-psi beta-barrel (DPBB) is one of the oldest protein folds and conserved in various fundamental enzymes, such as the core domain of RNA polymerase. Here, by reverse engineering a modern DPBB domain, we reconstructed its evolutionary pathway started by “interlacing homo- dimerization” of a half-size peptide, followed by gene duplication and fusion. Furthermore, by simplifying the amino acid repertoire of the peptide, we successfully created the DPBB fold with only seven amino acid types (Ala, Asp, Glu, Gly, Lys, Arg, and Val), which can be coded by only GNN and ARR (R = A or G) codons in the modern translation system. Thus, the DPBB fold could have been materialized by the early translation system and genetic code.
Chelator sensing and lipopeptide interplay mediates molecular interspecies interactions between soil bacilli and pseudomonads
Authors: Andric Sofija , Meyer Thibault , Rigolet Augustin , Arias Anthony Argüelles , Steels Sébastien , Hoff Grégory , Höfte Monica , De Mot René , McCann Andrea , De Pauw Edwin , Ongena Marc
Published: February 2021

Abstract

Some bacterial species are important members of the rhizosphere microbiome and confer protection to the host plant against pathogens. However, our knowledge of the multitrophic interactions determining the ecological fitness of these biocontrol bacteria in their highly competitive natural niche is still limited. In this work, we investigated the molecular mechanisms underlying interactions betweenB. velezensis,considered as model plant-associated and beneficial species in theBacillusgenus, andPseudomonasas a rhizosphere-dwelling competitor. Our data show thatB. velezensisboosts its arsenal of specialized antibacterials upon the perception of the secondary siderophore enantio-pyochelin produced by phylogenetically distinct pseudomonads and some other genera. We postulate thatB. velezensishas developed some chelator sensing systems to learn about the identity of its surrounding competitors. Illustrating the multifaceted molecular response ofBacillus, surfactin is another crucial component of the secondary metabolome mobilized in interbacteria competition. Its accumulation not only enhances motility but, unexpectedly, the lipopeptide also acts as a chemical trap that reduces the toxicity of other lipopeptides released byPseudomonaschallengers. This in turn favors the persistence ofBacilluspopulations upon competitive root colonization. Our work thus highlights new ecological roles for bacterial secondary metabolites acting as key drivers of social interactions.
A copper chaperone-mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
Authors: L. McAlary , V.K. Shephard , G.S.A. Wright , J.J. Yerbury
Published: February 2021

Amyotrophic lateral sclerosis (ALS)-associated mutations in Cu/Zn superoxide dismutase (SOD1) reduce folding stability, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS, however, the results have been mixed. Here, we utilise a small-molecule polytherapy of CuATSM and ebselen to mimic the metal delivery and disulfide bond promoting activity of SOD1’s cellular chaperone, the ‘copper chaperone for SOD1’ (CCS). We find that polytherapy using CuATSM and ebselen is highly effective at reducing inclusion formation in a cell model of SOD1 aggregation, reduces mutant SOD1-associated cell death, and promotes effective maturation of SOD1 beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may be an effective method of treating SOD1-associated ALS.
Collagen has a unique SEC24 preference for efficient export from the endoplasmic reticulum
Authors: Lu Chung-Ling , Ortmeier Steven , Brudvig Jon , Moretti Tamara , Cain Jacob , Boyadjiev Simeon A. , Weimer Jill M. , Kim Jinoh
Published: February 2021

SEC24 is mainly involved in cargo sorting during COPII vesicle assembly. There are four SEC24 paralogs (A to D) in mammals, which are classified into two subgroups (SEC24A/B and SEC24C/D). Pathological mutations inSEC24Dcause osteogenesis imperfecta with craniofacial dysplasia in humans.sec24dmutant fish also recapitulate the phenotypes. Consistent with the skeletal phenotypes, the secretion of collagen was severely defective in mutant fish, emphasizing the importance of SEC24D in collagen secretion. However, SEC24D patient-derived fibroblasts show only a mild secretion phenotype, suggesting tissue-specificity in the secretion process. UsingSec24dKO mice and cultured cells, we show that SEC24A and SEC24B also contribute to ER export of procollagen. In contrast, fibronectin 1 requires either SEC24C or SEC24D for ER export. On the basis of our results, we propose that procollagen interacts with multiple SEC24 paralogs for efficient export from the ER, and that this is the basis for tissue-specific phenotypes resulting from SEC24 paralog deficiency.