bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome
Authors: Navarro-Romero Alba , Galera-López Lorena , Ortiz-Romero Paula , Llorente-Ovejero Alberto , de los Reyes-Ramírez Lucía , Mas-Stachurska Aleksandra , Reixachs-Solé Marina , Pastor Antoni , de la Torre Rafael , Maldonado Rafael , Benito Begoña , Eyras Eduardo , Rodríguez-Puertas Rafael , Campuzano Victoria , Ozaita Andrés
Published: August 2021

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild to moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no available treatments to ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with sub-chronic (10 d) JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiac function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.
DARQ: Deep learning of quality control for stereotaxic registration of human brain MRI
Authors: Fonov Vladimir S. , Dadar Mahsa ,   The PREVENT-AD Research Group,   ADNI, Collins D. Louis
Published: August 2021

Linear registration to stereotaxic space is a common first step in many automated image-processing tools for analysis of human brain MRI scans. This step is crucial for the success of the subsequent image-processing steps. Several well-established algorithms are commonly used in the field of neuroimaging for this task, but none have a 100% success rate. Manual assessment of the registration is commonly used as part of quality control. To reduce the burden of this time-consuming step, we propose Deep Automated Registration Qc (DARQ), a fully automatic quality control method based on deep learning that can replace the human rater and accurately perform quality control assessment for stereotaxic registration of T1w brain scans.

In a recently published study from our group comparing linear registration methods, we used a database of 9325 MRI scans and 64476 registrations from several publicly available datasets and applied seven linear registration tools to them. In this study, the resulting images that were assessed and labeled by a human rater are used to train a deep neural network to detect cases when registration failed. We further validated the results on an independent dataset of patients with multiple sclerosis, with manual QC labels available (n=1200).

In terms of agreement with a manual rater, our automated QC method was able to achieve 89%accuracy and 85% true negative rate (equivalently 15% false positive rate) in detecting scans that should pass quality control in a balanced cross-validation experiments, and 96.1% accuracy and 95.5% true negative rate (or 4.5% FPR) when evaluated in a balanced independent sample, similar to manual QC rater (test-retest accuracy of 93%).

The results show that DARQ is robust, fast, accurate, and generalizable in detecting failure in linear stereotaxic registrations and can substantially reduce QC time (by a factor of 20 or more) when processing large datasets.
Learning to be on time: temporal coordination of neural dynamics by activity-dependent myelination
Authors: Talidou Afroditi , Frankland Paul W. , Mabbott Donald , Lefebvre Jérémie
Published: August 2021

Activity-dependent myelination is the mechanism by which myelin changes as a function of neural activity, and plays a fundamental role in brain plasticity. Mediated by structural changes in glia, activity-dependent myelination regulates axonal conduction velocity. It remains unclear how neural activity impacts myelination to orchestrate the timing of neural signaling. We developed a model of spiking neurons enhanced with neuron-glia feedback. Inspired by experimental data and use-dependent synaptic plasticity, we introduced a learning rule, called the Activity-Dependent Myelination (ADM) rule, by which conduction velocity scales with firing rates. We found that the ADM rule implements a homeostatic control mechanism that promotes and preserves synchronization. ADM-mediated plasticity was found to optimize synchrony by compensating for variability in axonal lengths by scaling conduction velocity in an axon-specific way. This property was maintained even when the network structure is altered. We further explored how external stimuli interact with the ADM rule to trigger bidirectional and reversible changes in conduction delays. These results highlight the role played by activity-dependent myelination in synchronous neural communication and brain plasticity.
Micromechanical Characterisation of 3D Bioprinted neural cell models using Brillouin Microscopy
Authors: Rad Maryam Alsadat , Mahmodi Hadi , Filipe Elysse C. , Cox Thomas R. , Kabakova Irina , Tipper Joanne L.
Published: August 2021

Biofabrication of artificial 3D in vitro neural cell models that closely mimic the central nervous system (CNS) is an emerging field of research with applications from fundamental biology to regenerative medicine, and far reaching benefits for the economy, healthcare and the ethical use of animals. The micromechanical properties of such models are an important factor dictating the success of modelling outcomes in relation to accurate reproduction of the processes in native tissues. Characterising the micromechanical properties of such models non-destructively and over a prolonged span of time, however, are key challenges. Brillouin microscopy (BM) could provide a solution to this problem since this technology is non-invasive, label-free and is capable of microscale 3D imaging. In this work, the viscoelasticity of 3D bioprinted neural cell models consisting of NG 108-15 neuronal cells and GelMA hydrogels of various concentrations were investigated using BM. We demonstrate changes in the micro- and macro-scale mechanical properties of these models over a 7 day period, in which the hydrogel component of the model are found to soften as the cells grow, multiply and form stiffer spheroid-type structures. These findings signify the necessity to resolve in microscopic detail the mechanics of in vitro 3D tissue models and suggest Brillouin microscopy to be a suitable technology to bridge this gap.
Working memory capacity of crows and monkeys arises from similar neuronal computations
Authors: Hahn Lukas Alexander , Balakhonov Dmitry , Fongaro Erica , Nieder Andreas , Rose Jonas
Published: August 2021

Complex cognition relies on flexible working memory, which is severely limited in its capacity. The neuronal computations underlying these capacity limits have been extensively studied in humans and in monkeys, resulting in competing theoretical models. We probed the working memory capacity of crows (Corvus corone) in a change detection task, developed for monkeys (Macaca mulatta), while we performed extracellular recordings of the prefrontal-like area nidopallium caudolaterale. We found that neuronal encoding and maintenance of information were affected by item load, in a way that is virtually identical to results obtained from monkey prefrontal cortex. Contemporary neurophysiological models of working memory employ divisive normalization as an important mechanism that may result in the capacity limitation. As these models are usually conceptualized and tested in an exclusively mammalian context, it remains unclear if they fully capture a general concept of working memory or if they are restricted to the mammalian neocortex. Here we report that carrion crows and macaque monkeys share divisive normalization as a neuronal computation that is in line with mammalian models. This indicates that computational models of working memory developed in the mammalian cortex can also apply to non-cortical associative brain regions of birds.
Visual recognition of social signals by a tecto-thalamic neural circuit
Authors: Kappel Johannes M. , Slangewal Katja , Förster Dominique , Shainer Inbal , Svara Fabian , Januszewski Michal , Sherman Shachar , Baier Herwig , Larsch Johannes
Published: August 2021

Social affiliation emerges from individual-level behavioral rules that are driven by conspecific signals1–5. Long-distance attraction and short-distance repulsion, for example, are rules that jointly set a preferred inter-animal distance in swarms6–8. However, little is known about their perceptual mechanisms and executive neuronal circuits3. Here we trace the neuronal response to self-like biological motion9,10(BM), a visual trigger for affiliation in developing zebrafish2,11. Unbiased activity mapping and targeted volumetric two-photon calcium imaging revealed 19 activity hotspots distributed throughout the brain and clustered BM-tuned neurons in a multimodal, socially activated nucleus of the dorsal thalamus (DT). Individual DT neurons encode fish-like local acceleration but are insensitive to global or continuous motion. Electron microscopic reconstruction of DT neurons revealed synaptic input from the optic tectum (TeO/superior colliculus) and projections into nodes of the conserved social behavior network12,13. Chemogenetic ablation of the TeO selectively disrupted DT responses to BM and social attraction without affecting short-distance repulsion. Together, we discovered a tecto-thalamic pathway that drives a core network for social affiliation. Our findings provide an example of visual social processing, and dissociate neuronal control of attraction from repulsion during affiliation, thus revealing neural underpinnings of collective behavior.
Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits Regenerative Response
Authors: Han Jin , Cherry Christopher , Mejias Joscelyn C. , Ruta Anna , Maestas David R. , Peña Alexis N. , Nguyen Helen Hieu , Yang Brenda , Gray-Gaillard Elise , Rutkowski Natalie , Krishnan Kavita , Tam Ada J. , Fertig Elana J. , Housseau Franck , Ganguly Sudipto , Moore Erika M. , Pardoll Drew M. , Elisseeff Jennifer H.
Published: August 2021

Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and could potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, we characterized how aging induces senescence and immunological changes that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Tissue signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improved healing and restored therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair.
Effects of climate warming on the pine processionary moth at the southern edge of its range: a retrospective analysis on egg survival in Tunisia
Authors: Bourougaaoui Asma , Robinet Christelle , Ben Jamaa Mohamed L. , Laparie Mathieu
Published: August 2021

In recent years, ectotherm species have largely been impacted by extreme climate events, essentially heatwaves. In Tunisia, the pine processionary moth (PPM),Thaumetopoea pityocampa, is a highly damaging pine defoliator, which typically lays eggs in summer. Its geographical range is expanding northwards in Europe while retracting from South Tunisia where summer temperatures can reach extremely high values. In this study, we aimed at exploring the effects of climate change on this species at its southern range edge. We investigated variations of fecundity and causes of egg mortality over time using historical and contemporary collections of egg masses from different Tunisian sites to seek relationships with regional climate change over three decades (1990-2019). Our results suggest negative effects of summer heat on egg survival, reflected in a decrease of hatching rate down to 0% in one site during a heatwave. Such a high hatching failure was found to result from both high egg sterility (our results did not allow distinguishing impeded mating success from failed egg maturation or early death of the embryo) and increased abortion of more developed embryos, but little effects of parasitism rate, thereby suggesting vulnerability to heat during embryonic development. We also observed decreasing female fecundity (i.e., number of eggs laid per female) in regions where data were available both in the 1990s and the 2010s, which was associated with a decrease in parasitism rate, while the climatic variability increased. This study investigated direct hatching failure in nature that may be related to the magnitude of warming in summer. Previous studies have confirmed the thermal sensitivity of early instars of the PPM to temperatures observed in the present work, including one population from South Tunisia. However, further work is required to evaluate the relative importance of warming summers among populations because the risk of heat stress depends on the phenology of sensitive instars, and populations from the warmest areas may not necessarily be the most vulnerable to climate change if they already evolved phenological heat avoidance. In addition to heat-induced mortality, the ultimate fitness of individuals that survive challenging heat stresses during early developmental stages should also be explored to determine potential carry-over effects on subsequent life stages.
Mechanical intercellular communication via matrix-borne cell force transmission during vascular network formation
Authors: Davidson Christopher D. , DePalma Samuel J. , Wang William Y. , Kamen Jordan L. , Jayco Danica Kristen P. , Baker Brendon M.
Published: August 2021

Intercellular communication is critical to the development and homeostatic function of all tissues. Previous work has shown that cells can communicate mechanically via transmission of cell-generated forces through their surrounding extracellular matrix, but this process is not well understood. Here, we utilized synthetic, electrospun fibrous matrices in conjunction with a microfabrication-based cell patterning approach to examine mechanical intercellular communication (MIC) between endothelial cells (ECs) during the assembly of microvascular networks. We found that cell force-mediated matrix displacements in deformable fibrous matrices underly directional migration of neighboring ECs towards each other prior to the formation of stable cell-cell connections. We also identified a critical role for intracellular calcium signaling mediated by focal adhesion kinase and TRPV4 during MIC that extends to multicellular assembly of vessel-like networks in 3D fibrin hydrogels. The results presented here are critical to the design of biomaterials that support cellular self-assembly for tissue engineering applications.
Features of peptide fragmentation spectra in single cell proteomics
Authors: Boekweg Hannah , Van Der Watt Daisha , Truong Thy , Guise Amanda J , Plowey Edward D , Kelly Ryan T , Payne Samuel H
Published: August 2021

The goal of proteomics is to identify and quantify the complete set of proteins in a biological sample. Single cell proteomics specializes in identification and quantitation of proteins for individual cells, often used to elucidate cellular heterogeneity. The significant reduction in ions introduced into the mass spectrometer for single cell samples could impact the features of MS2 fragmentation spectra. As all peptide identification software tools have been developed on spectra from bulk samples and the associated ion rich spectra, the potential for spectral features to change is of great interest. We characterize the differences between single cell spectra and bulk spectra by examining three fundamental spectral features that are likely to affect peptide identification performance. All features show significant changes in single cell spectra, including loss of annotated fragment ions, blurring signal and background peaks due to diminishing ion intensity and distinct fragmentation pattern compared to bulk spectra. As each of these features is a foundational part of peptide identification algorithms, it is critical to adjust algorithms to compensate for these losses.
An Endogenously activated antiviral state restricts SARS-CoV-2 infection in differentiated primary airway epithelial cells
Authors: Broadbent Lindsay , Bamford Connor G.G. , Campos Guillermo Lopez , Manzoor Sheerien , Courtney David , Ali Ahlam , Touzelet Olivier , McCaughey Conall , Mills Ken , Power Ultan F.
Published: August 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the coronavirus disease-19 (COVID-19) pandemic, was identified in late 2019 and went on to cause over 3.3 million deaths in 15 months. To date, targeted antiviral interventions against COVID-19 are limited. The spectrum of SARS-CoV-2 infection ranges from asymptomatic to fatal disease. However, the reasons for varying outcomes to SARS-CoV-2 infection are yet to be elucidated. Here we show that an endogenously activated interferon lambda (IFNλ) pathway leads to resistance against SARS-CoV-2 infection. Using a well-differentiated primary nasal epithelial cell (WD-PNEC) model from multiple adult donors, we discovered that susceptibility to SARS-CoV-2 infection, but not respiratory syncytial virus (RSV) infection, varied. One of four donors was resistant to SARS-CoV-2 infection. High baseline IFNλ expression levels and associated interferon stimulated genes correlated with resistance to SARS-CoV-2 infection. Inhibition of the JAK/STAT pathway in WD-PNECs with high endogenous IFNλ secretion resulted in higher SARS-CoV-2 titres. Conversely, prophylactic IFNλ treatment of WD-PNECs susceptible to infection resulted in reduced viral titres. An endogenously activated IFNλ response, possibly due to genetic differences, may be one explanation for the differences in susceptibility to SARS-CoV-2 infection in humans. Importantly, our work supports the continued exploration of IFNλ as a potential pharmaceutical against SARS-CoV-2 infection.
Bridge Category Models: Development of Bayesian Modelling Procedures to Account for Bridge Ordinal Ratings for Disease Staging
Authors: Levy Joshua , Bobak Carly , Azizgolshani Nasim , Andersen Michael , Suriawinata Arief , Liu Xiaoying , Lisovsky Mikhail , Ren Bing , Christensen Brock , Vaickus Louis , O’Malley A. James
Published: August 2021

Disease grading and staging is accomplished through the assignment of an ordinal rating. Bridge ratings occur when a rater assigns two adjacent categories. Most statistical methodology necessitates the use of a single ordinal category. Consequently, bridge ratings often go unreported in clinical research studies. We propose three methodologies (Expanded, Mixture, andCollapsed)Bridge Category Models, to account for bridge ratings. We perform simulations to examine the impact of our approaches on detecting treatment effects, and comment on a real-world scenario of staging liver biopsies. Results indicate that if bridge ratings are not accounted for, disease staging models may exhibit significant bias and precision loss. All models worked well when they corresponded to the data generating mechanism.
Accuracy of multiple sequence alignment methods in the reconstruction of transposable element families
Authors: Hubley Robert , Wheeler Travis J. , Smit Arian F.A.
Published: August 2021

The construction of a high-quality multiple sequence alignment (MSA) from copies of a transposable element (TE) is a critical step in the characterization of a new TE family. Most studies of MSA accuracy have been conducted on protein or RNA sequence families where structural features and strong signals of selection may assist with alignment. Less attention has been given to the quality of sequence alignments involving neutrally evolving DNA sequences such as those resulting from TE replication. Such alignments play an important role in understanding and representing TE family history. Transposable element sequences are challenging to align due to their wide divergence ranges, fragmentation, and predominantly-neutral mutation patterns. To gain insight into the effects of these properties on MSA accuracy, we developed a simulator of TE sequence evolution, and used it to generate a benchmark with which we evaluated the MSA predictions produced by several popular aligners, along with Refiner, a method we developed in the context of our RepeatModeler software. We find that MAFFT and Refiner generally outperform other aligners for low to medium divergence simulated sequences, while Refiner is uniquely effective when tasked with aligning high-divergent and fragmented instances of a family. As a result, consensus sequences derived from Refiner-based MSAs are more similar to the true consensus.
Intracellular glycosyl hydrolase PslG shapes bacterial cell fate, signaling, and the biofilm development of Pseudomonas aeruginosa
Authors: Zhang Jingchao , Wu Huijun , Wang Di , Zhang Chenxi , Zhao Kun , Ma Luyan Z.
Published: August 2021

Biofilm formation is one of most important causes leading to persistent infections. Exopolysaccharides are usually a main component of biofilm matrix. Genes encoding for glycosyl hydrolases are often found in gene clusters that are involved in the exopolysaccharide synthesis. It remains elusive about the functions of intracellular glycosyl hydrolase and why a polysaccharide synthesis gene cluster requires a glycosyl hydrolase. Here we systematically studied the role of intracellular PslG, a glycosyl hydrolase that is co-transcribed with 15 psl genes, which is responsible for the synthesis of exopolysaccharide Psl (ePsl), a key biofilm matrix polysaccharide in opportunistic pathogen Pseudomonas aeruginosa. We showed that lacking of PslG in this opportunistic pathogen alters the signaling function and structure of ePsl, changes the relative level of cyclic-di-GMP within daughter cells during cell division and shapes the localization of ePsl on bacterial periphery, thus results in long chains of bacterial cells, fast-forming and compact biofilm microcolonies. Our results reveal the important roles of intracellular PslG on the cell fate and biofilm development.
Selection for seed size has indirectly shaped specialized metabolite abundance in oat (Avena sativaL.)
Authors: Brzozowski Lauren J. , Hu Haixiao , Campbell Malachy T. , Broeckling Corey D. , Caffe-Treml Melanie , Gutiérrez Lucía , Smith Kevin P. , Sorrells Mark E. , Gore Michael A. , Jannink Jean-Luc
Published: August 2021

Plant breeding strategies to optimize metabolite profiles are necessary to develop health-promoting food crops. In oats (Avena sativaL.), seed metabolites are of interest for their antioxidant properties and their agronomic role in mitigating disease severity, yet have not been a direct target of selection in breeding. In a diverse oat germplasm panel spanning a century of breeding, we investigated the degree of variation of these specialized metabolites and how it has been molded by selection for other traits, like yield components. We also ask if these patterns of variation persist in modern breeding pools. Integrating genomic, transcriptomic, metabolomic and phenotypic analyses for three types of seed specialized metabolites – avenanthramides, avenacins, and avenacosides – we found reduced genetic variation in modern germplasm compared to diverse germplasm, in part due to increased seed size associated with more intensive breeding. Specifically, we found that abundance of avenanthramides increases with seed size, but additional variation is attributable to expression of biosynthetic enzymes, but avenacoside abundance decreases with seed size and plant breeding intensity. Overall, we show that increased seed size associated with plant breeding has uneven effects on the seed metabolome, and broadly contributes to understanding how selection shapes plant specialized metabolism.
Emerging harmful algal blooms caused by distinct seasonal assemblages of the toxic diatomPseudo-nitzschiain Narragansett Bay, RI, USA
Authors: Sterling Alexa R. , Kirk Riley D. , Bertin Matthew J. , Rynearson Tatiana A. , Borkman David G. , Caponi Marissa C. , Carney Jessica , Hubbard Katherine A. , King Meagan A. , Maranda Lucie , McDermith Emily J. , Santos Nina R. , Strock Jacob P. , Tully Erin M. , Vaverka Samantha B. , Wilson Patrick D. , Jenkins Bethany D.
Published: August 2021

The diatomPseudo-nitzschiaproduces the neurotoxin domoic acid (DA) that bioaccumulates in shellfish, causing illness in humans and marine animals upon ingestion. In 2017, high levels of DA in shellfish meat closed shellfish harvest in Narragansett Bay (NBay), Rhode Island for the first time in history, although abundantPseudo-nitzschiahave been observed for over 50 years. What caused these events is unknown: whether an environmental factor altered endemicPseudo-nitzschiaphysiology or new DA-producing strain(s) were introduced. To investigate, we conducted weekly sampling from 2017-2019 to compare with 2016 precautionary closure and 2017 closure samples. Particulate DA was quantified by highly sensitive LC-MS/MS and correlated with environmental metadata.Pseudo-nitzschiawere identified using high-throughput rDNA sequencing, yielding a detailed understanding of distinct seasonal multi-species assemblages. Low DA was detected throughout 2017-2019, except in recurring peaks in the fall and early summer. Fall DA peaks contained toxigenic species (P. pungensvar.pungens, P. multiseries, P. calliantha,andP. subpacifica) as well as a novelP. americanataxon. Fewer species were present during summer DA peaks including toxigenicP. multiseries, P. plurisecta,andP. delicatissima.Most 2017 closure samples containedP. australis.Our data showedP. australisas infrequent but particularly concerning. RecurringPseudo-nitzschiaassemblages were driven by seasonal temperature changes and DA correlated with low dissolved inorganic nitrogen. Thus, the NBay closures were likely caused by resident assemblages dependent on nutrient status as well as the episodic introductions of species that may be a result of oceanographic and climactic shifts.
svaRetro and svaNUMT: Modular packages for annotation of retrotransposed transcripts and nuclear integration of mitochondrial DNA in genome sequencing data
Authors: Dong Ruining , Cameron Daniel , Bedo Justin , Papenfuss Anthony T
Published: August 2021

Background

The biological significance of structural variation is now more widely recognized. However, due to the lack of available tools for downstream analysis, including processing and annotating, interpretation of structural variant calls remains a challenge.

Findings

Here we present svaRetro and svaNUMT, R packages that provide functions for annotating novel genomic events such as non-reference retro-copied transcripts and nuclear integration of mitochondrial DNA. We evaluate the performance of these packages to detect events using simulations and public benchmarking datasets, and annotate processed transcripts in a public structural variant database.

Conclusions

svaRetro and svaNUMT provide efficient, modular tools for downstream identification and annotation of structural variant calls.
Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and less functional
Authors: Nissley Daniel , Jiang Yang , Trovato Fabio , Sitarik Ian , Narayan Karthik , To Philip , Xia Yingzi , Fried Stephen D. , O’Brien Edward P.
Published: August 2021

Misfolded protein conformations with decreased functionality can bypass the proteostasis machinery and remain soluble in vivo. This is an unexpected phenomenon as several cellular quality control mechanisms have evolved to rid cells of misfolded proteins. Three questions, then, are: how is it structurally possible for long-lived, soluble, misfolded proteins to bypass the proteostasis machinery and processes? How widespread are these soluble, misfolded states across the proteome? And how long do they persist for? Here, we address these questions using coarse-grain molecular dynamics simulations of the synthesis, termination, and post-translational dynamics of a representative set of cytosolic E. coli proteins. We predict that half of all proteins exhibit subpopulations of misfolded conformations that are likely to bypass molecular chaperones, avoid aggregation, and not be rapidly degraded. These misfolded states may persist for months or longer for some proteins. Structurally characterizing these misfolded states, we observe they have a large amount of native structure, but also contain localized misfolded regions from non-native changes in entanglement, in which a protein segment threads through a loop formed by another portion of the protein that is not found in the native state. The surface properties of these misfolded states are native like, suggesting they may bypass the proteostasis machinery and its regulatory processes to remain soluble, while their entanglements make these states long-lived kinetic traps, as disentanglement requires unfolding of already folded portions of the protein. In terms of function, we predict that one-third of proteins have subpopulations that misfold into less-functional states that have structurally perturbed functional sites yet remain soluble. Data from limited-proteolysis mass spectrometry experiments, which interrogate the misfolded conformations populated by proteins upon unfolding and refolding, are consistent with the structural changes seen in the entangled states of glycerol-3-phosphate dehydrogenase upon misfolding. These results provide an explanation for how proteins can misfold into soluble conformations with reduced functionality that can bypass cellular quality controls, and indicate, unexpectedly, this may be a wide-spread phenomenon in proteomes. Such entanglements are observed in many native structures, suggesting the non-native entanglements we observe are plausible. More broadly, these near-native entangled structures suggest a hypothesis for how synonymous mutations can modulate downstream protein structure and function, with these mutations partitioning nascent proteins between these kinetically trapped states.
Range-wide habitat use and Key Biodiversity Area coverage for a lowland tropical forest raptor across an increasingly deforested landscape
Authors: Sutton Luke J. , Anderson David L. , Franco Miguel , McClure Christopher J.W. , Miranda Everton B.P. , Vargas F. Hernán , Vargas González José de J. , Puschendorf Robert
Published: August 2021

Quantifying habitat use is important for understanding how animals meet their requirements for survival and provides useful information for conservation planning. Currently, assessments of range-wide habitat use that delimit species distributions are incomplete for many taxa. The harpy eagle (Harpia harpyja) is a raptor of conservation concern, widely distributed across Neotropical lowland forests, that currently faces threats from increasing habitat loss and fragmentation. Here, we use a logistic regression modelling framework to identify habitat resource selection and predict habitat suitability based on a new method developed from the International Union for the Conservation of Nature Area of Habitat range metric. From the habitat use model, we performed a gap analysis to identify areas of high habitat suitability in regions with limited coverage in the Key Biodiversity Area (KBA) network. Range-wide habitat use indicated that harpy eagles prefer areas of 70-75 % evergreen forest cover, low elevation, and high vegetation heterogeneity. Conversely, harpy eagles avoid areas of >10 % cultivated landcover and mosaic forest, and topographically complex areas. Our habitat use model identified a large continuous area across the pan-Amazonia region, and a habitat corridor from the Chocó-Darién ecoregion of Colombia running north along the Caribbean coast of Central America. Little habitat was predicted across the Atlantic Forest biome, which is now severely degraded. The current KBA network covered ∼18 % of medium to high suitability harpy eagle habitat exceeding the target representation (10 %). Four major areas of high suitability habitat lacking coverage in the KBA network were identified in the Chocó-Darién ecoregion of Colombia, western Guyana, and north-west Brazil. We recommend these multiple gaps of habitat as new KBAs for strengthening the current KBA network. Modelled area of habitat estimates as described here are a useful tool for large-scale conservation planning and can be readily applied to many taxa.
Rapid radiation of Southern Ocean shags in response to receding sea ice
Authors: Rawlence Nicolas J. , Salis Alexander T. , Spencer Hamish G. , Waters Jonathan M. , Scarsbrook Lachie , Phillips Richard A. , Calderón Luciano , Cook Timothée R. , Bost Charles-André , Dutoit Ludovic , King Tania M. , Masello Juan F. , Nupen Lisa J. , Quillfeldt Petra , Ratcliffe Norman , Ryan Peter G. , Till Charlotte E. , Kennedy Martyn
Published: August 2021

Aim

Understanding how wild populations respond to climatic shifts is a fundamental goal of biological research in a fast-changing world. The Southern Ocean represents a fascinating system for assessing large-scale climate-driven biological change, as it contains extremely isolated island groups within a predominantly westerly, circumpolar wind and current system. The blue-eyed shags (Leucocarbospp.) represent a paradoxical Southern Ocean seabird radiation; a circumpolar distribution implies strong dispersal capacity yet their speciose nature suggests local adaptation and isolation. Here we use genetic tools in an attempt to resolve this paradox.

Location

Southern Ocean.

Taxa

17 species and subspecies of blue-eyed shags (Leucocarbospp.) across the geographical distribution of the genus.

Methods

Here we use mitochondrial and nuclear sequence data to conduct the first global genetic analysis of this group using a temporal phylogenetic framework to test for rapid speciation.

Results

Our analysis reveals remarkably shallow evolutionary histories among island-endemic lineages, consistent with a recent high-latitude circumpolar radiation. This rapid sub-Antarctic expansion contrasts with significantly deeper lineages detected in more temperate regions such as South America and New Zealand that may have acted as glacial refugia. The dynamic history of high-latitude expansions is further supported by ancestral demographic and biogeographic reconstructions.

Main conclusions

The circumpolar distribution of blue-eyed shags, and their highly dynamic evolutionary history, potentially makeLeucocarboa strong sentinel of past and ongoing Southern Ocean ecosystem change given their sensitivity to climatic impacts.
Functional cortical localization of the tongue using corticokinematic coherence with a deep learning-assisted motion capture system
Authors: Maezawa Hitoshi , Fujimoto Momoka , Hata Yutaka , Matsuhashi Masao , Hashimoto Hiroaki , Kashioka Hideki , Yanagida Toshio , Hirata Masayuki
Published: August 2021

Measuring the corticokinematic coherence (CKC) between magnetoencephalographic and movement signals using an accelerometer can evaluate the functional localization of the primary sensorimotor cortex (SM1) of the upper limbs. However, it is difficult to determine the tongue CKC because an accelerometer yields excessive magnetic artifacts. We introduce and validate a novel approach for measuring the tongue CKC using a deep learning-assisted motion capture system with videography, and compare it with an accelerometer in a control task measuring finger movement. Twelve healthy volunteers performed rhythmical side-to-side tongue movements in the whole-head magnetoencephalographic system, which were simultaneously recorded using a video camera and examined offline using a deep learning-assisted motion capture system. In the control task, right finger CKC measurements were simultaneously evaluated via motion capture and an accelerometer. The right finger CKC with motion capture was significant at the movement frequency peaks or its harmonics over the contralateral hemisphere; the motion-captured CKC was 84.9% similar to that with the accelerometer. The tongue CKC was significant at the movement frequency peaks or its harmonics over both hemispheres, with no difference between the left and right hemispheres. The CKC sources of the tongue were considerably lateral and inferior to those of the finger. Thus, the CKC based on deep learning-assisted motion capture can evaluate the functional localization of the tongue SM1. In this approach, because no devices are placed on the tongue, magnetic noise, disturbances due to tongue movements, risk of aspiration of the device, and risk of infection to the experimenter are eliminated.
Mutualists construct the ecological conditions that trigger the transition from parasitism
Authors: Ledru Leo , Garnier Jimmy , Rhor Matthias , Nous Camille , Ibanez Sebastien
Published: August 2021

The evolution of mutualism between hosts and initially parasitic symbionts represents a major transition in evolution. Although vertical transmission of symbionts during host reproduction and partner control both favour the stability of mutualism, these mechanisms require specifically evolved features that may be absent in the first place. Therefore, the first steps of the transition from parasitism to mutualism may suffer from the cost of mutualism at the organismic level. We hypothesize that spatial structure can lead to the formation of higher selection levels favouring mutualism. This resembles the evolution of altruism, with the additional requirement that the offspring of mutualistic hosts and symbionts must co-occur often enough. Using a spatially explicit agent-based model we demonstrate that, starting from a parasitic system with global dispersal, the joint evolution of mutualistic effort and local dispersal of hosts and symbionts leads to a stable coexistence between parasites and mutualists. The evolution of local dispersal mimics vertical transmission and triggers the formation of mutualistic clusters, counteracting the organismic selection level of parasites that maintain global dispersal. The transition occurs when mutualistic symbionts increase the density of hosts, which strengthens competition between hosts and disfavours hosts inhabiting areas dominated by parasitic symbionts: mutualists construct the ecological conditions that allow their own spread. Therefore, the transition to mutualism may come from an eco-evolutionary feedback loop involving spatially structured population dynamics.
Geometric Deep Learning of the Human Connectome Project Multimodal Cortical Parcellation
Authors: Williams Logan Z. J. , Fawaz Abdulah , Glasser Matthew F. , David Edwards A. , Robinson Emma C.
Published: August 2021

Understanding the topographic heterogeneity of cortical organisation is an essential step towards precision modelling of neuropsychiatric disorders. While many cortical parcellation schemes have been proposed, few attempt to model inter-subject variability. For those that do, most have been proposed for high-resolution research quality data, without exploration of how well they generalise to clinical quality scans. In this paper, we benchmark and ensemble four different geometric deep learning models on the task of learning the Human Connectome Project (HCP) multimodal cortical parcellation. We employ Monte Carlo dropout to investigate model uncertainty with a view to propagate these labels to new datasets. Models achieved an overall Dice overlap ratio of >0.85 ± 0.02. Regions with the highest mean and lowest variance included V1 and areas within the parietal lobe, and regions with the lowest mean and highest variance included areas within the medial frontal lobe, lateral occipital pole and insula. Qualitatively, our results suggest that more work is needed before geometric deep learning methods are capable of fully capturing atypical cortical topographies such as those seen in area 55b. However, information about topographic variability between participants was encoded in vertex-wise uncertainty maps, suggesting a potential avenue for projection of this multimodal parcellation to new datasets with limited functional MRI, such as the UK Biobank.
ATP hydrolysis tunes specificity of a AAA+ protease
Authors: Mahmoud Samar A. , Aldikacti Berent , Chien Peter
Published: August 2021

In bacteria, AAA+ proteases such as Lon and ClpXP degrade substrates with exquisite specificity. These machines capture the energy of ATP hydrolysis to power unfolding and degradation of target substrates. Here, we show that a mutation in the ATP binding site of ClpX shifts protease specificity to promote degradation of normally Lon-restricted substrates. However, this ClpX mutant is worse at degrading ClpXP targets, suggesting an optimal balance in substrate preference for a given protease that is surprisingly easy to alter. In vitro, wildtype ClpXP also degrades Lon-restricted substrates more readily when ATP levels are reduced, similar to the shifted specificity of mutant ClpXP, which has altered ATP hydrolysis kinetics. Based on these results, we suggest that rates of ATP hydrolysis not only power substrate unfolding and degradation, but also tune protease specificity. We consider various models for this effect based on emerging structures of AAA+ machines showing conformationally distinct states.

Abstract Figure

Graphical Abstract

eTOC

AAA+ proteases, such as Lon and ClpXP, select distinct targets for degradation to maintain proteostasis. Mahmoud et al. show that ATP hydrolysis can tune substrate specificity of ClpX, allowing ClpX to degrade Lon-restricted substrates under limiting ATP conditions or in the presence of a ClpX mutant.

Highlights

A Walker B mutation of the AAA+ protease ClpX alters substrate specificity

ClpX mutant degrades new substrates but degrades canonical substrates less well

Decreasing ATP levels enhances ClpXP mediated degradation of some classes of substrates

ATP-induced changes in conformational states accompany alterations in ClpX specificity
Genetic Analysis of Bphse: a Novel Gene Complementing Resistance to Bordetella pertussis-Induced Histamine Sensitization
Authors: Raza Abbas , Diehl Sean A. , Case Laure K. , Krementsov Dimitry N. , Li Dawei , Kost Jason , Ball Robyn L. , Chesler Elissa J. , Philip Vivek M. , Huang Rui , Chen Yan , Ma Runlin , Tyler Anna L. , Mahoney J. Mathew , Blankenhorn Elizabeth P. , Teuscher Cory
Published: August 2021

Abstract

Histamine is a bioactive amine associated with a plethora of normal and pathophysiological processes, with the latter being dependent on both genetic and environmental factors including infectious agents. Previously, we showed in mice that susceptibility to Bordetella pertussis and pertussis toxin (PTX) induced histamine sensitization (Bphs) is controlled by histamine receptor H1 (Hrh1/HRH1) alleles. Bphs susceptible and resistant alleles (Bphss/Bphsr) encode for two-conserved protein haplotypes. Given the importance of HRH1 signaling in health and disease, we sequenced Hrh1 across an extended panel of laboratory and wild-derived inbred strains and phenotyped them for Bphs. Unexpectedly, eight strains homozygous for the Bphsr allele phenotyped as Bphss, suggesting the existence of a modifying locus segregating among the strains capable of complementing Bphsr. Genetic analyses mapped this modifier locus to mouse chromosome 6; designated Bphs-enhancer (Bphse), within a functional linkage disequilibrium domain encoding multiple loci controlling responsiveness to histamine (Bphs/Hrh1 and Histh1-4). Interval-specific single-nucleotide polymorphism (SNP) based association testing across 50 laboratory and wild-derived inbred mouse strains and functional prioritization analyses resulted in the identification of candidate genes for Bphse within a ∼5.5 Mb interval (Chr6:111.0-116.4 Mb), including Atg7, Plxnd1, Tmcc1, Mkrn2, Il17re, Pparg, Lhfpl4, Vgll4, Rho and Syn2. Taken together, these results demonstrate the power of combining network-based computational methods with the evolutionarily significant diversity of wild-derived inbred mice to identify novel genetic mechanisms controlling susceptibility and resistance to histamine shock.
Interior of sand fly (Diptera: Psychodidae) abdomen reveals novel structures involved in pheromone release: discovering the Manifold
Authors: Tonelli G.B. , Andrade-Filho J.D. , Campos A.M. , Margonari C. , Amaral A.R. , Volf P. , Shaw E. , Hamilton J.G.C.
Published: August 2021

The males of many species of New World Phlebotomines produce volatile terpenoid chemicals which have been shown in Lutzomyia longipalpis s.l. and L. cruciata to be sex/aggregation pheromones which attract female and male conspecifics. Pheromone is produced in secretory cells surrounding a cuticular reservoir which collects the pheromone and passes it through a cuticular duct to the surface of the insect. On the surface the pheromone passes through a specialised structure prior to evaporation. The shape and distribution of the structures are highly diverse and differ according to species. They range in appearance from slightly raised domes (papules) to almost spherical apple shaped structures to slight depressions with central spikes and all with a central pore. They can occur either singly or in many hundreds distributed on most abdominal tergites or grouped on one. The pheromone secreting apparatus in sand flies and other insects have historically been examined from the exterior using scanning electron microscopy (SEM) and from the interior using transmission electron microscopy. In this study we used SEM to examine the interior cuticular structure of 3 members of the Lutzomyia longipalpis s.l. species complex and Migonemyia migonei and found a new structure associated with pheromone release which we have called the Manifold. The Manifold is a substantial structure siting in-line between the cuticular duct and the underside of the tergite. Differences in the size and shape of the Manifold may be related to the chemical structure of the pheromone. In addition to the importance of this hitherto unknown structure in the production, dissemination and ecology of the pheromone, as well as its potential taxonomic value, examination of the interior cuticle by SEM may help locate the secretory apparatus in important vector species where pheromonal activity has been inferred from behavioural studies but the external secretory structures or potential pheromones have not been found.