bluuebunny/crossref_metadata_2025 huggingface dataset:
Impacts of dietary exposure to pesticides on faecal microbiome metabolism in adult twins
Authors: Mesnage Robin , Bowyer Ruth C E , El Balkhi Souleiman , Saint-Marcoux Franck , Gardere Arnaud , Ducarmon Quinten Raymond , Geelen Anoecim Robecca , Zwittink Romy Daniëlle , Tsoukalas Dimitris , Sarandi Evangelia , Paramera Efstathia I. , Spector Timothy , Steves Claire J , Antoniou Michael N
Published: June 2021

Concerns have been raised as to whether the consumption of foodstuffs contaminated with pesticides can contribute to the development of chronic human diseases by affecting microbial community function in the gut. We provide the first associations between urinary pesticide excretion and the composition and function of the faecal microbiome in 65 twin pairs in the UK. Biomonitoring of exposure to 186 common insecticide, herbicide, or fungicide residues showed the presence of pyrethroid and/or organophosphorus insecticide residues in all urine samples, while the herbicide glyphosate was found in 45% of individuals. Other pesticides such as DEET, imidacloprid or dithiocarbamate fungicides were less frequently detected. While the geographic location or the rural/urban environment had no influence on pesticide urinary excretion, food frequency questionnaires showed that DMTP levels, a metabolite of organophosphates, was higher with increased consumption of fruit and vegetables. Multivariable association between urinary pesticide excretion and faecal microbial composition and function were determined with shotgun metagenomics and metabolomics. A total of 34 associations between pesticide residues concentrations and faecal metabolite concentrations were detected. Glyphosate excretion was positively associated to an increased bacterial species richness, as well as to fatty acid metabolites and phosphate levels. The insecticide metabolite Br2CA, reflecting deltamethrin exposure, was positively associated with the mammalian phytoestrogens enterodiol and enterolactone, and negatively associated with some N-methyl amino acids. Urine metabolomics performed on a subset of samples did not reveal associations with the excretion of pesticide residues. Our results highlight the need for future interventional studies to understand effects of pesticide exposure on the gut microbiome and possible health consequences.
Wearables-Only Analysis of Muscle and Joint Mechanics: An EMG-Driven Approach
Authors: Gurchiek Reed D. , Donahue Nicole , Fiorentino Niccolo M. , McGinnis Ryan S.
Published: June 2021

Complex sensor arrays prohibit practical deployment of existing wearables-based algorithms for free-living analysis of muscle and joint mechanics. Machine learning techniques have been proposed as a potential solution, however, they are less interpretable and generalizable when compared to physics-based techniques. Herein, we propose a hybrid method utilizing inertial sensor- and electromyography (EMG)-driven simulation of muscle contraction to characterize knee joint and muscle mechanics during walking gait. Machine learning is used only to map a subset of measured muscle excitations to a full set thereby reducing the number of required sensors. We demonstrate the utility of the approach for estimating net knee flexion moment (KFM) as well as individual muscle moment and work during the stance phase of gait across nine unimpaired subjects. Across all subjects, KFM was estimated with 0.91 %BW•H RMSE and strong correlations (r = 0.87) compared to ground truth inverse dynamics analysis. Estimates of individual muscle moments were strongly correlated (r = 0.81-0.99) with a reference EMG-driven technique using optical motion capture and a full set of electrodes as were estimates of muscle work (r = 0.88-0.99). Implementation of the proposed technique in the current work included instrumenting only three muscles with surface electrodes (lateral and medial gastrocnemius and vastus medialis) and both the thigh and shank segments with inertial sensors. These sensor locations permit instrumentation of a knee brace/sleeve facilitating a practically deployable mechanism for monitoring muscle and joint mechanics with performance comparable to the current state-of-the-art.
A Co-Fractionation Mass Spectrometry-based Prediction of Protein Complex Assemblies in the Developing Rice Aleurone-subaleurone
Authors: Lee Youngwoo , Okita Thomas W. , Szymanski Daniel B.
Published: June 2021

Multiprotein complexes execute and coordinate diverse cellular processes such as organelle biogenesis, vesicle trafficking, cell signaling, and metabolism. Knowledge about their composition and localization provides useful clues about the mechanisms of cellular homeostasis and systems-level control. This is of great biological importance and practical significance in heterotrophic rice endosperm and aleurone-subaleurone tissues that are a primary source of seed vitamins and stored energy. Dozens of protein complexes have been implicated in the synthesis, transport, and storage of seed proteins, lipids, vitamins, and minerals. Mutations in protein complexes that control RNA transport result in aberrant endosperm with shrunken and floury phenotypes, significantly reducing seed yield and quality. The purpose of this research is to broadly predict protein complex composition in the aleurone-subaleurone layers of developing rice seeds using co-fractionation mass spectrometry. Following orthogonal chromatographic separations of biological replicates, thousands of protein elution profiles were subjected to distance-based clustering to enable a large-scale determination of multimerization state and complex composition. Predictions included evolutionarily conserved proteins across diverse functional categories, including novel heteromeric RNA binding protein complexes that influence seed quality. This effective and open-ended proteomics pipeline provides useful clues about systems-level controls in the early stage of rice seed development.

One-sentence summary

A co-fractionation mass spectrometry pipeline predicts compositions of cytosolic protein complexes present in the early stages of rice seed development.
Metabolic model of nitrogen-fixing obligate aerobe Azotobacter vinelandii demonstrates adaptation to oxygen concentration and metal availability
Authors: Alleman Alexander B. , Mus Florence , Peters John W.
Published: June 2021

There is considerable interest in promoting biological nitrogen fixation as a mechanism to reduce the inputs of nitrogenous fertilizers in agriculture, a problem of agronomic, economic, and environmental importance. For the potential impact of biological nitrogen fixation in agriculture to be realized, there are considerable fundamental knowledge gaps that need to be addressed. Biological nitrogen fixation or the reduction of N2 to NH3 is catalyzed by nitrogenase which requires a large amount of energy in the form of ATP and low potential electrons. Nitrogen-fixing organisms that respire aerobically have an advantage in meeting the energy demands of biological nitrogen fixation but face challenges of protecting nitrogenase from inactivation in the presence of oxygen. Here, we have constructed a genome-scale metabolic model of the aerobic metabolism of nitrogen-fixing bacteria Azotobacter vinelandii, which uses a complex electron transport system, termed respiratory protection, to consume oxygen at a high rate keeping intracellular conditions microaerobic. Our model accurately determines growth rate under high oxygen and high substrate concentration conditions, demonstrating the large flux of energy directed to respiratory protection. While respiratory protection mechanisms compensate the energy balance in high oxygen conditions, it does not account for all substrate intake, leading to increased maintenance rates. We have also shown how A. vinelandii can adapt under different oxygen concentrations and metal availability by rearranging flux through the electron transport system. Accurately determining the energy balance in a genome-scale metabolic model is required for future engineering approaches.

Importance

The world’s dependence on industrially produced nitrogenous fertilizers has created a dichotomy of issues. Some parts of the globe lack access to fertilizers and associated poor crop yields, significantly limiting nutrition, contributing to disease and starvation. In contrast, in other parts of the world, abundant nitrogenous fertilizers and associated overuse result in compromised soil quality and downstream environmental issues. There is considerable interest in expanding the impacts of biological nitrogen fixation to promote improved crop yields in places struggling with access to industrial fertilizers and reducing fertilizers’ inputs in areas where overuse is resulting in the degradation of soil health and other environmental problems. A more robust and fundamental understanding of biological nitrogen fixation’s biochemistry and microbial physiology will enable strategies to promote new and more robust associations between nitrogen-fixing microorganisms and crop plants.
Land-use change from food to energy: meta-analysis unravels effects of bioenergy on biodiversity and amenity
Authors: Donnison Caspar , Holland Robert A. , Harris Zoe M. , Eigenbrod Felix , Taylor Gail
Published: June 2021

Most decarbonization scenarios of energy systems necessitate more than 500 Mha of land converted to non-food bioenergy crops to provide both energy substitutes for fossil fuels and negative emissions through bioenergy with carbon capture and storage (BECCS). Understanding the environmental and societal impact of this significant land-use change (LUC) is important in determining where and how bioenergy crops should be deployed, and the trade-offs and co-benefits to the environment and society. Here, we use two systematic reviews and a meta-analysis to assess the existing literature on impacts that are likely to have an important effect on public perceptions of the acceptability of such land use change: biodiversity and amenity value. We focus on the impact of LUC to non-food bioenergy crops on agricultural landscapes, where large-scale bioenergy planting may be required. Our meta-analysis finds strong benefits for biodiversity overall (up 75 % ± 13 %), with particular benefits for bird abundance (+ 81 % ± 32 %), bird species richness (+ 100 % ± 31 %), arthropod abundance (+ 52 % ± 36 %), microbial biomass (+ 77 % ± 24 %), and plant species richness (+ 25 % ± 22 %), when land moves out of either arable crops or grassland to bioenergy production. Conversions from arable land to energy trees led to particularly strong benefits, providing an insight into how future LUC to bioenergy crops could support biodiversity. There were inadequate data to complete a meta-analysis on the effects of bioenergy crops on landscape amenity value, and few generalizable conclusions from a systematic review of the literature, however, findings highlight the importance of landscape context and planting strategies in determining amenity values. Our findings demonstrate improved farm-scale biodiversity on agricultural land with bioenergy crops, but also limited knowledge concerning public response to this land use change which could prove crucial to the effective deployment of bioenergy crops for BECCS.
A Remarkable Genetic Shift in a Transmitted/Founder Virus Broadens Antibody Responses Against HIV-1
Authors: Jain Swati , Uritskiy Gherman , Mahalingam Marthandan , Batra Himanshu , Chand Subhash , Trinh Hung V. , Beck Charles , Shin Woong-Hee , AlSalmi Wadad , Kijak Gustavo , Eller Leigh A. , Kim Jerome , Kihara Daisuke , Tovanabutra Sodsai , Ferrari Guido , Robb Merlin L. , Rao Mangala , Rao Venigalla B.
Published: June 2021

A productive HIV-1 infection in humans is often established by transmission and propagation of a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective HIV-1 vaccine should elicit broad immune responses in order to block the entry of diverse T/F viruses. Currently, no such vaccine exists. An in-depth study of escape variants emerging under host immune pressure during very early stages of infection might provide insights into such a HIV-1 vaccine design. Here, in a rare longitudinal study involving HIV-1 infected individuals just days after infection in the absence of antiretroviral therapy, we discovered a remarkable genetic shift that resulted in near complete disappearance of the original T/F virus and appearance of a variant with H173Y mutation in the variable V2 domain of the HIV-1 envelope protein. This coincided with the disappearance of the first wave of strictly H173-specific antibodies and emergence of a second wave of Y173-specific antibodies with increased breadth. Structural analyses indicated conformational dynamism of the envelope protein which likely allowed selection of escape variants with a conformational switch in the V2 domain from an α-helix (H173) to a β-strand (Y173) and induction of broadly reactive antibody responses. This differential breadth due to a single mutational change was also recapitulated in a mouse model. Rationally designed combinatorial libraries containing 54 conformational variants of V2 domain around position 173 further demonstrated increased breadth of antibody responses elicited to diverse HIV-1 envelope proteins. These results offer new insights into designing broadly effective HIV-1 vaccines.
Age-related decline of the unfolded protein response in the heart promotes protein misfolding and cardiac pathology
Authors: Hofmann Christoph , Blackwood Erik A. , Jakobi Tobias , Sandmann Clara , Groß Julia , Herzog Nicole , Kaufman Randal J. , Katus Hugo A. , Völkers Mirko , Glembotski Christopher C. , Doroudgar Shirin
Published: June 2021

Cardiac myocyte death during heart failure is particularly detrimental, given that cardiac muscle exhibits limited regenerative potential. Protein aggregation was previously observed in end-stage heart failure, suggesting protein-misfolding in cardiac myocytes as a contributor to the disease process. However, the relationship between protein-misfolding, cardiac myocyte death, and myocardial dysfunction is yet to be clearly established. Here, we showed that protein synthesis and the unfolded protein response (UPR) declined as a function of mammalian postnatal development, especially in tissues with low mitotic activity, such as the heart. A deeper examination in animals models showed that compared to neonatal cardiac myocytes, adult cardiac myocytes expressed lower levels of the adaptive UPR transcription factor, ATF6, as well as lower levels of numerous ATF6-regulated genes, which was associated with susceptibility to ER stress-induced cell death. Further reduction of the ATF6-dependent gene program in ATF6 knock-out mice led to the accumulation of misfolded proteins in the myocardium and impaired myocardial function in response to cardiac stress, indicating that ATF6 plays a critical adaptive role in the setting of cardiac disease. Thus, strategies to increase ATF6 aimed at balancing proteostasis in cardiac myocytes might be a fruitful avenue for the development of novel therapies for heart disease and other age-associated diseases.

Highlights

The unfolded protein response (UPR) declines as a function of age in adult mammalian tissues with low mitotic activity, such as the heart

Decreases in the UPR in adult cardiac myocytes is associated with impaired survival during ER stress

ATF6 loss of function in adult hearts increases protein misfolding and cardiac disfunction during stress
HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160
Authors: Liu Weifeng , Chou Ting-Fang , Garrett-Thomson Sarah C. , Seo Goo-Young , Fedorov Elena , Ramagopal Udupi A. , Bonanno Jeffrey B. , Kakugawa Kiyokazu , Cheroutre Hilde , Kronenberg Mitchell , Almo Steven C.
Published: June 2021

HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM:LIGHT:CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knock-in mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.
Reduced light access promotes hypocotyl growth via autophagy-mediated recycling
Authors: Ince Yetkin Çaka , Fiorucci Anne Sophie , Trevisan Martine , Galvão Vinicius Costa , Krahmer Johanna , Wigger Leonore , Pradervand Sylvain , Fouillen Laeticia , Delft Pierre Van , Mongrand Sebastien , Gallart-Ayala Hector , Ivanisevic Julijana , Fankhauser Christian
Published: June 2021

Plant growth ultimately depends on fixed carbon, thus the available light for photosynthesis. Due to canopy light absorption properties, vegetative shade combines reduced light and a low red to far-red ratio (LRFR). In shade-avoiding plants, these two conditions independently promote growth adaptations to enhance light access. However, how these conditions, differing in photosynthetically-available light, similarly promote growth remains unknown. Here, we show that Arabidopsis seedlings adjust metabolism according to light conditions to supply resources for hypocotyl growth enhancement. Transcriptome analyses indicate that reduced light induces starvation responses, suggesting a switch to a catabolic state to promote growth. Accordingly, reduced light promotes autophagy. In contrast, LRFR promotes anabolism including biosynthesis of plasma-membrane sterols downstream of PHYTOCHROME-INTERACTING FACTORs (PIFs) acting in hypocotyls. Furthermore, sterol biosynthesis and autophagy are indispensable for shade-induced hypocotyl growth. We conclude that vegetative shade enhances hypocotyl growth by combining autophagy-mediated recycling and promotion of specific anabolic processes.

HIGHLIGHTS

Reduced light and LRFR induce catabolism and anabolism, respectively

Reduced light promotes autophagy to enhance hypocotyl growth in vegetative shade

LRFR enhances hypocotyl growth by promoting plasma membrane lipid biosynthesis

In LRFR, PIFs promote sterol biosynthesis specifically in the hypocotyl
GBS-SBG - GBS Serotyping by Genome Sequencing
Authors: Tiruvayipati Suma , Ying Tan Wen , Barkham Timothy , Chen Swaine L.
Published: June 2021

Group B Streptococcus agalactiae (GBS; Streptococcus agalactiae) is the most common cause of neonatal meningitis and a rising cause of sepsis in adults. Recently, it has also been shown to cause foodborne disease. As with many other bacteria, the polysaccharide capsule of GBS is antigenic, enabling its use for strain serotyping. Recent advances in DNA sequencing have made sequence-based typing attractive (as has been implemented for several other bacteria, including Escherichia coli, Klebsiella pneumoniae species complex, Streptococcus pyogenes, and others). For GBS, existing WGS-based serotyping systems do not provide complete coverage of all known GBS serotypes (specifically including subtypes of serotype III), and none are simultaneously compatible with the two most common data types, raw short reads and assembled sequences. Here, we create a serotyping database (GBS-SBG, GBS Serotyping by Genome Sequencing), with associated scripts and running instructions, that can be used to call all currently described GBS serotypes, including subtypes of serotype III, using both direct short-read- and assembly-based typing. We achieved higher concordance using GBS-SBG on a previously reported data set of 790 strains. We further validated GBS-SBG on a new set of 572 strains, achieving 99.8% concordance with PCR-based molecular serotyping using either short-read- or assembly-based typing. The GBS-SBG package is publicly available and will accelerate and simplify serotyping by sequencing for GBS.

DATA SUMMARY

The GBS-SBG package is open source and available for at Github under the MIT license (URL - https://github.com/swainechen/GBS-SBG)

Accession numbers of the sequencing reads and reference sequences used in the study from earlier reports have been provided within the article and the supplementary data

The WGS data for the 572 isolates used in the study is available at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA293392
Long-term quality assessment and monitoring of light microscope performance through accessible and reliable protocols, tools and metrics
Authors: Faklaris Orestis , Bancel-Vallée Leslie , Dauphin Aurélien , Monterroso Baptiste , Frère Perrine , Geny David , Manoliu Tudor , de Rossi Sylvain , Cordelières Fabrice P. , Schapman Damien , Nitschke Roland , Cau Julien , Guilbert Thomas
Published: June 2021

Reliable, reproducible and comparable results are what biology requires from microscopy. To achieve that level of confidence, monitoring the stability of the microscope performance over time with standardized quality testing routines is essential for mining quantitative data. Three levels of microscope quality control procedures should be considered: i) usage of accessible and affordable tools and samples, ii) execution of easy and fast, preferably automatized, acquisition protocols, iii) analysis of data in the most automated way possible with adequate metrics for long-term monitoring. In this paper, we test the acquisition protocols on the mainly used microscope techniques (wide-field, spinning disk and confocal microscopy) with simple quality control tools. Seven protocols specify metrics on measuring the lateral and axial resolution (Point-Spread Function) of the system, field flatness, chromatic aberrations and co-registration, illumination power monitoring and stability, stage drift and positioning repeatability and finally temporal and spatial noise sources of camera detectors. We designed an ImageJ/FiJi java plugin named MetroloJ_QC to incorporate the identified metrics and automatize the data processing for the analysis. After processing and comparing the data of microscopes from more than ten imaging facilities, we test the robustness of the metrics and the protocols by determining experimental limit values. Our results give a first extensive characterization of the quality control procedures of a light microscope, with an automated data processing and experimental limit values that can be used by core facility staff and researchers to monitor the microscope performance over time.
Ceylon cinnamon and its major compound Cinnamaldehyde can limit overshooting inflammatory signaling and angiogenesisin vitro: implications for COVID-19 treatment
Authors: Lucas Kurt , Ackermann Maximilian , Leifke Anna Lena , Li William W. , Pöschl Ulrich , Fröhlich-Nowoisky Janine
Published: June 2021

Overshooting immune reactions can occur during inflammatory responses that accompany severe infections, such as COVID-19. Cytokines, damage-associated molecular patterns (DAMPs), and reactive oxygen and nitrogen species can generate positive feedback loops of inflammation, leading to long-term complications such as vascular endothelialitis, thrombosis, endothelial dysfunction, neurological impairments, and chronic fatigue. Dexamethasone can limit inflammation by inhibiting the activation of pro-inflammatory transcription factors. High dose dexamethasone, however, has undesirable side effects. Here, we show that Ceylon cinnamon and its major compound cinnamaldehyde can mitigate inflammatory signalingin vitro. Cinnamaldehyde interferes with the dimerization of toll-like receptor 4 (TLR4), which can be activated by DAMPs like HSP60 and HMGB1. Our results suggest that supplementary treatment with Ceylon cinnamon may allow administration of lower doses of dexamethasone to avoid high dose steroid side effects. Moreover, preliminary results indicate that Ceylon cinnamon modulates angiogenesis, which is a reactive phenomenon in COVID-19.
Maturation of persistent and hyperpolarization-activated inward currents shapes the differential activation of motoneuron subtypes during postnatal development
Authors: Sharples Simon A. , Miles Gareth B.
Published: June 2021

The size principle underlies the orderly recruitment of motor units; however, motoneuron size is a poor predictor of recruitment amongst functionally defined motoneuron subtypes. Whilst intrinsic properties are key regulators of motoneuron recruitment, the underlying currents involved are not well defined. Whole-cell patch-clamp electrophysiology was deployed to study intrinsic properties, and the underlying currents, that contribute to the differential activation of delayed and immediate firing motoneuron subtypes. Motoneurons were studied during the first three postnatal weeks in mice to identify key properties that contribute to rheobase and may be important to establish orderly recruitment. We find that delayed and immediate firing motoneurons are functionally homogeneous during the first postnatal week and are activated based on size, irrespective of subtype. The rheobase of motoneuron subtypes become staggered during the second postnatal week, which coincides with the differential maturation of passive and active properties, particularly persistent inward currents. Rheobase of delayed firing motoneurons increases further in the third postnatal week due to the development of a prominent resting hyperpolarization-activated inward current. Our results suggest that motoneuron recruitment is multifactorial, with recruitment order established during postnatal development through the differential maturation of passive properties and sequential integration of persistent and hyperpolarization-activated inward currents.

Impact Statement

Electrophysiological recordings from mouse spinal motoneurons reveal key roles for ion channels in establishing the differential activation of motoneuron subtypes during postnatal development.
The role of epistasis in determining the fitness landscape of HIV proteins
Authors: Biswas Avik , Haldane Allan , Levy Ronald M
Published: June 2021

The rapid evolution of HIV is constrained by interactions between mutations which affect viral fitness. In this work, we explore the role of epistasis in determining the fitness landscape of HIV for multiple drug target proteins, including Protease, Reverse Transcriptase, and Integrase. Epistatic interactions between residues modulate the mutation patterns involved in drug resistance with unambiguous signatures of epistasis best seen in the comparison of a maximum entropy sequence co-variation (Potts) model predicted and experimental HIV sequence “prevalences” when expressed as higher-order marginals (beyond triplets) of the sequence probability distribution. In contrast, the evidence for epistasis based on experimental measures of fitness such as replicative capacity is weak; the correspondence with Potts model “prevalence”-based predictions is obscured by site conservation and limited precision. Double mutant cycles provide in principle one of the best ways to probe epistatic interactions experimentally without reference to a particular background, and we find they reveal that the most strongly interacting mutations in HIV involve correlated sets of drug-resistance-associated residues, however the analysis is complicated by the small dynamic range of measurements. The use of correlated models for the design of experiments to probe viral fitness can help identify the epistatic interactions involved in mutational escape, and lead to better inhibitor therapies.

Author summary

Protein covariation models provide an alternative to experimental measures for estimating the fitness of mutations in proteins from across a variety of organisms. Yet, for viral proteins, it has been shown that models including epistatic couplings between residues, or other machine learning models perform no better or even worse than a simpler independent model devoid of such epistatic couplings in estimating viral fitness measurements such as replicative capacities, providing weak or ambiguous evidence for epistasis. We show that the evidence for long-range epistasis is strong by the analysis of the high-order marginals of the MSA distribution (up to subsequences of length 14), which are accurately captured by a correlated Potts sequence-covariation model but not by an independent model. While double mutant cycles in principle provide well-established biophysical probes for epistatic interactions, we demonstrate that the analysis and comparison between model and experiment is difficult due to the much smaller dynamic range of the measurements, making them more susceptible to noise.
Amyloid-β, p-tau, and reactive microglia load are correlates of MRI cortical atrophy in Alzheimer’s disease
Authors: Frigerio Irene , Boon Baayla DC , Lin Chen-Pei , Graaf Yvon Galis-de , Bol John GJM , Preziosa Paolo , Twisk Jos , Barkhof Frederik , Hoozemans Jeroen JM , Bouwman Femke H , Rozemuller Annemieke JM , van de Berg Wilma DJ , Jonkman Laura E
Published: June 2021

INTRODUCTION

The aim of this study was to identify the histopathological correlates of MRI cortical atrophy in (a)typical Alzheimer’s disease (AD) donors.

METHODS

19 AD and 10 control donors underwent post-mortem in-situ 3T-3DT1-MRI, from which cortical thickness was calculated. Upon subsequent autopsy, 21 cortical brain regions were selected and immunostained for amyloid-beta, phosphorylated-tau, and reactive microglia. MRI-pathology associations were assessed using linear mixed models. Post-mortem MRI was compared to ante-mortem MRI when available.

RESULTS

Higher amyloid-beta load weakly correlated with a higher cortical thickness globally. Phosphorylated-tau strongly correlated with cortical atrophy in temporo-frontal regions. Reactive microglia load strongly correlated with cortical atrophy in the parietal region. Post-mortem scans showed high concordance with ante-mortem scans acquired <1 year before death.

DISCUSSION

Distinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegenerative process. This study contributes in understanding the pathological underpinnings of MRI atrophy patterns.
EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
Authors: Mazevet Marianne , Belhadef Anissa , Ribeiro Maxance , Dayde Delphine , Llach Anna , Laudette Marion , Belleville Tiphaine , Mateo Philippe , Gressette Mélanie , Lefebvre Florence , Chen Ju , Bachelot-Loza Christilla , Rucker-Martin Catherine , Lezoualc’h Frank , Crozatier Bertrand , Benitah Jean-Pierre , Vozenin Marie-Catherine , Fischmeister Rodolphe , Gomez Ana-Maria , Lemaire Christophe , Morel Eric
Published: June 2021

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administeredin vivo, Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 KO mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.
Reactive Astrocytes Prevent Maladaptive Plasticity after Ischemic Stroke
Authors: Aswendt Markus , Wilhelmsson Ulrika , Wieters Frederique , Stokowska Anna , Schmitt Felix Johannes , Pallast Niklas , de Pablo Yolanda , Mohammed Lava , Hoehn Mathias , Pekna Marcela , Pekny Milos
Published: June 2021

Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP−/−Vim−/−). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted MRI and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP−/−Vim−/− mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes are required for optimal recovery-promoting plasticity responses after ischemic stroke.
Tuning the immunostimulation properties of cationic lipid nanocarriers for nucleic acid delivery
Authors: Dey Arindam K , Nougarede Adrien , Clément Flora , Fournier Carole , Jouvin-Marche Evelyne , Escudé Marie , Jary Dorothée , Navarro Fabrice P. , Marche Patrice N
Published: June 2021

Nonviral systems, such as lipid nanoparticles, have emerged as reliable methods to enable nucleic acid intracellular delivery. The use of cationic lipids in various formulations of lipid nanoparticles enables the formation of complexes with nucleic acid cargo and facilitates their uptake by target cells. However, due to their small size and highly charged nature, these nanocarrier systems can interact in vivo with antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. As this might prove to be a safety concern for developing therapies based on lipid nanocarriers, we sought to understand how they could affect the physiology of APCs. In the present study, we investigate the cellular and metabolic response of primary macrophages or DCs exposed to the neutral or cationic variant of the same lipid nanoparticle formulation. We demonstrate that macrophages are the cells affected most significantly and that the cationic nanocarrier has a substantial impact on their physiology, depending on the positive surface charge. Our study provides a first model explaining the impact of charged lipid materials on immune cells and demonstrates that the primary adverse effects observed can be prevented by fine-tuning the load of nucleic acid cargo. Finally, we bring rationale to calibrate the nucleic acid load of cationic lipid nanocarriers depending on whether immunostimulation is desirable with the intended therapeutic application, for instance, gene delivery or messenger RNA vaccines.
Thalamocortical axons regulate neurogenesis and laminar fates in early sensory cortex
Authors: Monko Timothy , Rebertus Jaclyn , Stolley Jeff , Salton Stephen R. , Nakagawa Yasushi
Published: June 2021

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons increase the number of layer 4 neurons in primary sensory areas by enhancing neurogenesis and shifting the fate of superficial layer neurons to that of layer 4 by the neonatal stage. Part of these area-specific roles is played by the thalamus-derived molecule, VGF. Our work reveals that extrinsic cues from sensory thalamic projections have an early role in the formation of cortical cytoarchitecture by enhancing the production and specification of layer 4 neurons.
TheGossypium anomalumgenome as a resource for cotton improvement and evolutionary analysis of hybrid incompatibility
Authors: Grover Corrinne E. , Yuan Daojun , Arick Mark A. , Miller Emma R. , Hu Guanjing , Peterson Daniel G. , Wendel Jonathan F. , Udall Joshua A.
Published: June 2021

Cotton is an important crop that has been the beneficiary of multiple genome sequencing efforts, including diverse representatives of wild species for germplasm development.Gossypium anomalumis a wild African diploid species that harbors stress-resistance and fiber-related traits with potential application to modern breeding efforts. In addition, this species is a natural source of cytoplasmic male sterility and a resource for understanding hybrid lethality in the genus. Here we report a high-qualityde novogenome assembly forG. anomalumand characterize this genome relative to existing genome sequences in cotton. In addition, we use the synthetic allopolyploids 2(A2D1) and 2(A2D3) to discover regions in theG. anomalumgenome potentially involved in hybrid lethality, a possibility enabled by introgression of regions homologous to the D3 (G. davidsonii) lethality loci into the synthetic 2(A2D3) allopolyploid.
Blm Helicase Facilitates Rapid Replication of Repetitive DNA Sequences in earlyDrosophilaDevelopment
Authors: Ruchert Jolee M. , Brady Morgan M , McMahan Susan , Lacey Karly J. , Latta Leigh C. , Sekelsky Jeff , Stoffregen Eric P.
Published: June 2021

The absence of functional BLM DNA helicase, a member of the RecQ family of helicases, is responsible for the rare human disorder Bloom Syndrome, which results in developmental abnormalities, DNA repair defects, genomic instability, and a predisposition to cancer. InDrosophila melanogaster, the orthologous Blm protein is essential during early development when the embryo is under the control of maternal gene products. We show that lack of functional maternal Blm during the syncytial cell cycles ofDrosophilaembryonic development results in severe nuclear defects and lethality. Amongst the small fraction of embryos fromBlmmutant mothers that survive to adulthood, a prominent sex-bias favors the class that inherits less repetitive DNA content, which serves as an endogenous source of replication stress. This selection against repetitive DNA content reflects a role for Blm in facilitating replication through repetitive sequences during the rapid S-phases of syncytial cell cycles. During these syncytial cycles, Blm is not required for complex DNA double-strand break repair; however, the progeny sex-bias resulting from the absence of maternal Blm is exacerbated by repetitive DNA sequences and by the slowing of replication fork progression, suggesting that the essential role for Blm during this stage is to manage replication fork stress brought about by impediments to fork progression. Additionally, our data suggest that Blm is only required to manage this replication stress during embryonic development, and likely only during the early, rapid syncytial cell cycles, and not at later developmental stages. These results provide novel insights into Blm function throughout development.
Rhes Deletion Prevents Age-Dependent Selective Motor Deficits and Reduces Phosphorylation of S6K in Huntington Disease Hdh150Q(CAG) Knock-In Mice
Authors: Hernandez Jennifer , Shahani Neelam , Swarnkar Supriya , Subramaniam Srinivasa
Published: June 2021

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (mHTT) protein. This expansion is thought to promote striatal atrophy by a combination of cell- and non-cell-autonomous processes, but the mechanisms are unclear. Previous evidence suggests that the striatal-enriched SUMO E3-like protein Rhes could play a pathological role in HD. Rhes interacts with, and SUMOylates, mHTT and promotes toxicity and Rhes deletion ameliorates the HD phenotype in cell and severe mouse models of HD. However, the effect of Rhes on less severe knock-in models of HD remains obscure. Here, we report that a Hdh(CAG)150 knock-in murine model of HD showed diminished body weight but no changes in locomotor coordination or activity at 80 and 100 weeks of age. Conversely, Rhes deletion did not impact the body weight or behaviors but caused a significant reduction of gait, clasping, and tremor behaviors in Hdh150Q/150Q mice. Rhes deletion did not affect the loss of striatal DARPP-32 protein levels but abrogated the hyper ribosomal protein S6 kinase beta-1 (S6K) phosphorylation, which is a substrate for a mechanistic target of rapamycin complex 1 (mTORC1) signaling, in Hdh(CAG)150 mice. Interestingly, striatal Rhes protein levels were downregulated in the striatum of Hdh(CAG)150 mice, indicating a potential compensatory mechanisms at work. Thus, Rhes deletion prevents age-dependent behavioral deficits and diminishes hyperactive mTORC1-S6K signaling in Hdh(CAG)150 knock-in mice HD striatum.
Inflammation and Cellular Stress Induced Neurological Sequelae ofPlasmodium falciparumMalaria
Authors: Karikari Akua A. , Wruck Wasco , Adjaye James
Published: June 2021

Background

Malaria caused byPlasmodium falciparumresults in severe complications including cerebral malaria (CM) especially in children. While the majority offalciparummalaria survivors make a full recovery, there are reports of some patients ending up with neurological sequelae.

Methods

We performed an analysis of pooled transcriptome data of whole blood samples derived from two studies involving variousPlasmodium falciparuminfections, comprising mild malaria (MM), non-cerebral severe malaria (NCM) and CM. Pathways and gene ontologies (GOs) elevated in the distinctfalciparuminfections were identified.

Results

Contrary to other research findings, our analysis showed MM share similar biological processes with cancer and neurodegenerative diseases, NCM is associated with drug resistance and glutathione metabolism and CM is correlated with endocannabinoid signaling and non-alcoholic fatty liver disease (NAFLD). GO revealed the terms biogenesis, DNA damage response and IL-10 production in MM, down-regulation of cytoskeletal organization and amyloid-beta clearance in NCM and aberrant signaling, neutrophil degranulation and gene repression in CM. Differential gene expression analysis between CM and NCM showed the up-regulation of neutrophil activation and response to herbicides while regulation of axon diameter was down-regulated in CM.

Conclusions

The results of this study have demonstrated that the deleterious effect offalciparummalaria on the brain may not be limited to CM and NCM alone but also MM. However, the severity of neurological deficit in CM might be due to the down-regulation of various genes involved in cellular function through transcriptional repression, axonal dysfunction, dysregulation of signaling pathways and neurodegeneration as a result of inflammation and cellular stress. We anticipate that our data might form the basis for future hypothesis-driven malaria research.
Telomere shortening causes distinct cell division regimes during replicative senescence inSaccharomyces cerevisiae
Authors: Martin Hugo , Doumic Marie , Teixeira Maria Teresa , Xu Zhou
Published: June 2021

Background

Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known.

Results

Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states.

Conclusions

Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.
Evaluation of spontaneous seizure activity, sex-dependent differences, behavioral comorbidities, and alterations in CA1 neuron firing properties in a mouse model of Dravet Syndrome
Authors: Pernici Chelsea D. , Spink Alexa , Dahle E. Jill , Johnson Kristina J. , Metcalf Cameron S. , West Peter J. , Wilcox Karen S.
Published: June 2021

Dravet syndrome (DS) is a rare childhood epilepsy disorder resulting in spontaneous, recurrent seizures (SRS) and behavioral co-morbidities. To facilitate the discovery and development of anti-seizure drugs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has continued to evaluate a mouse model of DS. Scn1aA1783V/WT mice exhibited increased hyperactivity, thigmotaxis, and deficits in nest-building behavior. Ex-vivo brain slice electrophysiology experiments revealed increased excitability of hippocampal CA1 neurons specifically due to increased action potential firing frequency in response to brief depolarizations and decreased frequency of spontaneous GABAergic synaptic events. A video-EEG study revealed mice had on average, 1 seizure per day, with males seizing significantly more frequently than females. Increased proportion of seizure activity occurred during the dark phase of the light/dark cycle in both sexes. While clobazam, a drug commonly prescribed to patients with DS, had no effect on SRS activity at the tested doses, the seizure history and frequency observed in this study aids in determining the sample sizes and experimental timeline needed for adequately powered preclinical drug studies. Overall, this study provides a broad description of the Scn1aA1783V/WT mouse and highlights the utility of this model in therapy discovery.