bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuron-derived Thioredoxin-80: a novel regulator of type-I interferon response in microglia
Authors: Goikolea Julen , Roussarie Jean-Pierre , Gerenu Gorka , Loera-Valencia Raul , Latorre-Leal Maria , Cedazo-Minguez Angel , Rodriguez-Rodriguez Patricia , Maioli Silvia
Published: March 2022

Oxidative stress and neuroinflammation play a central role in Alzheimer’s Disease (AD) pathogenesis. However, the mechanism by which these processes lead to neurodegeneration is still not fully understood. Thioredoxin-1 (Trx1) is an antioxidant protein that can be cleaved into a peptide known as Thioredoxin-80 (Trx80), which modulates monocyte function in the periphery and shows anti-amyloidogenic properties in the brain. In this study we aimed to further clarify the biological function of this peptide and its regulation in the brain. We show that neurons are the main producers of Trx80 in the brain. Trx80 levels increase in vivo both in normal aging and in young APPNL-G-F mouse model of amyloid pathology. Trx80 levels were increased in neurons in primary culture treated with either rotenone or 27-hydroxycholesterol, what suggests that Trx80 production is stimulated upon oxidative stress. RNA-sequencing followed by differential gene expression analysis revealed that Trx80 induces microglia activation into a phenotype compatible with interferon response microglia. Finally, we determine that the induction of this microglia phenotype by Trx80 is Trem2-dependent. This study identifies Trx80 as a novel neuron-derived signaling mechanism that modulates microglia function under stress conditions. Strategies to regulate Trx80 levels could be beneficial against AD pathology.
PCA outperforms popular hidden variable inference methods for molecular QTL mapping
Authors: Zhou Heather J. , Li Lei , Li Yumei , Li Wei , Li Jingyi Jessica
Published: March 2022

Estimating and accounting for hidden variables is widely practiced as an important step in molecular quantitative trait locus (molecular QTL, henceforth “QTL”) analysis for improving the power of QTL identification. However, few benchmark studies have been performed to evaluate the efficacy of the various methods developed for this purpose. Here we benchmark popular hidden variable inference methods including surrogate variable analysis (SVA), probabilistic estimation of expression residuals (PEER), and hidden covariates with prior (HCP) against principal component analysis (PCA)—a well-established dimension reduction and factor discovery method—via 362 synthetic and 110 real data sets. We show that PCA not only underlies the statistical methodology behind the popular methods but is also orders of magnitude faster, better-performing, and much easier to interpret and use. To help researchers use PCA in their QTL analysis, we provide an R packagePCAForQTLalong with a detailed guide, both of which are freely available athttps://github.com/heatherjzhou/PCAForQTL.
Improved eukaryotic detection compatible with large-scale automated analysis of metagenomes
Authors: Bazant Wojtek , Blevins Ann S. , Crouch Kathryn , Beiting Daniel P.
Published: March 2022

Background

Eukaryotes such as fungi and protists frequently accompany bacteria and archaea in microbial communities. Unfortunately, their presence is difficult to study with ‘shotgun’ metagenomic sequencing since prokaryotic signals dominate in most environments. Recent methods for eukaryotic detection use eukaryote-specific marker genes, but they do not incorporate strategies to handle the presence of eukaryotes that are not represented in the reference marker gene set, and they are not compatible with web-based tools for downstream analysis.

Results

Here we present CORRAL (for Clustering□Of□Related Reference ALignments), a tool for identification of eukaryotes in shotgun metagenomic data based on alignments to eukaryote-specific marker genes and Markov clustering. Using a combination of simulated datasets, mock community standards, and large publicly available human microbiome studies, we demonstrate that our method is not only sensitive and accurate but is also capable of inferring the presence of eukaryotes notincluded in the marker gene reference, such as novel strains. Finally, we deploy CORRAL on ourMicrobiomeDB.orgresource, producing an atlas of eukaryotes present in various environments of the human body and linking their presence to study covariates.

Conclusions

CORRAL allows eukaryotic detection to be automated and carried out at scale. Implementation of CORRAL inMicrobiomeDB.orgcreates a running atlas of microbial eukaryotes in metagenomic studies. Since our approach is independent of the reference used, it may be applicable to other contexts where shotgun metagenomic reads are matched against redundant but non-exhaustive databases, such as identification of bacterial virulence genes or taxonomic classification of viral reads.
Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain
Authors: Zhou Yu-Peng , Sun Yang , Takahashi Kazue , Belov Vasily , Andrews Nick , Woolf Clifford J. , Brugarolas Pedro
Published: March 2022

Neuropathic pain affects 7-10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of α2δ-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in α2δ-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two 18F-labeled derivatives of gabapentin (trans-4-[18F]fluorogabapentin and cis-4-[18F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the α2δ-1 receptor with trans-4-[18F]fluorogabapentin having a higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to α2δ-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that α2δ-1 is a promising target for imaging specific features of neuropathic pain.
The vigor paradox: saccade velocity during deliberation encodes utility of effortful actions
Authors: Korbisch Colin C. , Apuan Daniel R. , Shadmehr Reza , Ahmed Alaa A.
Published: March 2022

During deliberation, as the brain considers its options, the neural activity representing the goodness of each option rises toward a threshold, and the choice is often dictated by the option for which the rise is fastest. Here we report a surprising correlate of these activities: saccade vigor. We engaged human subjects in a decision-making task in which they considered effortful options, each requiring walking various durations and inclines. As they deliberated, they made saccades between the symbolic representations of those options. These saccades had no bearing on the effort that they would later expend, yet as they deliberated, saccade velocities increased. The rate of rise in vigor was faster for saccades toward the option that they later indicated as their choice, and encoded the difference in the subjective value of the two effortful options. Once deliberation ended, following a brief delay the subjects indicated their choice by making another saccade. Remarkably, vigor for this saccade dropped to baseline and no longer encoded subjective value. These results are consistent with an urgency model of decision-making in which a global signal in the brain drives both the neural circuits that make decisions, and the neural circuits that make movements. Paradoxically, this common drive is shared between the oculomotor circuits and the decision-making circuits, even when the decision involves effortful expenditure during a future event.

Significance

There is a link between the decisions we make and the movements that follow. Not only do we prefer options of greater value, but we also move faster to acquire them. When deliberating between options, neural activity rises to a threshold and the option that wins this race is the one chosen. We report a potential correlate of this in the motor control circuits; during deliberation, saccade vigor to both options rise, but faster for the option ultimately chosen. Thus, our movements appear to mirror the neural activity conducting the decision-making process. Paradoxically, this is true even when the movements have no direct bearing on the decision at hand.
NLGC: Network Localized Granger Causality with Application to MEG Directional Functional Connectivity Analysis
Authors: Soleimani Behrad , Das Proloy , Karunathilake I.M. Dushyanthi , Kuchinsky Stefanie E. , Simon Jonathan Z. , Babadi Behtash
Published: March 2022

Identifying the directed connectivity that underlie networked activity between different cortical areas is critical for understanding the neural mechanisms behind sensory processing. Granger causality (GC) is widely used for this purpose in functional magnetic resonance imaging analysis, but there the temporal resolution is low, making it difficult to capture the millisecond-scale interactions underlying sensory processing. Magnetoencephalography (MEG) has millisecond resolution, but only provides low-dimensional sensor-level linear mixtures of neural sources, which makes GC inference challenging. Conventional methods proceed in two stages: First, cortical sources are estimated from MEG using a source localization technique, followed by GC inference among the estimated sources. However, the spatiotemporal biases in estimating sources propagate into the subsequent GC analysis stage, may result in both false alarms and missing true GC links. Here, we introduce the Network Localized Granger Causality (NLGC) inference paradigm, which models the source dynamics as latent sparse multivariate autoregressive processes and estimates their parameters directly from the MEG measurements, integrated with source localization, and employs the resulting parameter estimates to produce a precise statistical characterization of the detected GC links. We offer several theoretical and algorithmic innovations within NLGC and further examine its utility via comprehensive simulations and application to MEG data from an auditory task involving tone processing from both younger and older participants. Our simulation studies reveal that NLGC is markedly robust with respect to model mismatch, network size, and low signal-to-noise ratio, whereas the conventional two-stage methods result in high false alarms and mis-detections. We also demonstrate the advantages of NLGC in revealing the cortical network-level characterization of neural activity during tone processing and resting state by delineating task- and age-related connectivity changes.
Electroencephalographic dynamics of rhythmic breath-based meditation
Authors: Tripathi Vaibhav , Bhasker Lakshmi , Kharya Chhaya , Bhatia Manvir , Kochupillai Vinod
Published: March 2022

Meditation has been practised for millennia but the neuroscientific understanding of the dynamics is still lacking. Sudarshan Kriya Yoga (SKY) is an evidence based breathing based meditation technique that utilizes rhythmic breathing to induce a deep state of relaxation and calm. Multiple studies have found benefits of the SKY technique from genetic, physiological, psychological to behaviour levels. We collected Electroencephalographic (EEG) data in 43 subjects who underwent the SKY technique and analysed the brain rhythms at different stages of the technique namely preparatory breathing (Pranayama), rhythmic breathing (Kriya) and meditation (Yoga Nidra) using newly developed methods to analyse periodic and aperiodic components. Alpha waves amplitude in the parieto-occipital region decreased as the rhythmic breathing progressed and dropped sharply during the meditation period. Theta amplitudes and peak frequency increased in the centro-frontal region during the rhythmic breathing period but were marked by sustained low theta waves during the meditation period. The delta wave amplitude was not affected by breathing but both delta band power and peak frequency increased during the meditation period in the centro-frontal region. We also saw a decrease in the 1/f aperiodic signal across the brain during the meditation period suggesting a modification of excitation-inhibition balance. We see an overall slowing down of brain oscillations from alpha to theta to delta as the meditation progressed. The paper studies in depth the transitional dynamics of the SKY technique analysing the alpha, theta, delta waves and aperiodic signals and demonstrates that each phase in a breathing based meditation has a unique electrophysiological signature.
Blockade of redox second messengers inhibits JAK/STAT and MEK/ERK signaling sensitizing FLT3-mutant acute myeloid leukemia to targeted therapies
Authors: Germon Zacary P. , Sillar Jonathan R. , Mannan Abdul , Duchatel Ryan J. , Staudt Dilana , Murray Heather C. , Findlay Izac J. , Jackson Evangeline R. , McEwen Holly P. , Douglas Alicia M. , McLachlan Tabitha , Schjenken John E. , Skerrett-Bryne David A. , Huang Honggang , Melo-Braga Marcella N. , Plank Maximilian W. , Alvaro Frank , Chamberlain Janis , Iuliis Geoff De , Aitken R. John , Nixon Brett , Wei Andrew H. , Enjeti Anoop K. , Lock Richard B. , Larsen Martin R. , Lee Heather , de Bock Charles E. , Verrills Nicole M. , Dun Matthew D.
Published: March 2022

FLT3-mutations are diagnosed in 25-30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is associated with the overproduction of reactive oxygen species (ROS), which drives genomic instability through the oxidation of DNA bases, promoting clonal evolution, treatment resistance and poor outcomes. ROS are also important second messengers, triggering cysteine oxidation in redox sensitive signaling proteins, however, the specific pathways influenced by ROS in AML remain enigmatic. Here we have surveyed the posttranslational architecture of primary AML patient samples and assessed oncogenic second messenger signaling. Signaling proteins responsible for growth and proliferation were differentially oxidized and phosphorylated between patient subtypes either harboring recuring mutation in FLT3 compared to patients expressing the wildtype-FLT3 receptor, particularly those mapping to the Src family kinases (SFKs). Patients harboring FLT3-mutations also showed increased oxidative posttranslational modifications in the GTPase Rac activated-NADPH oxidase-2 (NOX2) complex to drive autocratic ROS production. Pharmacological and molecular inhibition of NOX2 was cytotoxic specifically to FLT3-mutant AMLs, and reduced phosphorylation of the critical hematopoietic transcription factor STAT5 and MAPK/ERK to synergistically increase sensitivity to FLT3-inhibitors. NOX2 inhibition also reduced phosphorylation and cysteine oxidation of FLT3 in patient derived xenograft mouse models in vivo, highlighting an important link between oxidative stress and oncogenic signaling. Together, these data raise the promising possibility of targeting NOX2 in combination with FLT3-inhibitors to improve treatment of FLT3-mutant AML.

One Sentence Summary

FLT3-precision therapies have entered the clinic for AML however, their durability is limited. Here we identify the Rac-NOX2 complex as the major driver of redox second messenger signaling in FLT3-mutant AML. Molecular and pharmacological inhibition of NOX2 decreased FLT3, STAT5 and MEK/ERK signaling to delay leukemia progression, and synergistically combined with FLT3 inhibitors.
Cost-effectively dissecting the genetic architecture of complex wool traits in rabbits by low-coverage sequencing
Authors: Wang Dan , Xie Kerui , Wang Yanyan , Hu Jiaqing , Li Wenqiang , Zhang Qin , Ning Chao , Fan Xinzhong
Published: March 2022

Wool traits of rabbits are important in fiber production and model organism research on hair growth, while the genetic architecture remains obscure. In this study, we focused on wool characteristics in Angora rabbits, a well-known fiber breed. Balancing genotyping cost and variant detection, we proposed low-coverage whole genome sequencing (LCS) followed by genotype imputation for genotyping. Different genotype imputation strategies, sequencing coverages and sample sizes were compared, and we found by BaseVar + STITCH, genotyping reached high accuracy (>0.97) at a depth of 1.0X and a sample size > 300. Multivariate GWAS followed by conditional GWAS and confidence interval estimation of QTLs were used to reveal the genetic architecture of wool traits. Six QTLs were detected with phenotypic variation contribution ranging from 0.42% to 7.50%. Gene-level mapping implicated FGF10 associated with fiber growth and diameter, which supported previous function research on fibroblast growth factor family in other species and provided genetic information for wool rabbit breeding. We suggest LCS as a cost-effective alternative for assessing common variants. GWAS combined with LCS can excavate QTLs and fine-map genes associated with quantitative traits. This study provides a powerful analysis mentality for investigating complex traits, which lays the foundation for genomic breeding.
The maternal X chromosome impairs cognition and accelerates brain aging through epigenetic modulation in female mice
Authors: Abdulai-Saiku Samira , Gupta Shweta , Wang Dan , Moreno Arturo J. , Huang Yu , Srivastava Deepak , Panning Barbara , Dubal Dena B.
Published: March 2022

Female mammalian cells harbor two X chromosomes, one of maternal and one of paternal origin. During development, one X randomly inactivates1–4. This renders either the maternal or paternal X active, causing X mosaicism that varies among individual females, with some showing considerable or complete skew in the general female population5–7. Parent-of-X-origin can modify epigenetics via DNA methylation8, 9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in aging and disease. However, whether X skewing – or its mosaicism – alters functions in females is largely unknown. Here we tested whether skew toward the maternal X (Xm) influences key functions of the body. Among cardiac, bone, metabolic, and brain functions, Xm selectively impaired cognition in female mice throughout the lifespan. Cognitive deficits were accompanied by Xm-mediated acceleration of biologic or epigenetic aging of the female hippocampus, a key center for learning and memory. Xm showed epigenetic imprinting of several genes within hippocampal neurons, suggesting silenced cognitive loci. Thus, the maternal X chromosome impaired cognition, accelerated brain aging, and silenced genes. Understanding how the maternal X impairs brain function could lead to new understanding of female heterogeneity in cognitive heath and to X chromosome-derived pathways against cognitive deficits and brain aging.
Evaluating the “cost of generating force” hypothesis across frequency in human running and hopping
Authors: Allen Stephen P. , Beck Owen N. , Grabowski Alena M.
Published: March 2022

The volume of active muscle and duration of extensor muscle force well-explain the associated metabolic energy expenditure across body mass and speed during level-ground running and hopping. However, if these parameters fundamentally drive metabolic energy expenditure, then they should pertain to multiple modes of locomotion and provide a simple framework for relating biomechanics to metabolic energy expenditure in bouncing gaits. Therefore, we evaluated the ability of the ‘cost of generating force’ hypothesis to link biomechanics and metabolic energy expenditure during human running and hopping across step frequencies. We asked participants to run and hop at 0%, ±8% and ±15% of preferred step frequency. We calculated changes in active muscle volume, force duration, and metabolic energy expenditure. Overall, as step frequency increased, active muscle volume decreased due to postural changes via effective mechanical advantage (EMA) or duty factor. Accounting for changes in EMA and muscle volume better related to metabolic energy expenditure during running and hopping at different step frequencies than assuming a constant EMA and muscle volume. Thus, to ultimately develop muscle mechanics models that can explain metabolic energy expenditure across different modes of locomotion, we suggest more precise measures of muscle force production that include the effects of EMA.
Analysis of the persistence and particle size distributional shift of sperm-derived environmental DNA to monitor Jack Mackerel spawning activity
Authors: Tsuji Satsuki , Murakami Hiroaki , Masuda Reiji
Published: March 2022

Environmental DNA (eDNA) analysis holds great promises as an efficient and noninvasive method to monitor not only the presence and biomass of organisms but also their spawning activity. In eDNA analysis-based monitoring of spawning activity, the detection of sperm-derived eDNA is a key point; however, its characteristics and dynamics are completely unknown. The present study focuses on the persistence and particle size distribution (PSD) of eDNA derived from the sperm of Japanese jack mackerel. First, we investigated the time-dependent degradation and the PSD of sperm-derived eDNA by artificially adding sperm to fish eDNA-free seawater. Next, we kept fish in tanks and examined the changes in DNA concentration and PSD before and after spawning. The data obtained from the two experiments showed that the degradation of sperm-derived eDNA proceeded rapidly, with PSD shifting to a smaller size, regardless of the DNA region (Cyt b or ITS1). Additionally, it was shown that the nuclei and mitochondria released from sperm through degradation had a size distribution that was not simply dependent on each organelle size. The results of this study will contribute to elucidating the characteristics and dynamics of eDNA specifically during the spawning season and to further developing eDNA analysis as a powerful tool for the monitoring of spawning activity.

Abstract Figure
Thymus formation in uncharted embryonic territories
Authors: Alcobia Isabel , Gama-Carvalho Margarida , Magalhães Leonor , Proa Vitor , Henrique Domingos , Neves Hélia
Published: March 2022

The thymus is a conserved organ among vertebrates, derived from the endoderm of distinct pharyngeal pouches (PP), whose location and number vary across species. Together with reports of sporadic ectopic thymus locations in mice and humans, this suggests that the potential to make a thymus resides in a broader region of the PP endoderm than previously ascribed.

Using the chick-quail chimera system, we explore this hypothesis and test the capacity of non-canonical pouches to participate in thymus formation. We further ask if the local mesenchyme of pharyngeal arches (PA) could also play a role in the regulation of thymus formation. After testing several embryonic tissue associations, we mapped the pharyngeal endoderm regions with thymus potential to the second and third/fourth pharyngeal pouches (2PP and 3/4PP). We further identified mesenchyme regions that regulate this potential to the 3/4 pharyngeal arches and to the dorsal region of the second arch, with positive and negative influences, respectively. Transcriptomic analysis of these tissues helped us revealing a common genetic program in the PP endoderm linked to thymus potential in addition to finding distinct signalling pathways involved in the cellular interactions with the mesenchyme of the pharyngeal arches that result in modulating this potential.

Together, these results provide new information about the initial specification of thymus primordia in the embryo that may contribute to improving the development of thymus organoid systems.

Graphical abstract
MitoSearch: Construction of fish species composition database with environmental DNA using public databases
Authors: Ito Takumi , Mizobata Hideaki , Yoshitake Kazutoshi , Kinoshita Shigeharu , Asakawa Shuichi
Published: March 2022

Existing fish species distribution databases have the following problems: the possibility of species identification errors due to plasticity of morphological characteristics, the impossibility of quantitative composition, and the difficulty of geographically and time-series integrated interpretation. To solve the above problems, we constructed MitoSearch database. It is a fish species distribution database using 2,160 samples of variable regions of 12S rRNA genes amplified by MiFish primers registered at NCBI/EBI/DDBJ, and visualizes the fish species composition data on a map. By integrating a large amount of data registered in public databases, MitoSearch was aimed to provide the comprehensive understanding of spatial and temporal distribution of organisms on a global scale.
Allosteric inhibitors of Zika virus NS2B-NS3 protease targeting protease in super-open conformation
Authors: Meewan Ittipat , Shiryaev Sergey A. , Huang Chun-Teng , Lin Yi-Wen , Chuang Chiao-Han , Terskikh Alexey V. , Abagyan Ruben
Published: March 2022

Zika virus (ZIKV) is a member of the Flaviviridae family and is considered a major health threat causing cases of microcephaly in newborns and Guillain-Barré syndrome in adults. Here we targeted a transient deep and hydrophobic pocket of the super-open conformation of ZIKV NS2B-NS3 protease to overcome the limitations of the orthosteric inhibitors. After virtual docking screening of approximately 7 million compounds against the novel allosteric site we selected the top seven candidates and tested them in an enzymatic assay. Six out of seven top candidates selected by the docking screen inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations, as well as suppressing viral replication. These six compounds, targeting the selected protease pocket conserved in ZIKV as well as several other Flaviviruses, have opened an opportunity for a new kind of drug candidate that might be useful to treat several flaviviral infections.
Circadian-period variation underlies the local adaptation of photoperiodism in the short-day plant Lemna aequinoctialis
Authors: Muranaka Tomoaki , Ito Shogo , Kudoh Hiroshi , Oyama Tokitaka
Published: March 2022

Phenotypic variation is the basis for trait adaptation via evolutionary selection.1, 2, 3 However, the driving forces behind the quantitative trait variations remain unclear owing to their complexity at the molecular level.4, 5, 6 This study focused on the natural variation of the free-running period (FRP) of the circadian clock because FRP is a determining factor of the internal clock phase (chronotype), which is responsible for physiological timing during a day.7 Although natural variations in FRP have been widely reported,8, 10, 11 few studies have shown the association between FRP and adaptive temporal traits. As a clock-dependent physiological process, photoperiodism is a typical target of local adaptation.12, 13Lemna aequinoctialis in Japan is a paddy-field duckweed exhibiting a latitudinal cline of critical day-lengths (CDLs) for short-day flowering.14 To investigate the relationship between FRP and CDL, we collected 72 strains of L. aequinoctialis within a latitudinal range between 31.5°N to 43.8°N. We found a significant correlation (P = 7.5E-8) between FRPs and locally adaptive CDLs, confirming that the variation in FRP-dependent chronotypes underlies geographically differentiated photoperiodism. Diel transcriptome analysis revealed that the induction timing of a florigen gene is key for connecting chronotypes to photoperiodism at the molecular level. Based on these results, we propose a fundamental rule concerning the “chronotype effect” in evolution: the variation of FRP functions as a resource for the variation of temporal traits. This study highlights the adaptive significance of FRP variation and provides a reason for the maintenance of FRP variation in natural populations.
Niche-based deterministic assembly processes strengthen the effects of β-diversity on metacommunity functioning of marine bacterioplankton
Authors: Chang Feng-Hsun , Yang Jinny Wu , Liu Ariana Chih-Hsien , Lu Hsiao-Pei , Gong Gwo Ching , Shiah Fuh-Kwo , Hsieh Chih-hao
Published: March 2022

Studies at a local community (α) level have shown that biodiversity positively affects ecosystem functioning due to niche-based deterministic processes like resource partitioning. Extending to a metacommunity (β) level, we hypothesize that β diversity also positively affects metacommunity functioning. We further hypothesize that the β diversity effect is stronger (more positive) when β diversity is increased by deterministic/non-random assembly processes. To test the hypotheses, we collected bacterioplankton along a transect of 6 stations in the southern East China Sea in 14 cruises. All 6 stations within a cruise were regarded as a metacommunity. For any pairs of the 6 stations, the Bray-Curtis index and summed bacterial biomass were calculated to represent β diversity and metacommunity functioning, respectively. We also calculated deviation of observed mean pairwise phylogenetic similarities among species from random to represent the deterministic influences of assembly processes. We found that bacterial β diversity generally positively affects metacommunity functioning; however, the β diversity effect varied among cruises. Cross-cruise comparison indicates that the β diversity effect increased with the deterministic assembly processes selecting for phylogenetically dissimilar species. This study extends the biodiversity-ecosystem functioning research to a metacommunity level, complementing the current framework by considering community assembly in natural environments.
Placental inflammation leads to abnormal embryonic heart development
Authors: Ward Eleanor J , Bert Serena , Fanti Silvia , Dufton Neil P , Malone Kerri M , Maughan Robert T , Prin Fabrice , Volpato Lia Karina , Piovezan Anna Paula , Perretti Mauro , Marelli-Berg Federica M , Nadkarni Suchita
Published: March 2022

Placental and embryonic heart development occurs in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease (CHD), an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to CHD remain unresolved. In the current study we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable to migrate to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Finally, we demonstrate that tempering placental inflammation can rescue this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life. Taken together, our observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development.
Focusing the GWASLenson days to flower using latent variable phenotypes derived from global multi-environment trials
Authors: Neupane Sandesh , Wright Derek M , Martinez Raul O , Butler Jakob , Weller James L , Bett Kirstin E
Published: March 2022

Adaptation constraints within crop species have resulted in limited genetic diversity in some breeding programs and/or areas where new crops have been introduced,e.g.,lentil(Lens culinarisMedik.) in North America. An improved understanding of the underlying genetics involved in phenology-related traits is valuable knowledge to aid breeders in overcoming limitations associated with unadapted germplasm and expanding their genetic diversity by introducing new, exotic material. We used a large, 18 site-year, multi-environment dataset, phenotyped for phenology-related traits across nine locations and over three years, along with accompanying latent variable phenotypes derived from a photothermal model and principal component analysis (PCA) of days from sowing to flower (DTF) data for a lentil diversity panel (324 accessions) which has also been genotyped with an exome capture array. Genomewide association studies (GWAS) on DTF across multiple environments helped confirm associations with known flowering time genes and identify new quantitative trait loci (QTL), which may contain previously unknown flowering time genes. Additionally, the use of latent variable phenotypes, which can incorporate environmental data such as temperature and photoperiod as both GWAS traits and as covariates, strengthened associations, revealed additional hidden associations, and alluded to potential roles of the associated QTL. Our approach can be replicated with other crop species, and the results from our GWAS serve as a resource for further exploration into the complex nature of phenology-related traits across the major growing environments for cultivated lentil.
Microscope Alignment Using Real-Time Imaging FCS
Authors: Aik Daniel Y. K. , Wohland Thorsten
Published: March 2022

Abstract

Modern EMCCD and sCMOS cameras read out fluorescence data with single-molecule sensitivity at a rate of thousands of frames per second. Exploiting these capabilities in full requires data evaluation in real-time. The direct camera-read-out tool presented here allows access to the data while the camera is recording. This provides simplified and accurate alignment procedures for Total Internal Reflection and Light Sheet Fluorescence Microscopy (TIRFM, LSFM), and simplifies and accelerates fluorescence experiments. The tool handles a range of widely used EMCCD and sCMOS cameras and uses Imaging Fluorescence Correlation Spectroscopy (Imaging FCS) for its evaluation. It is easily extendable to other camera models and other techniques and is a base for automated TIRMF and LSFM data acquisition.

Significance

We developed a direct camera readout (DCR) software tool that allows access to camera data during acquisition and provides real-time Imaging Fluorescence Correlation Spectroscopy (Imaging FCS) analysis. DCR displays live feedback and due to the sensitivity of correlation analysis provides a sensitive tool for microscope alignment using simple solutions of fluorescent particles. DCR is adaptable to different cameras and evaluation strategies, reduces alignment time, accelerates experiments, and can be used for automation.
Using Local Genetic Correlation Improves Polygenic Score Prediction Across Traits
Authors: Pain Oliver , Lewis Cathryn M.
Published: March 2022

Introduction

The predictive utility of polygenic scores (PGS) is steadily increasing as genome-wide association studies (GWAS) increase in sample size and diversity, and as PGS methodology is further developed. Multivariate PGS approaches incorporate GWAS results for secondary phenotypes which are genetically correlated with the target phenotype. These improve prediction over using PGS for only the target phenotype. However, previous methods have only considered the genome-wide estimates of SNP-based heritability (h2SNP) and genetic correlation (rg) between target and secondary phenotypes. In this study, we assess the impact of localh2SNPandrgwithin specific loci on cross-trait prediction.

Methods

We evaluate PGS using three target phenotypes (depression, intelligence, BMI) in the UK Biobank, with GWAS summary statistics matching the target phenotypes and 14 genetically correlated secondary phenotypes. PGS SNP-weights were derived using MegaPRS. Localh2SNPandrgwere estimated using LAVA. We then evaluated PGS after reweighting SNP-weights according to localh2SNPandrgestimates between the target and secondary phenotypes. Elastic net models containing PGS for multiple phenotypes were evaluated using nested 10-fold cross validation.

Results

Modelling target and secondary PGS significantly improved target phenotype prediction over the target PGS alone, with relative improvements ranging from 0.8-12.2%. Furthermore, we show reweighting PGS by localh2SNPandrgestimates can enhance the predictive utility of PGS across phenotypes, with additional relative improvements of 0.2%-2.8%. Reweighting PGS by localh2SNPandrgimproved target phenotype prediction most when there was a mixture of positive and negative localrgestimates between target and secondary phenotypes.

Conclusion

Modelling PGS for secondary phenotypes consistently improves prediction of target phenotypes, and this approach can be further enhanced by incorporating localh2SNPandrgestimates to highlight relevant genetic effects across phenotypes.
A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions
Authors: Detraux Damien , Caruso Marino , Feller Louise , Fransolet Maude , Meurant Sébastien , Mathieu Julie , Arnould Thierry , Renard Patricia
Published: March 2022

Using embryonic stem cells (ESCs) in regenerative medicine or in disease modeling requires a complete understanding of these cells. Two main distinct developmental states of ESCs have been stabilized in vitro, a naïve pre-implantation stage and a primed post-implantation stage. Based on two recently published CRISPR-Cas9 knockout functional screens, we show here that the exit of the naïve state is impaired upon heme biosynthesis pathway blockade, linked to the incapacity to activate MAPK- and TGFβ-dependent signaling pathways. In addition, heme synthesis inhibition promotes the acquisition of 2 cell-like cells in a heme-independent manner caused by a mitochondrial succinate accumulation and leakage out of the cell. We further demonstrate that extra-cellular succinate acts as a paracrine/autocrine signal, able to trigger the 2C-like reprogramming through the activation of its plasma membrane receptor, SUCNR1. Overall, this study unveils a new mechanism underlying the maintenance of pluripotency under the control of heme synthesis.
Genetic mapping of APP and amyloid-β biology modulation by trisomy 21
Authors: Mumford Paige , Tosh Justin , Anderle Silvia , Wikberg Eleni Gkanatsiou , Lau Gloria , Noy Sue , Cleverley Karen , Saito Takashi , Saido Takaomi C , Yu Eugene Y. , Brinkmalm Gunnar , Portelius Erik , Blennow Kaj , Zetterberg Henrik , Tybulewicz Victor , Fisher Elizabeth M.C. , Wiseman Frances K.
Published: March 2022

Individuals who have Down syndrome frequently develop early onset Alzheimer’s disease, a neurodegenerative condition caused by the build-up of aggregated amyloid-β and tau proteins in the brain. Amyloid-β is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer’s disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-β accumulation (AppNL-F) to determine how chromosome 21 genes other than APP modulate APP/amyloid-β in the brain when in three copies. We demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2. Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS compared to those who have familial AD caused by triplication of APP.
Insight into Polyproline II Helical Bundle Stability and Folding from NMR Spectroscopic Characterization of the Snow Flea Antifreeze Protein Denatured State
Authors: Treviño Miguel Á. , Moya María Redondo , Sánchez Rubén López , Pantoja-Uceda David , Mompeán Miguel , Laurents Douglas V.
Published: March 2022

The use of PPII helices in protein design is currently hindered by limitations in our understanding of their conformational stability and folding. Recent studies of the snow flea antifreeze protein (sfAFP), a useful model system composed of six PPII helices, suggested that a low denatured state entropy contributes to folding thermodynamics. To get atomic level information on the conformational ensemble and entropy of the reduced denatured state of sfAFP, we have analyzed its chemical shifts and {1H}-15N relaxation parameters by NMR spectroscopy at three experimental conditions. No significant populations of preferred secondary structure were detected. The stiffening of certain N-terminal residues at neutral versus acidic pH leads us to suggest that favorable charge-charge interactions could bias the conformational ensemble to favor the formation of the two disulfide bonds during nascent folding. Despite a high content of flexible glycine residues, the mobility of the sfAFP denatured ensemble is similar for denatured α/β proteins both on fast ps/ns as well as slower μs/ms timescales. These results are in line with a conformational entropy in the denatured ensemble resembling that of typical proteins and suggest that new structures based on PPII helical bundles should be amenable to protein design.
Mechanical stress driven by rigidity sensing governs epithelial stability
Authors: Sonam Surabhi , Balasubramaniam Lakshmi , Lin Shao-Zhen , Ivan Ying Ming Yow , Jaumà Irina Pi , Jebane Cecile , Karnat Marc , Toyama Yusuke , Marcq Philippe , Prost Jacques , Mège René-Marc , Rupprecht Jean-François , Ladoux Benoît
Published: March 2022

Epithelia act as a barrier against environmental stress and abrasion and in vivo they are continuously exposed to environments of various mechanical properties. The impact of this environment on epithelial integrity remains elusive. By culturing epithelial cells on 2D hydrogels, we observe a loss of epithelial monolayer integrity through spontaneous hole formation when grown on soft substrates. Substrate stiffness triggers an unanticipated mechanical switch of epithelial monolayers from tensile on soft to compressive on stiff substrates. Through active nematic modelling, we find unique patterns of cell shape texture called nematic topological defects that underpin large isotropic stress fluctuations at certain locations thereby triggering mechanical failure of the monolayer and hole opening. Our results show that substrate stiffness provides feedback on monolayer mechanical state and that topological defects can trigger stochastic mechanical failure, with potential application towards a mechanistic understanding of compromised epithelial integrity in bacterial infection, tumor progression and morphogenesis.
Cardiac ventricular myosin and slow skeletal myosin exhibit dissimilar chemo-mechanical properties despite the same myosin heavy chain isoform
Authors: Wang Tianbang , Spahiu Emrulla , Behrens Florentine , Osten Jennifer , Grünhagen Fabius , Scholz Tim , Kraft Theresia , Nayak Arnab , Amrute-Nayak Mamta
Published: March 2022

The myosin II motors are ATP-powered, force-generating machines driving cardiac and muscle contraction. Myosin II heavy chain isoform-beta (β-MyHC) is primarily expressed in the ventricular myocardium and slow-twitch muscle fibers, such as in M. soleus. M. soleus-derived myosin II (SolM-II) is often used as an alternative to the ventricular β-cardiac myosin (βM-II); however, the direct assessment of detailed biochemical and mechanical features of the native myosins is limited. By employing the optical trapping method, we examined the mechanochemical properties of the native myosins isolated from rabbit heart ventricle and M. soleus muscles at the single-molecule level. Contrary to previous reports, the purified motors from the two tissue sources, despite the same MyHC isoform, displayed distinct motile and ATPase kinetic properties. βM-II was ∼threefold faster in the actin filament-gliding assay than SolM-II. The maximum acto-myosin (AM) detachment rate derived in single-molecule assays was ∼threefold higher in βM-II. The stroke size for both myosins was comparable. The stiffness of the ‘AM rigor’ cross-bridge was also similar for both the motor forms. The stiffness of βM-II was found to be determined by the nucleotide state of the actin-bound myosin. Our analysis revealed distinct kinetic differences, i.e., a higher AM detachment rate for the βM-II, corresponding to the ADP release rates from the cross-bridge, thus elucidating the observed differences in the motility driven by βM-II and SolM-II. These studies have important implications for the future choice of tissue sources to gain insights into cardiomyopathies
Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling
Authors: Husanie Hussam , Abu-Remaileh Muhannad , Maroun Kian , Abu-Tair Lina , Safadi Hazem , Atlan Karine , Golan Talia , Aqeilan Rami I.
Published: March 2022

Pancreatic cancer is one of the most lethal cancers, owing to its late diagnosis and resistance to chemotherapy. The tumor suppressor WW domain-containing oxidoreductase (WWOX), one of the most active fragile sites in the human genome (FRA16D), is commonly altered in pancreatic cancer. However, the direct contribution of WWOX loss to pancreatic cancer development and progression remains largely unknown. Here, we report that combined conditional deletion ofWwoxand activation ofKRasG12DinPtf1a-CreER-expressing mice results in accelerated formation of precursor lesions and pancreatic carcinoma. At the molecular level, we found that WWOX physically interacts with SMAD3 and BMP2, which are known activators of the TGF-β signaling pathway. In the absence of WWOX, TGFβ/BMPs signaling was enhanced, leading to increased macrophage infiltration and enhanced cancer stemness. Finally, overexpression of WWOX in patient-derived xenografts led to diminished aggressiveness bothin vitroandin vivo. Overall, our findings reveal an essential role of WWOX in pancreatic cancer development and progression and underscore its role asa bona fidetumor suppressor.