bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-scale phylogenomics of the genus Macrostomum (Platyhelminthes) reveals cryptic diversity and novel sexual traits
Authors: Brand Jeremias N. , Viktorin Gudrun , Wiberg R. Axel W. , Beisel Christian , Schärer Lukas
Published: March 2021

Free-living flatworms of the genus Macrostomum are small and transparent animals, representing attractive study organisms for a broad range of topics in evolutionary, developmental, and molecular biology. The genus includes the model organism M. lignano for which extensive molecular resources are available, and recently there is a growing interest in extending work to additional species in the genus. These endeavours are currently hindered because, even though >200 Macrostomum species have been taxonomically described, molecular phylogenetic information and geographic sampling remain limited. We report on a global sampling campaign aimed at increasing taxon sampling and geographic representation of the genus. Specifically, we use extensive transcriptome and single-locus data to generate phylogenomic hypotheses including 145 species. Across different phylogenetic methods and alignments used, we identify several consistent clades, while their exact grouping is less clear, possibly due to a radiation early in Macrostomum evolution. Moreover, we uncover a large undescribed diversity, with 94 of the studied species likely being new to science, and we identify multiple novel morphological traits. Furthermore, we identify cryptic speciation in a taxonomically challenging assemblage of species, suggesting that the use of molecular markers is a prerequisite for future work, and we describe the distribution of possible synapomorphies and suggest taxonomic revisions based on our finding. Our large-scale phylogenomic dataset now provides a robust foundation for comparative analyses of morphological, behavioural and molecular evolution in this genus.
Epigenomic and transcriptomic differences between low-grade and acute inflammation in LPS-induced murine immune cells
Authors: Naler Lynette B. , Hsieh Yuan-Pang , Geng Shuo , Zhou Zirui , Li Liwu , Lu Chang
Published: March 2021

Chronic, low-grade inflammation has a widespread and significant impact on health, especially in Western society. While inflammation is beneficial for the removal of microbes, low-grade inflammation never resolves and can cause or worsen other diseases. The process by which low-grade inflammation occurs remains poorly understood. Here we exposed murine bone-marrow derived monocytes to chronic lipopolysaccharide (LPS) stimulation at low dose or high dose, as well as a PBS control. The cells were profiled for genome-wide H3K27ac modification and gene expression. The gene expression of TRAM-deficient and IRAK-M-deficient monocytes with LPS exposure was also analyzed. We discover that low-grade inflammation preferentially utilizes the TRAM/TRIF-dependent pathway of TLR4 signaling, and induces the expression of interferon response genes. In contrast, acute inflammation uniquely upregulates metabolic and proliferative pathways that also appear to be TRAM-dependent. The extensive differences in the epigenomic landscape between low-dose and high-dose conditions suggest the importance of epigenetic regulations in driving differential responses. Our data provide potential targets for future mechanistic or therapeutic studies.
A dynamical model of TGF-βactivation in asthmatic airways
Authors: Pybus Hannah J. , O’Dea Reuben D. , Brook Bindi S.
Published: March 2021

Excessive activation of the regulatory cytokine transforming growth factorβ(TGF-β) via contraction of airway smooth muscle (ASM) is associated with the development of asthma. In this study, we develop an ordinary differential equation model that describes the change in density of the key airway wall constituents, ASM and extracellular matrix (ECM), and their interplay with subcellular signalling pathways leading to the activation of TGF-β. We identify bistable parameter regimes where there are two positive steady states, corresponding to either reduced or elevated TGF-βconcentration, with the latter leading additionally to increased ASM and ECM density. We associate the former with a healthy homeostatic state and the latter with a diseased (asthmatic) state. We demonstrate that external stimuli, inducing TGF-βactivation via ASM contraction (mimicking an asthmatic exacerbation), can perturb the system irreversibly from the healthy state to the diseased one. We show that the properties of the stimuli, such as their frequency or strength, and the clearance of surplus active TGF-β, are important in determining the long-term dynamics and the development of disease. Finally we demonstrate the utility of this model in investigating temporal responses to bronchial thermoplasty, a therapeutic intervention in which ASM is ablated by applying thermal energy to the airway wall. The model predicts the parameter-dependent threshold damage required to obtain irreversible reduction in ASM content suggesting that certain asthma phenotypes are more likely to benefit from this intervention.
Transcriptome profiling of embryonic retinal pigment epithelium reprogramming
Authors: Tangeman Jared A , Luz-Madrigal Agustín , Sreeskandarajan Sutharzan , Esquivel Erika Grajales- , Liu Lin , Liang Chun , Tsonis Panagiotis A. , Rio-Tsonis Katia Del
Published: March 2021

The plasticity of human retinal pigment epithelium (RPE) has been observed during proliferative vitreoretinopathy, a defective repair process during which injured RPE gives rise to fibrosis. In contrast, following injury, the RPE of the embryonic chicken can be reprogrammed to regenerate neural retina in an FGF2-dependent manner. To characterize the mechanisms underlying embryonic RPE reprogramming, we used laser capture microdissection to isolate RNA from 1) intact RPE, 2) transiently reprogrammed RPE (t-rRPE) 6 hours post-retinectomy, and 3) reprogrammed RPE (rRPE) 6 hours post-retinectomy with FGF2 treatment. Using RNA-seq, we observed the acute repression of genes related to cell cycle progression in the injured t-rRPE, as well as up-regulation of genes associated with injury. In contrast, the rRPE was strongly enriched for MAPK-responsive genes and retina development factors, confirming that FGF2 and the downstream MAPK cascade are the main drivers of embryonic RPE reprogramming. Clustering and pathway enrichment analysis were used to create an integrated network of the core processes associated with RPE reprogramming, including key terms pertaining to injury response, migration, actin dynamics, and cell cycle progression. Finally, we employed gene set enrichment analysis to suggest a previously uncovered role for epithelial-mesenchymal transition (EMT) machinery in the initiation of embryonic chick RPE reprogramming. The EMT program is accompanied by extensive, coordinated regulation of extracellular matrix (ECM) regulators, and these observations together suggest an early role for ECM and EMT-like dynamics during reprogramming. Our study provides for the first time an in-depth transcriptomic analysis of embryonic RPE reprogramming and will prove useful in guiding future efforts to understand proliferative disorders of the RPE and to promote retinal regeneration.
Comprehensive machine-learning-based analysis of microRNA-target interactions reveals variable transferability of interaction rules across species
Authors: Or Gilad Ben , Veksler-Lublinsky Isana
Published: March 2021

Background

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally via base-pairing with complementary sequences on messenger RNAs (mRNAs). Due to the technical challenges involved in the application of high-throughput experimental methods, datasets of direct bona-fide miRNA targets exist only for a few model organisms. Machine learning (ML) based target prediction methods were successfully trained and tested on some of these datasets. There is a need to further apply the trained models to organisms where experimental training data is unavailable. However, it is largely unknown how the features of miRNA-target interactions evolve and whether there are features that have been fixed during evolution, questioning the general applicability of these ML methods across species.

Results

In this paper, we examined the evolution of miRNA-target interaction rules and used data science and ML approaches to investigate whether these rules are transferable between species. We analyzed eight datasets of direct miRNA-target interactions in four organisms (human, mouse, worm, cattle). Using ML classifiers, we achieved high accuracy for intra-dataset classification and found that the most influential features of all datasets significantly overlap. To explore the relationships between datasets we measured the divergence of their miRNA seed sequences and evaluated the performance of cross-datasets classification. We showed that both measures coincide with the evolutionary distance of the compared organisms.

Conclusions

Our results indicate that the transferability of miRNA-targeting rules between organisms depends on several factors, the most associated factors being the composition of seed families and evolutionary distance. Furthermore, our feature importance results suggest that some miRNA-target features have been evolving while some have been fixed during evolution. Our study lays the foundation for the future developments of target prediction tools that could be applied to “non-model” organisms for which minimal experimental data is available.

Availability and implementation The code is freely available at https://github.com/gbenor/TPVOD
Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: March 2021

Type 2 diabetes mellitus (T2DM) is etiologically related to metabolic disorder. The aim of our study was to screen out candidate genes of T2DM and to elucidate the underlying molecular mechanisms by bioinformatics methods. Expression profiling by high throughput sequencing data of GSE154126 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between T2DM and normal control were identified. And then, functional enrichment analyses of gene ontology (GO) and REACTOME pathway analysis was performed. Protein–protein interaction (PPI) network and module analyses were performed based on the DEGs. Additionally, potential miRNAs of hub genes were predicted by miRNet database. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst database. Further, validations were performed by receiver operating characteristic curve (ROC) analysis and real-time polymerase chain reaction (RT-PCR). In total, 925 DEGs were identified in T2DM, including 447 up regulated genes and 478 down-regulated genes. Functional enrichment analysis results showed that up regulated DEGs were significantly enriched in defense response, neutrophil degranulation, cell adhesion and extracellular matrix organization. The top 10 hub genes, JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 were identified from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Furthermore, ROC analysis and RT-PCR revealed that JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 might serve as biomarkers in T2DM. Bioinformatics analysis is a useful tool to explore the molecular mechanism and pathogenesis of T2DM. The identified hub genes may participate in the onset and advancement of T2DM and serve as therapeutic targets.
Brain-wide neuronal activation and functional connectivity are modulated by prior exposure to repetitive learning episodes
Authors: Terstege Dylan J. , Durante Isabella M. , Epp Jonathan R.
Published: March 2021

Memory storage and retrieval are shaped by past experiences. Prior learning and memory episodes have numerous impacts on brain structure from micro to macroscale. Previous experience with specific forms of learning increases the efficiency of future learning. It is less clear whether such practice effects on one type of memory might also have transferable effects to other forms of memory. Different forms of learning and memory rely on different brain-wide networks but there are many points of overlap in these networks. Enhanced structural or functional connectivity caused by one type of learning may be transferable to another type of learning due to overlap in underlying memory networks. Here, we investigated the impact of prior chronic spatial training on the task-specific functional connectivity related to subsequent contextual fear memory recall in mice. Our results show that mice exposed to prior spatial training exhibited decreased brain-wide activation compared to control mice during the retrieval of a context fear memory. With respect to functional connectivity, we observed changes in several network measures notably an increase in global efficiency. Interestingly, we also observed an increase in network resilience based on simulated targeted node deletion. Overall, this study suggests that chronic learning has transferable effects on the functional connectivity networks of other types of learning and memory. The generalized enhancements in network efficiency and resilience suggest that learning itself may protect brain networks against deterioration.
Turnip crinkle virus targets host ATG8 proteins to attenuate antiviral autophagy
Authors: Shukla Aayushi , Hoffmann Gesa , Hofius Daniel , Hafrén Anders
Published: March 2021

Autophagy has emerged as a central player in plant virus disease and resistance. In this study we have addressed the potential roles of autophagy in Turnip crinkle virus (TCV) infection. We found that autophagy attenuates disease severity and contributes to resistance against TCV by limiting virus accumulation. These autophagy-dependent disease phenotypes intensify further when combined with defects in RNA silencing, suggesting that these two major defence pathways are largely uncoupled in TCV disease. Intriguingly, as a counterdefence, TCV employs the viral silencing suppressor protein P38 to suppress antiviral autophagy, likely by directly sequestering ATG8 proteins. This strategy appears to be novel for plant viruses, yet resembles mechanisms described for other pathogen classes. Together, these results broaden our understanding of autophagy in plant virus disease, and strengthens our view of virus-specific adaptation to the autophagy pathway.
Evidence of an additional wild contributor,Malus orientalisUglitzk., to the genome of cultivated apple varieties in the Caucasus and Iran
Authors: Hamid Bina , Hamed Yousefzadeh , Anthony Venon , Carine Remoué , Agnès Rousselet , Matthieu Falque , Faramarzi Shadab , Chen Xilong , Samanchina Jarkyn , Gill David , Kabaeva Akylai , Tatiana Giraud , Batool Hossainpour , Hamid Abdollahi , Ivan Gabrielyan , Anush Nersesyan , Cornille A.
Published: March 2021

Anthropogenic and natural divergence processes remain poorly studied in crop-wild fruit tree complexes, especially in the Caucasus, a pivotal region for plant domestication. We investigated anthropogenic and natural divergence processes in apples in the Caucasus using 26 microsatellite markers amplified in 550 wild and cultivated samples. We found two genetically distinct cultivated populations in Iran that are differentiated fromMalus domestica, the standard cultivated apple worldwide. Coalescent-based inferences showed that these two cultivated populations originated from specific domestication events ofM. orientalisin Iran. One of the Iranian clusters comprised both cultivated and forest trees, suggesting that either farmers use local wild apple for cultivation or that some forest trees are feral cultivars. We found evidence of substantial wild-crop and crop-crop gene flow in the Caucasus, as has been described in apple in Europe. In the Caucasus, we identified seven genetically differentiated populations of wild apple (Malus orientalis). Niche modeling combined with genetic diversity estimates indicated that these populations likely resulted from range changes during past glaciations. This study identifies Iran as a key region in the domestication of apple andM. orientalisas an additional contributor to the cultivated apple gene pool. Domestication of the apple tree therefore involved multiple origins of domestication in different geographic locations and substantial crop-wild hybridization, as found in other fruit trees. This study also highlights the impact of climate change on the natural divergence of a wild fruit tree and provides a starting point for apple conservation and breeding programs in the Caucasus.
TOR represses stress responses through global regulation of H3K27 trimethylation in plants
Authors: Dong Yihan , Uslu Veli V. , Berr Alexandre , Singh Gaurav , Papdi Csaba , Steffens Victor A , Heitz Thierry , Ryabova Lyubov
Published: March 2021

Target of Rapamycin (TOR) functions as a central sensory hub to link a wide range of external stimuli to gene expression. However, the mechanisms underlying stimulus-specific transcriptional reprogramming by TOR remains elusive. Ourin silicoanalysis in Arabidopsis demonstrates that TOR-repressed genes are associated with either bistable or silent chromatin states. Both states regulated by TOR signaling pathway are associated with high level of H3K27me3 deposited by CURLY LEAF (CLF) in specific context with LIKE HETEROCHROMATIN PROTEIN1 (LHP1). Combinations of epigenetic modifications H3K4me3 and H3K27me3 implicate bistable feature which alternates between on and off state allowing rapid transcriptional changes upon external stimuli. Chromatin remodeler SWI2/SNF2 ATPase BRAHMA (BRM) activates TOR-repressed genes only at bistable chromatin domains to rapidly induce biotic stress responses. Here we demonstrated bothin silicoandin vivothat TOR represses transcriptional stress responses through global maintenance of H3K27me3.
Edge-strand of BepA interacts with immature LptD on the β-barrel assembly machine to direct it to on- and off-pathways
Authors: Miyazaki Ryoji , Watanabe Tetsuro , Yoshitani Kohei , Akiyama Yoshinori
Published: March 2021

The outer membrane (OM) of gram-negative bacteria functions as a selective permeability barrier.Escherichia coliperiplasmic Zn-metallopeptidase BepA contributes to the maintenance of OM integrity through its involvement in the biogenesis and degradation of LptD, a β-barrel protein component of the lipopolysaccharide translocon. BepA either promotes the maturation of LptD when it is on the normal assembly pathway (on-pathway) or degrades it when its assembly is compromised (off-pathway). BepA performs these functions probably on the β-barrel assembly machinery (BAM) complex. However, how BepA recognizes and directs an immature LptD to different pathways remains unclear. Here, we explored the interactions among BepA, LptD, and the BAM complex. We found that the interaction of the BepA edge-strand located adjacent to the active site with LptD was crucial not only for proteolysis but also, unexpectedly, for assembly promotion of LptD. Site-directed crosslinking analyses indicated that the unstructured N-terminal half of the β-barrel-forming domain of an immature LptD contacts with the BepA edge-strand. Furthermore, the C-terminal region of the β-barrel-forming domain of the BepA-bound LptD intermediate interacted with a “seam” strand of BamA, suggesting that BepA recognized LptD assembling on the BAM complex. Our findings provide important insights into the functional mechanism of BepA.
Unconventional Translation Initiation Factor EIF2A is required for Drosophila spermatogenesis
Authors: Lowe David D. , Montell Denise J.
Published: March 2021

The eukaryotic initiation factor EIF2A is an unconventional translation factor required for initiation of protein synthesis from non-AUG codons from a variety of transcripts, including oncogenes and stress related genes in mammalian cells. Its function in multicellular organisms has not been reported. Here, we identify and characterize mutant alleles of the CG7414 gene, which encodes the Drosophila EIF2A ortholog. We identified that CG7414 undergoes sex-specific splicing that regulates its male-specific expression. We characterized a Mi{Mic} transposon insertion that disrupts the coding regions of all predicted isoforms and is a genetic null allele, and a PBac transposon insertion into an intron, which is a hypomorph. The Mi{Mic} allele is homozygous lethal, while the viable progeny from the hypomorphic PiggyBac allele are male sterile and female fertile. In dEIF2A mutant flies, sperm failed to individualize due to defects in F-actin cones and failure to form and maintain cystic bulges, ultimately leading to sterility. These results demonstrate that EIF2A is essential in a multicellular organism, both for normal development and spermatogenesis, and provide an entree into the elucidation of the role of EIF2A and unconventional translation in vivo.
The opportunistic intracellular bacterial pathogenRhodococcus equielicits type I interferons by engaging cytosolic DNA sensing in macrophages
Authors: Vail Krystal J , da Silveira Bibiana Petri , Bell Samantha L , Bordin Angela I , Cohen Noah D , Patrick Krisitn L , Watson Robert O
Published: March 2021

Rhodococcus equiis a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche forR. equi, little is known about how intracellularR. equiis sensed by macrophages. Here, we discovered that that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected withR. equiinduce a robust type I IFN response, includingIfnband interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen,Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics, demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA surveillance pathway, suggesting thatR. equiperturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this we found that a population of ~12% ofR. equiphagosomes recruited the galectin-3, −8 and −9 danger receptors. Interesting, neither phagosomal damage nor induction of type I IFN required theR. equi’s virulence-associated plasmid. Importantly,R. equiinfection of both mice and foals stimulated ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating thatR. equiactivates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into howR. equiengages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

IMPORTANCE

Rhodococcus equiis a facultative intracellular bacterial pathogen of horses and other domestic animals, as well as an opportunistic pathogen of immunocompromised and rarely immunocompetent humans. In human patients,Rhodococcuspneumonia bears some pathological similarities to pulmonary tuberculosis, and poses a risk for misdiagnosis. In horses,R. equiinfection has a major detrimental impact on the equine breeding industry due to a lack of an efficacious vaccine and its ubiquitous distribution in soil. Given the prevalence of subclinical infection and high false positive rate in current screening methods, there exists a critical need to identify factors contributing to positive patient outcomes. Our research identifies innate immune sensing events and immune transcriptional signatures that may lead to biomarkers for clinical disease, more accurate screening methods, and insight into susceptibility to infection.
H2S Prodrug, SG-1002, Protects Against Myocardial Oxidative Damage and Hypertrophy via Induction of Cystathionine β-Synthase and Antioxidant Proteins
Authors: Islam Rahib K. , Donnelly Erinn , Hossain Fokhrul , Gardner Jason D. , Islam Kazi N.
Published: March 2021

Endogenously produced hydrogen sulfide (H2S) is critical for cardiovascular homeostasis. Therapeutic strategies aimed at increasing H2S levels have proven cardioprotective in models of acute myocardial infarction (MI) and heart failure (HF). The present study was undertaken to investigate the effects of a novel H2S prodrug, SG-1002, on stress induced hypertrophic signaling in murine HL-1 cardiac muscle cells. Treatment of HL-1 cells with SG-1002 under serum starvation without or with H2O2increased the levels of H2S, H2S producing enzyme, cystathionine β-synthase (CBS) as well as antioxidant protein levels, such as super oxide dismutase1 (SOD1) and catalase and decreased oxidative stress. SG-1002 also decreased the expression of hypertrophic/HF protein markers such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in stressed HL-1 cells. Treatment with SG-1002 caused a significant induction of cell viability and a marked reduction of cellular cytotoxicity in HL-1 cells under serum starvation incubated or with H2O2. Experimental results of this study suggest that SG-1002 attenuates myocardial cellular oxidative damage and/or hypertrophic signaling via increasing H2S levels or H2S producing enzyme, CBS and antioxidant proteins.
Asymmetric structures and conformational plasticity of the uncleaved full-length human immunodeficiency virus (HIV-1) envelope glycoprotein trimer
Authors: Zhang Shijian , Wang Kunyu , Wang Wei Li , Nguyen Hanh T. , Chen Shuobing , Lu Maolin , Go Eden P. , Ding Haitao , Steinbock Robert T. , Desaire Heather , Kappes John C. , Sodroski Joseph , Mao Youdong
Published: March 2021

The functional human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41)3] is produced by cleavage of a conformationally flexible gp160 precursor. Gp160 cleavage or the binding of BMS-806, an entry inhibitor, stabilizes the pre-triggered, “closed” (State-1) conformation recognized by rarely elicited broadly neutralizing antibodies. Poorly neutralizing antibodies (pNAbs) elicited at high titers during natural infection recognize more “open” Env conformations (States 2 and 3) induced by binding the receptor, CD4. We found that BMS-806 treatment and crosslinking decreased the exposure of pNAb epitopes on cell-surface gp160; however, after detergent solubilization, crosslinked and BMS-806-treated gp160 sampled non-State-1 conformations that could be recognized by pNAbs. Cryo-electron microscopy of the purified BMS-806-bound gp160 revealed two hitherto unknown asymmetric trimer conformations, providing insights into the allosteric coupling between trimer opening and structural variation in the gp41 HR1Nregion. The individual protomer structures in the asymmetric gp160 trimers resemble those of other genetically modified or antibody-bound cleaved HIV-1 Env trimers, which have been suggested to assume State-2-like conformations. Asymmetry of the uncleaved Env potentially exposes surfaces of the trimer to pNAbs. To evaluate the effect of stabilizing a State-1-like conformation of the membrane Env precursor, we treated cells expressing wild-type HIV-1 Env with BMS-806. BMS-806 treatment decreased both gp160 cleavage and the addition of complex glycans, implying that gp160 conformational flexibility contributes to the efficiency of these processes. Selective pressure to maintain flexibility in the precursor of functional Env allows the uncleaved Env to sample asymmetric conformations that potentially skew host antibody responses toward pNAbs.

IMPORTANCE

The envelope glycoprotein (Env) trimers on the surface of human immunodeficiency virus (HIV-1) mediate the entry of the virus into host cells and serve as targets for neutralizing antibodies. The functional Env trimer is produced by cleavage of the gp160 precursor in the infected cell. We found that the HIV-1 Env precursor is highly plastic, allowing it to assume different asymmetric shapes. This conformational plasticity is potentially important for Env cleavage and proper modification by sugars. Having a flexible, asymmetric Env precursor that can misdirect host antibody responses without compromising virus infectivity would be an advantage to a persistent virus like HIV-1.
The ArabidopsisWRR4AandWRR4Bparalogous NLR proteins both confer recognition of multipleAlbugo candidaeffectors
Authors: Redkar Amey , Cevik Volkan , Bailey Kate , Furzer Oliver J. , Fairhead Sebastian , Borhan M. Hossein , Holub Eric B. , Jones Jonathan D.G.
Published: March 2021

The oomyceteAlbugo candidacauses white blister rust, an important disease of Brassica crops. Distinct races ofA. candidaare defined by their specificity for infecting different host species.

TheWhite Rust Resistance 4(WRR4) locus in Col-0 accession ofArabidopsis thalianacontains three genes that encode TIR-NLR resistance proteins. The Col-0 alleles ofWRR4AandWRR4Bconfer resistance to at least fourA. candidaraces (2, 7 and 9 fromB. juncea, B. rapaandB. oleracea, respectively, and Race 4 fromCapsella bursa-pastoris). Resistance mediated by both paralogs can be overcome by Col-0-virulent isolates of Race 4.

After comparing repertoires of candidate effectors in resisted and resistance-breaking strains, we used transient co-expression in tobacco orArabidopsisto identify effectors recognized byWRR4AandWRR4B. A library of CCG effectors from fourA. candidaraces was screened forWRR4A-orWRR4B-dependent elicitation of hypersensitive response (HR). These CCG genes were validated for WRR-dependent HR by bombardment assays in wild type Col-0,wrr4Aorwrr4Bmutants.

Our analysis revealed eightWRR4A-recognized CCGs and fourWRR4B-recognized CCGs. Remarkably, the N-terminal region of 100 amino acids after the secretion signal is sufficient forWRR4Arecognition of these eight recognized effectors. This multiple recognition capacity potentially explains the broad-spectrum resistance to manyA. candidaraces conferred byWRR4paralogs.
Revisiting the evolutionary history of pigs via de novo mutation rate estimation by deep genome sequencing on a three-generation pedigree
Authors: Zhang Mingpeng , Yang Qiang , Ai Huashui , Huang Lusheng
Published: March 2021

The mutation rate used in the previous analyses of pig evolution and demographics was cursory and brought potential bias in inferring its history. Herein, we estimated de novo mutation rate of pigs using high-quality whole-genome sequencing data from nine individuals in a three-generation pedigree through stringent filtering and validation. The estimated mutation rate was 3.6 × 10−9per generation, corresponding to 1.2 × 10−9per site per year. Using this mutation rate, we re-investigated the evolutionary history of pigs. Our estimates agreed to the divergence time of ~10 kiloyears ago (Kya) between European wild and domesticated pigs, consistent with the domestication time of European pigs based on archaeological evidence. However, other divergence events inferred here were not as ancient as previously described. Our estimates suggested that: Sus speciation occurred ~1.36 Million years ago (Mya); European pigs split up with Asian ones only ~219 Kya; South and North Chinese wild pig split ~25 Kya. Meanwhile, our results showed that the most recent divergence event between Chinese wild and domesticated pigs occurred in the Hetao plain, North China, approximately 20 Kya, supporting the possibly independent domestication in North China along the middle Yellow River. We also found the maximum effective population size of pigs was ~6 times larger than the previous estimate. Notably by simulation, we confirmed an archaic migration from other Sus species originating ~ 2 Mya to European pigs during pigs’ western colonization, which possibly interfered with the previous demographic inference. Our findings advance the understanding of pig evolutionary history.
Astrocyte-neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade
Authors: Paumier Adrien , Boisseau Sylvie , Pernet-Gallay Karin , Buisson Alain , Albrieux Mireille
Published: March 2021

Background

The sequence of cellular dysfunctions in preclinical Alzheimer’s disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer’s disease in both humans and mouse models. The most common hypothesis describes amyloid β accumulation as the triggering factor of the disease but the effects of such accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection brought by an early chronic pharmacological inhibition of TRPA1 channel on Alzheimer’s disease progression.

Methods

We administered a specific inhibitor of TRPA1 channel (HC030031) intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer’s disease. We characterized short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade on Alzheimer’s disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels.

Results

Our results revealed that the first observable disruptions in the Alzheimer’s disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction, preserves structural synaptic integrity and strengthens the glial plaque barrier. These protective effects preserved spatial working-memory in this Alzheimer’s disease mouse model.

Conclusion

The toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer’s disease progression. TRPA1 blockade prevent irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.
Sexually dimorphic placental responses to maternal SARS-CoV-2 infection
Authors: Bordt Evan A , Shook Lydia L , Atyeo Caroline , Pullen Krista M , De Guzman Rose M , Meinsohn Marie-Charlotte , Chauvin Maeva , Fischinger Stephanie , Yockey Laura J. , James Kaitlyn , Lima Rosiane , Yonker Lael M , Fasano Alessio , Brigida Sara , Bebell Lisa M , Roberts Drucilla J , Pépin David , Huh Jun R , Bilbo Staci D , Li Jonathan Z , Kaimal Anjali , Schust Danny , Gray Kathryn J , Lauffenburger Douglas , Alter Galit , Edlow Andrea G
Published: March 2021

There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
Reciprocal allostery arising from a bi-enzyme assembly controls aromatic amino acid biosynthesis inPrevotella nigrescens
Authors: Bai Yu , Parker Emily J.
Published: March 2021

Modular protein assembly has been widely reported as a mechanism for constructing allosteric machinery. Recently, a distinctive allosteric system has been identified in a bi-enzyme assembly comprising a 3-deoxy-d-arabinoheptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM). These enzymes catalyze the first and branch point reactions of aromatic amino acid biosynthesis in the bacteriumPrevotella nigrescens(PniDAH7PS), respectively. The interactions between these two distinct catalytic domains support functional inter-reliance within this bifunctional enzyme. The binding of prephenate, the product of CM-catalyzed reaction, to the CM domain is associated with a striking rearrangement of overall protein conformation that alters the interdomain interactions and allosterically inhibits the DAH7PS activity. In this study, we observed allosteric activation of CM activity in the presence of all DAH7PS substrates. Using small angle X-ray scattering (SAXS) experiments we show that changes in overall protein conformations and dynamics are associated with the presence of different DAH7PS substrates and the allosteric inhibitor prephenate. Furthermore, we have identified an extended interhelix loop located in CM domain, loopC320-F333, as a crucial segment for the interdomain structural and catalytic communications. Our results suggest that the dual function enzymePniDAH7PS contains a reciprocal allosteric system between the two enzymatic moieties, as a result of this bidirectional interdomain communication. This arrangement allows for a complex feedback and feedforward system for control of pathway flux by connecting the initiation and branch point of aromatic amino acid biosynthesis.
The small acid-soluble proteins ofClostridioides difficileare important for UV resistance and serve as a check point for sporulation
Authors: Nerber Hailee N. , Sorg Joseph A.
Published: March 2021

Clostridioides difficileis a nosocomial pathogen which causes severe diarrhea and colonic inflammation.C. difficilecauses disease in susceptible patients when endospores germinate into the toxin-producing vegetative form. The action of these toxins results in diarrhea and the spread of spores into the hospital and healthcare environments. Thus, the destruction of spores is imperative to prevent disease transmission between patients. However, spores are resilient and survive extreme temperatures, chemical exposure, and UV treatment. This makes their elimination from the environment difficult and perpetuates their spread between patients. In the model spore-forming organism,Bacillus subtilis,the small acid-soluble proteins (SASPs) contribute to these resistances. The SASPs are a family of small proteins found in all endospore-forming organisms,C. difficileincluded. Although these proteins have high sequence similarity between organisms, the role(s) of the proteins differ. Here, we investigated the role of the main α/β SASPs, SspA and SspB, and two annotated SASPs, CDR20291_1130 and CDR20291_3080, in protectingC. difficilespores from environmental insults. We found that SspA is necessary for conferring spore UV resistance, SspB minorly contributes, and the annotated SASPs do not contribute to UV resistance. In addition, none of these SASPs contribute to the resistance of tested chemicals. Surprisingly, the combined deletion ofsspAandsspBprevented spore formation. Overall, our data indicate that UV resistance ofC. difficilespores is dependent on SspA and that SspA and SspB regulate / serve as a checkpoint for spore formation, a previously unreported function of SASPs.

Importance

C. difficileinfections remain problematic and elimination of spores within an environment is essential to limit person-to-person spread. A deeper understanding of how spores resist cleaning efforts could lead to better strategies to eradicate the spores in a contaminated environment. The small acid-soluble proteins (SASPs), found in all endospore-forming organisms, are one mechanism that allows for spore resilience. Here, we find thatC. difficileSspA and SspB protect against UV light. Unexpectedly, these SASPs also regulate spore formation, a role not described for any SASP to date.
Degradation of Visible Autumn Icons and Conservation Opportunities: Trends in Deciduous Forest Loss in the Contiguous US
Authors: Dreiss L. M. , Malcom J.W.
Published: March 2021

Temperate deciduous forests are one of the most visible biomes on Earth because of their autumn aesthetics and because they harbor some of the most heavily populated regions. Their ability to attract visitors may increase opportunities for people to experience nature, which has been linked to greater conservation action. Identifying regions with high leaf-peeping opportunities and regions where color has been lost to landscape conversion may help to inform these connections. We use spatial overlay analyses to quantify temperate deciduous forest coverage, disturbance, and protections in each U.S. ecoregion. We evaluated recent (1984-2016) and predicted (2016-2050) disturbance under extreme future scenarios. Almost all ecoregions saw a decline in deciduous forest cover between 1985 and 2016. Some ecoregions with the greatest opportunities for leaf-peeping are also underrepresented in the protected areas network and vulnerable to additional losses. Under economic-growth forecasting scenarios, losses are predicted to continue. However, environmentally focused scenarios suggest there is still opportunity to reverse deciduous forest loss in some ecoregions. Differences in forest loss between predictions scenarios emphasize the importance of human approaches in securing environmental stability. Increasing public exposure to temperate forests may help ensure conservation of more natural areas and preserve the quantity and quality of autumn forest viewing.

Key Points

Temperate deciduous forests aesthetics attract visitors to experience nature, but degradation and loss can hinder connections.

US ecoregions with the greatest leaf-peeping opportunities are underrepresented in the protected areas and vulnerable to additional losses.

Differences in predictions scenarios emphasize the importance of conservation action, which may be linked to human connections with nature.
Bayesian metamodeling of complex biological systems across varying representations
Authors: Raveh Barak , Sun Liping , White Kate L. , Sanyal Tanmoy , Tempkin Jeremy , Zheng Dongqing , Bharat Kala , Singla Jitin , Wang ChenXi , Zhao Jihui , Li Angdi , Graham Nicholas A. , Kesselman Carl , Stevens Raymond C. , Sali Andrej
Published: March 2021

Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide-and-conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are (i) converted to a standardized statistical representation relying on Probabilistic Graphical Models, (ii) coupled by modeling their mutual relations with the physical world, and (iii) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic ß-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic ß-Cell Consortium.

Significance Statement

Cells are the basic units of life, yet their architecture and function remain to be fully characterized. This work describes Bayesian metamodeling, a modeling approach that divides-and-conquers a large problem of modeling numerous aspects of the cell into computing a number of smaller models of different types, followed by assembling these models into a complete map of the cell. Metamodeling enables a facile collaboration of multiple research groups and communities, thus maximizing the sharing of expertise, resources, data, and models. A proof-of-principle is provided by a model of glucose-stimulated insulin secretion produced by the Pancreatic ß-Cell Consortium.
Phase Resolution of Heterozygous Sites in Diploid Genomes is Important to Phylogenomic Analysis under the Multispecies Coalescent Model
Authors: Huang Jun , Bennett Jeremy , Flouri Tomáš , Leaché Adam D. , Yang Ziheng
Published: March 2021

Abstract

Genome sequencing projects routinely generate haploid consensus sequences from diploid genomes, which are effectively chimeric sequences with the phase at heterozygous sites resolved at random. The impact of phasing errors on phylogenomic analyses under the multispecies coalescent (MSC) model is largely unknown. Here we conduct a computer simulation to evaluate the performance of four phase-resolution strategies (the true phase resolution, the diploid analytical integration algorithm which averages over all phase resolutions, computational phase resolution using the program PHASE, and random resolution) on estimation of the species tree and evolutionary parameters in analysis of multi-locus genomic data under the MSC model. We found that species tree estimation is robust to phasing errors when species divergences were much older than average coalescent times but may be affected by phasing errors when the species tree is shallow. Estimation of parameters under the MSC model with and without introgression is affected by phasing errors. In particular, random phase resolution causes serious overestimation of population sizes for modern species and biased estimation of cross-species introgression probability. In general the impact of phasing errors is greater when the mutation rate is higher, the data include more samples per species, and the species tree is shallower with recent divergences. Use of phased sequences inferred by the PHASE program produced small biases in parameter estimates. We analyze two real datasets, one of East Asian brown frogs and another of Rocky Mountains chipmunks, to demonstrate that heterozygote phase-resolution strategies have similar impacts on practical data analyses. We suggest that genome sequencing projects should produce unphased diploid genotype sequences if fully phased data are too challenging to generate, and avoid haploid consensus sequences, which have heterozygous sites phased at random. In case the analytical integration algorithm is computationally unfeasible, computational phasing prior to population genomic analyses is an acceptable alternative.