bluuebunny/crossref_metadata_2025 huggingface dataset:
Signatures of mitonuclear coevolution in a warbler species complex
Authors: Wang Silu , Ore Madelyn J. , Mikkelsen Else K. , Lee-Yaw Julie , Toews David P. L. , Rohwer Sievert , Irwin Darren
Published: April 2020

Mitochondrial (mtDNA) and nuclear (nDNA) genes interact to govern metabolic pathways of mitochondria. When differentiated populations interbreed at secondary contact, incompatibilities between mtDNA of one population and nDNA of the other could result in low fitness of hybrids. In northwestern North America, two hybridizing species of warblers, Setophaga occidentalis (abbreviated as SOCC) and S. townsendi (STOW), provide an excellent system to investigate the potential co-adaptation of mitochondrial and nuclear DNA. The inland population of STOW (inland STOW) harbors mtDNA haplotype that is half a million years divergent from the SOCC mtDNA, and these populations also differ strongly in a few nDNA regions. Coastal populations of STOW (coastal STOW) have mixed ancestry, consistent with ancient hybridization of SOCC and inland STOW-like population. Of the few highly-differentiated nDNA regions between inland STOW and SOCC, one of these regions (on chromosome 5) is also differentiated between coastal STOW and inland STOW, and covaries with mtDNA among coastal STOW populations. Genes in this 1.2Mb region of chromosome 5 are associated with fatty acid oxidation and energy-related signaling transduction, both of which are closely associated with mitochondrial function. This chromosome 5 region is correlated with mtDNA haplotypes both within and across sampling sites, a pattern consistent with mitonuclear co-adaptation. We show that such mitonuclear coevolution might be maintained by climate-related selection, because mitonuclear ancestry is correlated with climatic conditions among sampling sites. Together, our observation suggests climatic-associated adaptation shaping mitonuclear differentiation and introgression in this species complex.
Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
Authors: Zhang Shuang , Iyer Sonia , Ran Hao , Dolgalev Igor , Wei Wei , Foster Connor , Weinberg Robert A. , Neel Benjamin G.
Published: April 2020

The paucity of genetically informed, immune-competent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube (FT) organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high grade serous ovarian carcinoma (HGSOC) models exhibiting mutational combinations seen in patients. Detailed analysis of homologous recombination (HR)-proficient (Tp53-/-;Ccne1OE;Akt2OE;KrasOE), HR-deficient (Tp53-/-;Brca1-/-;MycOE) and unclassified (Tp53-/-;Pten-/-;Nf1-/-) organoids revealed differences inin vitroproperties and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSOC chemotherapeutics and evoked distinct immune microenvironments. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T-cell dependent responses inTp53-/-;Ccne1OE;Akt2OE;KrasHGSOC; by contrast,Tp53-/-;Pten-/-;Nf1-/-tumors failed to respond. Genotype-informed, syngeneic organoid models could provide an improved platform for rapid evaluation of tumor biology and therapeutics.

HIGHLIGHTS

Orthotopic injection of genetically defined fallopian tube organoids yield HGSOC.

Ovarian tumors with different genotypes evoke distinct immune microenvironments

Combining Gemcitabine, anti-PD-L1, and anti-CTLA-4 result in complete responses inTp53-/-;Ccne1OE;Akt2OE;KrasOEorganoid-derived HGSOC

Therapeutic response is tumor genotype-specific
Voxel Carving Based 3D Reconstruction of Sorghum Identifies Genetic Determinants of Radiation Interception Efficiency
Authors: Gaillard Mathieu , Miao Chenyong , Schnable James C. , Benes Bedrich
Published: April 2020

Changes in canopy architecture traits have been shown to contribute to yield increases. Optimizing both light interception and radiation use efficiency of agricultural crop canopies will be essential to meeting growing needs for food. Canopy architecture is inherently 3D, but many approaches to measuring canopy architecture component traits treat the canopy as a two dimensional structure in order to make large scale measurement, selective breeding, and gene identification logistically feasible. We develop a high throughput voxel carving strategy to reconstruct three dimensional representations of maize and sorghum from a small number of RGB photos. This approach was employed to generate three dimensional reconstructions of a sorghum association population at the late vegetative stage of development. Light interception parameters estimated from these reconstructions enabled the identification of both known and previously unreported loci controlling light interception efficiency in sorghum. The approach described here is generalizable and scalable and it enables 3D reconstructions from existing plant high throughput phenotyping datasets. For future datasets we propose a set of best practices to increase the accuracy of three dimensional reconstructions.
Insulin/IGF signaling and TOR promote vitellogenesis via inducing juvenile hormone biosynthesis
Authors: Zhu Shiming , Liu Fangfang , Zeng Huanchao , Li Na , Ren Chonghua , Su Yunlin , Zhou Shutang , Wang Guirong , Palli Subba Reddy , Wang Jian , Qin Yiru , Li Sheng
Published: April 2020

Vitellogenesis, including vitellogenin (Vg) production in the fat body and Vg uptake by maturing oocytes, is of great importance for the successful reproduction of adult females. The endocrinal and nutritional regulation of vitellogenesis differs distinctly in insects. Here, the complex crosstalk between juvenile hormone (JH) and the two nutrient sensors, insulin/IGF signaling (IIS) and target of rapamycin (TOR), was investigated to elucidate the molecular mechanisms regulating vitellogenesis in the American cockroach,Periplaneta americana.Our data showed that a block of JH biosynthesis or JH action arrested vitellogenesis, partially by inhibiting the expression ofdoublesex (Dsx),a key transcription factor gene involved in the sex determination cascade. Depletion of IIS and TOR blocked both JH biosynthesis and vitellogenesis. Importantly, the JH analog methoprene, but not bovine insulin (to restore IIS) and amino acids (to restore TOR activity), restored vitellogenesis in the neck-ligated (both nutrient- and JH-deficient) cockroaches. Combining classic physiology with modern molecular techniques, we have demonstrated that JH signaling alone is able to induce vitellogenesis and thus ovarian maturation. By contrast, IIS and TOR do not induce vitellogenesis independent of JH, the nutrient sensors promote vitellogenesis in an indirect manner via activating JH biosynthesis.
Mathematical modeling of genetic pest management through female-specific lethality: Is one locus better than two?
Authors: Vella Michael R. , Gould Fred , Lloyd Alun L.
Published: April 2020

Many novel genetic approaches are under development to combat insect pests. One genetic strategy aims to suppress or locally eliminate a species through large, repeated releases of genetically engineered strains that render female offspring unviable under field conditions. Strains with this female-killing (FK) characteristic have been developed either with all of the molecular components in a single construct or with the components in two constructs inserted at independently assorting loci. Strains with two constructs are typically considered to be only of value as research tools and for producing solely male offspring in rearing factories which are subsequently sterilized by radiation before release. A concern with the two-construct strains is that once released, the two constructs would become separated and therefore non-functional. The only FK strains that have been released in the field without sterilization are single-construct strains. Here, we use a population genetics model with density dependence to evaluate the relative effectiveness of female killing approaches based on single- and two-construct arrangements. We find that, in general, the single-construct arrangement results in slightly faster population suppression, but the two-construct arrangement can eventually cause stronger suppression and cause local elimination with a smaller release size. Based on our results, there is no a priori reason that males carrying two independently segregating constructs need to be sterilized prior to release. In some cases, a fertile release would be more efficient for population suppression.
WD 40 domain of RqkA regulates its kinase activity and role in extraordinary radioresistance inDeinococcus radiodurans
Authors: Sharma Dhirendra Kumar , Bihani Subhash C. , Misra Hari S , Rajpurohit Yogendra S.
Published: April 2020

RqkA, a DNA damage responsive Serine / Threonine kinase is characterized for its role in DNA repair and cell division inD. radiodurans. It has a unique combination of a kinase domain at N-terminus and a WD40 type domain at C-terminus joined through a linker. WD40 domain is comprised of eight β propeller repeats held together via “tryptophan-docking motifs” and forming a typical ‘velcro’ closure structure. RqkA mutants lacking the WD40 region (hereafter referred to as WD mutant) could not complement RqkA loss in γ radiation resistance inD. radioduransand lacked γ radiation mediated activation of kinase activityin vivo. WD mutants failed to phosphorylate its cognate substrate (e.g. DrRecA) in surrogateE. colicells. Further, unlike wild type enzyme, the kinase activity of its WD40 mutants was not stimulated by Pyrroloquinoline quinine (PQQ) indicating the role of the WD motifs in PQQ interaction and stimulation of its kinase activity. Together, results highlighted the importance of the WD40 domain in the regulation of RqkA kinase signaling functionsin vivoand thus the role of WD40 domain in the regulation of any STPK is the first time demonstrated in bacteria.

Importance

This study highlights the importance of the WD40 domain in activity regulation and signaling activity of bacterial serine/ threonine kinase for the first time in the bacterial response to gamma radiation and DNA damage.
Capsid Proteins are Necessary for Replication of a Parvovirus
Authors: Labadie Thomas , Garcia Deborah , Mutuel Doriane , Ogliastro Mylène , Cambray Guillaume
Published: April 2020

Abstract

Despite tight genetic compression, viral genomes are often organized in functional gene clusters, a modular structure that might favor their evolvability. This has greatly facilitated biotechnological developments, such as the recombinant Adeno-Associated Virus (AAV) systems for gene therapy. Following this lead, we endeavored to engineer the related insect parvovirusJunonia coeniadensovirus (JcDV) to create addressable vectors for insect pest biocontrol. To enable safer manipulation of capsid mutants, we translocated the non-structural (ns) gene cluster outside the viral genome. To our dismay, this yielded a virtually non-replicable clone. We linked the replication defect to an unexpected modularity breach, asnstranslocation truncated the overlapping 3’ UTR of the capsid transcript (vp). We found that nativevp3’UTR is necessary to high VP production, but that decreased expression do not adversely impact the expression of NS proteins, which are known replication effectors. As nonsensevpmutations recapitulate the replication defect, VP proteins appear directly implicated in the replication process. Our findings suggest intricate replication-encapsidation couplings that favor maintenance of genetic integrity. We discuss possible connections with an intriguing cis-packaging phenomenon previously observed in parvoviruses, whereby capsids preferentially package the genome from which they were expressed.

Importance

Densoviruses could be used as biological control agents to manage insect pests. Such applications require in depth biological understanding and associated molecular tools. However, the genomes of these viruses remain hard to manipulate due too poorly tractable secondary structures at their extremities. We devised a construction strategy that enable precise and efficient molecular modifications. Using this approach, we endeavored to create a split clone of theJunonia coeniadensovirus (JcDV) that can be used to safely study the impact of capsid mutations on host specificity. Our original construct proved to be non-functional. Fixing this defect led us to uncover that capsid proteins and their correct expression are essential for continued rolling-hairpin replication. This points to an intriguing link between replication and packaging, which might be shared with related viruses. This serendipitous discovery illustrates the power of synthetic biology approaches to advance our knowledge of biological systems.
Similar gut bacterial microbiota in two fruit-feeding moth pests collected from different host species and locations
Authors: Gong Qiang , Cao Li-Jun , Chen Jin-Cui , Gong Ya-Jun , Pu De-Qiang , Huang Qiong , Hoffmann Ary Anthony , Wei Shu-Jun
Published: April 2020

Numerous gut microbes are associated with insects, but their composition remains largely unknown for many insect groups, along with factors influencing their composition. Here, we compared gut bacterial microbiota of two co-occurring agricultural pests, the peach fruit moth (PFM) and the oriental fruit moth (OFM), collected from different orchards and host plant species. Gut microbiota of both species was mainly composed of bacteria from Proteobacteria, followed by Firmicutes. The two species shared bacteria from the generaPseudomonas,Gluconobacter,Acetobacter, andPantoea, although endosymbioticWolbachiawas the most abundant genus in PFM andLactobacilluswas the most abundant in OFM. PFM tended to have lower diversity and richness of gut microbiota than OFM; however, only some of the comparisons were statistically significant. Orchards can influence gut microbiota in terms of richness, particularly for PFM, but not so much for diversity parameters. Functional prediction of gut microbiota showed that the top pathways are amino acid metabolism, translation, and membrane transport in both species, but their abundance varied between the two moth species. These results show that two fruit moths share many features of gut microbiota, and the bacterial species are relatively stable within moth species even when they use different host plants. Our study suggests that fruit-feeding behavior may play a role in shaping gut microbiota of the two fruit moths, which may provide microbial targets for pest control.

Importance

Understanding the associated microbes with insects can point to new targets for pest control. Here we compared bacterial community in the gut of two co-occurring agricultural pests, the peach fruit moth (PFM) and the oriental fruit moth (OFM), collected from different orchards and host plant species. We found that the bacterial generaPseudomonas,Gluconobacter,Acetobacter, andPantoeaare abundant and shared in two moths. The composition of the bacterial species is relatively stable within moth species even when they use different host plants, indicating that the gut microbiota community in the PFM and OFM is likely to be related to their fruit-feeding behavior. The findings have implications for developing novel pest control approaches by targeting gut microbes associated with the two moths.
The impact of early social distancing at COVID-19 Outbreak in the largest Metropolitan Area of Brazil
Authors: Ganem Fabiana , Mendes Fabio Macedo , de Oliveira Silvano Barbosa , Porto Victor Bertollo Gomes , de Araújo Wildo Navegantes , Nakaya Helder I. , Diaz-Quijano Fredi A. , Croda Julio
Published: April 2020

We calculated the impact of early social distancing on the COVID-19 transmission in the São Paulo metropolitan area and forecasted the ICU beds needed to cope the epidemic demand by using an age-stratified SEIR model. Within 60 days, these measures would avoid 89,133 deaths.
Unsupervised learning predicts human perception and misperception of gloss
Authors: Storrs Katherine R. , Anderson Barton L. , Fleming Roland W.
Published: April 2020

Reflectance, lighting, and geometry combine in complex ways to create images. How do we disentangle these to perceive individual properties, like surface glossiness? We suggest that brains disentangle properties by learning to model statistical structure in proximal images. To test this, we trained unsupervised generative neural networks on renderings of glossy surfaces and compared their representations with human gloss judgments. The networks spontaneously cluster images according to distal properties such as reflectance and illumination, despite receiving no explicit information about them. Intriguingly, the resulting representations also predict the specific patterns of ‘successes’ and ‘errors’ in human perception. Linearly decoding specular reflectance from the model’s internal code predicts human gloss perception better than ground truth, supervised networks, or control models, and predicts, on an image-by-image basis, illusions of gloss perception caused by interactions between material, shape, and lighting. Unsupervised learning may underlie many perceptual dimensions in vision, and beyond.
Unsupervised protein embeddings outperform hand-crafted sequence and structure features at predicting molecular function
Authors: Villegas-Morcillo Amelia , Makrodimitris Stavros , van Ham Roeland C.H.J. , Gomez Angel M. , Sanchez Victoria , Reinders Marcel J.T.
Published: April 2020

Motivation

Protein function prediction is a difficult bioinformatics problem. Many recent methods use deep neural networks to learn complex sequence representations and predict function from these. Deep supervised models require a lot of labeled training data which are not available for this task. However, a very large amount of protein sequences without functional labels is available.

Results

We applied an existing deep sequence model that had been pre-trained in an unsupervised setting on the supervised task of protein function prediction. We found that this complex feature representation is effective for this task, outperforming hand-crafted features such as one-hot encoding of amino acids,k-mer counts, secondary structure and backbone angles. Also, it partly negates the need for deep prediction models, as a two-layer perceptron was enough to achieve state-of-the-art performance in the third Critical Assessment of Functional Annotation benchmark. We also show that combining this sequence representation with protein 3D structure information does not lead to performance improvement, hinting that three-dimensional structure is also potentially learned during the unsupervised pre-training.

Availability

Implementations of all used models can be found athttps://github.com/stamakro/GCN-for-Structure-and-Function.

Contact

ameliavm@ugr.es

Supplementary information

Supplementary data are available online.
Lamin B2 follows lamin A/C- mediated nuclear mechanics and cancer cell invasion efficacy
Authors: Vortmeyer-Krause Marina , Lindert Mariska te , Riet Joost te , Boekhorst Veronika te , Marke Rene , Perera Ramanil , Isermann Philipp , van Oorschot Tom , Zwerger Monika , Yang Fengwei , Svoreň Martin , Madzvamuse Anotida , Lammerding Jan , Friedl Peter , Wolf Katarina
Published: April 2020

Interstitial tumor cell invasion depends upon complex mechanochemical adaptation of both cell body and the rigid nucleus in response to extracellular tissue topologies. Nuclear mechanics during cell migration through confined environments is controlled by A-type lamins, however, the contribution of B-type lamins to the deformability of the nucleus remains unclear. Using systematic expression regulation of different lamin isoforms, we applied multi-parameter wet-lab and in silico analysis to test their impact on nuclear mechanics, shape regulation, and cancer cell migration. Modulation of lamin A/C and B2 but not B1 isoforms controlled nuclear deformation and viscoelasticity, whereby lamin B2 generally followed lamin A/C-mediated effects. Cell migration rates were altered by 5 to 9-fold in dense collagen environments and synthetic devices, with accelerated rates after lamin downregulation and reverse effects after lamin upregulation, with migration rates strongly depending on nuclear shape change. These findings implicate cooperation of lamin B2 with lamin A/C in regulating nuclear mechanics for shape adaptation and migration efficacy.

Nuclear deformability during cancer cell invasion and metastasis is critically regulated by lamin A. Here, researchers showed that lamin B2 also contributes to nuclear mechanics, implicating cooperating lamin networks regulating nuclear integrity, migration efficacy, and metastatic tumor progression.
Targeting c-Myc with a novel Peptide Nuclear Delivery Device
Authors: Ting Trinda Anne , Chaumet Alexandre , Bard Frederic
Published: April 2020

Biologics such as peptides and antibodies are a well-established class of therapeutics. However, their intracellular delivery remains problematic. In particular, methods to efficiently inhibit intra-nuclear targets are lacking. We previously described that Pseudomonas Exotoxin A reaches the nucleoplasm via the endosomes-to-nucleus trafficking pathway. Here, we show that a non-toxic truncated form of PE can be coupled to peptides and efficiently reach the nucleoplasm. It can be used as a Peptide Nuclear Delivery Device (PNDD) to deliver polypeptidic cargos as large as Glutathione-S-transferase (GST) to the nucleus. PNDD1 is a fusion of PNDD to the c-myc inhibitor peptide H1. PNDD1 is able to inhibit c-Myc dependent transcription at nanomolar concentration. In contrast, H1 fused to various cell-penetrating peptides are active only in the micromolar range. PNDD1 attenuates cell proliferation and induces cell death in various tumor cell lines. In particular, several patient-derived Diffuse Large B-Cell Lymphomas cell lines die after exposure to PNDD1, while normal B-cells survive. Altogether, our data indicate that PNDD is a powerful tool to bring active cargo to the nucleus and PNDD1 could be the basis of a new therapy against lymphoma.
Disseminating cells in human oral tumours acquire an EMT cancer stem cell state that is predictive of metastasis
Authors: Youssef Gehad , Gammon Luke , Ambler Leah , Lunetto Sophia , Scemama Alice , Cottom Hannah , Piper Kim , Mackenzie Ian C. , Philpott Michael P. , Biddle Adrian
Published: April 2020

Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as markers of EMT CSCs with enhanced plasticity. This afforded the opportunity to investigate whether retention of EpCAM and CD24 alongside upregulation of the EMT marker Vimentin can identify disseminating EMT CSCs in human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 84 human oral cancer specimens, we see a significant enrichment of single EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.
Distribution of disease-causing germline mutations in coiled-coils suggests essential role of their N-terminal region
Authors: Kalman Zsofia E. , Mészáros Bálint , Gáspári Zoltán , Dobson Laszlo
Published: April 2020

Next-generation sequencing resulted in the identification of a huge number of naturally occurring variations in human proteins. The correct interpretation of the functional effects of these variations necessitates the understanding of how they modulate protein structure. Coiled-coils are α-helical structures responsible for a diverse range of functions, but most importantly, they facilitate the structural organization of macromolecular scaffoldsviaoligomerization. In this study, we analyzed a comprehensive set of disease-associated germline mutations in coiled-coil structures. Our results highlight the essential role of residues near the N-terminal part of coiled-coil regions, possibly critical for superhelix assembly and folding in some cases. We also show that coiled-coils of different oligomerization states exhibit characteristically distinct patterns of disease-causing mutations. Our study provides structural and functional explanations on how disease emerges through the mutation of these structural motifs.
Gain and Loss of Function mutations in biological chemical reaction networks: a mathematical model with application to colorectal cancer cells
Authors: Sommariva Sara , Caviglia Giacomo , Piana Michele
Published: April 2020

This paper studies a system of Ordinary Differential Equations modeling a chemical reaction network and derives from it a simulation tool mimicking Loss of Function and Gain of Function mutations found in cancer cells. More specifically, from a theoretical perspective, our approach focuses on the determination of moiety conservation laws for the system and their relation with the corresponding stoichiometric surfaces. Then we show that Loss of Function mutations can be implemented in the model via modification of the initial conditions in the system, while Gain of Function mutations can be implemented by eliminating specific reactions. Finally, the model is utilized to examine in detail the G1-S phase of a colorectal cancer cell.
Decoding transcriptional regulation via a human gene expression predictor
Authors: Wang Yuzhou , Zhang Yu , Gong Jiazhen , Bao Jianqiang , Ma Shisong
Published: April 2020

Transcription factors (TF) regulate cellular activities via controlling gene expression, but a predictive model describing how TFs quantitatively modulate human transcriptomes was lacking. We constructed a universal human gene expression predictor and utilized it to decode transcriptional regulation. Using 1613 TFs’ expression, the predictor reconstituted highly accurate transcriptomes for samples derived from a wide range of tissues and conditions. The predictor’s broad applicability indicated it had recapitulated the quantitative relationships between TFs and target genes ubiquitous across tissues. Significant interacting TF-target gene pairs were then extracted from the predictor and enabled downstream inference of TF regulators for diverse pathways involved in development, immunity, metabolism, and stress response. Thus, we present a novel approach to study human transcriptional regulation following the “understanding by modeling” principle.
The histone variant H2A.Z is required to establish normal patterns of H3K27 methylation inNeurospora crassa
Authors: Courtney Abigail J. , Kamei Masayuki , Ferraro Aileen R. , Gai Kexin , He Qun , Honda Shinji , Lewis Zachary A.
Published: April 2020

Neurospora crassacontains a minimal Polycomb repression system, which provides rich opportunities to explore Polycomb-mediated repression across eukaryotes and enables genetic studies that can be difficult in plant and animal systems. Polycomb Repressive Complex 2 is a multi-subunit complex that deposits mono-, di-, and tri-methyl groups on lysine 27 of histone H3, and tri-methyl H3K27 is a molecular marker of transcriptionally repressed facultative heterochromatin. In mouse embryonic stem cells and multiple plant species, H2A.Z has been found to be co-localized with H3K27 methylation. H2A.Z is required for normal H3K27 methylation in these experimental systems, though the regulatory mechanisms are not well understood. We report here thatNeurospora crassamutants lacking H2A.Z or SWR-1, the ATP-dependent histone variant exchanger, exhibit a striking reduction in levels of H3K27 methylation. RNA-sequencing revealed downregulation ofeed, encoding a subunit of PRC2, in anhH2Azmutant compared to wild type and overexpression of EED in a ΔhH2Az;Δeedbackground restored most H3K27 methylation. Reducedeedexpression leads to region-specific losses of H3K27 methylation suggesting that EED-dependent mechanisms are critical for normal H3K27 methylation at certain regions in the genome.

AUTHOR SUMMARY

Eukaryotic DNA is packaged with histone proteins to form a DNA-protein complex called chromatin. Inside the nucleus, chromatin can be assembled into a variety of higher-order structures that profoundly impact gene expression. Polycomb Group proteins are important chromatin regulators that control assembly of a highly condensed form of chromatin. The functions of Polycomb Group proteins are critical for maintaining stable gene repression during development of multicellular organisms, and defects in Polycomb proteins are linked to disease. There is significant interest in elucidating the molecular mechanisms that regulate the activities of Polycomb Group proteins and the assembly of transcriptionally repressed chromatin domains. In this study, we used a model fungus to investigate the regulatory relationship between a histone variant, H2A.Z, and a conserved histone modifying enzyme complex, Polycomb Repressive Complex 2 (PRC2). We found that H2A.Z is required for normal expression of a PRC2 component. Mutants that lack H2A.Z have defects in chromatin structure at some parts of the genome, but not others. Identification of PRC2-target domains that are differentially dependent on EED provides insights into the diverse mechanisms that regulate assembly and maintenance of facultative heterochromatin in a simple model system.

Data Reference Numbers

GSE146611
Diffusion MRI of the Unfolded Hippocampus
Authors: Hussain Uzair , DeKraker Jordan , Rajakumar Nagalingam , Baron Corey A. , Khan Ali R.
Published: April 2020

The hippocampus is implicated in numerous neurological disorders and the ability to detect subtle or focal hippocampal abnormalities earlier in disease progression could significantly improve the treatment of patients. Ex vivo studies with ultra-high field have revealed that diffusion MRI (dMRI) can reveal microstructural variations within the hippocampal subfields and lamina, and may also be sensitive to intra-hippocampal pathways. However, translation to lower resolution in vivo dMRI studies of the hippocampus is challenging due to its complicated geometry. One novel way to overcome some of these obstacles is by transforming the usual Cartesian coordinates in an MRI image to coordinates that are crafted to curve themselves according to the complicated geometry of the hippocampus. This procedure allows us to virtually unfold the hippocampus into a thin sheet. In this work, we introduce an algorithm to map diffusion MRI data to this sheet, allowing us to overcome the difficulties associated with the hippocampus’ complicated geometry. We demonstrate how our method can be readily integrated into existing implementations of traditional tractography methods and how it leads to enhancements in the resulting tracts. Further, our results on high quality in vivo dMRI acquisitions show that unfolding the hippocampus leads to a more anatomically plausible modelling of the connectivity of the hippocampus as probed by probabilistic tractography, revealing key elements of the polysynaptic pathway and anterior-posterior connectivity gradients.
Comparative analysis of the modulation of perineuronal nets in the prefrontal cortex of rats during protracted withdrawal from cocaine, heroin and sucrose self-administration
Authors: Roura-Martínez David , Díaz-Bejarano Paula , Ucha Marcos , Ambrosio Emilio , Higuera-Matas Alejandro
Published: April 2020

Relapse into drug use is a significant problem for people recovering from addiction. The ability that conditioned cues have to reinstate and reinvigorate drug-seeking is potentiated over time (incubation of seeking), posing an additional difficulty for maintaining abstinence. While the prefrontal cortex has been involved in the incubation phenomenon and the extracellular matrix, perineuronal nets (PNN) in particular, may play a vital role in brain plasticity associated to drug relapse, there are no comparative analyses between different drug classes and natural reinforcers. Here, we compare the effects of early (1 day) and protracted (30 days) withdrawal from to cocaine, heroin and sucrose self-administration on the PNN content of different territories of the prefrontal cortex of male Lewis rats. Our results show that cocaine self-administration and protracted withdrawal decreased PNN content in the prelimbic cortex. Also, heroin self-administration increased PNN content in the infralimbic cortex, but this effect was lost after 30 days of withdrawal. Heroin self-administration also decreased PNNs in the insula, an effect that remained even after protracted withdrawal from the drug. Finally, the self-administration of sucrose-sweetened water decreased PNN content in the dorsomedial prefrontal cortex and increased PNNs in the insular cortex, which was still evident after protracted withdrawal. Our results show that three different rewards with specific pharmacological and physiological actions differentially modulate PNNs in specific areas of the rodent prefrontal cortex with potential implications for the incubation of seeking phenomenon.
Cell – ECM interactions play distinct and essential roles at multiple stages during the development of the aortic arch
Authors: Warkala Michael , Chen Dongying , Jubran Ali , Ramirez AnnJosette , Schonning Michael , Wang Xia , Zhao Huaning , Astrof Sophie
Published: April 2020

Rationale

Defects in the morphogenesis of the 4thpharyngeal arch arteries (PAAs) give rise to lethal birth defects. Understanding genes and mechanisms regulating PAA formation will provide important insights into the etiology and treatments for congenital heart disease.

Objective

Cell-ECM interactions play essential roles in the morphogenesis of PAAs and their derivatives, the aortic arch artery (AAA) and its major branches; however, their specific functions are not well-understood. Previously, we demonstrated that integrin α5β1 and fibronectin (Fn1) expressed in theIsl1lineages regulate PAA formation. The objective of these studies was to investigate cellular mechanisms by which integrin α5β1 and Fn1 regulate AAA morphogenesis.

Methods and Results

Using temporal lineage tracing, whole-mount confocal imaging, and quantitative analysis of the second heart field (SHF) and endothelial cell (EC) dynamics, we show that the majority of PAA EC progenitors arise by E7.5 in the SHF and populate pharyngeal arch mesenchyme between E7.5 and E9.5. Consequently, SHF-derived ECs in the pharyngeal arches become organized into a uniform plexus of small blood vessels, which becomes remodeled into the PAAs between 31 – 35 somites. The remodeling of the vascular plexus is orchestrated by signals dependent on pharyngeal ECM microenvironment extrinsic to the endothelium. Conditional ablation of integrin α5β1 or Fn1 in the Isl1 lineages showed that signaling by the ECM regulates AAA morphogenesis at multiple steps: 1) the recruitment of the SHF-derived ECs into the pharyngeal arches, 2) the remodeling of the uniform EC plexus in the 4tharches into the PAAs; and 3) differentiation of neural crest-derived cells abutting the PAA endothelium into vascular smooth muscle cells.

Conclusions

PAA formation is a multi-step process entailing dynamic contribution of SHF-derived ECs to pharyngeal arches, the remodeling of endothelial plexus into the PAAs, and the remodeling of the PAAs into the AAA and its major branches. Cell-ECM interactions regulated by integrin α5β1 and Fn1 play essential roles at each of these developmental stages.
Neuronal adaptation in the course of the prolonged task improves visual stimuli processing
Authors: Maksimenko Vladimir , Kuc Alexander , Frolov Nikita S. , Hramov Alexander , Pisarchik Alexander , Lebedev Mikhail
Published: April 2020

Brain optimally utilizes resources to resist mental fatigue during the prolonged period of cognitive activity. Neural mechanisms underlying long-term cognitive performance remain unknown. We show that during the 40-minutes visual stimuli classification task, subjects improve behavioral performance in terms of response time and correctness. We observe that the prestimulusθandαpower grows during the experiment manifesting the mental fatigue. The prestimulusβpower, in its turn, increases locally in the region, engaged in the ongoing stimulus processing, that may reflect the neuronal adaptation. Our results evidence that the neuronal adaptation is enhanced in the course of the experiment reducing the cognitive demands required to activate the stimulus-related brain regions.
The missing role of gray matter in studying brain controllability
Authors: Jamalabadi Hamidreza , Zuberer Agnieszka , Kumar Vinod Jangir , Li Meng , Alizadeh Sarah , Moradi Ali Amani , Gaser Christian , Esterman Michael , Walter Martin
Published: April 2020

1

Brain controllability properties are normally derived from the white matter fiber tracts in which the neural substrate of the actual energy consumption, namely the gray matter, has been widely ignored. Here, we study the relationship between gray matter volume of regions across the whole cortex and their respective control property derived from the structural architecture of the white matter fiber tracts. The data suggests that the ability of white fiber tracts to exhibit control at specific nodes not only depends on the connection strength of the structural connectome but additionally strongly depends on gray matter volume at the host nodes. Our data indicates that connectivity strength and gray matter volume interact with respect to the brain’s control properties, such that gray matter exerts the great impact in regions with high structural connectivity. Disentangling effects of the regional gray matter volume and connectivity strength, we found that frontal and sensory areas play crucial roles in controllability. Together these results suggest that structural and regional properties of the white matter and gray matter provide complementary information in studying the control properties of the intrinsic structural and functional architectural of the brain.
Programmed trade-offs in protein folding networks
Authors: Pechmann Sebastian
Published: April 2020

Maintaining protein homeostasis, i.e. a folded and functional proteome, depends on the efficient allocation of cellular protein quality control resources. Decline and dysregulation of protein homeostasis are directly associated to conditions of aging and neurodegeneration. Molecular chaperones as specialized protein quality control enzymes form the core of protein homeostasis. However, how chaperones selectively interact with their substrate proteins thus allocate their overall limited capacity remains poorly understood. Here, I present an integrated analysis of sequence and structural determinants that define interactions of theSaccharomyces cerevisiaeHsp70 Ssb. Structural homologues that differentially interact with Ssb forde novofolding were found to systematically differ in complexity of their folding landscapes, selective use of nonoptimal codons, and presence of short discriminative sequences. All analyzed characteristics contributed to the prediction of Ssb interactions in highly complementary manner, highlighting pervasive trade-offs in chaperone-assisted protein folding landscapes. However, short discriminative sequences were found to contribute by far the strongest signal towards explaining Ssb interactions. This observation suggested that some chaperone interactions may be directly programmed in the amino acid sequences rather than responding to folding challenges, possibly for regulatory advantages.
Effect ofphyBandphyCloss-of-function mutations on the wheat transcriptome under short and long day photoperiods
Authors: Kippes Nestor , VanGessel Carl , Hamilton James , Akpinar Ani , Budak Hikmet , Dubcovsky Jorge , Pearce Stephen
Published: April 2020

Background

Photoperiod signals provide important cues by which plants regulate their growth and development in response to predictable seasonal changes. Phytochromes, a family of red and far-red light receptors, play critical roles in regulating flowering time in response to changing photoperiods. A previous study showed that loss-of-function mutations in eitherPHYBorPHYCresult in large delays in heading time and in the differential regulation of a large number of genes in wheat plants grown in an inductive long day (LD) photoperiod.

Results

We found that under non-inductive short-day (SD) photoperiods,phyB-null andphyC-null mutants were taller, had a reduced number of tillers, longer and wider leaves, and headed later than wild-type plants. Unexpectedly, both mutants flowered earlier in SD than LD, the inverse response to that of wild-type plants. We observed a larger number of differentially expressed genes between mutants and wild-type under SD than under LD, and in both cases, the number was larger forphyBthan forphyC. We identified subsets of differentially expressed and alternatively spliced genes that were specifically regulated byPHYBandPHYCin either SD or LD photoperiods, and a smaller set of genes that were regulated in both photoperiods. We observed significantly higher transcript levels of the flowering promoting genesVRN-A1,PPD-B1andGIGANTEAin thephy-null mutants in SD than in LD, which suggests that they could contribute to the earlier flowering of thephy-null mutants in SD than in LD.

Conclusions

Our study revealed an unexpected reversion of the wheat LD plants into SD plants in thephyB-null andphyC-null mutants and identified candidate genes potentially involved in this phenomenon. Our RNA-seq data provides insight into light signaling pathways in inductive and non-inductive photoperiods and a set of candidate genes to dissect the underlying developmental regulatory networks in wheat.
A Versatile Oblique Plane Microscope for Large-Scale and High-Resolution Imaging of Subcellular Dynamics
Authors: Sapoznik Etai , Chang Bo-Jui , Huh Jaewon , Ju Robert J. , Azarova Evgenia V. , Pohlkamp Theresa , Welf Erik S. , Broadbent David , Carisey Alexandre F. , Stehbens Samantha J. , Lee Kyung-min , Marín Arnaldo , Hanker Ariella B. , Schmidt Jens C. , Arteaga Carlos L. , Yang Bin , Kobayashi Yoshihiko , Tata Purushothama Rao , Kruithoff Rory , Doubrovinski Konstantin , Shepherd Douglas P. , Millett-Sikking Alfred , York Andrew G. , Dean Kevin M. , Fiolka Reto
Published: April 2020

We present an Oblique Plane Microscope that uses a bespoke glass-tipped tertiary objective to improve the resolution, field of view, and usability over previous variants. Owing to its high numerical aperture optics, this microscope achieves lateral and axial resolutions that are comparable to the square illumination mode of Lattice Light-Sheet Microscopy, but in a user friendly and versatile format. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and Natural Killer-mediated cytotoxicity. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through confined spaces within a microfluidic device, subcellular photoactivation of Rac1, diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz, and large field of view imaging of neurons, developing embryos, and centimeter-scale tissue sections.
Optimize Clinical Laboratory Diagnosis of COVID-19 from Suspect Cases by Likelihood Ratio of SARS-CoV-2 IgM and IgG antibody
Authors: Yangchun Feng
Published: April 2020

Objective

To optimize clinical laboratory diagnosis of COVID-19 from suspect cases by Likelihood Ratio of SARS-CoV-2 IgM and IgG antibody.

Methods

By reinterpreting the data in the article “Diagnostic Value of Combined Detection of Serum 2019 novel coronavirus IgM and IgG Antibodies in novel coronavirusin Infection”, the positive likelihood ratio of IgM and IgG antibody in diagnosis of COVID-19 (nucleic acid positive patients) was calculated, and the posterior probability of IgM and IgG antibodies and their tandem detection to diagnose was finally calculated.

Results

The positive likelihood ratios of single IgM and IgG antibody were 18.50 and 12.65 respectively, and the posterior probabilities were 90.18% and 86.26% respectively. However, the posterior probability of the two antibodies tandem detection is 99.15%, which can give clinicians quantitative confidence in the diagnosis of COVID-19 from suspected cases. According to the results of this study, combining the advantages and disadvantages of nucleic acid detection and antibody detection, the clinical pathway for clinicians to diagnose COVID-19 is found.

Conclusion

For suspected cases, IgM and IgG antibody tests should be firstly done at the same time. If the antibody tests are all positive, COVID-19 can be confirmed. If not, nucleic acid detection (one or more times) is performed, and in extreme cases, high-throughput viral genome sequencing is performed.
Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression
Authors: Di Domenico Annunziata , Pipinikas Christodoulos P. , Maire Renaud Sylvain , Bräutigam Konstantin , Simillion Cedric , Dettmer Matthias S. , Vassella Erik , Thirlwell Christina , Perren Aurel , Marinoni Ilaria
Published: April 2020

Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. We examined whether tumour DNA methylation (DNAme) profiling combined with genomic data could identify cell of origin and reveal pathways involved in PanNET progression. We analysed genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confirm cell identity, we investigated ARX and PDX1 expression. Based on epigenetic similarities, PanNETs clustered in α-like, β-like and intermediate tumours. The epigenetic similarity to α-cells progressively decreased in the intermediate tumours, which presented unclear differentiation. Specific transcription factor methylation and expression varied in the respective α/β-tumour groups. Depending on DNAme similarity to α/β-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.
Discount models in intertemporal choice: an empirical analysis
Authors: Parra Oller Isabel María , Cruz Rambaud Salvador , Valls Martínez María del Carmen
Published: April 2020

Purpose

The main purpose of this paper is to determine the discount function which better fits the individuals' preferences through the empirical analysis of the different functions used in the field of intertemporal choice.

Design/methodology/approach

After an in-depth revision of the existing literature and unlike most studies which only focus on exponential and hyperbolic discounting, this manuscript compares the adjustment of data to six different discount functions. To do this, the analysis is based on the usual statistical methods, and the non-linear least squares regression, through the algorithm of Gauss-Newton, in order to estimate the models' parameters; finally, the AICc method is used to compare the significance of the six proposed models.

Findings

This paper shows that the so-calledq-exponential function deformed by the amount is the model which better explains the individuals' preferences on both delayed gains and losses. To the extent of the authors' knowledge, this is the first time that a function different from the general hyperbola fits better to the individuals' preferences.

Originality/value

This paper contributes to the search of an alternative model able to explain the individual behavior in a more realistic way.