bluuebunny/crossref_metadata_2025_split huggingface dataset:
Out of the blue: Phototropins of the leaf vascular bundle sheath mediate the regulation of leaf hydraulic conductance by blue light
Authors: Grunwald Yael , Gosa Sanbon Chaka , Srivastava Tanmayee Torne , Moran Nava , Moshelion Menachem 
Published: August 2019

ABSTRACTThe Arabidopsis leaf veins bundle sheath cells (BSCs) – a selective barrier to water and solutes entering the mesophyll – increase the leaf radial hydraulic conductance (Kleaf) by acidifying the xylem sap by their plasma membrane H+-ATPase, AHA2. Based on this and on the BSCs’ expression of PHOT1 and PHOT2, and the known blue-light (BL)-induced Kleaf increase, we hypothesized that, resembling the guard cells, BL perception by the BSCs’ phots activates its H+-ATPase, which, consequently, upregulates Kleaf. Indeed, under BL, the Kleaf of the knockout mutant lines phot1-5, phot2-1, phot1-5phot2-1, and aha2-4 was lower than that of the WT. BSC-only-directed complementation of phot1-5 or aha2-4 by PHOT1 or AHA2, respectively, restored the BL-induced Kleaf increase. BSC-specific silencing of PHOT1 or PHOT2 prevented such Kleaf increase. A xylem-fed kinase inhibitor (tyrphostin 9) replicated this also in WT plants. White light – ineffective in the phot1-5 mutant – acidified the xylem sap (relative to darkness) in WT and in the PHOT1-complemented phot1-5. These results, supported by BL increase of BSC protoplasts’ water permeability and cytosolic pH and their hyperpolarization by BL, identify the BSCs as a second phot-controlled water conductance element in leaves, in series with stomatal conductance. Through both, BL regulates the leaf water balance.One-Sentence summaryBlue light regulates the leaf hydraulic conductance via the bundle-sheath cells’ blue light PHOT receptors which, via an autonomous signaling pathway, activate the BSCs’ AHA2 H+-pump.
The genome ofPeronospora belbahriireveals high heterozygosity, a low number of canonical effectors and CT-rich promoters
Authors: Thines Marco , Sharma Rahul , Rodenburg Sander Y. A. , Gogleva Anna , Judelson Howard S. , Xia Xiaojuan , van den Hoogen Johan , Kitner Miloslav , Klein Joël , Neilen Manon , de Ridder Dick , Seidl Michael F. , Van den Ackerveken Guido , Govers Francine , Schornack Sebastian , Studholme David J. 
Published: August 2019

AbstractAlong withPlasmopara destructor, Peronosopora belbahriihas arguably been the economically most important newly emerging downy mildew pathogen of the past two decades. Originating from Africa, it has started devastating basil production throughout the world, most likely due to the distribution of infested seed material. Here we present the genome of this pathogen and results from comparisons of its genomic features to other oomycetes. The assembly of the nuclear genome was ca. 35.4 Mbp in length, with an N50 scaffold length of ca. 248 kbp and an L50 scaffold count of 46. The circular mitochondrial genome consisted of ca. 40.1 kbp. From the repeat-masked genome 9049 protein-coding genes were predicted, out of which 335 were predicted to have extracellular functions, representing the smallest secretome so far found in peronosporalean oomycetes. About 16 % of the genome consists of repetitive sequences, and based on simple sequence repeat regions, we provide a set of microsatellites that could be used for population genetic studies ofPe. belbahrii. Peronospora belbahriihas undergone a high degree of convergent evolution, reflecting its obligate biotrophic lifestyle. Features of its secretome, signalling networks, and promoters are presented, and some patterns are hypothesised to reflect the high degree of host specificity inPeronosporaspecies. In addition, we suggest the presence of additional virulence factors apart from classical effector classes that are promising candidates for future functional studies.
LXR alters CD4+ T cell function through direct regulation of glycosphingolipid synthesis
Authors: Waddington Kirsty E , Robinson George A , Rubio-Cuesta Beatriz , Chrifi-Alaoui Eden , Andreone Sara , Poon Kok-Siong , Ivanova Iveta , Martin-Gutierrez Lucia , Owen Dylan M , Jury Elizabeth C , Pineda-Torra Inés 
Published: August 2019

AbstractThe liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells, and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol) which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase (UGCG) as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened pro-inflammatory T cell function. Finally, compared to responder T cells, regulatory T cells had a distinct pattern of LXR-target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a novel mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism, and demonstrate its relevance in modulating T cell function.
The polyQ expansion modulates the configuration and phosphorylation of huntingtin
Authors: Jung Taeyang , Shin Baehyun , Tamo Giorgio , Kim Hyeongju , Vijayvargia Ravi , Leitner Alexander , Marcaida Maria Jose , Astorga-Wells Juan , Jung Roy , Aebersold Ruedi , Peraro Matteo Dal , Hebert Hans , Seong Ihn Sik , Song Ji-Joon 
Published: August 2019

ABSTRACTThe polyQ-expansion at the N-terminus of huntingtin (HTT) is the prime cause of Huntington’s disease. The recent cryo-EM structure of HTT with HAP40 provides information on the protein’s prominent HEAT-repeats. Here, we present analyses of the impact of polyQ-length on the conformation of HTT by cryo-EM, the domain-interactions by cross-linking mass spectrometry and the phosphorylation of HTT. The cryo-EM analysis of normal (Q23-) and disease (Q78-) type HTTs in their apo forms shows that the structures of apo HTTs significantly differ from the structure of HTT-HAP40, and that the polyQ expansion induces global structural changes consisting of significant domain movements of the C-HEAT domain relative to the N-HEAT domain. In addition, we show that the polyQ-expansion alters the phosphorylation pattern across the full-length HTT and that the specific phosphorylation (Ser2116p) in turn affects the global structure of HTT, which influences the activity of polyQ-expanded HTT. These results provide a molecular basis for the effect of the N-terminal polyQ segment on HTT structure and activity, that may be important for the cell-selective toxicity of mutant HTT.
Shifting roles ofDrosophilapair-rule gene orthologs: segmental expression and function in the milkweed bugOncopeltus fasciatus
Authors: Reding Katie , Chen Mengyao , Lu Yong , Jarvela Alys M. Cheatle , Pick Leslie 
Published: August 2019

AbstractThe discovery of pair-rule genes (PRGs) inDrosophilarevealed the existence of an underlying two-segment-wide prepattern directing embryogenesis. The milkweed bugOncopeltus, a hemimetabolous insect, is a more representative arthropod: most of its segments form sequentially after gastrulation. Here we report the expression and function of orthologs of the complete set of nineDrosophilaPRGs inOncopeltus. SevenOf-PRG-orthologs are expressed in stripes in the primordia of every segment, rather than every-other segment,Of-runtis PR-like, and several are also expressed in the segment addition zone. RNAi-mediated knockdown ofOf-odd-skipped,pairedandsloppy-pairedimpacted all segments, with no indication of PR-like register. We confirm thatOf-E75Ais expressed in PR-like stripes, although it is not PR inDrosophila, demonstrating the existence of an underlying PR-like prepattern inOncopeltus. These findings reveal that a switch occurred in regulatory circuits leading to segment formation: while several holometabolous insects are “Drosophila-like,” utilizing PRG-orthologs for PR-patterning, mostOf-PRGs are expressed segmentally inOncopeltus, a more basally-branching insect. Thus, an evolutionarily stable phenotype – segment formation – is directed by alternate regulatory pathways in diverse species.Summary StatementDespite the broad of conservation of segmentation in insects, the regulatory genes underlying this process inDrosophilahave different roles in the hemipteran,Oncopeltus fasciatus.
Structural Basis of the Transmembrane Domain Dimerization in the Activation Mechanism of TrkA by NGF
Authors: Franco María L. , Nadezhdin Kirill D. , Goncharuk Sergey A. , Mineev Konstantin S , Arseniev Alexander S. , Vilar Marçal 
Published: August 2019

AbstractTrk receptors are essential for the nervous system development. The molecular mechanism of TrkA activation by its ligand NGF is still unsolved. Recent data indicates that at endogenous levels most of TrkA is in an equilibrium monomer-dimer and the binding of NGF induces an increase of the dimer and oligomer forms of the receptor. An unsolved issue is the role of the transmembrane domain (TMD) in the dimerization of TrkA and the structural details of the TMD in the active dimer receptor. We found that TrkA-TMD can form dimers, identified the structural determinants of the dimer interface in the active receptor and validated this interface using site-directed mutagenesis together with functional and cell differentiation studies. Usingin vivocrosslinking we identified a reordering of the extracellular juxtamembrane (JTM) region after ligand binding. Replacement of some residues in the JTM region with cysteine form ligand-independent active dimers and reveal a preferred dimer interface. In addition to that, insertion of leucine residues into the TMD helix induces a ligand-independent TrkA activation suggesting that a rotation of the TMD dimers could be behind TrkA activation by NGF. Altogether our data indicates that the transmembrane and juxtamembrane regions of the receptor play a key role in the dimerization and activation of TrkA by NGF.
Post-acute administration of the GABAA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats
Authors: Pace Marta , Falappa Matteo , Machado Patricia , Facchin Laura , Hermann Dirk M. , Bassetti Claudio L. 
Published: August 2019

AbstractBackgroundIschemic stroke induces hypoexcitability of the peri-infarct cortex by increased tonic GABA activity, which impairs stroke recovery. The GABAA α5 antagonist S44819 has recently been shown to promote post-ischemic motor-coordination recovery after transient proximal middle cerebral artery occlusion (MCAO) in mice. The effects of S44819 on post-ischemic skilled limb movement recovery have so far not yet been assessed in rats.MethodsMale Sprague-Dawley rats were subjected to permanent distal MCAO. Starting 3 days post-stroke, vehicle or S44819 (3 or 10 mg/kg) were delivered orally twice a day for 28 days. A single pellet reaching test was performed at baseline, before treatment onset and at weekly intervals thereafter. Animals were sacrificed at 45 days post-stroke (that is, at 42 days post-treatment onset) after 14 days of drug washout. Body weight was monitored, and infarct size was determined by histology.ResultsS44819, administered at 10 mg/kg but not 3 mg/kg significantly improved single pellet reaching performance over 45 days (F(2,96)=22.43, p<0.001). Body weight was not altered. S44819 had no effect on infarct size.ConclusionOur data indicate that post-acute administration of S44819 at 10 mg/kg promotes skilled forelimb movements. The effect was maintained after S44819 wash out.
Joint reconstruction of cis-regulatory interaction networks across multiple tissues using single-cell chromatin accessibility data
Authors: Dong Kangning , Zhang Shihua 
Published: August 2019

ABSTRACTThe rapid accumulation of single-cell chromatin accessibility data offers a unique opportunity to investigate common and specific regulatory mechanisms across different cell types. However, existing methods for cis-regulatory network reconstruction using single-cell chromatin accessibility data were only designed for cells belonging to one cell type, and resulting networks may be incomparable directly due to diverse cell numbers of different cell types. Here, we adopt a computational method to jointly reconstruct cis-regulatory interaction maps (JRIM) of multiple cell populations based on patterns of co-accessibility in single-cell data. We applied JRIM to explore common and specific regulatory interactions across multiple tissues from single-cell ATAC-seq dataset containing ~80,000 cells across 13 mouse tissues. Reconstructed common interactions among 13 tissues indeed relate to basic biological functions, and individual cis-regulatory network shows strong tissue specificity and functional relevance. More importantly, tissue-specific regulatory interactions are mediated by coordination of histone modifications and tissue related TFs, and many of them reveal novel regulatory mechanisms (e.g., a kidney-specific promoter-enhancer loop of clock-controlled gene Gys2).
Variants of intrinsic disorder: structural characterization
Authors: Forcelloni Sergio , Deiana Antonio , Giansanti Andrea 
Published: August 2019

AbstractIn a recent study, we have introduced an operational classification of the human proteome in three variants of disorder: ordered proteins (ORDPs), structured proteins with intrinsically disordered protein regions (IDPRs), intrinsically disordered proteins (IDPs). That classification was useful in functionally separating IDPRs from IDPs, which up until now have been generally considered as a whole. In this study, we corroborate this distinction by considering different physical-chemical and structural properties. Both ORDPs and IDPRs are enriched in order-promoting amino acids, whereas only IDPs show an enrichment in disordered-promoting amino acids. Consistently, ORDPs and IDPRs are preferentially located in the ordered phase of the charge-hydropathy plot, whereas IDPs are widespread over the disordered phase. We introduce the mean packing - mean pairwise energy (MP-MPE) plane to structurally characterize these variants even in the absence of a structural model. As expected for well-packed proteins, a negative linear correlation is observed between MP and MPE for ORDPs and IDPRs, whereas IDPs break this linear dependence. Finally, we find that IDPs have a more extended conformation as measured by the scaling law between the radius of gyration and the length of these proteins, and accordingly they have higher solubility and accessible surface area than ORDPs and IDPRs. Overall, our results confirm the relevance of our operational separation of IDPRs from IDPs and provide further validation of our criteria to separate IDPs from the rest of human proteome.
LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome
Authors: Bozal-Basterra Laura , Gonzalez-Santamarta María , Bermejo-Arteagabeitia Aitor , Da Fonseca Carolina , Pampliega Olatz , Andrade Ricardo , Martín-Martín Natalia , Branon Tess C , Ting Alice Y , Carracedo Arkaitz , Rodríguez Jose A. , Elortza Felix , Sutherland James D. , Barrio Rosa 
Published: August 2019

ABSTRACTPrimary cilia are sensory organelles that are crucial for cell signaling during development and organ homeostasis. Cilia arise from the centrosome and their formation is governed by numerous regulatory factors. We show that the leucine-zipper protein LUZP1 localizes to the pericentriolar material and actin cytoskeleton. Using TurboID proximity labeling and pulldowns, LUZP1 associates with factors linked to centrosome and actin filaments. Loss of LUZP1 reduces F-actin levels, facilitating ciliogenesis and altering Sonic Hedgehog signaling, pointing to a key role in the cytoskeleton-cilia interdependency. Moreover, we show that LUZP1 interacts with a truncated form of the transcription factor SALL1 that causes Townes-Brocks Syndrome. TBS is characterized by digit, heart and kidney malformations and is linked in part to defective cilia. Truncated SALL1 increases the ubiquitin proteasome-mediated degradation of LUZP1. Alteration of LUZP1 levels may be a contributing factor to TBS, suggesting possible therapies using modulators of cilia and cytoskeletal function.
Distance to trait optimum is a crucial factor determining the genomic signature of polygenic adaptation
Authors: Christodoulaki Eirini , Barghi Neda , Schlötterer Christian 
Published: August 2019

AbstractPolygenic adaptation is frequently associated with small allele frequency changes of many loci. Recent works suggest, that large allele frequency changes can be also expected. Laboratory natural selection (LNS) experiments provide an excellent experimental framework to study the adaptive architecture under controlled laboratory conditions: time series data in replicate populations evolving independently to the same trait optimum can be used to identify selected loci. Nevertheless, the choice of the new trait optimum in the laboratory is typically an ad hoc decision without consideration of the distance of the starting population to the new optimum. Here, we used forward-simulations to study the selection signatures of polygenic adaptation in populations evolving to different trait optima. Mimicking LNS experiments we analyzed allele frequencies of the selected alleles and population fitness at multiple time points. We demonstrate that the inferred adaptive architecture strongly depends on the choice of the new trait optimum in the laboratory and the significance cut-off used for identification of selected loci. Our results not only have a major impact on the design of future Evolve and Resequence (E&R) studies, but also on the interpretation of current E&R data sets.
The association between mineralised tissue formation and the mechanical local in vivo environment: Time-lapsed quantification of a mouse defect healing model
Authors: Tourolle né Betts Duncan C , Wehrle Esther , Paul Graeme R , Kuhn Gisela A , Christen Patrik , Hofmann Sandra , Müller Ralph 
Published: August 2019

AbstractAn improved understanding of how local mechanical stimuli guide the fracture healing process has the potential to enhance clinical treatment of bone injury. Recent preclinical studies of bone defect in animal models have used cross-sectional data to examine this phenomenon indirectly. In this study, a direct time-lapsed imaging approach was used to investigate the local mechanical strains that precede the formation of mineralised tissue at the tissue scale. The goal was to test two hypotheses: 1) the local mechanical signal that precedes the onset of tissue mineralisation is higher in areas which mineralise, and 2) this local mechanical signal is independent of the magnitude of global mechanical loading of the tissue in the defect. Two groups of mice with femoral defects of length 0.85 mm (n=10) and 1.45 mm (n=9) were studied, allowing for distinct distributions of tissue scale strains in the defects. The regeneration and (re)modelling of mineralised tissue was observed weekly using in vivo micro-computed tomography (micro-CT), which served as a ground truth for resolving areas of mineralised tissue formation. The mechanical environment was determined using micro-finite element analysis (micro-FE) on baseline images. The formation of mineralised tissue showed strong association with areas of higher mechanical strain (area-under-the-curve: 0.91±0.04, true positive rate: 0.85±0.05) while surface based strains could correctly classify 43% of remodelling events. These findings support our hypotheses by showing a direct association between the local mechanical strains and the formation of mineralised tissue.
Adaptive thermogenesis in mice requires adipocyte light-sensing via Opsin 3
Authors: Nayak Gowri , Vemaraju Shruti , Zhang Kevin X. , Odaka Yoshinobu , Buhr Ethan D. , Holt-Jones Amanda , Smith April N. , Upton Brian A. , Zhan Jesse J. , Diaz Nicolás , Murakami Kazutoshi , D’Souza Shane , Nguyen Minh-Thanh , Gordon Shannon A. , Wu Gang , Schmidt Robert , Mei Xue , Petts Nathan T. , Batie Matthew , Rao Sujata , Nakamura Takahisa , Sweeney Alison M. , Hogenesch John B. , Van Gelder Russell N. , Sanchez-Gurmaches Joan , Lang Richard A. 
Published: August 2019

SummaryAlmost all life forms can decode light information for adaptive advantage. Examples include the visual system, where photoreceptor signals are interpreted as images, and the circadian system, where light entrains a physiological clock. Here we describe a local, non-visual light response in mice that employs encephalopsin (OPN3, a 480 nm, blue light responsive opsin) to regulate the function of adipocytes. Germ line null and adipocyte-specific conditional null mice show a deficit in thermogenesis that is phenocopied in mice under blue-light deficient conditions. We show that blue light stimulation of adipocytes activates hormone sensitive lipase, the rate limiting enzyme in the lipolysis pathway, and that this is OPN3-dependent. Opn3 adipocyte conditional null mice also use reduced levels of fat mass when fasted and cold exposed further suggesting a lipolysis deficit. These data suggest the hypothesis that in mice, a local, OPN3-dependent light response in adipocytes is a mechanism for regulation of energy homeostasis.
Bivalent and Broad Chromatin Domains Regulate Pro-metastatic Drivers in Melanoma
Authors: Terranova Christopher , Tang Ming , Maitituoheti Mayinuer , Raman Ayush T. , Schulz Jonathan , Amin Samir B. , Orouji Elias , Tomczak Katarzyna , Sarkar Sharmistha , Oba Junna , Creasy Caitlin , Wu Chang-Jiun , Zhao Dongyu , Chen Kaifu , Haydu Lauren E. , Wang Wei-Lien , Lazar Alexander J. , Woodman Scott E. , Bernatchez Chantale , Rai Kunal 
Published: August 2019

ABSTRACTChromatin deregulation is an emerging hallmark of cancer. However, the extent of epigenetic aberrations during tumorigenesis and their relationship with genetic aberrations are poorly understood. Using ChIP-sequencing for enhancers (H3K27ac and H3K4me1), promoters (H3K4me3), active transcription (H3K79me2) and polycomb (H3K27me3) or heterochromatin (H3K9me3) repression we generated chromatin state profiles in metastatic melanoma using 46 tumor samples and cell lines. We identified a strong association of NRAS, but not BRAF mutations, with bivalent states harboring H3K4me3 and H3K27me3 marks. Importantly, the loss and gain of bivalent states occurred on important pro-metastasis regulators including master transcription factor drivers of mesenchymal phenotype including ZEB1, TWIST1, SNAI1 and CDH1. Unexpectedly, a subset of these and additional pro-metastatic drivers (e.g. POU3F2, SOX9 and PDGFRA) as well as melanocyte-specific master regulators (e.g. MITF, ZEB2, and TFAP2A) were regulated by exceptionally wide H3K4me3 domains that can span tens of thousands of kilobases suggesting roles of this new epigenetic element in melanoma metastasis. Overall, we find that BRAF, NRAS and WT melanomas may use bivalent states and broad H3K4me3 domains in a specific manner to regulate pro-metastatic drivers. We propose that specific epigenetic traits – such as bivalent and broad domains – get assimilated in the epigenome of pro-metastatic clones to drive evolution of cancer cells to metastasis.