bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-Omics Binary Integration via Lasso Ensembles (MOBILE) for identification of context-specific networks and new regulatory mechanisms
Authors: Erdem Cemal , Gross Sean M. , Heiser Laura M. , Birtwistle Marc R. 
Published: July 2022

AbstractCell phenotypes are dictated by both extra- and intra-cellular contexts, and robust identification of context-specific network features that control phenotypes remains challenging. Here, we developed a multi-omics data integration strategy called MOBILE (Multi-Omics Binary Integration via Lasso Ensembles) to nominate molecular features associated with specific cellular phenotypes. We applied this method to chromatin accessibility, mRNA, protein, and phospho-protein time course datasets and focus on two illustrative use cases after we show MOBILE could recover known biology. First, MOBILE nominated new mechanisms of interferon-γ (IFNγ) regulated PD-L1 expression, where analyses suggested, and literature supported that IFNγ-controlled PD-L1 expression involves BST2, CLIC2, FAM83D, ACSL5, and HIST2H2AA3 genes. Second, we explored differences between the highly similar transforming growth factor-beta 1 (TGFβ1) and bone morphogenetic protein 2 (BMP2) and showed that differential cell size and clustering properties induced by TGFβ1, but not BMP2, were related to the laminin/collagen pathway activity. Given the ever-growing availability of multi-omics datasets, we envision that MOBILE will be broadly applicable to identify context-specific molecular features associated with cellular phenotypes.Graphical SummaryMulti-Omics Binary Integration via Lasso Ensembles (MOBILE) pipeline yields statistically robust, context-specific association networksThe MOBILE pipeline integrates omics datasets in a data-driven, biologically-structured manner.The pipeline outputs are gene-level, contextspecific association networks.These association networks nominate differentially enriched pathways, subnetworks, and new connections.Broadly applicable to find condition specific networks using multi-omics datasets.
Chromatin Remodeling in Patient-Derived Colorectal Cancer Models
Authors: Xiang Kun , Wang Ergang , Rupprecht Gabrielle , Mantyh John , Negrete Marcos , Sanati Golshid , Hsu Carolyn , Randon Peggy , Dohlman Anders , Kretzschmar Kai , Giroux Nicholas , Ding Shengli , Wang Lihua , Balcazar Jorge Prado , Huang Qiang , Sundaramoorthy Pasupathi , Xi Rui , McCall Shannon Jones , Wang Zhaohui , Kang Yubin , Kopetz Scott , Crawford Gregory E. , Clevers Hans , Hsu David , Shen Xiling 
Published: July 2022

AbstractPatient-Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, we compared the transcriptomic and chromatin accessibility landscapes of six matched sets of colorectal cancer (CRC) PDO, PDX, PDO-derived PDX (PDOX), and original patient tumors (PT) and discovered two major remodeling axes. The first axis delineates PDX and PDO from PT, and the second axis distinguishes PDX and PDO. PDOX were more similar to PDX than they were to PDO, indicating that the growth environment is a driving force for chromatin adaptation. Using bivariate genomic footprinting analysis, we identified transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX. Among them, KLF14 and EGR2 footprints were enriched in all six PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient-derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.
Immunity priming uncouples the growth-defense tradeoff in tomato
Authors: Leibman-Markus Meirav , Schneider Anat , Gupta Rupali , Marash Iftah , Rav-David Dalia , Carmeli-Weissberg Mira , Elad Yigal , Bar Maya 
Published: July 2022

AbstractPlants have developed an array of mechanisms to protect themselves against pathogen invasion. The deployment of defense mechanisms is imperative for plant survival, but can come at the expense of plant growth, leading to the “growth- defense trade-off” phenomenon. Following pathogen exposure, plants can develop resistance to further attack. This is known as induced resistance, or priming. Here, we investigated the growth-defense trade-off, examining how defense priming via Systemic Acquired Resistance (SAR), or Induced Systemic Resistance (ISR), affects tomato development and growth. We found that defense priming can promote, rather than inhibit, plant development, and that defense priming and growth tradeoffs can be uncoupled. Cytokinin response was activated during induced resistance, and found to be required for the observed growth and disease resistance resulting from ISR activation. ISR was found to have a stronger effect on plant development than SAR. Our results suggest that growth promotion and induced resistance can be co-dependent, and that in certain cases, defense priming can drive developmental processes and promote plant yield.Summary statementGrowth-defense tradeoffs in plants result in loss of yield. Here, we demonstrate that immunity priming in different pathways uncouples this tradeoff and allows for disease resistant plants with robust growth.
Linking collective migration/growth to differentiation boosts global shaping of the transcriptome and exhibits a grasshopper effect for driving maturation
Authors: Ogoke Ogechi , Guiggey Daniel , Chiang Alexander , Thompson Sarah , Anh Nguyen Tram Hoang , Berke Daniel , Ott Cortney , Kalinousky Allison , Shamul Claire , Chen Peter , Ross Shatoni , Chen Zhaowei , Srivastava Pooja , Gaughan Chris , Mahajan Supriya , Zhao Ruogang , Gunawan Rudyanto , Parashurama Natesh 
Published: July 2022

ABSTRACTThe shift from collective migration to differentiation is a crucial process in epithelial biology but recreating this intricate transition has thus far proved elusive. We provide experimental, mechanistic,in vivo, and bioinformatic data supporting an undoubtable link between human pluripotent stem cell (hPSC)- derived collectively migrating hepatoblasts (MHB), and transcriptionally mature, functional hPSC- hepatocytes (HEPs), which incorporates two unrecognized steps. The protocol induces FOXA-dependent induction of HBs, leading to TBX3-positive, YAP-TEAD active MHB’s which provide a transcriptional match with murine liver E9.5 MHBs. Simple cultivation changes trigger MHB’s to rapidly form functional day 18 HEPs, predicted by a deep-learning designed gene circuit, resulting in a ∼236% fold- increase in maturation (PACNet), on par with the highest score, but with enhanced global transcriptional shaping. Overall, incorporating the MHB to HEP transition establishes a new, unrecognized, and highly efficient mechanism for differentiation that can be cumulatively integrated with existing methods to overcome barriers to maturation.
Variation of length and sequence of the nuclear ribosomal DNA internal transcribed spacer 1 supports “hermit-to-king” crab hypothesis
Authors: Chow Seinen , Hamasaki Katsuyuki , Konishi Kooichi , Yanagimoto Takashi , Wagatsuma Ryota , Takeyama Haruko 
Published: July 2022

AbstractLithodoid and paguroid crabs are morphologically assigned to the superfamilies Lithodoidea and Paguroidea, respectively. Molecular analyses, however, have revealed closer genetic proximity of the lithodoid crabs to the family Paguridae than to other families of Paguroidea, provoking a long debate. We investigated the length and nucleotide sequence variation of the nuclear ribosomal DNA internal transcribed spacer 1 (ITS1) in lithodoid and paguroid species. Uniquely short ITS1s (215–253 bp) were observed in seven lithodoid species belonging to the families Lithodidae and Hapalogastridae. In contrast, ITS1 length varied considerably in 13 paguroid species belonging to the families Coenobitidae, Diogenidae, and Paguridae. Short-to-long ITS1s (238–1090 bp) were observed in five species of the family Paguridae, and medium to long ITS1s (573–1166 bp) were observed in eight species of the families Coenobitidae and Diogenidae. Interestingly, ITS1s of considerably different sizes coexist in individual paguroid species. Nucleotide sequence analysis indicated that the short ITS1s observed in the family Paguridae were descendants of longer ITS1s and were homologous to the short ITS1 of lithodoid species. ITS1 sequences of the families Coenobitidae and Diogenidae shared no nucleotide elements similar to those of lithodoid and pagurid species. These molecular signals indicate that the short ITS1 in pagurid lineage was passed on to lithodoid lineage, strongly supporting the “hermit-to-king” crab hypothesis.
Encoding of Dynamic Facial Information in the Middle Dorsal Face Area
Authors: Yang Zetian , Freiwald Winrich A. 
Published: July 2022

AbstractFaces in motion reveal a plethora of information through visual dynamics. Faces can move in complex patterns while transforming facial shape, e.g. during the generation of different emotional expressions. While motion and shape processing have been studied extensively in separate research enterprises, much less is known about their conjunction during biological motion. Here we took advantage of the discovery in brain-imaging studies of an area in the dorsal portion of the macaque monkey superior temporal sulcus (STS), the middle dorsal face area (MD), with selectivity for naturalistic face motion. To gain mechanistic insights into the coding of facial motion, we recorded single-unit activity from MD, testing whether and how MD cells encode face motion. The MD population was highly sensitive to naturalistic facial motion and facial shape. Some MD cells responded only to the conjunction of facial shape and motion, others were selective for facial shape even without movement, and yet others were suppressed by facial motion. We found that this heterogeneous MD population transforms face motion into a higher-dimensional activity space, a representation that would allow for high sensitivity to relevant small-scale movements. Indeed we show that many MD cells carry such sensitivity for eye movements. We further found that MD cells encode motion of head, mouth, and eyes in a separable manner, requiring the use of multiple reference frames. Thus, MD is a bona-fide face-motion area that uses highly heterogeneous cell populations to create codes capturing even complex facial motion trajectories.
Deep embedded clustering by relevant scales and genome-wide association study in autism
Authors: Ueno Fumihiko , Onuma Tomomi , Takahashi Ippei , Ohseto Hisashi , Narita Akira , Obara Taku , Ishikuro Mami , Murakami Keiko , Noda Aoi , Matsuzaki Fumiko , Metoki Hirohito , Tamiya Gen , Kure Shigeo , Kuriyama Shinichi 
Published: July 2022

AbstractThe etiology of autism spectrum disorders (ASD) remains unclear. Stratifying patients with ASD may help to identify genetically homogeneous subgroups. Using a deep embedded clustering algorithm, we conducted cluster analyses of Simons Foundation Powering Autism Research for Knowledge (SPARK) datasets and performed genome-wide association studies (GWAS) of the clusters. We observed no significant associations in the conventional GWAS comparing all patients to all controls. However, in the GWAS, comparing patients divided into clusters with similar phenotypes to controls (cluster-based GWAS), we identified 90 chromosomal loci that satisfied the P < 5.0 × 10−8, several of which were located within or near previously reported candidate genes for ASD. Our findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies.
A bead-based GPCR phosphorylation immunoassay for high-throughput ligand profiling and GRK inhibitor screening
Authors: Kaufmann Johanna , Blum Nina Kathleen , Nagel Falko , Schuler Anna , Drube Julia , Degenhart Carsten , Engel Julian , Eickhoff Jan Eicke , Dasgupta Pooja , Fritzwanker Sebastian , Guastadisegni Maria , Schulte Clemens , Miess-Tanneberg Elke , Maric Hans Michael , Spetea Mariana , Kliewer Andrea , Baumann Matthias , Klebl Bert , Reinscheid Rainer K. , Hoffmann Carsten , Schulz Stefan 
Published: July 2022

AbstractAnalysis of agonist-driven phosphorylation of G protein-coupled receptors (GPCRs) can provide valuable insights into the receptor activation state and ligand pharmacology. However, to date, assessment of GPCR phosphorylation using high-throughput applications has been challenging. We have developed and validated a bead-based immunoassay for the quantitative assessment of agonist-induced GPCR phosphorylation that can be performed entirely in multiwell cell culture plates. The assay involves immunoprecipitation of affinity-tagged receptors using magnetic beads followed by protein detection using phosphorylation-state-specific and phosphorylation state-independent anti-GPCR antibodies. As proof of concept, five prototypical GPCRs (MOP, C5a1, D1, SST2, CB2) were treated with different agonists and antagonists, and concentration-response curves were generated. We then extended our approach to establish selective cellular GPCR kinase (GRK) inhibitor assays, which led to the rapid identification of a selective GRK5/6 inhibitor (LDC8988) and a highly potent pan-GRK inhibitor (LDC9728). In conclusion, this versatile GPCR phosphorylation assay can be used extensively for ligand profiling and inhibitor screening.
Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors
Authors: Goebel Lisa , Kirschner Tonia , Koska Sandra , Rai Amrita , Janning Petra , Maffini Stefano , Vatheuer Helge , Czodrowski Paul , Goody Roger S. , Müller Matthias P. , Rauh Daniel 
Published: July 2022

AbstractMutations within Ras proteins represent major drivers in human cancer. In this study, we report the structure-based design, synthesis, as well as biochemical and cellular evaluation of nucleotide-based covalent inhibitors for KRasG13C, an important oncogenic mutant of Ras that has not been successfully addressed in the past. Mass spectrometry experiments and kinetic studies reveal promising molecular properties of these covalent inhibitors, and X-ray crystallographic analysis has yielded the first reported crystal structures of KRasG13C covalently locked with these GDP analogues. Importantly, KRasG13C covalently modified with these inhibitors can no longer undergo SOS-catalysed nucleotide exchange. As a final proof-of-concept, we show that in contrast to KRasG13C, the covalently locked protein is unable to induce oncogenic signalling in cells, further highlighting the possibility of using nucleotide-based inhibitors with covalent warheads in KRasG13C-driven cancer.
Tracing the origin of Oriental beech stands across Western Europe and reporting hybridization with European beech – implications for assisted gene flow
Authors: Kurz Mirjam , Kölz Adrian , Gorges Jonas , Carmona Beatriz Pablo , Brang Peter , Vitasse Yann , Kohler Martin , Rezzonico Fabio , Smits Theo H. M. , Bauhus Jürgen , Rudow Andreas , Hansen Ole Kim , Vatanparast Mohammad , Sevik Hakan , Zhelev Petar , Gömöry Dušan , Paule Ladislav , Sperisen Christoph , Csilléry Katalin 
Published: July 2022

AbstractHuman-aided translocation of individuals within the species’ range, assisted gene flow (AGF), has been suggested as a climate change mitigation strategy, especially for foundational species, such as forest trees. The benefits and risks of AGF largely depend on the genetic divergence between host and donor populations, their rate and direction of hybridization, and the climate distance that the transfer involves. In this study, we explored the use of Oriental beech (Fagus sylvatica subsp. orientalis), growing from Iran to the Balkans, for AGF in populations of European beech (F. sylvatica subsp. sylvatica), which grow throughout Europe and are increasingly affected by climate warming. Using 16 microsatellite loci and samples from 13 and 6 natural populations of Oriental and European beech, respectively, we identified 5 distinct genetic clusters in Oriental beech with a divergence (FST) of 0.15 to 0.25 from European beech. Using this knowledge, we tracked the origin of 11 Oriental beech stands in Western Europe, some established in the early 1900s. In two stands of Greater Caucasus origin, we additionally genotyped offspring and found evidence for extensive hybridization, with 41.3% and 17.8% of the offspring having a hybrid status. Further, climate data revealed a higher degree of seasonality across the Oriental beech growing sites than across the planting sites in Western Europe, with some sites additionally having a warmer and drier climate. Accordingly, in one of these stands, we found evidence that bud burst of Oriental beech occurs four days earlier than in European beech. These results suggest that AGF of Oriental beech could increase the genetic diversity of European beech stands and may even help the introgression of variants that are more adapted to future climatic conditions. Our study showcases an evaluation of the benefits and risks of AGF and calls for similar studies on other native tree species.
Synthetic HNK-1 containing glycans provide insight into binding properties of serum antibodies from MAG-neuropathy patients
Authors: Bunyatov Mehman , Wolfert Margreet A. , Huizinga Ruth , Schreurs Marco W.J. , Jacobs Bart C. , Boons Geert-Jan 
Published: July 2022

AbstractAnti-myelin-associated glycoprotein (anti-MAG) neuropathy is an autoimmune disease in which IgM autoantibodies target glycoconjugates of peripheral nerves resulting in progressive demyelination. To examine fine specificities of serum IgM autoantibodies and develop a more robust platform for diagnosis and disease monitoring, we describe here a chemoenzymatic approach that readily provided a panel of HNK-1 containing oligosaccharides presented on type 2 oligo-N-acetyl lactosamine (LacNAc) chains typical of glycosphingolipids. The compounds were prepared by a chemoenzymatic strategy in which an oligo-LacNAc structure was assembled enzymatically and then subjected to protecting group manipulation to chemically install a 3-O-sulfate glucuronic acid moiety. The synthetic strategy is highly divergent and made it possible to prepare from key precursors, additional compounds lacking sulfate of HNK-1 and derivatives in which the HNK-1 epitope is replaced by sulfate or sialic acid. The oligosaccharides were printed as a microarray to examine binding specificities of several monoclonal antibodies and serum antibodies of anti-MAG neuropathy patients. Surprisingly, three distinct patient subgroups were identified with variable dependance on the length of the LacNAc chain and sulfation of the glucuronyl moiety. In most cases, a lacto-neohexaose backbone was required for binding indicating the antibodies target corresponding glycosphingolipids.Significance statementA chemoenzymatic strategy is introduced in which a glycan backbone is assembled by glycosyltransferases to give a core oligosaccharide that is subjected to protecting group manipulations and chemical glycosylations to install terminal epitopes. It addresses limitations of enzymatic synthesis when specific glycosyltransferases or glycan-modifying enzymes for terminal epitope synthesis are not readily available. It provided an unprecedented panel of HNK-1 containing oligosaccharides, which was used to develop a glycan microarray that uncovered distinct binding preferences of serum antibodies of anti-MAG patients. The clinical spectrum of IgM monoclonal gammopathy varies substantially and an understanding of binding properties of IgM auto-antibodies will provide opportunities to monitor disease progression and develop personalized treatment options.
Parallel duplication and loss of aquaporin-coding genes during the ‘out of the sea’ transition as potential key drivers of animal terrestrialization
Authors: Martínez-Redondo Gemma I. , Guerrero Carolina Simón , Aristide Leandro , Balart-García Pau , Tonzo Vanina , Fernández Rosa 
Published: July 2022

AbstractOne of the most important physiological challenges animals had to overcome during terrestrialization (i.e., the transition from sea to land) is water loss, which alters their osmotic and hydric homeostasis. Aquaporins are a superfamily of membrane water transporters heavily involved in osmoregulatory processes. Their diversity and evolutionary dynamics in most animal lineages remain unknown, hampering our understanding of their role in marine-terrestrial transitions. Here, we interrogated aquaporin gene repertoire evolution across the main terrestrial animal lineages. We annotated aquaporin-coding genes in genomic data from 458 species from 7 animal phyla where terrestrialization episodes occurred. We then explored aquaporin gene evolutionary dynamics to assess differences between terrestrial and aquatic species through phylogenomics and phylogenetic comparative methods. Our results revealed parallel aquaporin-coding gene duplications in aquaporins during the transition from marine to non-marine environments (e.g., brackish, freshwater and terrestrial), rather than from aquatic to terrestrial ones, with some notable duplications in ancient lineages. Contrarily, we also recovered a significantly lower number of superaquaporin genes in terrestrial arthropods, suggesting that more efficient oxygen homeostasis in land arthropods might be linked to a reduction in this type of aquaporins. Our results thus indicate that aquaporin-coding gene duplication and loss might have been one of the key steps towards the evolution of osmoregulation across animals, facilitating the ‘out of the sea’ transition and ultimately the colonisation of land.
Adipose tissue mitochondrial respiration in Atlantic salmon: implications for sex-dependent life-history variation
Authors: Prokkola Jenni M. , Wagner Anita , Koskinen Elisabeth , Debes Paul V. , House Andrew , Åsheim Eirik R. , Primmer Craig R. , Pirinen Eija , Aykanat Tutku 
Published: July 2022

AbstractAdipose tissue is essential for energy homeostasis, with mitochondria having a central role in its function. Mitochondria-mediated white adipose tissue dysfunction has been linked to several metabolic disorders in humans but surprisingly little is known about natural variation in mitochondrial function in wild animal populations, and its evolutionary significance. Early sexual maturation (low age-at-maturity) in Atlantic salmon (Salmo salar) is promoted by higher adiposity and has a strong genetic association with thevgll3locus. This makes Atlantic salmon a convenient wild model to study the potential role of mitochondria-mediated adipose tissue processes in relation to the timing of maturation. Yet, mitochondrial respiration has not been measured in the adipose tissue in fish, and the lack of data is restricting the development of informed hypotheses. Here, using 13 Atlantic salmon individuals reared in common-garden conditions, we first verified the feasibility of measuring mitochondrial respiration in the adipose tissue. As expected, the respiration level was generally low, but nonetheless we successfully quantified its biological variation in the adipose tissue. Next, we analysed the potential association of mitochondrial respiration with mitochondrial DNA (mtDNA) content, adipocyte size, sex, and thevgll3genotype. Despite low samples sizes, mitochondrial respiration, leak respiration, and coupling capacity (P/E ratio) were marginally significantly decreased in immature females carrying with thevgll3early maturation compared to the alternative genotype. Based on these results, we suggested two new hypotheses on how the coupling capacity of oxidative phosphorylation could be linked with the timing of maturation via adiposity and pave the way to study the mechanistic relationships between life-history variation and mitochondrial bioenergetics in wild populations.