bluuebunny/crossref_metadata_2025_split huggingface dataset:
4EBP1/2 support tumorigenicity and cell survival during energetic stress by translationally regulating fatty acid synthesis
Authors: Levy Tal , Voeltzke Kai , Hauffe Laura , Alasad Khawla , Snaebjörnsson Marteinn , Marciano Ran , Scharov Katerina , Planque Mélanie , Vriens Kim , Christen Stefan , Funk Cornelius M , Hassiepen Christina , Kahler Alisa , Heider Beate , Picard Daniel , Lim Jonathan KM , Bas Zuelal , Bendrin Katja , Vargas-Toscano Andres , Kahlert Ulf , Remke Marc , Elkabets Moshe , Grünewald Thomas GP , Reichert Andreas S. , Fendt Sarah-Maria , Schulze Almut , Reifenberger Guido , Rotblat Barak , Leprivier Gabriel 
Published: September 2022

SUMMARYEnergetic stress compels cells to evolve adaptive mechanisms to maintain homeostasis. Here, we report that the negative regulators of mRNA translation initiation eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) are essential to promote the survival of mammalian cells and budding yeast under glucose starvation. Functionally, 4EBP1/2 inhibit fatty acid synthesis upon energetic stress via repression of Acetyl-CoA Carboxylase Alpha (ACACA) mRNA translation, sparing NADPH, to maintain intracellular redox balance. This has important relevance in cancers, as we uncovered that oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACACA expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 (encoding 4EBP1) expression is associated with poor outcomes in several cancer types, including glioma. Our data reveal that 4EBP1/2 are conserved mediators of the survival response to energetic stress which are exploited by cancer cells for metabolic adaptation.
Bone marrow hemogenic endothelial cells contribute multilineage hematopoietic progenitors in adult mice
Authors: Feng Jing-Xin , Yang Mei-Ting , Li Caiyi C. , Livák Ferenc , Abdelmaksoud Abdalla , Wang Dunrui , Tosato Giovanna 
Published: September 2022

SUMMARYDuring development, hematopoietic stem/progenitor cells (HSPCs) originate from a subset of hemogenic endothelial cells (ECs) through a process of endothelial-to-hematopoietic transition (EHT). This process is temporally restricted to short developmental windows and generates HSPC with distinct capabilities for hematopoiesis. Although it is generally thought that adult hematopoiesis is sustained by HSCs derived from hemogenic endothelium during development, some observations point to EHT persistence in the late fetus/perinatally. Here we use lineage tracking and bioinformatics analysis to assess the presence of hemogenic endothelial cells in the adult mouse. Our analysis identifies a subset of bone marrow-resident adult endothelial cells, characterized by the expression of VE-Cadherin and the transcription factor RUNX1, that produce CD45+ hematopoietic cells. This EHT generates hematopoietic progenitors, and mature myeloid and lymphoid cells in the adult mouse. Our results reveal the identification of a distinct source of adult blood.
A novel overlapping geneazyx-1affects the translation of zyxin inC. elegans
Authors: Parmar Bhavesh S. , Geens Ellen , Vandewyer Elke , Kieswetter Amanda , Ludwig Christina , Temmerman Liesbet 
Published: September 2022

AbstractOverlapping genes are widely prevalent, however, their expression and consequences are poorly understood. Here, we describe and functionally characterize a novelzyx-1overlapping gene,azyx-1, with distinct regulatory functions inC. elegans. We observed conservation of alternative open reading frames overlapping the 5’ region of zyxin family members in several animal species, and find shared sites ofazyx-1and zyxin proteoform expression inC. elegans. In line with a standard ribosome scanning model, our results supportcisregulation ofzyx-1long isoform(s) by upstream initiatingazyx-1a. Moreover, we report on a rare observation oftransregulation ofzyx-1byazyx-1, with evidence of increased ZYX-1 uponazyx-1overexpression. Our results suggest a dual role forazyx-1in influencingzyx-1proteoform heterogeneity and highlights its impact onC. elegansmuscular integrity and locomotion.
Low noise HRTFs and delay line corrections are detrimental to the prediction of ITD discrimination thresholds from environmental statistics
Authors: Gutiérrez Camperos Maria Juliana , Gonçalves Thaís Caroline , Marin Bóris , Pavão Rodrigo 
Published: September 2022

AbstractInteraural Time Difference (ITD) is the main cue for azimuthal auditory perception in humans. ITDs at each frequency contribute differently to azimuth discrimination, which can be quantified by their azimuthal Fisher Information. Consistently, human ITD discrimination thresholds are predicted by the azimuthal information. However, this prediction is poor for frequencies below 500 Hz. Such poor prediction could be ascribed to the strategy of quantifying azimuthal information using HRTFs obtained in unnaturalistic anechoic chambers or by using a direct method which does not incorporate the delay lines proposed by the Jeffress-Colburn model. In the present study, we obtained ITD discrimination thresholds from extensive sampling across frequency and ITD, and applied multiple strategies for quantifying azimuthal information. These strategies employed HRTFs obtained in realistic and anechoic chambers, with and without considering delay lines. We found that ITD discriminability thresholds across the complete range of frequencies are better predicted by azimuthal information conveyed by ITD cues when (1) we use naturalistic high-noise HRTFs, and (2) ITD delay compensation is not applied. Our results support that auditory perception is shaped by natural environments, which include high reverberation in low frequencies. Moreover, we also suggest that delay lines are not a crucial feature for determining ITD discrimination thresholds in the human auditory system.GRAPHICAL ABSTRACT
Dual role of brain endothelial Gpr126 in blood-brain barrier development and ischemic stroke
Authors: Kakogiannos Nikolaos , Scalise Anna Agata , Martini Emanuele , Maderna Claudio , Magni Serena , Gullotta Giorgia Serena , Lampugnani Maria Grazia , Iannelli Fabio , Beznoussenko Galina V. , Mironov Alexander A. , Cerutti Camilla , Bentley Katie , Philippides Andrew , Zanardi Federica , Bacigaluppi Marco , Martino Gianvito , Dejana Elisabetta , Giannotta Monica 
Published: September 2022

AbstractThe blood–brain barrier (BBB) acquires unique properties for regulation of the neuronal function during development. The genesis of the BBB coupled with angiogenesis is orchestrated by the Wnt/β-catenin signaling pathway. Aside from the importance of Wnt/β-catenin signaling, the molecular mechanisms that regulate these processes are poorly understood. Here, we identify the brain endothelial adhesion G-protein–coupled receptor Gpr126 as a novel target gene of Wnt/β-catenin signaling that is required for postnatal BBB development, and its expression is detrimental for ischemic stroke in adults. We show that Gpr126 expression is high in mouse brain endothelium during BBB formation, but decreases in the adult. Inactivation of Gpr126 in postnatal endothelial cells results in vessel enlargement and impairs acquisition of the BBB characteristics, such as increased neurovascular permeability, and reduced basement membrane protein deposition and pericyte coverage. Mechanistically, Gpr126 is required during developmental angiogenesis to promote endothelial cell migration, acting via an interaction between Lrp1 and α3β1-integrin, which couples vessel morphogenesis to BBB formation. Interestingly, in adult mice with an established BBB, the lack of Gpr126 expression in acute ischemic stroke is protective and coupled with reduced microglia activation, which contributes to an improved neurological outcome. These data identify Gpr126 as a promising therapeutic target to treat ischemic stroke.
A small-molecule myosin inhibitor as a targeted multi-stage antimalarial
Authors: Trivedi Darshan V. , Karabina Anastasia , Bergnes Gustave , Racca Alice , Wander Heba , Jung Seongwon , Mittal Nimisha , Huijs Tonnie , Ouchida Stephanie , Ruijgrok Paul V. , Song Dan , Wittlin Sergio , Mukherjee Partha , Chakraborty Arnish , Winzeler Elizabeth A. , Burrows Jeremy N. , Laleu Benoît , Spudich Annamma , Ruppel Kathleen , Dechering Koen , Nag Suman , Spudich James A. 
Published: September 2022

AbstractMalaria is a devastating disease that resulted in an estimated 627,000 deaths in 2020. About 80% of those deaths were among children under the age of five. Our approach is to develop small molecule inhibitors against cytoskeletal targets that are vital components of parasite function, essential at multiple stages of parasite infection, can be targeted with high specificity, and are highly druggable. Here we describe KNX-115, which inhibits purifiedPlasmodium falciparummyosin A (PfMyoA) actin-activated ATPase with a potency in the 10s of nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 inhibits the blood and liver stages ofPlasmodiumwith an EC50of about 100 nanomolar, with negligible liver cell toxicity. In addition, KNX-115 inhibits sporozoite cell traversal and blocks the gametocyte to oocyst conversion in the mosquito. KNX-115 displays a similar killing profile to pyrimethamine and parasites are totally killed after 96 hours of treatment. In line with its novel mechanism of action, KNX-115 is equally effective at inhibiting a panel ofPlasmodiumstrains resistant to experimental and marketed antimalarials.In vitroevolution data likely suggests a refractory potential of KNX-115 in developing parasite resistance.
An unwanted association: the threat to papaya crops by a novel potexvirus in northwest Argentina
Authors: Mederos Dariel Cabrera , Debat Humberto , Torres Carolina , Portal Orelvis , Zapata Margarita Jaramillo , Trucco Verónica , Flores Ceferino , Ortiz Claudio , Badaracco Alejandra , Acuña Luis , Nome Claudia , Quito-Ávila Diego , Bejerman Nicolás , Collazo Onias Castellanos , Sánchez-Rodríguez Aminael , Giolitti Fabián 
Published: September 2022

AbstractAn emerging virus isolated from papaya (Carica papaya) crops in northwestern (NW) Argentina was sequenced and characterized using next-generation sequencing. The resulting genome is 6,667-nt long and encodes five open reading frames in an arrangement typical of other potexviruses. This virus appears to be a novel member within the genus Potexvirus. Blast analysis of RNA-dependent RNA polymerase (RdRp) and coat protein (CP) genes showed the highest amino acid sequence identity (67% and 71%, respectively) with pitaya virus X. Based on nucleotide sequence similarity and phylogenetic analysis, the name papaya virus X is proposed for this newly characterized potexvirus that was mechanically transmitted to papaya plants causing chlorotic patches and severe mosaic symptoms. RT-PCR based detection of papaya virus X (PapVX) revealed that it is widely present in papaya crops from NW Argentina. The prevalence of PapVX, which seems to be restricted to the NW region of Argentina, and the fact that it has only been detected in this region could be associated with a recent emergence or adaptation of this virus to papaya in NW Argentina.
The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1
Authors: Sandovici Ionel , Fernandez-Twinn Denise S. , Campbell Niamh , Cooper Wendy N. , Sekita Yoichi , Zvetkova Ilona , Ferland-McCollough David , Prosser Haydn M. , Oyama Lila M. , Cimadomo Danilo , de Queiroz Karina Barbosa , Cheuk Cecilia S.K. , Smith Nicola M. , Kay Richard G. , Hoelle Katharina , Smith Noel H. , Geyer Stefan H. , Reissig Lukas F. , Weninger Wolfgang J. , Siddle Kenneth , Willis Anne E. , Bushell Martin , Ozanne Susan E. , Constância Miguel 
Published: September 2022

AbstractMir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.
Acetylation of a fungal effector that translocates host PR1 facilitates virulence
Authors: Li Jingtao , Ma Xiaoying , Wang Chenyang , Liu Sihui , Yu Gang , Gao Mingming , Qian Hengwei , Liu Mengjie , Luisi Ben F. , Gabriel Dean W. , Liang Wenxing 
Published: September 2022

AbstractPathogens utilize a panoply of effectors to manipulate plant defense. However, despite their importance, relatively little is actually known about regulation of these virulence factors. Here, we show that the effector FolSvp1, secreted from fungal pathogenFusarium oxysporumf. sp.lycopersici(Fol) directly binds and translocates the tomato pathogenesis-related protein1, SlPR1, from the apoplast outside the plasma membrane to the host nucleus via its nuclear localization signal. Relocation of SlPR1 abolishes generation of the defense signaling peptide, CAPE1, from its C-terminus, and as a consequence, facilitates pathogen invasion of plants. The action of FolSvp1 requires covalent modification by acetylation for full virulence in host tomato tissues. The modification is catalyzed by theFolFolArd1 lysine acetyltransferase prior to secretion. Addition of an acetyl group to one residue, K167, prevents ubiquitination-dependent degradation of FolSvp1 in bothFoland plant cells with different mechanisms, allowing it to function normally in fungal invasion. Either inactivation of FolSvp1 or removal of the acetyl group on K167 leads to impaired pathogenicity ofFol. These findings indicate that acetylation can regulate the stability of effectors of fungal plant pathogens with impact on virulence.
Accurate prediction of nucleic acid and protein-nucleic acid complexes using RoseTTAFoldNA
Authors: Baek Minkyung , McHugh Ryan , Anishchenko Ivan , Baker David , DiMaio Frank 
Published: September 2022

AbstractProtein-nucleic acid complexes play critical roles in biology. Despite considerable recent advances in protein structure prediction, the prediction of the structures of protein-nucleic acid complexes without homology to known complexes is a largely unsolved problem. Here we extend the RoseTTAFold end-to-end deep learning approach to modeling of nucleic acid and protein-nucleic acid complexes. We develop a single trained network, RoseTTAFoldNA, that rapidly produces 3D structure models with confidence estimates for protein-DNA and protein-RNA complexes, and for RNA tertiary structures. In all three cases, confident predictions have considerably higher accuracy than current state of the art methods. RoseTTAFoldNA should be broadly useful for modeling the structure of naturally occurring protein-nucleic acid complexes, and for designing sequence specific RNA and DNA binding proteins.
STAT3 promotes RNA polymerase III-directed transcription by controlling the miR-106a-5p/TP73 axis
Authors: Zhang Cheng , Zhao Shahsha , Deng Huan , Zhang Shihua , Wang Juan , Song Xiaoye , Yu Deen , Zhang Yue , Deng Wensheng 
Published: September 2022

AbstractsDeregulation of Pol III products causes a range of diseases, including neural diseases and cancers. However, the pathways and factors that control Pol III-directed transcription have yet to be elucidated. Here, we show that STAT3 positively regulates the activities of Pol III-dependent transcription and cancer cell growth. RNA-seq analysis revealed that STAT3 inhibits the expression of TP73, a member of the p53 family. We found that TP73 is not only required for the regulation of Pol III-directed transcription mediated by STAT3 but also independently suppresses the synthesis of Pol III products. Mechanistically, TP73 can disrupt the assembly of TFIIIB subunits and inhibit their occupancies at Pol III target loci by interacting with TFIIB subunit TBP. MiR-106a-5p can activate Pol III-directed transcription by targeting the TP73 mRNA 3’ UTR to reduce TP 73 expression. We show that STAT3 activates the expression of miR-106a-5p by binding to the microRNA promoter, indicating that miR-106a-5p links STAT3 to TP73 and Pol III transcription. Collectively, these findings indicate that STAT3 functions as a positive regulator in Pol III-directed transcription by controlling the miR-106a-5p/TP73 axis.
Does Functional Recovery Imply Stable Circuitry in the Spinal Animal?
Authors: Refy Omar , Geyer Hartmut 
Published: September 2022

AbstractSpinal animals can regain locomotor function through gait training. However, the neural processes involved in this recovery are poorly understood. Here we use computer simulation to address if the reorganization of spinal circuits associated with the functional recovery leads to meaningful, stable circuitry function. Specifically, we develop a neuromuscular model of a spinalized rat whose circuitry can adapt based on two alternative Hebbian learning strategies, one designed to guide the circuitry back to its normal pre-injury state and the other designed to destabilize it and drive it into saturation. Exposing the model to simulated gait training, we find that both strategies lead to recovery of locomotor function as defined by the outcome measures reported in studies with spinal rats. If anything, the results obtained with the destabilizing learning strategy seem to agree more with animal observations, since it produces similarly excessive amplitudes in muscle activity. Our results suggest that gait training of spinalized animals does not necessarily effect a meaningful recovery of their spinal circuitry function. More experimental work should be directed to clarify this point, as it may have grave implications for the potential of gait rehabilitation in patients with motor complete injuries of the spinal cord.
Silicon as a microfluidic material for imaging and incubation of droplets
Authors: Lobato-Dauzier Nicolas , Deteix Robin , Gines Guillaume , Baccouche Alexandre , Hapsianto Benediktus Nixon , Okumura Shu , Mariette Guilhem , Belharet Djaffar , Queste Samuel , Jalabert Laurent , Denoual Matthieu , Rondelez Yannick , Toshiyoshi Hiroshi , Fujita Hiroyuki , Kim Soo Hyeon , Fujii Teruo , Genot Anthony J. 
Published: September 2022

AbstractDroplet microfluidics has become a powerful tool in life sciences, underlying digital assays, single-cell sequencing or directed evolution, and it is making foray in physical sciences as well. Imaging and incubation of droplets are crucial, yet they are encumbered by the poor optical, thermal and mechanical properties of PDMS - thede factomaterial for microfluidics. Here we show that silicon is an ideal material for droplet chambers. Si chambers pack droplets in a crystalline and immobile monolayer, are immune to evaporation or sagging, boost the number of collected photons, and tightly control the temperature field sensed by droplets. We use the mechanical and optical benefits of Si chambers to image ∼1 million of droplets from a multiplexed digital assay - with an acquisition rate similar to the best in-line methods. Lastly, we demonstrate their applicability with a demanding assay that maps the thermal dependence of Michaelis-Menten constants with an array of ∼150,000. The design of the Si chambers is streamlined to avoid complicated fabrication and improve reproducibility, which makes Silicon a complementary material to PDMS in the toolbox of droplet microfluidics.Significance StatementAs the technological engine behind single-cell sequencing and digital assays, droplets microfluidics has revolutionized life science and molecular diagnosis, and is making foray into physical sciences as well. Observing droplets in a controlled manner is becoming crucial, but PDMS - thede factomaterial of microfluidics – hampers imaging and incubation. Here we revisit silicon as a microfluidic material and show that its superior mechanical, optical and thermal performances improve the throughput and operation of droplets assay.
GLKs directly regulate carotenoid biosynthesis via interacting with GBFs in nuclear condensates in plants
Authors: Sun Tianhu , Zeng Shaohua , Wang Xin , Owens Lauren A. , Fe Zhangjun , Zhao Yunde , Mazourek Michael , Giovannoni James G. , Li Li 
Published: September 2022

ABSTRACTCarotenoids are vital photosynthetic pigments for plants and provide essential nutrients for humans. However, our knowledge of the regulatory control of carotenoid biosynthesis remains limited. Golden2-like transcription factors (GLKs) are widely recognized as essential and conserved factors for chloroplast development and the major regulators of chlorophyll biosynthesis. Yet the molecular mechanisms by which GLKs transcriptionally activate their target genes are unclear. Here, we report that GLKs directly regulate carotenoid biosynthesis in a G-box Binding Factor (GBF)-dependent manner. Bothin vitroandin vivostudies reveal that GLKs physically interact with GBFs. Through the direct binding of GBFs to the G-box motif, the GLK-GBF regulatory module transcriptionally activatesphytoene synthase(PSY), the gene encoding the rate-limiting enzyme for carotenoid biosynthesis. The ability ofGLKsto promote carotenoid and chlorophyll biosynthesis is greatly diminished in the Arabidopsisgbf1/2/3triple knockout mutants, showing the requirement of GBFs for GLK function. GLKs and GBFs form liquid-liquid phase separation-mediated nuclear condensates as the compartmented and concentrated transcriptional complexes. Our findings uncover a novel and conserved regulatory module for photosynthetic pigment biosynthesis through formation of GLK-GBF transcriptional complexes and nuclear biomolecular condensates in plants.One-sentence summaryGLKs transcriptionally regulate photosynthetic pigment synthesis in a GBF-dependent manner and are associated with the formation of phase separation-mediated nuclear condensates.
Thyroid Ablation Alters Passive Stiffness and Swimming Kinematics in Zebrafish
Authors: Parikh Pranav , Nguyen Stacy , McMenamin Sarah , Kenaley Christopher P. 
Published: September 2022

AbstractLocomotion behavior is ultimately determined by the integration between active and passive tissues of an organism, but little is known about how these properties develop or are maintained. In this study, we used zebrafish (Danio rerio) to address the effects of a developmental hormone on morphogenesis and mechanical integration during swimming. We analyzed common kinematic variables and estimated intervertebral joint (IVJ) stiffness of zebrafish reared under different thyroid hormone profiles (euthyroid and hypothyroid) swimming during two different forward speeds, 5 and 10 BL·s−1. We found that zebrafish reared under hypothyroid conditions swam with higher trailing-edge amplitude, a larger amplitude envelope, longer propulsive wavelengths, and lower values of lateral strain in posterior regions at both speeds. IVJ second moment area about the bending axis was greater in the TH-, a result of a change in vertebral shape compared to wildtype fish. We conclude that thyroid hormone contributes to axial design during development and therefore has an important role in determining flexural stiffness and the swimming behaviors that are affected by this important property.