bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prrx1-driven LINC complex disruption in vivo reduces osteoid deposition but not bone quality after voluntary wheel running
Authors: Birks Scott , Howard Sean , Wright Christian S. , O’Rourke Caroline , Day Elicza A. , Lamb Alexander J. , Walsdorf James R. , Lau Anthony , Thompson William R. , Uzer Gunes 
Published: September 2023

AbstractThe Linker of Nucleoskeleton and Cytoskeleton (LINC) complex serves to connect the nuclear envelope and the cytoskeleton, influencing cellular processes such as nuclear arrangement, architecture, and mechanotransduction. The role LINC plays in mechanotransduction pathways in bone progenitor cells has been well studied; however, the mechanisms by which LINC complexes governin vivobone formation remain less clear. To bridge this knowledge gap, we established a murine model disrupting LINC using transgenic Prx-Cre mice and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Prx-Cre mice express the Cre recombinase enzyme controlled by the paired-related homeobox gene-1 promoter (Prrx1), a pivotal regulator of skeletal development. Prx-Cre animals have been widely used in the bone field to target bone progenitor cells. Tg(CAG-LacZ/EGFP-KASH2) mice carry a lox-stop-lox flanked LacZ gene allowing for the overexpression of an EGFP-KASH2 fusion protein via cre recombinase mediated deletion of the LacZ cassette. This disrupts endogenous Nesprin-Sun binding in a dominant negative manner disconnecting nesprin from the nuclear envelope. By combining these lines, we generated a Prrx1(+) cell-specific LINC disruption model to study its impact on the developing skeleton and subsequently exercise-induced bone accrual. The findings presented here indicate Prx-driven LINC disruption (PDLD) cells exhibit no change in osteogenic and adipogenic potential compared to controlsin vitronor are there bone quality changes when compared to in sedentary animals at 8 weeks. While PDLD animals displayed increased voluntary running activity andPrrx1(+) cell-specific LINC disruption abolished the exercise-induced increases in osteoid volume and surface after a 6-week exercise intervention, no other changes in bone microarchitecture or mechanical properties were found.
The lactonase BxdA mediates metabolic adaptation of maize root bacteria to benzoxazinoids
Authors: Thoenen Lisa , Kreuzer Marco , Florean Matilde , Mateo Pierre , Züst Tobias , Giroud Caitlin , Rouyer Liza , Gfeller Valentin , Notter Matheus D. , Knoch Eva , Hapfelmeier Siegfried , Becker Claude , Schandry Niklas , Robert Christelle A. M. , Köllner Tobias G. , Bruggmann Rémy , Erb Matthias , Schlaeppi Klaus 
Published: September 2023

AbstractRoot exudates contain secondary metabolites that affect the plant’s root microbiome. How microbes cope with these bioactive compounds, and how this ability shapes root microbiomes remain largely unknown. We investigated how maize root bacteria metabolise benzoxazinoids, the main specialised metabolites of maize. Diverse and abundant bacteria metabolised the major compound (6-methoxy-benzoxazolin-2-one, MBOA) in the maize rhizosphere to 2-amino-7-methoxyphenoxazin-3-one (AMPO). By contrast, bacteria isolated from Arabidopsis, which does not produce benzoxazinoids, were unable to metabolise MBOA. AmongMicrobacteriastrains, this differential metabolisation allowed to identify a conserved gene cluster containing the lactonasebxdA. BxdA converts MBOA to AMPO in vitro and we show that this capacity provided bacteria a growth benefit under carbon-limiting conditions. Together these results reveal that maize root bacteria - through BxdA - are metabolically adapted to the benzoxazinoids of their host. We propose that metabolic adaptation to plant-specialised compounds shapes root bacterial communities across the plant kingdom.
Structural insights into abscisic acid exporter AtABCG25
Authors: Xin Jian , Zhou Yeling , Qiu Yichun , Geng He , Wang Yuzhu , Song Yi , Liang Jiansheng , Yan Kaige 
Published: September 2023

AbstractCellular hormone homeostasis is essential for the precise spatial and temporal signaling responses and plant fitness. Abscisic acid (ABA) plays pivotal roles in orchestrating various developmental and stress responses and confers fitness benefits over ecological and evolutionary timescales in terrestrial plants. Cellular ABA levels is regulated by complex processes including biosynthesis, catabolism, and transport. AtABCG25 is the first identified ABA exporter through genetic screen which affects diverse ABA responses. Resolving the structure basis of ABCG25 in ABA exporting is critical for further manipulating ABA homeostasis and plant fitness. We utilized cryo-electron microscopy to elucidate the structural dynamics of AtABCG25, and successfully characterized different states including apo AtABCG25, ABA-bound AtABCG25 and ATP-bound AtABCG25(E232Q). Notably, AtABCG25 forms a homodimer, featuring a deep, slit-like cavity in the transmembrane domain. The critical residues in the cavity where ABA binds are precisely characterized. Moreover, ATP binding triggers the closure of nucleotide-binding domains and conformational transitions in the transmembrane domains. Collectively, these findings provide valuable insights into the intricate substrate recognition and transport mechanisms of ABA exporter ABCG25, paving the way towards genetical manipulating of ABA homeostasis and plant fitness.
Differential Modulation of Polycomb-Associated Histone Marks by cBAF, pBAF, and gBAF Complexes
Authors: Bergwell Mary , Park JinYoung , Kirkland Jacob G. 
Published: September 2023

AbstractChromatin regulators are a group of proteins that can alter the physical properties of chromatin to make it more or less permissive to transcription by modulating another protein’s access to a specific DNA sequence through changes in nucleosome occupancy or histone modifications at a particular locus. Mammalian SWI/SNF complexes (mSWI/SNF) are a group of ATPase-dependent chromatin remodelers that alter chromatin states. In mouse embryonic stem cells (mESCs), there are three primary forms of mSWI/SNF: canonical BAF (cBAF), polybromo-associated BAF (pBAF), and GLTSCR-associated BAF (gBAF or ncBAF). While cBAF and gBAF contain the SS18 protein subunit, pBAF lacks SS18. Previous studies used a novel dCas9-mediated inducible recruitment (FIRE-Cas9) of mSWI/SNF complexes via SS18 to theNkx2.9locus.Nkx2.9is a developmentally regulated gene that requires mSWI/SNF for transcriptional activation during neural differentiation. However, in mESCs,Nkx2.9is bivalent, meaning nucleosomes at the locus have both active and polycomb-associated repressive modifications. Upon recruitment of SS18-containing complexes, polycomb-associated histone marks are removed, followed by transcriptional activation ofNkx2.9. However, since both cBAF and gBAF share the SS18 subunit, it is unclear whether one or both complexes oppose the polycomb repressive marks. The ability of pBAF to do the same also remains unknown. In this study, we used unique subunits to recruit each of the three complexes to the Nkx2.9 locus individually. Here, we show that cBAF most effectively opposes polycomb repressive marks atNkx2.9, leading to transcriptional activation of the gene. Recruitment of cBAF complexes leads to a significant loss of the polycomb repressive-2 H3K27me3 and polycomb repressive-1 H2AK119ub histone marks, whereas gBAF and pBAF do not. Moreover, nucleosome occupancy alone cannot explain the loss of these marks. Our results demonstrate that cBAF has a unique role in the direct opposition of polycomb-associated histone modifications that gBAF and pBAF do not share.Cell Cycle and Cancer Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, 73104
Single-Cell Profiling Reveals a Naive-Memory Relationship between CD56brightand Adaptive Human Natural Killer Cells
Authors: Panjwani M. Kazim , Grassmann Simon , Sottile Rosa , Le Luduec Jean-Benoît , Kontopoulos Theodota , van der Ploeg Kattria , Sun Joseph C. , Hsu Katharine C. 
Published: September 2023

AbstractDevelopment of antigen-specific memory upon pathogen exposure is a hallmark of the adaptive immune system. While natural killer (NK) cells are considered part of the innate immune system, humans exposed to the chronic viral pathogen cytomegalovirus (CMV) often possess a distinct NK cell population lacking in individuals who have not been exposed, termed “adaptive” NK cells. To identify the “naïve” population from which this “memory” population derives, we performed phenotypic, transcriptional, and functional profiling of NK cell subsets. We identified immature precursors to the Adaptive NK cells that are equally present in both CMV+ and CMV-individuals, resolved an Adaptive transcriptional state distinct from most mature NK cells and sharing a common gene program with the immature CD56brightpopulation, and demonstrated retention of proliferative capacity and acquisition of superior IFNγ production in the Adaptive population. Furthermore, we distinguish the CD56brightand Adaptive NK populations by expression of the transcription factor CXXC5, positioning these memory NK cells at the inflection point between innate and adaptive lymphocytes.
Direct ionic stress sensing and mitigation by the transcription factor NFAT5
Authors: Khandwala Chandni B. , Sarkar Parijat , Schmidt H. Broder , Ma Mengxiao , Kinnebrew Maia , Pusapati Ganesh V. , Patel Bhaven B. , Tillo Desiree , Lebensohn Andres M. , Rohatgi Rajat 
Published: September 2023

SUMMARYHomeostatic control of intracellular ionic strength is essential for protein, organelle and genome function, yet mechanisms that sense and enable adaptation to ionic stress remain poorly understood in animals. We find that the transcription factor NFAT5 directly senses solution ionic strength using a C-terminal intrinsically disordered region. Both in intact cells and in a purified system, NFAT5 forms dynamic, reversible biomolecular condensates in response to increasing ionic strength. This self-associative property, conserved from insects to mammals, allows NFAT5 to accumulate in the nucleus and activate genes that restore cellular ion content. Mutations that reduce condensation or those that promote aggregation both reduce NFAT5 activity, highlighting the importance of optimally tuned associative interactions. Remarkably, human NFAT5 alone is sufficient to reconstitute a mammalian transcriptional response to ionic or hypertonic stress in yeast. Thus NFAT5 is both the sensor and effector of a cell-autonomous ionic stress response pathway in animal cells.
Single-Cell Analysis Reveals Cryptic Prophage Protease LfgB ProtectsEscherichia coliDuring Oxidative Stress by Cleaving Antitoxin MqsA
Authors: Fernández-García Laura , Gao Xinyu , Battisti Michael E. , Kirigo Joy , García-Contreras Rodolfo , Tomas Maria , Guo Yunxue , Wang Xiaoxue , Wood Thomas K. 
Published: September 2023

ABSTRACTAlthough toxin/antitoxin (TA) systems are ubiquitous, beyond phage inhibition and mobile element stabilization, their role in host metabolism is obscure. One of the best-characterized TA systems is MqsR/MqsA ofEscherichia coli, which has been linked previously to protecting this gastrointestinal species during the stress it encounters from the bile salt deoxycholate as it colonizes humans. However, some recent whole-population studies have challenged the role of toxins such as MqsR in bacterial physiology, since themqsRAlocus is induced over a hundred-fold during stress, but a phenotype was not found upon its deletion. Here, we investigate further the role MqsR/MqsA by utilizing single cells and demonstrate that upon oxidative stress, the TA system MqsR/MqsA has a heterogeneous effect on the transcriptome of single cells. Furthermore, we discovered that MqsR activation leads to induction of the poorly-characterizedyfjXY ypjJ yfjZFoperon of cryptic prophage CP4-57. Moreover, deletion ofyfjYmakes the cells sensitive to H2O2, acid, and heat stress, and this phenotype was complemented. Hence, we recommendyfjYbe renamed tolfgB(less fatalitygeneB). Critically, MqsA represseslfgBby binding the operon promoter, and LfgB is a protease that degrades MqsA to derepressrpoSand facilitate the stress response. Therefore, the MqsR/MqsA TA system facilitates the stress response through cryptic phage protease LfgB.
Construction and reconfiguration of dynamic DNA origami assemblies with coiled-coil patches and patterns
Authors: Teng T. , Bernal-Chanchavac J. , Stephanopoulos N. , Castro C.E. 
Published: September 2023

AbstractDNA origami nanodevices achieve programmable structure and tunable mechanical and dynamic properties by leveraging the sequence specific interactions of nucleic acids. Previous advances have also established DNA origami as a useful building block to make well-defined micron-scale structures through hierarchical self-assembly, but these efforts have largely leveraged the structural features of DNA origami. The tunable dynamic and mechanical properties also provide an opportunity to make assemblies with adaptive structure and properties. Here we report the integration of DNA origami hinge nanodevices and coiled-coil peptides into hybrid reconfigurable assemblies. With the same dynamic device and peptide interaction, we make multiple higher order assemblies by organizing clusters of peptides (i.e. patches) or arranging single peptides (i.e. patterns) on the surfaces of DNA origami to control the relative orientation of devices. We use coiled-coil interactions to construct circular and linear assemblies whose structure and mechanical properties can be modulated with DNA-based actuation. Actuation of linear assemblies leads to micron scale motions and ∼2.5-10-fold increase in bending stiffness. Our results provide a foundation for stimulus responsive hybrid assemblies that can adapt their structure and properties in response to nucleic acid, peptide, protein, or other triggers.
Rhythm Receptive Fields in Striatum of Mice Executing Complex Continuous Movement Sequences
Authors: Hirokane Kojiro , Nakamura Toru , Terashita Takuma , Kubota Yasuo , Hu Dan , Yagi Takeshi , Graybiel Ann M. , Kitsukawa Takashi 
Published: September 2023

SummaryBy the use of a novel experimental system, the step-wheel, we investigated the neural underpinnings of complex and continuous movements. We recorded neural activities from the dorsolateral striatum and found neurons sensitive to movement rhythm parameters. These neurons responded to specific combinations of interval, phase, and repetition of movement, effectively forming what we term “rhythm receptive fields.” Some neurons even responsive to the combination of movement phases of multiple body parts. In parallel, cortical recordings in sensorimotor areas highlighted a paucity of neurons responsive to multiple parameter combinations, relative to those in the striatum. These findings have implications for comprehending motor coordination deficits seen in brain disorders including Parkinson’s disease. Movement encoding by rhythm receptive fields should streamline the brain’s capacity to encode temporal patterns, help to resolve the degrees of freedom problem. Such rhythm fields hint at the neural mechanisms governing effective motor control and processing of rhythmic information.
Acetylcholine signaling in the medial prefrontal cortex mediates the ability to learn an active avoidance response following learned helplessness training
Authors: Abdulla Zuhair I. , Mineur Yann S. , Crouse Richard B. , Etherington Ian M. , Yousuf Hanna , Na Jessica J. , Picciotto Marina R. 
Published: September 2023

AbstractIncreased brain levels of acetylcholine (ACh) are observed in subsets of patients with depression and increasing ACh levels chronically can precipitate stress-related behaviors in humans and animals. Conversely, optimal ACh levels are required for cognition and memory. We hypothesize that ACh signaling is important for encoding both appetitive and stress-relevant memories, but that excessive increases in ACh result in a negative encoding bias in which memory formation of a stressful event is aberrantly strengthened, potentially contributing to the excessive focus on negative experience that could lead to depressive symptoms. The medial prefrontal cortex (mPFC) is critical to control the limbic system to filter exteroceptive cues and stress-related circuits. We therefore evaluated the role of ACh signaling in the mPFC in a learned helplessness task in which mice were exposed to repeated inescapable stressors followed by an active avoidance task. Using fiber photometry with a genetically-encoded ACh sensor, we found that ACh levels in the mPFC during exposure to inescapable stressors were positively correlated with later escape deficits in an active avoidance test in males, but not females. Consistent with these measurements, we found that both pharmacologically- and chemogenetically-induced increases in mPFC ACh levels resulted in escape deficits in both male and female mice, whereas chemogenetic inhibition of ACh neurons projecting to the mPFC improved escape performance in males, but impaired escape performance in females. These results highlight the adaptive role of ACh release in stress response, but also support the idea that sustained elevated ACh levels contribute to maladaptive behaviors. Furthermore, mPFC ACh signaling may contribute to depressive symptomology differentially in males and females.
Target DNA-dependent activation mechanism of the prokaryotic immune system SPARTA
Authors: Finocchio Giada , Koopal Balwina , Potocnik Ana , Heijstek Clint , Jinek Martin , Swarts Daan C. 
Published: September 2023

ABSTRACTIn both prokaryotic and eukaryotic innate immune systems, TIR domains function as NADases that degrade the key metabolite NAD+or generate signaling molecules. Catalytic activation of TIR domains requires oligomerization, but how this is achieved varies in distinct immune systems. In theShortprokaryoticArgonaute (pAgo)/TIR-APAZ (SPARTA) immune system, TIR NADase activity is triggered upon guide RNA-mediated recognition of invading DNA by an unknown mechanism. Here, we describe cryo-EM structures of SPARTA in the inactive monomeric and target DNA-activated tetrameric states. The monomeric SPARTA structure reveals that in the absence of target DNA, a C-terminal tail of TIR-APAZ occupies the nucleic acid binding cleft formed by the pAgo and TIR-APAZ subunits, suppressing SPARTA activation. In the active tetrameric SPARTA complex, guide RNA-mediated target DNA binding displaces the C-terminal tail and induces conformational changes in pAgo that facilitate SPARTA-SPARTA dimerization. Concurrent release and rotation of one TIR domain allow it to form a composite NADase catalytic site with the other TIR domain within the dimer, and generate a self-complementary interface that mediates cooperative tetramerization. Combined, this study provides critical insights into the structural architecture of SPARTA and the molecular mechanism underlying target DNA-dependent oligomerization and catalytic activation.KEY POINTSInactive monomeric SPARTA is autoinhibited by the C-terminal tail of TIR-APAZTarget DNA recognition causes C-terminal tail release, pAgo restructuring, and dimerizationTIR domain rotation enables catalytic activation and cooperative tetramer formation
The lipid Gb3 promotes germinal center B cell responses and anti-viral immunity
Authors: Sharma Pankaj , Zhang Xiaolong , Ly Kevin , Zhang Yuxiang , Hu Yu , Ye Adam Yongxin , Hu Jianqiao , Kim Ji Hyung , Lou Mumeng , Wang Chong , Celuzza Quinton , Kondo Yuji , Furukawa Keiko , Bundle David R. , Furukawa Koichi , Alt Frederick W. , Winau Florian 
Published: September 2023

Influenza viruses escape immunity due to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. Here, we demonstrate that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 binds and disengages CD19 from its chaperone CD81 for subsequent translocation to the B cell receptor (BCR) complex to trigger signaling. Abundance of Gb3 amplifies the PI3-kinase/Akt/Foxo1 pathway to drive affinity maturation. Moreover, this lipid regulates MHC-II expression to increase diversity of T follicular helper (Tfh) and GC B cells reactive with subdominant epitopes. In influenza infection, Gb3 promotes broadly reactive antibody responses and cross-protection. Thus, we show that Gb3 determines affinity as well as breadth in B cell immunity and propose this lipid as novel vaccine adjuvant against viral infection.One Sentence SummaryGb3 abundance on GC B cells selects antibodies with high affinity and broad epitope reactivities, which are cross-protective against heterologous influenza infection.
Unveiling fetal brain changes in congenital diaphragmatic hernia: hypoxic injury with loss of progenitor cells, neurons, and oligodendrocytes
Authors: Biouss George , Antounians Lina , Aguet Julien , Kopcalic Katarina , Fakhari Nikan , Baranger Jerome , Mertens Luc , Villemain Olivier , Zani Augusto 
Published: September 2023

AbstractCongenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets.