bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinesin family motors modify transcription mediated by ERR1 using a conserved nuclear receptor box motif
Authors: Seneviratne A.M.P.B , Lidagoster S. , Valbuena-Castor S. , Lashley K. , Saha S. , Alimova A. , Kreitzer Geri 
Published: November 2022

AbstractKinesin family motors are microtubule (MT)-stimulated ATPases known best as transporters of cellular cargoes through the cytoplasm, regulators of MT dynamics, organizers of the mitotic spindle, and for insuring equal division of DNA during mitosis. Several kinesins have also been shown to regulate transcription by interacting with transcriptional cofactors and regulators, nuclear receptors, or with specific promotor elements on DNA. We previously showed that an LxxLL nuclear receptor box motif in the kinesin-2 family motor KIF17 mediates binding to the orphan nuclear receptor estrogen related receptor alpha (ERR1) and is responsible for the suppression of ERR1-dependent transcription by KIF17. Analysis of all kinesin family proteins revealed that multiple kinesins contain this LxxLL motif, raising the question as to whether additional kinesins motors contribute to regulation of ERR1. In this study, we interrogated the effects of multiple kinesins with LxxLL motifs on ERR1-mediated transcription. We demonstrate that the kinesin-3 motor KIF1B contains two LxxLL motifs, one of which binds to ERR1. In addition, we show that expression of a KIF1B fragment containing this LxxLL motif inhibits ERR1-dependent transcription by regulating nuclear entry of ERR1. We also provide evidence that the effects of expressing the KIF1B-LxxLL fragment on ERR1 activity are mediated by a mechanism distinct from that of KIF17. Because LxxLL domains are found in many kinesins, our data suggest an expanded role for kinesins in nuclear receptor mediated transcriptional regulation.
The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues inDrosophilalarvae
Authors: Johannessen Julie A. , Formica Miriam , Bråthen Nora Rojahn , Outa Amani Al , Aarsund Miriam , Therrien Marc , Enserink Jorrit M. , Knævelsrud Helene 
Published: November 2022

AbstractMLL-rearranged leukemias are among the leukemic subtypes with poorest survival, and treatment options have barely improved over the last decades. Furthermore, despite increasing molecular understanding of the mechanisms behind these hematopoietic malignancies, this knowledge has had poor translation into the clinic. Identification of novel treatment methods is hampered by the lack of relevantin vivomodels that allow for rapid identification of actionable drug targets and small molecule inhibitors. Here, we report aDrosophila melanogastermodel system to explore the pathways affected inMLL-rearranged leukemia. We show that expression of the human leukemic oncogene MLL-AF4 in theDrosophilahematopoietic system resulted in increased levels of circulating hemocytes and an enlargement of the larval hematopoietic organ, the lymph gland. Strikingly, depletion ofDrosophilaorthologs of known interactors of MLL-AF4, such as DOT1L, rescued the leukemic phenotype. In agreement, treatment with small-molecule inhibitors of DOT1L also prevented the MLL-AF4-induced leukemia-like phenotype. Taken together, this model provides anin vivosystem to unravel the genetic interactors involved in leukemogenesis and offers a strategy for a prompt identification of potential therapeutic options for treatment ofMLL-rearranged leukemia.
Exosome-mediated viral nucleic acid presentation in a crustacean reveals innate immunity evolution from a novel perspective
Authors: Gong Yi , Hu Hang , Zhao Xinshan , Wei Weiqian , Zhang Ming , Tuan Tran Ngoc , Ma Hongyu , Zhang Yueling , Chan Kok-Gan , Li Shengkang 
Published: November 2022

AbstractAs an enduring hot topic in the field of innate immunity, apoptosis is widely considered as an effective approach to eliminate pathogenic microbes, and possesses crucial role during host-pathogen interactions. Recently, researchers have found that virus-containing host cells could transmit apoptotic signals to surrounding uninfected cells during infection, but the mechanism remains unclear. Here, we found that exosomes secreted by WSSV-infected mud crab hemocytes contain viral nucleic acid wsv277, which could be transported to the recipient cells and further expressed viral protein with phosphokinase activity. Besides, by using transcriptome, proteome, ChIP-seq and coIP techniques, the results revealed that wsv277 could activate the transcription and translation of apoptotic genes via interacting with CBF and EF-1α, so as to suppress the spread of virus infection by inducing apoptosis of the surrounding cells. Therefore, for the first time, our study proved that the components of DNA virus could be encapsulated into exosomes, and elucidated the mechanism of apoptotic signal transduction between cells from the perspective of exosome. Moreover, comparing those of invertebrates, we hypothesized that the innate immune system of vertebrate was weakened or degenerated, allowing exosomes to be employed by virus as the vehicle for immune escape.Significance statementOur study revealed that the components of DNA virus could be packaged and transmitted through the exosomes of lower invertebrates, which strongly demonstrated the diversity of exosome-mediated viral immunity and its universality in animals. Furthermore, we elucidated the mechanism of apoptotic signal transduction between cells from the perspective of exosome, and revealed a novel strategy for the host to cope with viral infection. Since exosome is an important innate immune regulation approach, we hypothesize that the innate immune system of vertebrates is weakened or degenerated, allowing exosomes to be employed by virus as the vehicle for immune escape.
Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in rats
Authors: Janz Philipp , Knoflach Frederic , Bleicher Konrad , Belli Sara , Biemans Barbara , Schnider Patrick , Ebeling Martin , Grundschober Christophe , Benekareddy Madhurima 
Published: November 2022

AbstractSocial behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA). Chemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which has a significantly improved pharmacokinetic profile over oxytocin. CPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes. These results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery.
Different outcomes of neonatal and adult Zika virus infection on startle reflex and prepulse inhibition in mice
Authors: Souza Isis N. O. , Andrade Brenda S. , Frost Paula S. , Neris Romulo L. S. , Gavino-Leopoldino Daniel , Da Poian Andrea T. , Assunção-Miranda Iranaia , Figueiredo Claudia P. , Clarke Julia R. , Neves Gilda A. 
Published: November 2022

AbstractZika virus (ZIKV) infection causes severe neurological consequences in both gestationally-exposed infants and adults. Sensorial gating deficits strongly correlate to the motor, sensorial and cognitive impairments observed in ZIKV-infected patients. However, to date, no startle response or prepulse inhibition (PPI) assessment has been made in patients or animal models. In this study, we identified different outcomes for the age of infection and sex in wild-type mice: neonatally infected animals presented an increase in PPI and startle latency in both sexes, while adult infected males presented lower startle amplitude but preserved PPI. Our data further the understanding of the functional impacts of ZIKV on the developing and mature nervous system, which could help explain other behavioral and cognitive alterations caused by the virus. With this study, we support the use of startle reflex testing in ZIKV exposed patients, especially infants, allowing for early detection of functional neuromotor damage and early intervention.
The in-tissue molecular architecture of β-amyloid in the mammalian brain
Authors: Leistner Conny , Wilkinson Martin , Burgess Ailidh , Goodbody Stanley , Xu Yong , Deuchars Susan , Radford Sheena E. , Ranson Neil A. , Frank René A. W. 
Published: November 2022

ABSTRACTAmyloid plaques composed of extracellular focal deposition of Aβ fibrils are a hallmark of Alzheimer’s disease (AD). Cryo-EM structures of Aβ fibrils purified from human AD brain tissue post mortem have recently been determined. However, the molecular architecture of amyloid plaques in the context of fresh, unfixed mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report the native,in situmolecular architecture of Aβ fibrils in the brain of a mouse model containing the Arctic familial AD mutation (AppNL-G-F) and an atomic model of Arctic Aβ fibril purified from the brains of these animals. We show that in-tissue Aβ fibrils are arranged in a lattice or in parallel bundles within a plaque, and are interdigitated by subcellular compartments, exosomes, extracellular droplets and extracellular multilamellar bodies. At the atomic level, the Arctic Aβ fibril differs significantly from earlier structures of Aβ amyloid extracted fromAppNL-Fmice models and human AD brain tissue, showing a striking effect of the Arctic mutation (E22G) on fibril structure. Cryo-electron tomography ofex vivopurified and in-tissue amyloid revealed an ensemble of additional fibrillar species, including thin protofilament-like rods and branched fibrils. Together, these results provide a structural model for the dense network architecture that characterises β-amyloid plaque pathology.
Tailoring confocal microscopy for in-cell photophysiology studies
Authors: Storti Mattia , Hsine Haythem , Uwizeye Clarisse , Bastien Olivier , Yee Daniel , Chevalier Fabien , Giustini Cécile , Béal Daniel , Decelle Johan , Curien Gilles , Tolleter Dimitri , Finazzi Giovanni 
Published: November 2022

SummaryPhotoautotrophs environmental responses have been extensively studied at the organism and ecosystem level. However, less is known about their photosynthesis at the single cell level. This information is needed to understand photosynthetic acclimation processes, as light changes as it penetrates cells, layers of cells or organs. Furthermore, cells within the same tissue may behave differently, being at different developmental/physiological stages. Here we describe a new approach for single-cell and subcellular photophysiology based on the customisation of confocal microscopy to assess chlorophyll fluorescence quenching by the saturation pulse method. We exploit this setup to: i. reassess the specialisation of photosynthetic activities in developing tissues of non-vascular plants; ii. identify a specific subpopulation of phytoplankton cells in marine photosymbiosis, which are consolidating metabolic connections with their animal hosts, and iii. testify to the link between light penetration and photoprotection responses inside the different tissues that constitute a plant leaf anatomy.MotivationVisualising photosynthetic responses in 3D is essential for understanding most acclimation processes, as light changes within photosynthetic tissues as it penetrates the absorbing/diffusing layers of the cells. To achieve this goal, we developed a new imaging workflow merging confocal microscopy and saturating pulse chlorophyll fluorescence detection. This method applies to samples characterised by increasing complexity and its simplicity will contribute to its widespread use in plant and microalgae photoacclimation studies.
Rapid iPSC inclusionopathy models shed light on formation, consequence and molecular subtype of α-synuclein inclusions
Authors: Lam Isabel , Ndayisaba Alain , Lewis Amanda J. , Fu YuHong , Sagredo Giselle T. , Zaccagnini Ludovica , Sandoe Jackson , Sanz Ricardo L. , Vahdatshoar Aazam , Martin Timothy D. , Morshed Nader , Ichihashi Toru , Tripathi Arati , Ramalingam Nagendran , Oettgen-Suazo Charlotte , Bartels Theresa , Schäbinger Max , Hallacli Erinc , Jiang Xin , Verma Amrita , Tea Challana , Wang Zichen , Hakozaki Hiroyuki , Yu Xiao , Hyles Kelly , Park Chansaem , Theunissen Thorold W. , Wang Haoyi , Jaenisch Rudolf , Lindquist Susan , Stevens Beth , Stefanova Nadia , Wenning Gregor , Luk Kelvin C. , Pernaute Rosario Sanchez , Gómez-Esteban Juan Carlos , Felsky Daniel , Kiyota Yasujiro , Sahni Nidhi , Yi S. Stephen , Chung Chee-Yeun , Stahlberg Henning , Ferrer Isidro , Schöneberg Johannes , Elledge Stephen J. , Dettmer Ulf , Halliday Glenda M. , Bartels Tim , Khurana Vikram 
Published: November 2022

ABSTRACTIntracellular inclusions accompanying neurodegeneration are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. iPSC models, while promising for disease modeling, do not form inclusions in a reasonable timeframe and suffer from limited tractability. Here, we developed an iPSC toolbox utilizing piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of aggregation-prone proteins. This system is amenable to screening and longitudinal tracking at single-cell and single-inclusion resolution. For proof-of-principle, cortical neuron α-synuclein “inclusionopathy” models were engineered to form inclusions through exogenous seeding or α-synuclein mutation. These models recapitulated known fibril- and lipid-rich inclusion subtypes, uncovering dynamic interactions between them, and refined the classification of inclusions in postmortem brain. Genetic-modifier and protein-interaction screens pinpointed proteins like RhoA whose sequestration into specific inclusion subtypes is likely to be toxic. This iPSC platform should enhance our understanding of proteinaceous pathologies in neurodegeneration and facilitate therapeutics development.
Asymmetric cell division safeguards memory CD8 T cell development
Authors: Gräbnitz Fabienne , Stark Dominique , Shlesinger Danielle , Petkidis Anthony , Borsa Mariana , Yermanos Alexander , Carr Andreas , Barandun Niculò , Wehling Arne , Balaz Miroslav , Schroeder Timm , Oxenius Annette 
Published: November 2022

AbstractThe strength of T cell receptor (TCR) stimulation and asymmetric distribution of fate determinants are both implied to affect T cell differentiation. Here, we uncovered asymmetric cell division (ACD) as a safeguard mechanism for memory CD8 T cell generation specifically upon strong TCR stimulation. Using live imaging approaches, we found that strong TCR stimulation induced elevated ACD rates and subsequent single cell derived colonies comprised both effector and memory precursor cells. The abundance of memory precursor cells emerging from a single activated T cell positively correlated with first mitosis ACD. Accordingly, preventing ACD by inhibition of PKCζ during the first mitosis upon strong TCR stimulation markedly curtailed the formation of memory precursor cells. Conversely, no effect of ACD on fate commitment was observed upon weak TCR stimulation. Our data provide new mechanistic insights into the role of ACD for CD8 T cell fate regulation upon different activation conditions.
Human Nucleolar Protein 7 (NOL7) is required for pre-rRNA transcription and pre-18S rRNA processing
Authors: McCool Mason A. , Bryant Carson J. , Huang Hannah , Ogawa Lisa M. , Farley-Barnes Katherine I. , Sondalle Samuel B. , Abriola Laura , Surovtseva Yulia V. , Baserga Susan J. 
Published: November 2022

AbstractThe main components of the essential cellular process of eukaryotic ribosome biogenesis are highly conserved from yeast to humans. Among these, the transcription-U3 Associated Proteins (t-UTPs) are a small subunit processome subcomplex that coordinate the first two steps of ribosome biogenesis in transcription and pre-18S processing. While we have identified the human counterparts of most of the yeast Utps, the homologs of yeast Utp9 and Bud21 (Utp16) have remained elusive. In this study, we find NOL7 is the likely ortholog of Bud21. Previously described as a tumor suppressor through regulation of antiangiogenic transcripts, we now show that NOL7 is required for early pre-rRNA stability and pre-18S processing in human cells. These roles lead to decreased protein synthesis, induction of the nucleolar stress response, and defects in cell cycle progression upon NOL7 depletion. Beyond Bud21’s nonessential role in yeast, we establish human NOL7 as an essential UTP that is necessary for both pre-rRNA transcription and processing.
Autonomous behaviour and the limits of human volition
Authors: Ota Keiji , Charles Lucie , Haggard Patrick 
Published: November 2022

AbstractHumans and some other animals can autonomously generate action choices that contribute to solving complex problems. However, experimental investigations of the cognitive bases of human autonomy are challenging, because experimental paradigms typically constrain behaviour using controlled contexts, and elicit behaviour by external triggers. In contrast, autonomy and freedom imply unconstrained behaviour initiated by endogenous triggers. Here we propose a new theoretical construct of adaptive autonomy, meaning the capacity to make behavioural choices that are free from constraints of both immediate external triggers and of routine response patterns, but nevertheless show appropriate coordination with the environment. Participants (N = 152) played a competitive game in which they had to choose the right time to act, in the face of an opponent who punished (in separate blocks) either choice biases (such as always responding early), sequential patterns of action timing across trials (such as early, late, early, late…), or predictable action-outcome dependence (such as win-stay, lose-shift). Adaptive autonomy was quantified as the ability to maintain performance when each of these influences on action selection was punished. We found that participants could become free from habitual choices regarding when to act and could also become free from sequential action patterns. However, they were not able to free themselves from influences of action-outcome dependence, even when these resulted in poor performance. These results point to a new concept of autonomous behaviour as flexible adaptation of voluntary action choices in a way that avoids stereotypy. In a sequential analysis, we also demonstrated that participants increased their reliance on belief learning in which they attempt to understand the competitor’s beliefs and intentions, when transition bias and reinforcement bias were punished. Taken together, our study points to a cognitive mechanism of adaptive autonomy in which competitive interactions with other agents could promote both social cognition and volition in the form of non-stereotyped action choices.
The genome of the brackish-water malaria vectorAnopheles aquasalis
Authors: Sepulveda Cesar C. P. , Alencar Rodrigo M. , Martinez-Villegas Luiz , Bahia Ana Cristina , Santana Rosa A. , de Souza Igor B. , D’Elia Gigliola M. A. , Duarte Ana Paula M. , de Lacerda Marcus V. G. , Monteiro Wuelton M. , F. Costa Secundino Nágila , Koerich Leonardo B. , Pimenta Paulo F. P. 
Published: November 2022

AbstractAnopheles aquasalisis a primary malaria vector in coastal South America that grows in brackish waters of mangroves. Its importance has increased in recent years as it has been established as a model for parasite-vector studies for non-modelPlasmodiumspecies, such asP. yoelli. In this study, we present the complete genome ofAn. aquasalisand offer some insights into evolution and physiology. With a 162Mb and 12,446 coding proteins, theAn. aquasalisgenome is similar in size and gene content as other neotropical anophelines. 1,038 single-copy orthologs are present inAn. aquasalisand all Diptera and it was possible to infer thatAn. aquasalisdiverged fromAn. darlingi(the main malaria vector in inland South America) nearly 14 million years ago (mya). Ion transport and metabolism proteins is one the major gene families inAn. aquasaliswith 660 genes. Amongst these genes, important gene families relevant for osmosis control (e.g., aquaporins, vacuolar-ATPases, Na+/K+-ATPases and carbonic anhydrases) were identified in one-to-one orthologs with other anophelines. Evolutionary analysis suggests that all osmotic regulation genes are under strong purifying selection. We also observed low copy number variation in immunity-related genes (for which all classical pathways were described) and insecticide resistance genes. This is the third genome of a neotropical anopheline published so far. The data provided by this study may offer candidate genes for further studies on parasite-vector interactions and for studies on how brackish water anophelines deals with high fluctuation in water salinity.Significance StatementThe brackish water mosquitoAnopheles aquasalisis a primary malaria vector in coastal South America. Besides its peculiar ecological features (it is one of the few anopheline mosquitoes that survives high fluctuation of water salinity),An. aquasalishas gained relevance in recent years as a model for parasite-vector studies for non-modelPlasmodiumparasites. Still, the physiology and genetics ofAn. aquasalisare poorly understood. Here we present the genome ofAn. aquasaliswith more than 12,000 annotated genes, offering insights in genome evolution, osmoregulation related, immunity, chemosensory and insecticide resistance genes. The data presented here will help to further advance the studies onAn. aquasalisgenetics and physiology to better understand parasite-vector interactions in non-model organisms.
Clinical PARP inhibitors allosterically induce PARP2 retention on DNA
Authors: Langelier Marie-France , Lin Xiaohui , Zha Shan , Pascal John M. 
Published: November 2022

AbstractPARP1 and PARP2 detect DNA breaks, which activates their catalytic production of poly(ADP-ribose) that recruits repair factors and releases PARP1/2 from DNA. PARP inhibitors (PARPi) are used in cancer treatment and target PARP1/2 catalytic activity, interfering with repair and increasing PARP1/2 persistence on DNA damage. Additionally, certain PARPi exert allosteric effects that increase PARP1 retention on DNA. However, no clinical PARPi exhibit this allosteric behavior toward PARP1. In contrast, we show that certain clinical PARPi exhibit an allosteric effect that retains PARP2 on DNA breaks in a manner that depends on communication between the catalytic and DNA-binding regions. Using a PARP2 mutant that mimics an allosteric inhibitor effect, we observed increased PARP2 retention at cellular damage sites. The new PARPi AZD5305 also exhibited a clear reverse allosteric effect on PARP2. Our results can help explain the toxicity of clinical PARPi and suggest ways to improve PARPi moving forward.