bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trp53 controls chondrogenesis and endochondral ossification by negative regulation of TAZ activity and stability via β-TrCP-mediated ubiquitination
Authors: Li Yang , Yang Shu-ting , Yang Shuying 
Published: July 2022

AbstractTransformation-related protein 53 (Trp53) is a critical regulator of cell fate determination by controlling cell proliferation and differentiation. Ablation of Trp53 signaling in osteoblast lineages significantly promotes osteogenesis, bone formation, and bone remodeling. However, how Trp53 regulates chondrogenesis and endochondral bone formation is undefined. In this study, we found that Trp53 expression gradually decreased in tibia growth plates during embryonic development in vivo and during chondrogenesis in vitro. By deleting Trp53 in chondrocyte lineage using Col2-Cre transgenic line, we found that loss of Trp53 in chondrocytes significantly increased growth plate growth and bone formation by increasing chondrocyte proliferation, matrix production and maturation, and bone dynamic formation rate. Mechanistically, our data revealed loss of Trp53 significantly promoted TAZ transcriptional activity through inhibition of TAZ phosphorylation and nuclear translocation, whereas its activity was pronouncedly inhibited after forced expression of Trp53. Furthermore, Co-IP data demonstrated that Trp53 associated with TAZ. Moreover, Trp53 decreased the stability of TAZ protein and promoted its degradation through β-TrCP-mediated ubiquitination. Ablation of TAZ in Col2-Cre;Trp53f/fmice rescued the phenotypes of enhanced chondrogenesis and bone formation caused by Trp53 deletion. Collectively, this study revealed that Trp53 modulates chondrogenesis and endochondral ossification through negative regulation of TAZ activity and stability, suggesting that targeting Trp53 signaling may be a potential strategy for fracture healing, heterotopic ossification, arthritis, and other bone diseases.
Grb2 interacts with necrosome components and is involved in rasfonin-induced necroptosis
Authors: Hou Bolin , Huang Haiwen , Li Yueqian , Liang Jingnan , Xi Zhijun , Jiang Xuejun , Liu Ling , Li Erwei 
Published: July 2022

AbstractThe underlying mechanism by which growth factor receptor-bound protein 2 (Grb2) regulates necroptosis remains unexplored. In the present study, we found that rasfonin, a fungal natural product and an activator of necroptosis, enhanced Grb2 binding to receptor-interacting serine/threonine kinase 1 (RIP1), which plays a critical role in regulating programmed necrosis. Moreover, we observed that SQSTM/p62 (p62), a protein that can form necrosomes with RIP1, increased its interaction with Grb2 upon rasfonin challenge. Although it has been used as an activator of autophagy in our previous study, here we found that a high dose of rasfonin was able to inhibit autophagic process. Inhibition of RIP1 either chemically or genetically reversed the inhibition of rasfonin on autophagy, whereas knockdown of Grb2 markedly reduced rasfonin-induced necrosis. Additionally, we found that the compound failed to upregulate the expression of RIP1 in Grb2-deprived cells. In summary, our data revealed that Grb2 actively participated in rasfonin-induced necroptosis by interacting with the components of necrosome and mediating their expression.
Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients
Authors: Serrano-Maciá Marina , Lachiondo-Ortega Sofia , Iruzubieta Paula , Goikoetxea-Usandizaga Naroa , Bosch Alexandre , Egia-Mendikute Leire , Jiménez-Lasheras Borja , Azkargorta Mikel , Elortza Félix , Martinez-Redondo Diana , Castro Begoña , Lozano Juan J. , Nogueiras Ruben , Irure-Ventura Juan , Crespo Javier , Palazón Asís , Fariñas María Carmen , Delgado Teresa C. , López-Hoyos Marcos , Martínez-Chantar Maria L. 
Published: July 2022

AbstractThe COVID-19 pandemic caused by SARS-CoV-2 has reached 5.5 million deaths worldwide, generating a huge impact globally. This highly contagious viral infection produces a severe acute respiratory syndrome that includes cough, mucus, fever and pneumonia. Likewise, many hospitalized patients develop severe pneumonia associated with acute respiratory distress syndrome (ARDS), along an exacerbated and uncontrolled systemic inflammation that in some cases induces a fatal cytokine storm. Although vaccines clearly have had a beneficial effect, there is still a high percentage of unprotected patients that develop the pathology, due to an ineffective immune response. Therefore, a thorough understanding of the modulatory mechanisms that regulate the response to SARS-CoV-2 is crucial to find effective therapeutic alternatives. Previous studies describe the relevance of Neddylation in the activation of the immune system and its implications in viral infection. In this context, the present study postulates Neddylation, a reversible ubiquitin-like post-translational modification of proteins that control their stability, localization and activity, as a key regulator in the immune response against SARS-CoV-2. For the first time, we describe an increase in global neddylation levels in COVID-19 in the serum of patients, which is particularly associated with the early response to infection. In addition, the results showed that overactivation of neddylation controls activation, proliferation, and response of peripheral blood mononuclear cells (PBMCs) isolated from COVID-19 patients. Inhibition of neddylation, and the subsequent avoidance of activated PBMCs, reduces cytokine production, mainly IL-6 and MCP-1 and induce proteome modulation, being a critical mechanism and a potential approach to immunomodulate COVID-19 patients.
‘Diagnostic shock’: the impact of results from ultrarapid genomic sequencing of critically unwell children on aspects of family functioning
Authors: Bowman-Smart Hilary , Vears Danya F. , Brett Gemma R. , Martyn Melissa , Stark Zornitza , Gyngell Christopher 
Published: July 2022

AbstractRapid genomic sequencing (rGS) is being increasingly used in neonatal and paediatric intensive care units. While there is emerging evidence of clinical utility and cost-effectiveness, concerns have been raised regarding the impact of delivering genomic results in an acute care setting. To help investigate these concerns, we analysed survey data collected from caregivers whose children had received rGS through a national rapid genomic diagnosis program. The impact of rGS on families was assessed through the PedsQL2.0 Family Impact Module and the State-Trait Anxiety Inventory (STAI-6). Sixty-one parents/carers completed the survey during the study period (response rate 48%; 61/128). Mean parent and family functioning was reduced in this sample, reflecting the stressful conditions facing families with critically unwell children. We found caregivers whose children had received a diagnostic result through rGS reported a reduced family relationships score compared to caregivers of children who did not receive a diagnosis. These findings have implications for genetic counselling practice in this setting.
Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains
Authors: Hoyt Forrest , Standke Heidi G. , Artikis Efrosini , Schwartz Cindi L. , Hansen Bryan , Li Kunpeng , Hughson Andrew G. , Manca Matteo , Thomas Olivia R. , Raymond Gregory J. , Race Brent , Baron Gerald S. , Caughey Byron , Kraus Allison 
Published: July 2022

AbstractLittle is known about the structural basis of prion strains. Here we provide a high (3.0 Å) resolution cryo-electron microscopy-based structure of infectious brain-derived fibrils of the mouse anchorless RML scrapie strain which, like the recently determined hamster 263K strain, has a parallel in-register β-sheet-based core. Several structural motifs are shared between these ex vivo prion strains, including an amino-proximal steric zipper and three β-arches. However, detailed comparisons reveal variations in these shared structural topologies and other features. Unlike 263K and wildtype RML prions, the anchorless RML prions lack glycophosphatidylinositol anchors and are severely deficient in N-linked glycans. Nonetheless, the similarity of our anchorless RML structure to one reported for wildtype RML prion fibrils in an accompanying paper indicates that these post-translational modifications do not substantially alter the amyloid core conformation. This work demonstrates both common and divergent structural features of prion strains at the near-atomic level.
Central tropical Pacific convection drives extreme high temperatures and surface melt on the Larsen C Ice Shelf, Antarctic Peninsula
Authors: Clem Kyle R. , Bozkurt Deniz , Kennett Daemon , King John C. , Turner John 
Published: July 2022

AbstractNorthern sections of the Larsen Ice Shelf, eastern Antarctic Peninsula (AP) have experienced dramatic break-up and collapse since the early 1990s due to strong summertime surface melt, linked to strengthened circumpolar westerly winds. Here we show that extreme summertime surface melt and record-high temperature events over the eastern AP and Larsen C Ice Shelf are triggered by deep convection in the central tropical Pacific (CPAC), which produces an elongated cyclonic anomaly across the South Pacific coupled with a strong high pressure anomaly over Drake Passage. Together these atmospheric circulation anomalies transport very warm and moist air to the southwest AP, often in the form of “atmospheric rivers”, producing strong foehn warming and surface melt on the eastern AP and Larsen C Ice Shelf. Therefore, variability in CPAC convection, in addition to the circumpolar westerlies, is a key driver of AP surface mass balance and the occurrence of extreme high temperatures.
Tropical forests as drivers of lake carbon burial
Authors: Amora-Nogueira Leonardo , Sanders Christian J. , Enrich-Prast Alex , Sanders Luciana Silva Monteiro , Abuchacra Rodrigo Coutinho , Moreira-Turcq Patricia F. , Cordeiro Renato Campello , Gauci Vincent , Moreira Luciane Silva , Machado-Silva Fausto , Libonati Renata , Fonseca Thairiny , Francisco Cristiane Nunes , Marotta Humberto 
Published: July 2022

AbstractA significant proportion of carbon (C) captured by terrestrial primary production is buried in lacustrine ecosystems, which have been substantially affected by anthropogenic activities globally. However, there is a scarcity of sedimentary organic carbon (OC) accumulation information for lakes surrounded by highly productive rainforests at warm tropical latitudes, or in response to land cover and climate change. Here, we combine new data from intensive campaigns spanning 13 lakes across remote Amazonian regions with a broad literature compilation, to produce the first spatially-weighted global analysis of recent OC burial in lakes (over ~50-100-years) that integrates both biome type and forest cover. We find that humid tropical forest lake sediments are a disproportionately important global OC sink of 7.4 Tg C yr−1 with implications for climate change. Further, we demonstrate that temperature and forest conservation are key factors in maintaining massive organic carbon pools in tropical lacustrine sediments.
Massively targeted evaluation of therapeutic CRISPR off-targets in cells
Authors: Pan Xiaoguang , Qu Kunli , Yuan Hao , Xiang Xi , Anthon Christian , Pashkova Liubov , Liang Xue , Han Peng , Corsi Giulia I. , Xu Fengping , Liu Ping , Zhong Jiayan , Zhou Yan , Ma Tao , Jiang Hui , Liu Junnian , Wang Jian , Jessen Niels , Bolund Lars , Yang Huanming , Xu Xun , Church George M. , Gorodkin Jan , Lin Lin , Luo Yonglun 
Published: July 2022

AbstractMethods for sensitive and high-throughput evaluation of CRISPR RNA-guided nucleases (RGNs) off-targets (OTs) are essential for advancing RGN-based gene therapies. Here we report SURRO-seq for simultaneously evaluating thousands of therapeutic RGN OTs in cells. SURRO-seq captures RGN-induced indels in cells by pooled lentiviral OTs libraries and deep sequencing, an approach comparable and complementary to OTs detection by T7 endonuclease 1, GUIDE-seq, and CIRCLE-seq. Application of SURRO-seq to 8150 OTs from 110 therapeutic RGNs identifies significantly detectable indels in 783 OTs, of which 37 OTs are found in cancer genes and 23 OTs are further validated in five human cell lines by targeted amplicon sequencing. Finally, SURRO-seq reveals that thermodynamically stable wobble base pair (rG•dT) and free binding energy strongly affect RGN specificity. Our study emphasizes the necessity of thoroughly evaluating therapeutic RGN OTs to minimize inevitable off-target effects.
The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors
Authors: Bartl Jasmin , Zanini Marco , Bernardi Flavia , Forget Antoine , Blümel Lena , Talbot Julie , Picard Daniel , Qin Nan , Cancila Gabriele , Gao Qingsong , Nath Soumav , Koumba Idriss Mahoungou , Wolter Marietta , Kuonen François , Langini Maike , Beez Thomas , Munoz Christopher , Pauck David , Marquardt Viktoria , Yu Hua , Souphron Judith , Korsch Mascha , Mölders Christina , Berger Daniel , Göbbels Sarah , Meyer Frauke-Dorothee , Scheffler Björn , Rotblat Barak , Diederichs Sven , Ramaswamy Vijay , Suzuki Hiromishi , Oro Anthony , Stühler Kai , Stefanski Anja , Fischer Ute , Leprivier Gabriel , Willbold Dieter , Steger Gerhard , Buell Alexander , Kool Marcel , Lichter Peter , Pfister Stefan M. , Northcott Paul A. , Taylor Michael D. , Borkhardt Arndt , Reifenberger Guido , Ayrault Olivier , Remke Marc 
Published: July 2022

AbstractMost lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.
Harnessing many-body spin environment for long coherence storage and high-fidelity single-shot qubit readout
Authors: Gillard George , Clarke Edmund , Chekhovich Evgeny A. 
Published: July 2022

AbstractThere is a growing interest in hybrid solid-state quantum systems where nuclear spins, interfaced to the electron spin qubit, are used as quantum memory or qubit register. These approaches require long nuclear spin coherence, which until now seemed impossible owing to the disruptive effect of the electron spin. Here we study InGaAs semiconductor quantum dots, demonstrating millisecond-long collective nuclear spin coherence even under inhomogeneous coupling to the electron central spin. We show that the underlying decoherence mechanism is spectral diffusion induced by a fluctuating electron spin. These results provide new understanding of the many-body coherence in central spin systems, required for development of electron-nuclear spin qubits. As a demonstration, we implement a conditional gate that encodes electron spin state onto collective nuclear spin coherence, and use it for a single-shot readout of the electron spin qubit with >99% fidelity.
Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer
Authors: Kubota Yuji , Fujioka Yuko , Patil Ashwini , Takagi Yusuke , Matsubara Daisuke , Iijima Masatomi , Momose Isao , Naka Ryosuke , Nakai Kenta , Noda Nobuo N. , Takekawa Mutsuhiro 
Published: July 2022

AbstractPoint-mutations of MEK1, a central component of ERK signaling, are present in cancer and RASopathies, but their precise biological effects remain obscure. Here, we report a mutant MEK1 structure that uncovers the mechanisms underlying abnormal activities of cancer- and RASopathy-associated MEK1 mutants. These two classes of MEK1 mutations differentially impact on spatiotemporal dynamics of ERK signaling, cellular transcriptional programs, gene expression profiles, and consequent biological outcomes. By making use of such distinct characteristics of the MEK1 mutants, we identified cancer- and RASopathy-signature genes that may serve as diagnostic markers or therapeutic targets for these diseases. In particular, two AKT-inhibitor molecules, PHLDA1 and 2, are simultaneously upregulated by oncogenic ERK signaling, and mediate cancer-specific ERK-AKT crosstalk. The combined expression of PHLDA1/2 is critical to confer resistance to ERK pathway-targeted therapeutics on cancer cells. Finally, we propose a therapeutic strategy to overcome this drug resistance. Our data provide vital insights into the etiology, diagnosis, and therapeutic strategy of cancers and RASopathies.
Model building of protein complexes from intermediate-resolution cryo-EM maps with deep learning-guided automatic assembly
Authors: He Jiahua , Lin Peicong , Chen Ji , Cao Hong , Huang Sheng-You 
Published: July 2022

AbstractAdvances in microscopy instruments and image processing algorithms have led to an increasing number of cryo-electron microscopy (cryo-EM) maps. However, building accurate models into intermediate-resolution EM maps remains challenging and labor-intensive. Here, we propose an automatic model building method of multi-chain protein complexes from intermediate-resolution cryo-EM maps, named EMBuild, by integrating AlphaFold structure prediction, FFT-based global fitting, domain-based semi-flexible refinement, and graph-based iterative assembling on the main-chain probability map predicted by a deep convolutional network. EMBuild is extensively evaluated on diverse test sets of 47 single-particle EM maps at 4.0–8.0 Å resolution and 16 subtomogram averaging maps of cryo-ET data at 3.7–9.3 Å resolution, and compared with state-of-the-art approaches. We demonstrate that EMBuild is able to build high-quality complex structures that are comparably accurate to the manually built PDB structures from the cryo-EM maps. These results demonstrate the accuracy and reliability of EMBuild in automatic model building.
De-etiolation-induced protein 1 (DEIP1) mediates assembly of the cytochrome b6f complex in Arabidopsis
Authors: Sandoval-Ibáñez Omar , Rolo David , Ghandour Rabea , Hertle Alexander P. , Armarego-Marriott Tegan , Sampathkumar Arun , Zoschke Reimo , Bock Ralph 
Published: July 2022

AbstractThe conversion of light energy to chemical energy by photosynthesis requires the concerted action of large protein complexes in the thylakoid membrane. Recent work has provided fundamental insights into the three-dimensional structure of these complexes, but how they are assembled from hundreds of parts remains poorly understood. Particularly little is known about the biogenesis of the cytochromeb6fcomplex (Cytb6f), the redox-coupling complex that interconnects the two photosystems. Here we report the identification of a factor that guides the assembly of Cytb6fin thylakoids of chloroplasts. The protein, DE-ETIOLATION-INDUCED PROTEIN 1 (DEIP1), resides in the thylakoid membrane and is essential for photoautotrophic growth. Knock-out mutants show a specific loss of Cytb6f, and are defective in complex assembly. We demonstrate that DEIP1 interacts with the two cytochrome subunits of the complex, PetA and PetB, and mediates the assembly of intermediates in Cytb6fbiogenesis. The identification of DEIP1 provides an entry point into the study of the assembly pathway of a crucial complex in photosynthetic electron transfer.
A SOX17-PDGFB signaling axis regulates aortic root development
Authors: Lu Pengfei , Wang Ping , Wu Bingruo , Wang Yidong , Liu Yang , Cheng Wei , Feng Xuhui , Yuan Xinchun , Atteya Miriam M. , Ferro Haleigh , Sugi Yukiko , Rydquist Grant , Esmaily Mahdi , Butcher Jonathan T. , Chang Ching-Pin , Lenz Jack , Zheng Deyou , Zhou Bin 
Published: July 2022

AbstractDevelopmental etiologies causing complex congenital aortic root abnormalities are unknown. Here we show that deletion ofSox17in aortic root endothelium in mice causes underdeveloped aortic root leading to a bicuspid aortic valve due to the absence of non-coronary leaflet and mispositioned left coronary ostium. The respective defects are associated with reduced proliferation of non-coronary leaflet mesenchyme and aortic root smooth muscle derived from the second heart field cardiomyocytes. Mechanistically, SOX17 occupies aPdgfbtranscriptional enhancer to promote its transcription andSox17deletion inhibits the endothelialPdgfbtranscription and PDGFB growth signaling to the non-coronary leaflet mesenchyme. Restoration of PDGFB in aortic root endothelium rescues the non-coronary leaflet and left coronary ostium defects inSox17nulls. These data support a SOX17-PDGFB axis underlying aortic root development that is critical for aortic valve and coronary ostium patterning, thereby informing a potential shared disease mechanism for concurrent anomalous aortic valve and coronary arteries.
Trichoderma-amended biofertilizer stimulates soil resident Aspergillus population for joint plant growth promotion
Authors: Hang Xinnan , Meng Lingxue , Ou Yannan , Shao Cheng , Xiong Wu , Zhang Nan , Liu Hongjun , Li Rong , Shen Qirong , Kowalchuk George A. 
Published: July 2022

AbstractApplication of plant growth-promoting microbes (PGPMs) can contribute to sustainable agricultural ecosystems. From a three-year field experiment, we already found that the addition of Trichoderma bio-organic fertilizer (BF) significantly improved crop growth and yield compared to the application of organic fertilizer (OF). Here, we tracked the responses of soil bacterial and fungal communities to these treatments to find the key soil microbial taxa that contribute to the crop yield enhancement. We also examined if bacterial and fungal suspensions from resulting soils could improve plant growth upon inoculation into sterilized soil. Lastly, we isolated a number of fungal strains related to populations affected by treatments to examine their role in plant growth promotion. Results showed that consecutive application of BF impacted soil fungal communities, and the biological nature of plant growth promotion was confirmed via pot experiments using γ-sterilized versus none-sterilized soils collected from the field. Soil slurry experiments suggested that fungal, but not bacterial communities, played an important role in plant growth promotion, consistent with the results of our field experimental data. Fungal community analysis of both field and slurry experimental soils revealed increases in specific resident Aspergillus spp. Interestingly, Aspergillus tamarii showed no plant growth promotion by itself, but strongly increased the growth promotion activity of the Trichoderma amendment strain upon their co-inoculation. The effectiveness of the fungal amendment appears to stem not only from its own action, but also from synergetic interactions with resident fungal populations activated upon biofertilizer application.