bluuebunny/crossref_metadata_2025 huggingface dataset:
A lead figurine from Toprakhisar Höyük: magico-ritual objects in the Syro-Anatolian Middle Bronze Age
Authors: Akar Murat , Kara Demet
Published: July 2022

This article examines supra-regional trends in magico-ritual objects through a mould-made lead figurine in the form of a foundation peg found in a disturbed Early Bronze IVB to Middle Bronze I transitional deposit at Toprakhisar Höyük (Altınözü, Hatay). The stylised object is interpreted as a bull standing atop a peg, pointing to the adoption of hybrid Syro-Anatolian and Mesopotamian technological, iconographic and apotropaic values. It is suggested the object is ritual paraphernalia, likely in relation to the cult of the Storm God, used in a foundation ritual. Together with this peculiar metal product, the presence of other magico-ritual objects that point to northern Mesopotamian connections at the small hinterland site of Toprakhisar Höyük, on the outskirts of the Amuq valley, is considered to be a possible material reflection of new groups in the region, including Hurrians and Amorites, which contributed to the unity and regionality of the cults and rituals of Syro-Anatolian communities of the Middle Bronze Age.
The variable use of diacritics in synchronous computer-mediated French discourse: Replication research
Authors: Blattner Geraldine , Williams Lawrence
Published: July 2022

This study promotes replication research as a methodological approach that is needed in order to compare earlier and more recent analyses of digital discourse. When much of the existing research was conducted, the primary means of communication included the use of a computer keyboard, (presumably) less bandwidth, and fewer devices. However, with an increase of the range of device types, the study of diacritics deserves another look within the Digital Media landscape. The present study examines the variable use of diacritics in synchronous (i.e., real-time) French chat discourse. We have replicated a study with different data sets from the same chat corpus, which is composed of data from a European chat server. We have also compared the data from the 2008 half of the corpus to data from the same chat channels collected in 2016 (just over 60,000 words in each half of the corpus, which included a total of 7,569 tokens that were coded). Our analysis of the 2008 corpus showed that one main finding was not the same as ours (from a different part of the 2008 corpus). Moreover, a diachronic analysis (2008 vs. 2016) revealed reversed trends between the two age-based channels (i.e., 20s vs. 50s).
Old and New in Language Variation in French Digital Media: A Commentary
Authors: Fagyal Zsuzsanna
Published: July 2022

Abstract/Excerpt

Papers in this Special Issue fill a gap in French sociolinguistics by providing a coherent and yet diverse sample of empirical studies on a variety of structural aspects of French digital media. Collectively, their thematic focus reflects a traditional framing of language variation, well known from variationist sociolinguistics, correlating empirically observed phonological, morphological, and lexical patterns with social and linguistic variables, among them age, gender, and genre. In this commentary, I reflect on each paper’s unique contribution to recent sociolinguistic research on digital media, and the volume’s goal to examine socially conditioned variation in selected contexts of twenty-first-century digital writing in French.
Sound Velocity Measurements of B2‐Fe‐Ni‐Si Alloy Under High Pressure by Inelastic X‐Ray Scattering: Implications for the Composition of Earth's Core
Authors: Dominijanni S. , McCammon C. A. , Ohtani E. , Ikuta D. , Sakamaki T. , Ishii T. , Criniti G. , Dubrovinsky L. S. , Khandarkhaeva S. , Fedotenko T. , Glazyrin K. , Uchiyama H. , Fukui H. , Baron A. Q. R.
Published: July 2022

Elastic properties of B2‐Fe0.67Ni0.06Si0.27 (15 wt.% Si) alloy have been investigated by combined high‐resolution inelastic X‐ray scattering and powder X‐ray diffraction in diamond anvil cells up to 100 GPa at room temperature. Densities (ρ), compressional (VP) and shear (VS) wave velocities were extrapolated to inner core conditions to enable comparison with the preliminary reference Earth model. The modeled aggregate compressional and shear wave velocities and densities of the two‐phase mixture of B2‐Fe0.67Ni0.06Si0.27 and hcp‐Fe‐Ni are consistent with inner core PREM values of VP, VS, and ρ based on a linear mixing model with 30(5) vol % B2‐Fe0.67Ni0.06Si0.27 and 70(5) vol % hcp Fe‐Ni, which corresponds to ∼3–5 wt.% Si and ∼5–12 wt.% Ni.
The First Look at Our New Astronomy Paradigm
Authors: Cartier Kimberly
Published: July 2022

Five galaxies, two nebulae, an exoplanet, and the early universe—JWST’s first images provide a cross section of the science yet to come.
Improved Modeling of Mars' HDO Cycle Using a Mars' Global Climate Model
Authors: Vals Margaux , Rossi Loïc , Montmessin Franck , Lefèvre Franck , Gonzalez‐Galindo Francisco , Fedorova Anna , Luginin Mikhail , Forget François , Millour Ehouarn , Korablev Oleg , Trokhimovskiy Alexander , Shakun Alexey , Bierjon Antoine , Montabone Luca
Published: July 2022

HDO and the D/H ratio are essential to understand Mars past and present climate, in particular with regard to the evolution through ages of the Martian water cycle. We present here new modeling developments of the HDO cycle with the Laboratoire de Météorologie Dynamique Mars Global Climate Model (GCM). The present study aims at exploring the behavior of the D/H ratio cycle and its sensitivity to the modeling of water ice clouds and the formulation of the fractionation by condensation. Our GCM simulations are compared with observations provided by the Atmospheric Chemistry Suite (ACS) on board the ESA/Roscosmos Trace Gas Orbiter (TGO), and reveal that the model quite well reproduces the temperature and water vapor fields, which offers a good basis for representing the D/H ratio cycle. The comparison also emphasizes the importance of modeling the state of supersaturation, resulting from the microphysical processes of water ice clouds, to correctly account for the water vapor and the D/H ratio of the middle‐to‐upper atmosphere. This work comes jointly with a detailed comparison of the measured D/H profiles by TGO/ACS and the model outputs, conducted in the companion paper of Rossi et al. (2022, https://doi.org/10.1029/2022JE007201) (this issue).
Non‐Linear Dimensionality Reduction With a Variational Encoder Decoder to Understand Convective Processes in Climate Models
Authors: Behrens Gunnar , Beucler Tom , Gentine Pierre , Iglesias‐Suarez Fernando , Pritchard Michael , Eyring Veronika
Published: July 2022

Deep learning can accurately represent sub‐grid‐scale convective processes in climate models, learning from high resolution simulations. However, deep learning methods usually lack interpretability due to large internal dimensionality, resulting in reduced trustworthiness in these methods. Here, we use Variational Encoder Decoder structures (VED), a non‐linear dimensionality reduction technique, to learn and understand convective processes in an aquaplanet superparameterized climate model simulation, where deep convective processes are simulated explicitly. We show that similar to previous deep learning studies based on feed‐forward neural nets, the VED is capable of learning and accurately reproducing convective processes. In contrast to past work, we show this can be achieved by compressing the original information into only five latent nodes. As a result, the VED can be used to understand convective processes and delineate modes of convection through the exploration of its latent dimensions. A close investigation of the latent space enables the identification of different convective regimes: (a) stable conditions are clearly distinguished from deep convection with low outgoing longwave radiation and strong precipitation; (b) high optically thin cirrus‐like clouds are separated from low optically thick cumulus clouds; and (c) shallow convective processes are associated with large‐scale moisture content and surface diabatic heating. Our results demonstrate that VEDs can accurately represent convective processes in climate models, while enabling interpretability and better understanding of sub‐grid‐scale physical processes, paving the way to increasingly interpretable machine learning parameterizations with promising generative properties.
Pathogenic fungus uses volatiles to entice male flies into fatal matings with infected female cadavers
Authors: Naundrup Andreas , Bohman Björn , Kwadha Charles A , Jensen Annette B , Becher Paul G , De Fine Licht Henrik H
Published: July 2022

To ensure dispersal, many parasites and pathogens behaviourally manipulate infected hosts. Other pathogens and certain insect-pollinated flowers use sexual mimicry and release deceptive mating signals. However, it is unusual for pathogens to rely on both behavioural host manipulation and sexual mimicry. Here, we show that the host-specific and behaviourally manipulating pathogenic fungus, Entomophthora muscae, generates a chemical blend of volatile sesquiterpenes and alters the profile of natural host cuticular hydrocarbons in infected female housefly (Musca domestica) cadavers. Healthy male houseflies respond to the fungal compounds and are enticed into mating with female cadavers. This is advantageous for the fungus as close proximity between host individuals leads to an increased probability of infection. The fungus exploits the willingness of male flies to mate and benefits from altering the behaviour of uninfected male host flies. The altered cuticular hydrocarbons and emitted volatiles thus underlie the evolution of an extended phenotypic trait.
Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR
Authors: Lee Boah , Park Seung Ju , Lee Seulgi , Lee Jinwook , Lee Eunbeol , Yoo Eun-Seon , Chung Won-Suk , Sohn Jong-Woo , Oh Byung-Chul , Kim Seyun
Published: July 2022

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.
Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth
Authors: Xue Yuhang , Jiang Kanqiu , Ou Li , Shen Mingjing , Yang Yi , Lu Jingjing , Xu Weihua
Published: July 2022

Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC). SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 potently inhibited cell proliferation, cell cycle progression, migration and viability. The dual inhibitor induced mitochondrial depolarization and apoptosis activation in NSCLC cells, but it was non-cytotoxic to human lung epithelial cells. SKI-349 inhibited SphK activity and induced ceramide accumulation in primary NSCLC cells, without affecting SphK1/2 expression. SKI-349-induced NSCLC cell death was attenuated by sphingosine-1-phosphate and by the SphK activator K6PC-5, but was potentiated by the short-chain ceramide C6. Moreover, SKI-349 induced Akt-mTOR inactivation, JNK activation, and oxidative injury in primary NSCLC cells. In addition, SKI-349 decreased bromodomain-containing protein 4 (BRD4) expression and downregulated BRD4-dependent genes (Myc, cyclin D1 and Klf4) in primary NSCLC cells. At last, SKI-349 (10 mg/kg) administration inhibited NSCLC xenograft growth in nude mice. Akt-mTOR inhibition, JNK activation, oxidative injury and BRD4 downregulation were detected in SKI-349-treated NSCLC xenograft tissues. Taken together, targeting SphK1/2 by SKI-349 potently inhibits NSCLC cell growth in vitro and in vivo.
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

Transformation-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

The 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

The 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

Rapid 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

Little 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

Northern 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

A 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

Methods 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

Most 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

There 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

Point-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

Advances 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

The 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

Developmental 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

Application 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.
Do titanium biomaterials get immediately and entirely repassivated? A perspective
Authors: Asserghine Abdelilah , Filotás Daniel , Nagy Lívia , Souto Ricardo M. , Nagy Géza
Published: July 2022

Titanium and its alloys have been widely used for clinical applications because of their biocompatibility and exceptional chemical inertness, in addition to their outstanding osseointegration characteristics. They are well known to form a robust protective film on the surface that provides a high corrosion resistance with the surrounding environment. Although this passive state of titanium-based materials is often considered to be achieved very rapidly, even when damaged, and to be chemically stable in physiological environments, evidences of passivity breakdown and electron transfer reactions have been collected using high resolution microelectrochemical techniques. Thus, further optimizations are required for their forthcoming applications.
Implementation of quantum measurements using classical resources and only a single ancillary qubit
Authors: Singal Tanmay , Maciejewski Filip B. , Oszmaniec Michał
Published: July 2022

We propose a scheme to implement general quantum measurements, also known as Positive Operator Valued Measures (POVMs) in dimension d using only classical resources and a single ancillary qubit. Our method is based on probabilistic implementation of d-outcome measurements which is followed by postselection of some of the received outcomes. We conjecture that success probability of our scheme is larger than a constant independent of d for all POVMs in dimension d. Crucially, this conjecture implies the possibility of realizing arbitrary nonadaptive quantum measurement protocol on d-dimensional system using a single auxiliary qubit with only a constant overhead in sampling complexity. We show that the conjecture holds for typical rank-one Haar-random POVMs in arbitrary dimensions. Furthermore, we carry out extensive numerical computations showing success probability above a constant for a variety of extremal POVMs, including SIC-POVMs in dimension up to 1299. Finally, we argue that our scheme can be favorable for experimental realization of POVMs, as noise compounding in circuits required by our scheme is typically substantially lower than in the standard scheme that directly uses Naimark’s dilation theorem.
Impaired verbal memory function is related to anterior cingulate glutamate levels in schizophrenia: findings from the STRATA study
Authors: Griffiths Kira , Egerton Alice , Millgate Edward , Anton Adriana , Barker Gareth J. , Deakin Bill , Drake Richard , Eliasson Emma , Gregory Catherine J. , Howes Oliver D. , Kravariti Eugenia , Lawrie Stephen M. , Lewis Shôn , Lythgoe David J. , Murphy Anna , McGuire Philip , Semple Scott , Stockton-Powdrell Charlotte , Walters James T. R. , Williams Stephen R. , MacCabe James H.
Published: July 2022

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.
Elastocaloric determination of the phase diagram of Sr2RuO4
Authors: Li You-Sheng , Garst Markus , Schmalian Jörg , Ghosh Sayak , Kikugawa Naoki , Sokolov Dmitry A. , Hicks Clifford W. , Jerzembeck Fabian , Ikeda Matthias S. , Hu Zhenhai , Ramshaw B. J. , Rost Andreas W. , Nicklas Michael , Mackenzie Andrew P.
Published: July 2022

One of the main developments in unconventional superconductivity in the past two decades has been the discovery that most unconventional superconductors form phase diagrams that also contain other strongly correlated states. Many systems of interest are therefore close to more than one instability, and tuning between the resultant ordered phases is the subject of intense research1. In recent years, uniaxial pressure applied using piezoelectric-based devices has been shown to be a particularly versatile new method of tuning2,3, leading to experiments that have advanced our understanding of the fascinating unconventional superconductor Sr2RuO4 (refs. 4–9). Here we map out its phase diagram using high-precision measurements of the elastocaloric effect in what we believe to be the first such study including both the normal and the superconducting states. We observe a strong entropy quench on entering the superconducting state, in excellent agreement with a model calculation for pairing at the Van Hove point, and obtain a quantitative estimate of the entropy change associated with entry to a magnetic state that is observed in proximity to the superconductivity. The phase diagram is intriguing both for its similarity to those seen in other families of unconventional superconductors and for extra features unique, so far, to Sr2RuO4.
Visual recognition of social signals by a tectothalamic neural circuit
Authors: Kappel Johannes M. , Förster Dominique , Slangewal Katja , Shainer Inbal , Svara Fabian , Donovan Joseph C. , Sherman Shachar , Januszewski Michał , Baier Herwig , Larsch Johannes
Published: July 2022

Social affiliation emerges from individual-level behavioural rules that are driven by conspecific signals1–5. Long-distance attraction and short-distance repulsion, for example, are rules that jointly set a preferred interanimal distance in swarms6–8. However, little is known about their perceptual mechanisms and executive neural circuits3. Here we trace the neuronal response to self-like biological motion9,10, a visual trigger for affiliation in developing zebrafish2,11. Unbiased activity mapping and targeted volumetric two-photon calcium imaging revealed 21 activity hotspots distributed throughout the brain as well as clustered biological-motion-tuned neurons in a multimodal, socially activated nucleus of the dorsal thalamus. Individual dorsal thalamus neurons encode local acceleration of visual stimuli mimicking typical fish kinetics but are insensitive to global or continuous motion. Electron microscopic reconstruction of dorsal thalamus neurons revealed synaptic input from the optic tectum and projections into hypothalamic areas with conserved social function12–14. Ablation of the optic tectum or dorsal thalamus selectively disrupted social attraction without affecting short-distance repulsion. This tectothalamic pathway thus serves visual recognition of conspecifics, and dissociates neuronal control of attraction from repulsion during social affiliation, revealing a circuit underpinning collective behaviour.
Post-extinction recovery of the Phanerozoic oceans and biodiversity hotspots
Authors: Cermeño Pedro , García-Comas Carmen , Pohl Alexandre , Williams Simon , Benton Michael J. , Chaudhary Chhaya , Le Gland Guillaume , Müller R. Dietmar , Ridgwell Andy , Vallina Sergio M.
Published: July 2022

The fossil record of marine invertebrates has long fuelled the debate as to whether or not there are limits to global diversity in the sea1–5. Ecological theory states that, as diversity grows and ecological niches are filled, the strengthening of biological interactions imposes limits on diversity6,7. However, the extent to which biological interactions have constrained the growth of diversity over evolutionary time remains an open question1–5,8–11. Here we present a regional diversification model that reproduces the main Phanerozoic eon trends in the global diversity of marine invertebrates after imposing mass extinctions. We find that the dynamics of global diversity are best described by a diversification model that operates widely within the exponential growth regime of a logistic function. A spatially resolved analysis of the ratio of diversity to carrying capacity reveals that less than 2% of the global flooded continental area throughout the Phanerozoic exhibits diversity levels approaching ecological saturation. We attribute the overall increase in global diversity during the Late Mesozoic and Cenozoic eras to the development of diversity hotspots under prolonged conditions of Earth system stability and maximum continental fragmentation. We call this the ‘diversity hotspots hypothesis’, which we propose as a non-mutually exclusive alternative to the hypothesis that the Mesozoic marine revolution led this macroevolutionary trend12,13.
Structure of the MRAS–SHOC2–PP1C phosphatase complex
Authors: Hauseman Zachary J. , Fodor Michelle , Dhembi Anxhela , Viscomi Jessica , Egli David , Bleu Melusine , Katz Stephanie , Park Eunyoung , Jang Dong Man , Porter Kathryn A. , Meili Fabian , Guo Hongqiu , Kerr Grainne , Mollé Sandra , Velez-Vega Camilo , Beyer Kim S. , Galli Giorgio G. , Maira Saveur-Michel , Stams Travis , Clark Kirk , Eck Michael J. , Tordella Luca , Thoma Claudio R. , King Daniel A.
Published: July 2022

RAS–MAPK signalling is fundamental for cell proliferation and is altered in most human cancers1–3. However, our mechanistic understanding of how RAS signals through RAF is still incomplete. Although studies revealed snapshots for autoinhibited and active RAF–MEK1–14-3-3 complexes4, the intermediate steps that lead to RAF activation remain unclear. The MRAS–SHOC2–PP1C holophosphatase dephosphorylates RAF at serine 259, resulting in the partial displacement of 14-3-3 and RAF–RAS association3,5,6. MRAS, SHOC2 and PP1C are mutated in rasopathies—developmental syndromes caused by aberrant MAPK pathway activation6–14—and SHOC2 itself has emerged as potential target in receptor tyrosine kinase (RTK)–RAS-driven tumours15–18. Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we determine, using X-ray crystallography, the structure of the MRAS–SHOC2–PP1C complex. SHOC2 bridges PP1C and MRAS through its concave surface and enables reciprocal interactions between all three subunits. Biophysical characterization indicates a cooperative assembly driven by the MRAS GTP-bound active state, an observation that is extendible to other RAS isoforms. Our findings support the concept of a RAS-driven and multi-molecular model for RAF activation in which individual RAS–GTP molecules recruit RAF–14-3-3 and SHOC2–PP1C to produce downstream pathway activation. Importantly, we find that rasopathy and cancer mutations reside at protein–protein interfaces within the holophosphatase, resulting in enhanced affinities and function. Collectively, our findings shed light on a fundamental mechanism of RAS biology and on mechanisms of clinically observed enhanced RAS–MAPK signalling, therefore providing the structural basis for therapeutic interventions.