bluuebunny/crossref_metadata_2025_split huggingface dataset:
Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial–mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer
Authors: Lu Ziwen , Yuan Sirui , Ruan Lingling , Tu Zhigang , Liu Hanqing 
Published: April 2022

AbstractPartitioning-defective protein 6 (Par6) family proteins have been demonstrated to be closely associated with the occurrence and development of cancers. It is well accepted that dysregulation of epithelial–mesenchymal transition (EMT) greatly contributes to carcinogenesis and metastases of ovarian cancer. So far, the roles of Par6 in EMT of ovarian cancer are not clear. Functional experiments were carried out to study the roles of PARD6A in EMT of ovarian cancer in vitro and in vivo, and EMT pathways potentially affected by PARD6A expression were screened. We found that PARD6A was significantly highly expressed in tissues of ovarian cancer patients in III-IV stages, poorly differentiated or with lymphatic metastases versus I-II stages, moderately or well differentiated, or without lymphatic metastases, respectively. PARD6A knockdown suppressed EMT of SKOV3 and A2780 cells in vitro and ovarian cancer metastasis in vivo, while overexpression of PARD6A promoted EMT in HO8910 and OVCAR8 cells. It was indicated that PARD6A affected EMT of ovarian cancer cells through SNAIL1 signaling pathway and subsequently modulated the expression of VIMENTIN and E-cadherin, which was further confirmed by knockdown and overexpression of SNAIL1 experiments. PARD6A was also demonstrated to regulate expression of SNAIL1 by modulating integrin β1 and ILK proteins, specifically it was shown that the transcription of SNAIL1 was regulated by ILK in this study. In addition, expression of ILK in ovarian cancer tissues was demonstrated to be correlated with tumor stages and lymphatic metastases clinically. In this study, we identified a novel role of PARD6A as an inducer of cell migration and invasion, which is likely to play an important role in metastasis of ovarian cancer. The molecular pathways of EMT mediated by PARD6A-Integrin β1-ILK-SNAIL1 and finally implemented by E-cadherin and VIMENTIN may provide a novel strategy for drug development for ovarian cancer therapy in the near future.
The nociceptin receptor promotes autophagy through NF-kB signaling and is transcriptionally regulated by E2F1 in HCC
Authors: Zhou Xiaoshuang , Chen Dongtai , Yan Yan , Li Qiang , Xing Wei , Liu Yanling , Chen Yonghua , Wang Dongyin , Yuan Yunfei , Xie Jingdun , Zeng Weian , Pan Jiahao 
Published: April 2022

AbstractOpioids and their receptors are involved in cancer progression. However, the roles of the nociceptin receptor (NOP) and its antagonist (JTC801) in hepatocellular carcinoma (HCC) are poorly understood. The prognostic value of NOP expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HCC cohort. The biological role and mechanism of NOP in HCC tumor growth were determined in vitro and in vivo. We found that NOP was associated with the clinicopathological features and survival outcomes of HCC patients. NOP overexpression promoted HCC growth in vitro and in vivo. Mechanistically, NOP activated NF-kB signaling to promote autophagy, which inhibited apoptosis, in HCC cells. An inhibitor of autophagy, 3-MA, and an inhibitor of NF-kB, JSH-23, attenuated the function of NOP in HCC. E2F1 was identified as a transcription factor of NOP. The oncogenic role of NOP was positively regulated by E2F1. Furthermore, JTC801, a selective antagonist of NOP, abolished the function of NOP by inhibiting NF-kB signaling and autophagy. Our study demonstrates that NOP is an oncogene in HCC. We provide a potential therapeutic candidate and prognostic predictor for HCC. JTC801 could become a potential drug for HCC therapy.
Revealing global risks of labor abuse and illegal, unreported, and unregulated fishing
Authors: Selig Elizabeth R. , Nakayama Shinnosuke , Wabnitz Colette C. C. , Österblom Henrik , Spijkers Jessica , Miller Nathan A. , Bebbington Jan , Decker Sparks Jessica L. 
Published: April 2022

AbstractLabor abuse on fishing vessels and illegal, unreported and unregulated (IUU) fishing violate human rights, jeopardize food security, and deprive governments of revenues. We applied a multi-method approach, combining new empirical data with satellite information on fishing activities and vessel characteristics to map risks of labor abuse and IUU fishing, understand their relationships, and identify major drivers. Port risks were globally pervasive and often coupled, with 57% of assessed ports associated with labor abuse or IUU fishing. For trips ending in assessed ports, 82% were linked to labor abuse or IUU fishing risks. At-sea risk areas were primarily driven by fishing vessel flags linked to poor control of corruption by the flag state, high ownership by countries other than the flag state, and Chinese-flagged vessels. Transshipment risk areas were related to the gear type of fishing vessels engaged in potential transshipment and carrier vessel flags. Measures at port offer promise for mitigating risks, through the Port State Measures Agreement for IUU fishing, and ensuring sufficient vessel time at port to detect and respond to labor abuse. Our results highlight the need for coordinated action across actors to avoid risk displacement and make progress towards eliminating these socially, environmentally and economically unsustainable practices.
Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells
Authors: Shah Kathleen , Maradana Muralidhara Rao , Joaquina Delàs M. , Metidji Amina , Graelmann Frederike , Llorian Miriam , Chakravarty Probir , Li Ying , Tolaini Mauro , Shapiro Michael , Kelly Gavin , Cheshire Chris , Bhurta Deendyal , Bharate Sandip B. , Stockinger Brigitta 
Published: April 2022

AbstractThe aryl hydrocarbon receptor (AHR) is an environmental sensor that integrates microbial and dietary cues to influence physiological processes within the intestinal microenvironment, protecting against colitis and colitis-associated colorectal cancer development. Rapid tissue regeneration upon injury is important for the reinstatement of barrier integrity and its dysregulation promotes malignant transformation. Here we show that AHR is important for the termination of the regenerative response and the reacquisition of mature epithelial cell identity post injury in vivo and in organoid cultures in vitro. Using an integrative multi-omics approach in colon organoids, we show that AHR is required for timely termination of the regenerative response through direct regulation of transcription factors involved in epithelial cell differentiation as well as restriction of chromatin accessibility to regeneration-associatedYap/Teadtranscriptional targets. Safeguarding a regulated regenerative response places AHR at a pivotal position in the delicate balance between controlled regeneration and malignant transformation.
Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies
Authors: Absalom Nathan L. , Liao Vivian W. Y. , Johannesen Katrine M. H. , Gardella Elena , Jacobs Julia , Lesca Gaetan , Gokce-Samar Zeynep , Arzimanoglou Alexis , Zeidler Shimriet , Striano Pasquale , Meyer Pierre , Benkel-Herrenbrueck Ira , Mero Inger-Lise , Rummel Jutta , Chebib Mary , Møller Rikke S. , Ahring Philip K. 
Published: April 2022

AbstractMany patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.
Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition
Authors: Liang Wenguang G. , Wijaya Juwina , Wei Hui , Noble Alex J. , Mancl Jordan M. , Mo Swansea , Lee David , Lin King John V. , Pan Man , Liu Chang , Koehler Carla M. , Zhao Minglei , Potter Clinton S. , Carragher Bridget , Li Sheng , Tang Wei-Jen 
Published: April 2022

AbstractPresequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption. Thereby, we elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP at 3.3–4.6 Å resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives a rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.
ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury
Authors: Rohlfing Anne-Katrin , Kolb Kyra , Sigle Manuel , Ziegler Melanie , Bild Alexander , Münzer Patrick , Sudmann Jessica , Dicenta Valerie , Harm Tobias , Manke Mailin-Christin , Geue Sascha , Kremser Marcel , Chatterjee Madhumita , Liang Chunguang , von Eysmondt Hendrik , Dandekar Thomas , Heinzmann David , Günter Manina , von Ungern-Sternberg Saskia , Büttcher Manuela , Castor Tatsiana , Mencl Stine , Langhauser Friederike , Sies Katharina , Ashour Diyaa , Beker Mustafa Caglar , Lämmerhofer Michael , Autenrieth Stella E. , Schäffer Tilman E. , Laufer Stefan , Szklanna Paulina , Maguire Patricia , Heikenwalder Matthias , Müller Karin Anne Lydia , Hermann Dirk M. , Kilic Ertugrul , Stumm Ralf , Ramos Gustavo , Kleinschnitz Christoph , Borst Oliver , Langer Harald F. , Rath Dominik , Gawaz Meinrad 
Published: April 2022

AbstractPlatelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.
Chiral structures of electric polarization vectors quantified by X-ray resonant scattering
Authors: Kim Kook Tae , McCarter Margaret R. , Stoica Vladimir A. , Das Sujit , Klewe Christoph , Donoway Elizabeth P. , Burn David M. , Shafer Padraic , Rodolakis Fanny , Gonçalves Mauro A. P. , Gómez-Ortiz Fernando , Íñiguez Jorge , García-Fernández Pablo , Junquera Javier , Susarla Sandhya , Lovesey Stephen W. , van der Laan Gerrit , Park Se Young , Martin Lane W. , Freeland John W. , Ramesh Ramamoorthy , Lee Dong Ryeol 
Published: April 2022

AbstractResonant elastic X-ray scattering (REXS) offers a unique tool to investigate solid-state systems providing spatial knowledge from diffraction combined with electronic information through the enhanced absorption process, allowing the probing of magnetic, charge, spin, and orbital degrees of spatial order together with electronic structure. A new promising application of REXS is to elucidate the chiral structure of electrical polarization emergent in a ferroelectric oxide superlattice in which the polarization vectors in the REXS amplitude are implicitly described through an anisotropic tensor corresponding to the quadrupole moment. Here, we present a detailed theoretical framework and analysis to quantitatively analyze the experimental results of Ti L-edge REXS of a polar vortex array formed in a PbTiO3/SrTiO3 superlattice. Based on this theoretical framework, REXS for polar chiral structures can become a useful tool similar to x-ray resonant magnetic scattering (XRMS), enabling a comprehensive study of both electric and magnetic REXS on the chiral structures.
Group testing via hypergraph factorization applied to COVID-19
Authors: Hong David , Dey Rounak , Lin Xihong , Cleary Brian , Dobriban Edgar 
Published: April 2022

AbstractLarge scale screening is a critical tool in the life sciences, but is often limited by reagents, samples, or cost. An important recent example is the challenge of achieving widespread COVID-19 testing in the face of substantial resource constraints. To tackle this challenge, screening methods must efficiently use testing resources. However, given the global nature of the pandemic, they must also be simple (to aid implementation) and flexible (to be tailored for each setting). Here we propose HYPER, a group testing method based on hypergraph factorization. We provide theoretical characterizations under a general statistical model, and carefully evaluate HYPER with alternatives proposed for COVID-19 under realistic simulations of epidemic spread and viral kinetics. We find that HYPER matches or outperforms the alternatives across a broad range of testing-constrained environments, while also being simpler and more flexible. We provide an online tool to aid lab implementation: http://hyper.covid19-analysis.org.
Structure-based design of stabilized recombinant influenza neuraminidase tetramers
Authors: Ellis Daniel , Lederhofer Julia , Acton Oliver J. , Tsybovsky Yaroslav , Kephart Sally , Yap Christina , Gillespie Rebecca A. , Creanga Adrian , Olshefsky Audrey , Stephens Tyler , Pettie Deleah , Murphy Michael , Sydeman Claire , Ahlrichs Maggie , Chan Sidney , Borst Andrew J. , Park Young-Jun , Lee Kelly K. , Graham Barney S. , Veesler David , King Neil P. , Kanekiyo Masaru 
Published: April 2022

AbstractInfluenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an “open” state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the “closed” state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.
Non-invasive digital etching of van der Waals semiconductors
Authors: Zhou Jian , Zhang Chunchen , Shi Li , Chen Xiaoqing , Kim Tae Soo , Gyeon Minseung , Chen Jian , Wang Jinlan , Yu Linwei , Wang Xinran , Kang Kibum , Orgiu Emanuele , Samorì Paolo , Watanabe Kenji , Taniguchi Takashi , Tsukagoshi Kazuhito , Wang Peng , Shi Yi , Li Songlin 
Published: April 2022

AbstractThe capability to finely tailor material thickness with simultaneous atomic precision and non-invasivity would be useful for constructing quantum platforms and post-Moore microelectronics. However, it remains challenging to attain synchronized controls over tailoring selectivity and precision. Here we report a protocol that allows for non-invasive and atomically digital etching of van der Waals transition-metal dichalcogenides through selective alloying via low-temperature thermal diffusion and subsequent wet etching. The mechanism of selective alloying between sacrifice metal atoms and defective or pristine dichalcogenides is analyzed with high-resolution scanning transmission electron microscopy. Also, the non-invasive nature and atomic level precision of our etching technique are corroborated by consistent spectral, crystallographic, and electrical characterization measurements. The low-temperature charge mobility of as-etched MoS2reaches up to 1200 cm2 V−1s−1, comparable to that of exfoliated pristine counterparts. The entire protocol represents a highly precise and non-invasive tailoring route for material manipulation.
Local large temperature difference and ultra-wideband photothermoelectric response of the silver nanostructure film/carbon nanotube film heterostructure
Authors: Lv Bocheng , Liu Yu , Wu Weidong , Xie Yan , Zhu Jia-Lin , Cao Yang , Ma Wanyun , Yang Ning , Chu Weidong , Jia Yi , Wei Jinquan , Sun Jia-Lin 
Published: April 2022

AbstractPhotothermoelectric materials have important applications in many fields. Here, we joined a silver nanostructure film and a carbon nanotube film by van der Waals force to form a heterojunction, which shows excellent photothermal and photoelectric conversion properties. The local temperature difference and the output photovoltage increase rapidly when the heterojunction is irradiated by lasers with wavelengths ranging from ultraviolet to terahertz. The maximum temperature difference reaches 215.9 K, which is significantly higher than that of other photothermoelectric materials reported in the literature. The photothermal and photoelectric responsivity depend on the wavelength of lasers, which are 175~601 K W-1 and 9.35~40.4 mV W-1, respectively. We demonstrate that light absorption of the carbon nanotube is enhanced by local surface plasmons, and the output photovoltage is dominated by Seebeck effect. The proposed heterostructure can be used as high-efficiency sensitive photothermal materials or as ultra-wideband fast-response photoelectric materials.
Black carbon-climate interactions regulate dust burdens over India revealed during COVID-19
Authors: Wei Linyi , Lu Zheng , Wang Yong , Liu Xiaohong , Wang Weiyi , Wu Chenglai , Zhao Xi , Rahimi Stefan , Xia Wenwen , Jiang Yiquan 
Published: April 2022

AbstractIndia as a hotspot for air pollution has heavy black carbon (BC) and dust (DU) loadings. BC has been identified to significantly impact the Indian climate. However, whether BC-climate interactions regulate Indian DU during the premonsoon season is unclear. Here, using long-term Reanalysis data, we show that Indian DU is positively correlated to northern Indian BC while negatively correlated to southern Indian BC. We further identify the mechanism of BC-dust-climate interactions revealed during COVID-19. BC reduction in northern India due to lockdown decreases solar heating in the atmosphere and increases surface albedo of the Tibetan Plateau (TP), inducing a descending atmospheric motion. Colder air from the TP together with warmer southern Indian air heated by biomass burning BC results in easterly wind anomalies, which reduces dust transport from the Middle East and Sahara and local dust emissions. The premonsoon aerosol-climate interactions delay the outbreak of the subsequent Indian summer monsoon.
Structural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1
Authors: Li Ying , Varejão Nathalia , Reverter David 
Published: April 2022

AbstractPost-translational protein modifications by ubiquitin and ubiquitin-like modifiers regulate many major pathways in the cell. These modifications can be reversed by de-ubiquitinating enzymes such as ubiquitin-specific proteases (USPs). Proteolytic activity towards ubiquitin-modified substrates is common to all USP family members except for USPL1, which shows a unique preference for the ubiquitin-like modifier SUMO. Here, we present the crystal structure of USPL1 bound to SUMO2, defining the key structural elements for the unusual deSUMOylase activity of USPL1. We identify specific contacts between SUMO2 and the USPL1 subdomains, including a unique hydrogen bond network of the SUMO2 C-terminal tail. In addition, we find that USPL1 lacks major structural elements present in all canonical USPs members such as the so-called blocking loops, which facilitates SUMO binding. Our data give insight into how a structural protein scaffold designed to bind ubiquitin has evolved to bind SUMO, providing an example of divergent evolution in the USP family.
acorde unravels functionally interpretable networks of isoform co-usage from single cell data
Authors: Arzalluz-Luque Angeles , Salguero Pedro , Tarazona Sonia , Conesa Ana 
Published: April 2022

AbstractAlternative splicing (AS) is a highly-regulated post-transcriptional mechanism known to modulate isoform expression within genes and contribute to cell-type identity. However, the extent to which alternative isoforms establish co-expression networks that may be relevant in cellular function has not been explored yet. Here, we present acorde, a pipeline that successfully leverages bulk long reads and single-cell data to confidently detect alternative isoform co-expression relationships. To achieve this, we develop and validate percentile correlations, an innovative approach that overcomes data sparsity and yields accurate co-expression estimates from single-cell data. Next, acorde uses correlations to cluster co-expressed isoforms into a network, unraveling cell type-specific alternative isoform usage patterns. By selecting same-gene isoforms between these clusters, we subsequently detect and characterize genes with co-differential isoform usage (coDIU) across cell types. Finally, we predict functional elements from long read-defined isoforms and provide insight into biological processes, motifs, and domains potentially controlled by the coordination of post-transcriptional regulation. The code for acorde is available at https://github.com/ConesaLab/acorde.