bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUMOylation inhibition enhances multiple myeloma sensitivity to lenalidomide
Authors: Du Li , Liu Wei , Pichiorri Flavia , Rosen Steven T. 
Published: March 2022

AbstractDespite the potent effect of lenalidomide (Len) in multiple myeloma (MM) treatment, patients develop Len resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms mediating Len resistance. Our study identified SUMOylation as a potential mechanism regulating Len resistance in MM. Len-resistant MM cell line MMR10R presented much higher SUMO E1 (SAE2) expression and more global SUMOylation than Len-sensitive MM1S cell line. SUMOylation inhibition by using TAK-981, a novel and specific SUMO E1 inhibitor, significantly enhances myeloma sensitivity to Len in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Len combination has been validated using primary relapsing MM patient samples. Overexpression of IRF4 and c-Myc is a major mechanism of Len resistance. Len showed limited effect on IRF4 and c-Myc level in Len-resistance cell line, but TAK-981 treatment reduced IRF4 and c-Myc expression in Len-resistant line and caused further decrease when combined with Len. We found SUMOylation inhibition decreases IRF4 at transcriptional and post-translational level. SUMOylation inhibition reduced DOT1L with decreased methylation of histone H3 lysine 79, to suppress IRF4 gene transcription. SUMOylation inhibition also reduced IRF4 protein level by enhancing degradation. Overall, our data revealed SUMOylation inhibition enhances Len sensitivity through downregulating IRF4.
Pseudophosphatase STYX is induced by Helicobacter pylori and promotes gastric cancer progression by inhibiting FBXO31 function
Authors: Liu Jiansong , Zang Yichen , Ma Cunying , Wang Dandan , Tian Zhuangfei , Xu Xia , Li Wenjuan , Jia Jihui , Liu Zhifang 
Published: March 2022

AbstractGastric cancer (GC) is one of the most common malignancies in the world and ranks third in terms of cancer-related deaths. The catalytically inactive pseudophosphatase STYX (serine/threonine/tyrosine interacting protein) is a member of the protein tyrosine phosphatase family. It has been recently reported that STYX functions as a potential oncogene in different types of cancers. However, the potential role and regulatory mechanism of STYX in GC remains unknown. In this study, we find that STYX is highly expressed in GC tissues compared with adjacent noncancerous tissues and closely correlates with the prognosis of GC patients. STYX overexpression facilitates the proliferation and migration in GC cells, whereas STYX knockdown has the opposite effects. Nude mice experiments indicate that STYX knockdown in GC cells dramatically suppresses the tumor growth and lung metastasis in vivo. Mechanically, our results suggest that STYX interacts with the F-box protein FBXO31 and disrupts the degradation function of FBXO31 to its target proteins CyclinD1 and Snail1, thereby increasing the level of CyclinD1 and Snail1 in GC. STYX-mediated biological changes can be reversed by the co-expression of STYX and FBXO31 in GC cells. In addition, transcription factor c-Jun can enhance the expression of STYX in GC. The expression of STYX can also be induced by Helicobacter pylori (H. pylori) infection in c-Jun-dependent manner. Together, our present study suggests that STYX plays an oncogenic role in GC by inhibiting FBXO31 function and represents a potential therapeutic target and prognostic biomarker in GC.
Targeting tumor innervation: premises, promises, and challenges
Authors: Li Xinyu , Peng Xueqiang , Yang Shuo , Wei Shibo , Fan Qing , Liu Jingang , Yang Liang , Li Hangyu 
Published: March 2022

AbstractA high intratumoral nerve density is correlated with poor survival, high metastasis, and high recurrence across multiple solid tumor types. Recent research has revealed that cancer cells release diverse neurotrophic factors and exosomes to promote tumor innervation, in addition, infiltrating nerves can also mediate multiple tumor biological processes via exosomes and neurotransmitters. In this review, through seminal studies establishing tumor innervation, we discuss the communication between peripheral nerves and tumor cells in the tumor microenvironment (TME), and revealed the nerve-tumor regulation mechanisms on oncogenic process, angiogenesis, lymphangiogenesis, and immunity. Finally, we discussed the promising directions of ‘old drugs newly used’ to target TME communication and clarified a new line to prevent tumor malignant capacity.
Avian influenza viruses suppress innate immunity by inducing trans-transcriptional readthrough via SSU72
Authors: Zhao Yan , Huang Fengming , Zou Zhen , Bi Yuhai , Yang Yang , Zhang Cong , Liu Qiang , Shang Daozhen , Yan Yiwu , Ju Xiangwu , Mei Song , Xie Peng , Li Xiao , Tian Mingyao , Tan Shuguang , Lu Huijun , Han Zongsheng , Liu Kangtai , Zhang Yuqing , Liang Junbo , Liang Zhu , Zhang Qingchao , Chang Jiahui , Liu William J. , Feng Cong , Li Tanshi , Zhang Michael Q. , Wang Xiaoyue , Gao George F. , Liu Yingxia , Jin Ningyi , Jiang Chengyu 
Published: March 2022

AbstractInnate immunity plays critical antiviral roles. The highly virulent avian influenza viruses (AIVs) H5N1, H7N9, and H5N6 can better escape host innate immune responses than the less virulent seasonal H1N1 virus. Here, we report a mechanism by which transcriptional readthrough (TRT)-mediated suppression of innate immunity occurs post AIV infection. By using cell lines, mouse lungs, and patient PBMCs, we showed that genes on the complementary strand (“trans” genes) influenced by TRT were involved in the disruption of host antiviral responses during AIV infection. The trans-TRT enhanced viral lethality, and TRT abolishment increased cell viability and STAT1/2 expression. The viral NS1 protein directly bound to SSU72, and degradation of SSU72 induced TRT. SSU72 overexpression reduced TRT and alleviated mouse lung injury. Our results suggest that AIVs infection induce TRT by reducing SSU72 expression, thereby impairing host immune responses, a molecular mechanism acting through the NS1-SSU72-trans-TRT-STAT1/2 axis. Thus, restoration of SSU72 expression might be a potential strategy for preventing AIV pandemics.
Integrating deep learning and unbiased automated high-content screening to identify complex disease signatures in human fibroblasts
Authors: Schiff Lauren , Migliori Bianca , Chen Ye , Carter Deidre , Bonilla Caitlyn , Hall Jenna , Fan Minjie , Tam Edmund , Ahadi Sara , Fischbacher Brodie , Geraschenko Anton , Hunter Christopher J. , Venugopalan Subhashini , DesMarteau Sean , Narayanaswamy Arunachalam , Jacob Selwyn , Armstrong Zan , Ferrarotto Peter , Williams Brian , Buckley-Herd Geoff , Hazard Jon , Goldberg Jordan , Coram Marc , Otto Reid , Baltz Edward A. , Andres-Martin Laura , Pritchard Orion , Duren-Lubanski Alyssa , Daigavane Ameya , Reggio Kathryn ,   NYSCF Global Stem Cell Array® Team, Nelson Phillip C. , Frumkin Michael , Solomon Susan L. , Bauer Lauren , Aiyar Raeka S. , Schwarzbach Elizabeth , Noggle Scott A. , Monsma Frederick J. , Paull Daniel , Berndl Marc , Yang Samuel J. , Johannesson Bjarki 
Published: March 2022

AbstractDrug discovery for diseases such as Parkinson’s disease are impeded by the lack of screenable cellular phenotypes. We present an unbiased phenotypic profiling platform that combines automated cell culture, high-content imaging, Cell Painting, and deep learning. We applied this platform to primary fibroblasts from 91 Parkinson’s disease patients and matched healthy controls, creating the largest publicly available Cell Painting image dataset to date at 48 terabytes. We use fixed weights from a convolutional deep neural network trained on ImageNet to generate deep embeddings from each image and train machine learning models to detect morphological disease phenotypes. Our platform’s robustness and sensitivity allow the detection of individual-specific variation with high fidelity across batches and plate layouts. Lastly, our models confidently separate LRRK2 and sporadic Parkinson’s disease lines from healthy controls (receiver operating characteristic area under curve 0.79 (0.08 standard deviation)), supporting the capacity of this platform for complex disease modeling and drug screening applications.
Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay
Authors: Cairrão Fátima , Santos Cristiana C. , Le Thomas Adrien , Marsters Scot , Ashkenazi Avi , Domingos Pedro M. 
Published: March 2022

AbstractThe unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum (ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. Here, we identify binding sites for the RNA-binding protein Pumilio in the 3′UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio binds both the Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stress, which is required for its stabilization of Xbp1spliced. hIRE1 can phosphorylate Pumilio directly, and phosphorylated Pumilio protects Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an unexpected regulatory link between an RNA-binding protein and the UPR.
Adrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19
Authors: Paul Tanja , Ledderose Stephan , Bartsch Harald , Sun Na , Soliman Sarah , Märkl Bruno , Ruf Viktoria , Herms Jochen , Stern Marcel , Keppler Oliver T. , Delbridge Claire , Müller Susanna , Piontek Guido , Kimoto Yuki Schneider , Schreiber Franziska , Williams Tracy Ann , Neumann Jens , Knösel Thomas , Schulz Heiko , Spallek Ria , Graw Matthias , Kirchner Thomas , Walch Axel , Rudelius Martina 
Published: March 2022

AbstractProgressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.
Genetic regulation of post-translational modification of two distinct proteins
Authors: Landini Arianna , Trbojević-Akmačić Irena , Navarro Pau , Tsepilov Yakov A. , Sharapov Sodbo Z. , Vučković Frano , Polašek Ozren , Hayward Caroline , Petrović Tea , Vilaj Marija , Aulchenko Yurii S. , Lauc Gordan , Wilson James F. , Klarić Lucija 
Published: March 2022

AbstractPost-translational modifications diversify protein functions and dynamically coordinate their signalling networks, influencing most aspects of cell physiology. Nevertheless, their genetic regulation or influence on complex traits is not fully understood. Here, we compare the genetic regulation of the same PTM of two proteins – glycosylation of transferrin and immunoglobulin G (IgG). By performing genome-wide association analysis of transferrin glycosylation, we identify 10 significantly associated loci, 9 of which were not reported previously. Comparing these with IgG glycosylation-associated genes, we note protein-specific associations with genes encoding glycosylation enzymes (transferrin - MGAT5, ST3GAL4, B3GAT1; IgG - MGAT3, ST6GAL1), as well as shared associations (FUT6, FUT8). Colocalisation analyses of the latter suggest that different causal variants in the FUT genes regulate fucosylation of the two proteins. Glycosylation of these proteins is thus genetically regulated by both shared and protein-specific mechanisms.
Guide RNAs containing universal bases enable Cas9/Cas12a recognition of polymorphic sequences
Authors: Krysler Amanda R. , Cromwell Christopher R. , Tu Tommy , Jovel Juan , Hubbard Basil P. 
Published: March 2022

AbstractCRISPR/Cas complexes enable precise gene editing in a wide variety of organisms. While the rigid identification of DNA sequences by these systems minimizes the potential for off-target effects, it consequently poses a problem for the recognition of sequences containing naturally occurring polymorphisms. The presence of genetic variance such as single nucleotide polymorphisms (SNPs) in a gene sequence can compromise the on-target activity of CRISPR systems. Thus, when attempting to target multiple variants of a human gene, or evolved variants of a pathogen gene using a single guide RNA, more flexibility is desirable. Here, we demonstrate that Cas9 can tolerate the inclusion of universal bases in individual guide RNAs, enabling simultaneous targeting of polymorphic sequences. Crucially, we find that specificity is selectively degenerate at the site of universal base incorporation, and remains otherwise preserved. We demonstrate the applicability of this technology to targeting multiple naturally occurring human SNPs with individual guide RNAs and to the design of Cas12a/Cpf1-based DETECTR probes capable of identifying multiple evolved variants of the HIV protease gene. Our findings extend the targeting capabilities of CRISPR/Cas systems beyond their canonical spacer sequences and highlight a use of natural and synthetic universal bases.
CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity
Authors: Joung Julia , Kirchgatterer Paul C. , Singh Ankita , Cho Jang H. , Nety Suchita P. , Larson Rebecca C. , Macrae Rhiannon K. , Deasy Rebecca , Tseng Yuen-Yi , Maus Marcela V. , Zhang Feng 
Published: March 2022

AbstractThe cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (CD274 (PD-L1), MCL1, JUNB, and B3GNT2) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway. JUNB encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway. B3GNT2 encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.
Electrical manipulation of skyrmions in a chiral magnet
Authors: Wang Weiwei , Song Dongsheng , Wei Wensen , Nan Pengfei , Zhang Shilei , Ge Binghui , Tian Mingliang , Zang Jiadong , Du Haifeng 
Published: March 2022

AbstractWriting, erasing and computing are three fundamental operations required by any working electronic device. Magnetic skyrmions could be essential bits in promising in emerging topological spintronic devices. In particular, skyrmions in chiral magnets have outstanding properties like compact texture, uniform size, and high mobility. However, creating, deleting, and driving isolated skyrmions, as prototypes of aforementioned basic operations, have been a grand challenge in chiral magnets ever since the discovery of skyrmions, and achieving all these three operations in a single device is even more challenging. Here, by engineering chiral magnet Co8Zn10Mn2 into the customized micro-devices for in-situ Lorentz transmission electron microscopy observations, we implement these three operations of skyrmions using nanosecond current pulses with a low current density of about 1010 A·m−2 at room temperature. A notched structure can create or delete magnetic skyrmions depending on the direction and magnitude of current pulses. We further show that the magnetic skyrmions can be deterministically shifted step-by-step by current pulses, allowing the establishment of the universal current-velocity relationship. These experimental results have immediate significance towards the skyrmion-based memory or logic devices.
Metabolic engineering strategies to produce medium-chain oleochemicals via acyl-ACP:CoA transacylase activity
Authors: Yan Qiang , Cordell William T. , Jindra Michael A. , Courtney Dylan K. , Kuckuk Madeline K. , Chen Xuanqi , Pfleger Brian F. 
Published: March 2022

AbstractMicrobial lipid metabolism is an attractive route for producing oleochemicals. The predominant strategy centers on heterologous thioesterases to synthesize desired chain-length fatty acids. To convert acids to oleochemicals (e.g., fatty alcohols, ketones), the narrowed fatty acid pool needs to be reactivated as coenzyme A thioesters at cost of one ATP per reactivation - an expense that could be saved if the acyl-chain was directly transferred from ACP- to CoA-thioester. Here, we demonstrate such an alternative acyl-transferase strategy by heterologous expression of PhaG, an enzyme first identified in Pseudomonads, that transfers 3-hydroxy acyl-chains between acyl-carrier protein and coenzyme A thioester forms for creating polyhydroxyalkanoate monomers. We use it to create a pool of acyl-CoA’s that can be redirected to oleochemical products. Through bioprospecting, mutagenesis, and metabolic engineering, we develop three strains of Escherichia coli capable of producing over 1 g/L of medium-chain free fatty acids, fatty alcohols, and methyl ketones.
Spin-orbit enabled all-electrical readout of chiral spin-textures
Authors: Lima Fernandes Imara , Blügel Stefan , Lounis Samir 
Published: March 2022

AbstractChirality and topology are intimately related fundamental concepts, which are heavily explored to establish spin-textures as potential magnetic bits in information technology. However, this ambition is inhibited since the electrical reading of chiral attributes is highly non-trivial with conventional current perpendicular-to-plane (CPP) sensing devices. Here we demonstrate from extensive first-principles simulations and multiple scattering expansion the emergence of the chiral spin-mixing magnetoresistance (C-XMR) enabling highly efficient all-electrical readout of the chirality and helicity of respectively one- and two-dimensional magnetic states of matter. It is linear with spin-orbit coupling in contrast to the quadratic dependence associated with the unveiled non-local spin-mixing anisotropic MR (X-AMR). Such transport effects are systematized on various non-collinear magnetic states – spin-spirals and skyrmions – and compared to the uncovered spin-orbit-independent multi-site magnetoresistances. Owing to their simple implementation in readily available reading devices, the proposed magnetoresistances offer exciting and decisive ingredients to explore with all-electrical means the rich physics of topological and chiral magnetic objects.
Coexistence of electron whispering-gallery modes and atomic collapse states in graphene/WSe2 heterostructure quantum dots
Authors: Zheng Qi , Zhuang Yu-Chen , Sun Qing-Feng , He Lin 
Published: March 2022

AbstractThe relativistic massless charge carriers with a Fermi velocity of about c/300 in graphene enable us to realize two distinct types of resonances (here, c is the speed of light in vacuum). One is the electron whispering-gallery mode in graphene quantum dots arising from the Klein tunneling of the massless Dirac fermions. The other is the atomic collapse state, which has never been observed in experiment with real atoms due to the difficulty of producing heavy nuclei with charge Z > 170; however, they can be realized near a Coulomb impurity in graphene with a charge Z ≥ 1 because of the “small” velocity of the Dirac excitations. Here we demonstrate that both the electron whispering-gallery modes and atomic collapse states coexist in graphene/WSe2 heterostructure quantum dots due to the Coulomb-like potential near their edges. By applying a perpendicular magnetic field, we explore the evolution from the atomic collapse states to unusual Landau levels in the collapse regime.
The speed limit of optoelectronics
Authors: Ossiander M. , Golyari K. , Scharl K. , Lehnert L. , Siegrist F. , Bürger J. P. , Zimin D. , Gessner J. A. , Weidman M. , Floss I. , Smejkal V. , Donsa S. , Lemell C. , Libisch F. , Karpowicz N. , Burgdörfer J. , Krausz F. , Schultze M. 
Published: March 2022

AbstractLight-field driven charge motion links semiconductor technology to electric fields with attosecond temporal control. Motivated by ultimate-speed electron-based signal processing, strong-field excitation has been identified viable for the ultrafast manipulation of a solid’s electronic properties but found to evoke perplexing post-excitation dynamics. Here, we report on single-photon-populating the conduction band of a wide-gap dielectric within approximately one femtosecond. We control the subsequent Bloch wavepacket motion with the electric field of visible light. The resulting current allows sampling optical fields and tracking charge motion driven by optical signals. Our approach utilizes a large fraction of the conduction-band bandwidth to maximize operating speed. We identify population transfer to adjacent bands and the associated group velocity inversion as the mechanism ultimately limiting how fast electric currents can be controlled in solids. Our results imply a fundamental limit for classical signal processing and suggest the feasibility of solid-state optoelectronics up to 1 PHz frequency.
Ultrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium
Authors: Pinto Andreia L. , Rai Ranjit K. , Brown Jonathan C. , Griffin Paul , Edgar James R. , Shah Anand , Singanayagam Aran , Hogg Claire , Barclay Wendy S. , Futter Clare E. , Burgoyne Thomas 
Published: March 2022

AbstractUltrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.