bluuebunny/crossref_metadata_2025_split huggingface dataset:
USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer
Authors: Nelson Jessica K. , Thin May Zaw , Evan Theodore , Howell Steven , Wu Mary , Almeida Bruna , Legrave Nathalie , Koenis Duco S. , Koifman Gabriela , Sugimoto Yoichiro , Llorian Sopena Miriam , MacRae James , Nye Emma , Howell Michael , Snijders Ambrosius P. , Prachalias Andreas , Zen Yoh , Sarker Debashis , Behrens Axel 
Published: April 2022

AbstractDeubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.
Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo
Authors: Solis Gonzalo P. , Kazemzadeh Arghavan , Abrami Laurence , Valnohova Jana , Alvarez Cecilia , van der Goot F. Gisou , Katanaev Vladimir L. 
Published: April 2022

AbstractPeripheral membrane proteins (PMPs) associate with cellular membranes through post-translational modifications like S-palmitoylation. The Golgi apparatus is generally viewed as the transitory station where palmitoyl acyltransferases (PATs) modify PMPs, which are then transported to their ultimate destinations such as the plasma membrane (PM). However, little substrate specificity among the many PATs has been determined. Here we describe the inherent partitioning of Gαo – α-subunit of heterotrimeric Go proteins – to PM and Golgi, independent from Golgi-to-PM transport. A minimal code within Gαo N-terminus governs its compartmentalization and re-coding produces G protein versions with shifted localization. We establish the S-palmitoylation at the outer nuclear membrane assay (“SwissKASH”) to probe substrate specificity of PATs in intact cells. With this assay, we show that PATs localizing to different membrane compartments display remarkable substrate selectivity, which is the basis for PMP compartmentalization. Our findings uncover a mechanism governing protein localization and establish the basis for innovative drug discovery.
Loss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures
Authors: Fleig Susanne , Kapanadze Tamar , Bernier-Latmani Jeremiah , Lill Julia K. , Wyss Tania , Gamrekelashvili Jaba , Kijas Dustin , Liu Bin , Hüsing Anne M. , Bovay Esther , Jirmo Adan Chari , Halle Stephan , Ricke-Hoch Melanie , Adams Ralf H. , Engel Daniel R. , von Vietinghoff Sibylle , Förster Reinhold , Hilfiker-Kleiner Denise , Haller Hermann , Petrova Tatiana V. , Limbourg Florian P. 
Published: April 2022

AbstractTertiary lymphoid structures (TLS) are lymph node-like immune cell clusters that emerge during chronic inflammation in non-lymphoid organs like the kidney, but their origin remains not well understood. Here we show, using conditional deletion strategies of the canonical Notch signaling mediatorRbpj, that loss of endothelial Notch signaling in adult mice induces the spontaneous formation of bona fide TLS in the kidney, liver and lung, based on molecular, cellular and structural criteria. These TLS form in a stereotypical manner around parenchymal arteries, while secondary lymphoid structures remained largely unchanged. This effect is mediated by endothelium of blood vessels, but not lymphatics, since a lymphatic endothelial-specific targeting strategy did not result in TLS formation, and involves loss of arterial specification and concomitant acquisition of a high endothelial cell phenotype, as shown by transcriptional analysis of kidney endothelial cells. This indicates a so far unrecognized role for vascular endothelial cells and Notch signaling in TLS initiation.
Anti-drude metal of bosons
Authors: Masella Guido , Prokof’ev Nikolay V. , Pupillo Guido 
Published: April 2022

AbstractIn the absence of frustration, interacting bosons in their ground state in one or two dimensions exist either in the superfluid or insulating phases. Superfluidity corresponds to frictionless flow of the matter field, and in optical conductivity is revealed through a distinct δ-functional peak at zero frequency with the amplitude known as the Drude weight. This characteristic low-frequency feature is instead absent in insulating phases, defined by zero static optical conductivity. Here we demonstrate that bosonic particles in disordered one dimensional chains can also exist in a conducting, non-superfluid, phase when their hopping is of the dipolar type, often viewed as short-ranged in one dimension. This phase is characterized by finite static optical conductivity, followed by a broad anti-Drude peak at finite frequencies. Off-diagonal correlations are also unconventional: they feature an integrable algebraic decay for arbitrarily large values of disorder. These results do not fit the description of any known quantum phase, and strongly suggest the existence of an unusual conducting state of bosonic matter in the ground state.
Low complexity RGG-motif sequence is required for Processing body (P-body) disassembly
Authors: Roy Raju , Das Gitartha , Kuttanda Ishwarya Achappa , Bhatter Nupur , Rajyaguru Purusharth I. 
Published: April 2022

AbstractP-bodies are conserved mRNP complexes that are implicated in determining mRNA fate by affecting translation and mRNA decay. In this report, we identify RGG-motif containing translation repressor protein Sbp1 as a disassembly factor of P-bodies since disassembly of P-bodies is defective in Δsbp1. RGG-motif is necessary and sufficient to rescue the PB disassembly defect in Δsbp1. Binding studies using purified proteins revealed that Sbp1 physically interacts with Edc3 and Sbp1-Edc3 interaction competes with Edc3-Edc3 interaction. Purified Edc3 forms assemblies, promoted by the presence of RNA and NADH and the addition of purified Sbp1, but not the RGG-deletion mutant, leads to significantly decreased Edc3 assemblies. We further note that the aggregates of human EWSR1 protein, implicated in neurodegeneration, are more persistent in the absence of Sbp1 and overexpression of EWSR1 in Δsbp1 leads to a growth defect. Taken together, our observations suggest a role of Sbp1 in disassembly, which could apply to disease-relevant heterologous protein-aggregates.
Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis
Authors: Xia Hui , Scholtes Charlotte , Dufour Catherine R. , Ouellet Carlo , Ghahremani Majid , Giguère Vincent 
Published: April 2022

AbstractInsulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response resulting from the dysregulation of a wide range of insulin-controlled cellular processes. However, how insulin affects cellular energy metabolism via long-term transcriptional regulation and whether boosting mitochondrial function alleviates insulin resistance remains to be elucidated. Herein we reveal that insulin directly enhances the activity of the nuclear receptor ERRα via a GSK3β/FBXW7 signaling axis. Liver-specific deletion of GSK3β or FBXW7 and mice harboring mutations of ERRα phosphosites (ERRα3SA) co-targeted by GSK3β/FBXW7 result in accumulated ERRα proteins that no longer respond to fluctuating insulin levels. ERRα3SA mice display reprogrammed liver and muscle transcriptomes, resulting in compromised energy homeostasis and reduced insulin sensitivity despite improved mitochondrial function. This crossroad of insulin signaling and transcriptional control by a nuclear receptor offers a framework to better understand the complex cellular processes contributing to the development of insulin resistance.
Cavβ1 regulates T cell expansion and apoptosis independently of voltage-gated Ca2+ channel function
Authors: Erdogmus Serap , Concepcion Axel R. , Yamashita Megumi , Sidhu Ikjot , Tao Anthony Y. , Li Wenyi , Rocha Pedro P. , Huang Bonnie , Garippa Ralph , Lee Boram , Lee Amy , Hell Johannes W. , Lewis Richard S. , Prakriya Murali , Feske Stefan 
Published: April 2022

AbstractTCR stimulation triggers Ca2+ signals that are critical for T cell function and immunity. Several pore-forming α and auxiliary β subunits of voltage-gated Ca2+ channels (VGCC) were reported in T cells, but their mechanism of activation remains elusive and their contribution to Ca2+ signaling in T cells is controversial. We here identify CaVβ1, encoded by Cacnb1, as a regulator of T cell function. Cacnb1 deletion enhances apoptosis and impairs the clonal expansion of T cells after lymphocytic choriomeningitis virus (LCMV) infection. By contrast, Cacnb1 is dispensable for T cell proliferation, cytokine production and Ca2+ signaling. Using patch clamp electrophysiology and Ca2+ recordings, we are unable to detect voltage-gated Ca2+ currents or Ca2+ influx in human and mouse T cells upon depolarization with or without prior TCR stimulation. mRNAs of several VGCC α1 subunits are detectable in human (CaV3.3, CaV3.2) and mouse (CaV2.1) T cells, but they lack transcription of many 5’ exons, likely resulting in N-terminally truncated and non-functional proteins. Our findings demonstrate that although CaVβ1 regulates T cell function, these effects are independent of VGCC channel activity.
Structure, gating, and pharmacology of human CaV3.3 channel
Authors: He Lingli , Yu Zhuoya , Geng Ze , Huang Zhuo , Zhang Changjiang , Dong Yanli , Gao Yiwei , Wang Yuhang , Chen Qihao , Sun Le , Ma Xinyue , Huang Bo , Wang Xiaoqun , Zhao Yan 
Published: April 2022

AbstractThe low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type CaV3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. CaV3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type CaV channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the CaV3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.
Achieving gas pressure-dependent luminescence from an AIEgen-based metal-organic framework
Authors: Li Zhijia , Jiang Feilong , Yu Muxin , Li Shengchang , Chen Lian , Hong Maochun 
Published: April 2022

AbstractMaterials exhibiting aggregation-induced emission (AIE) behaviour enable strong emission in solid state and can respond to various external stimuli, which may facilitate the development of materials for optical sensing, bioimaging or optoelectronic devices. Herein, we use an AIE luminogen 2’,5’-diphenyl-[1,1’:4’,1”-terphenyl]-4,4”-dicarboxylic acid as the ligand to prepare an AIEgen-based MOF (metal-organic framework) named FJI-H31. FJI-H31 exhibits bright luminescence under ambient conditions (under air and at room temperature), but almost no emission is observed under vacuum. Our investigation shows that the emission intensity displays a smooth and reversible enhancement with increased gas pressure, which may be attributed to the restriction of intramolecular motion brought by structural deformation under pressure stimulus. Unlike most pressure-responsive MOFs, the luminescence reverts to its original state once gas pressure recovers. By virtue of its unique optical properties, a luminescent MOF with sensing ability of gas-pressure is realized.
Anisotropy-driven quantum criticality in an intermediate valence system
Authors: Grbić Mihael S. , O’Farrell Eoin C. T. , Matsumoto Yosuke , Kuga Kentaro , Brando Manuel , Küchler Robert , Nevidomskyy Andriy H. , Yoshida Makoto , Sakakibara Toshiro , Kono Yohei , Shimura Yasuyuki , Sutherland Michael L. , Takigawa Masashi , Nakatsuji Satoru 
Published: April 2022

AbstractIntermetallic compounds containing f-electron elements have been prototypical materials for investigating strong electron correlations and quantum criticality (QC). Their heavy fermion ground state evoked by the magnetic f-electrons is susceptible to the onset of quantum phases, such as magnetism or superconductivity, due to the enhanced effective mass (m*) and a corresponding decrease of the Fermi temperature. However, the presence of f-electron valence fluctuations to a non-magnetic state is regarded an anathema to QC, as it usually generates a paramagnetic Fermi-liquid state with quasiparticles of moderate m*. Such systems are typically isotropic, with a characteristic energy scale T0 of the order of hundreds of kelvins that require large magnetic fields or pressures to promote a valence or magnetic instability. Here we show the discovery of a quantum critical behaviour and a Lifshitz transition under low magnetic field in an intermediate valence compound α-YbAlB4. The QC origin is attributed to the anisotropic hybridization between the conduction and localized f-electrons. These findings suggest a new route to bypass the large valence energy scale in developing the QC.
Communication-efficient federated learning via knowledge distillation
Authors: Wu Chuhan , Wu Fangzhao , Lyu Lingjuan , Huang Yongfeng , Xie Xing 
Published: April 2022

AbstractFederated learning is a privacy-preserving machine learning technique to train intelligent models from decentralized data, which enables exploiting private data by communicating local model updates in each iteration of model learning rather than the raw data. However, model updates can be extremely large if they contain numerous parameters, and many rounds of communication are needed for model training. The huge communication cost in federated learning leads to heavy overheads on clients and high environmental burdens. Here, we present a federated learning method named FedKD that is both communication-efficient and effective, based on adaptive mutual knowledge distillation and dynamic gradient compression techniques. FedKD is validated on three different scenarios that need privacy protection, showing that it maximally can reduce 94.89% of communication cost and achieve competitive results with centralized model learning. FedKD provides a potential to efficiently deploy privacy-preserving intelligent systems in many scenarios, such as intelligent healthcare and personalization.
Boron encapsulated in a liposome can be used for combinational neutron capture therapy
Authors: Li Jiyuan , Sun Qi , Lu Chuanjie , Xiao Han , Guo Zhibin , Duan Dongban , Zhang Zizhu , Liu Tong , Liu Zhibo 
Published: April 2022

AbstractBoron neutron capture therapy (BNCT) is an attractive approach to treat invasive malignant tumours due to binary heavy-particle irradiation, but its clinical applications have been hindered by boron delivery agents with low in vivo stability, poor biocompatibility, and limited application of combinational modalities. Here, we report boronsome, a carboranyl-phosphatidylcholine based liposome for combinational BNCT and chemotherapy. Theoretical simulations and experimental approaches illustrate high stability of boronsome. Then positron emission tomography (PET) imaging with Cu-64 labelled boronsome reveals high-specific tumour accumulation and long retention with a clear irradiation background. In particular, we show the suppression of tumour growth treated with boronsome with neutron irradiation and therapeutic outcomes are further improved by encapsulation of chemotherapy drugs, especially with PARP1 inhibitors. In sum, boronsome may be an efficient agent for concurrent chemoradiotherapy with theranostic properties against malignancies.
Multilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation
Authors: Vuong John K. , Ergin Volkan , Chen Liang , Zheng Sika 
Published: April 2022

AbstractThe gene regulation underlying axon formation and its exclusiveness to neurons remains elusive. TRIM46 is postulated to determine axonal fate. We show Trim46 mRNA is expressed before axonogenesis, but TRIM46 protein level is inhibited by alternative splicing of two cassette exons coupled separately to stability controls of Trim46 mRNA and proteins, effectively inducing functional knockout of TRIM46 proteins. Exon 8 inclusion causes nonsense-mediated mRNA decay of Trim46 transcripts. PTBP2-mediated exon 10 skipping produces transcripts encoding unstable TRIM46 proteins. During axonogenesis, transcriptional activation, decreased exon 8 inclusion, and enhanced exon 10 inclusion converge to increase TRIM46 proteins, leading to its neural-specific expression. Genetic deletion of these exons alters TRIM46 protein levels and shows TRIM46 is instructive though not always required for AnkG localization nor a determinant of AnkG density. Therefore, two concurrently but independently regulated alternative exons orchestrate the temporal induction and tissue-specific expression of TRIM46 proteins to mediate axon formation.
Genomic and transcriptomic analysis of a library of small cell lung cancer patient-derived xenografts
Authors: Caeser Rebecca , Egger Jacklynn V. , Chavan Shweta , Socci Nicholas D. , Jones Caitlin Byrne , Kombak Faruk Erdem , Asher Marina , Roehrl Michael H. , Shah Nisargbhai S. , Allaj Viola , Manoj Parvathy , Tischfield Sam E. , Kulick Amanda , Meneses Maximiliano , Iacobuzio-Donahue Christine A. , Lai W. Victoria , Bhanot Umeshkumar , Baine Marina K. , Rekhtman Natasha , Hollmann Travis J. , de Stanchina Elisa , Poirier John T. , Rudin Charles M. , Sen Triparna 
Published: April 2022

AbstractAccess to clinically relevant small cell lung cancer (SCLC) tissue is limited because surgical resection is rare in metastatic SCLC. Patient-derived xenografts (PDX) and circulating tumor cell-derived xenografts (CDX) have emerged as valuable tools to characterize SCLC. Here, we present a resource of 46 extensively annotated PDX/CDX models derived from 33 patients with SCLC. We perform multi-omic analyses, using targeted tumor next-generation sequencing, RNA-sequencing, and immunohistochemistry to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these SCLC models. SCLC subtypes characterized by transcriptional regulators, ASCL1, NEUROD1 and POU2F3 are confirmed in this cohort. A subset of SCLC clinical specimens, including matched PDX/CDX and clinical specimen pairs, confirm that the primary features and genomic and proteomic landscapes of the tumors of origin are preserved in the derivative PDX models. This resource provides a powerful system to study SCLC biology.
Anisotropic nanocrystal superlattices overcoming intrinsic light outcoupling efficiency limit in perovskite quantum dot light-emitting diodes
Authors: Kumar Sudhir , Marcato Tommaso , Krumeich Frank , Li Yen-Ting , Chiu Yu-Cheng , Shih Chih-Jen 
Published: April 2022

AbstractQuantum dot (QD) light-emitting diodes (LEDs) are emerging as one of the most promising candidates for next-generation displays. However, their intrinsic light outcoupling efficiency remains considerably lower than the organic counterpart, because it is not yet possible to control the transition-dipole-moment (TDM) orientation in QD solids at device level. Here, using the colloidal lead halide perovskite anisotropic nanocrystals (ANCs) as a model system, we report a directed self-assembly approach to form the anisotropic nanocrystal superlattices (ANSLs). Emission polarization in individual ANCs rescales the radiation from horizontal and vertical transition dipoles, effectively resulting in preferentially horizontal TDM orientation. Based on the emissive thin films comprised of ANSLs, we demonstrate an enhanced ratio of horizontal dipole up to 0.75, enhancing the theoretical light outcoupling efficiency of greater than 30%. Our optimized single-junction QD LEDs showed peak external quantum efficiency of up to 24.96%, comparable to state-of-the-art organic LEDs.
Installation of synergistic binding sites onto porous organic polymers for efficient removal of perfluorooctanoic acid
Authors: Liu Xiongli , Zhu Changjia , Yin Jun , Li Jixin , Zhang Zhiyuan , Li Jinli , Shui Feng , You Zifeng , Shi Zhan , Li Baiyan , Bu Xian-He , Nafady Ayman , Ma Shengqian 
Published: April 2022

AbstractHerein, we report a strategy to construct highly efficient perfluorooctanoic acid (PFOA) adsorbents by installing synergistic electrostatic/hydrophobic sites onto porous organic polymers (POPs). The constructed model material of PAF-1-NDMB (NDMB = N,N-dimethyl-butylamine) demonstrates an exceptionally high PFOA uptake capacity over 2000 mg g−1, which is 14.8 times enhancement compared with its parent material of PAF-1. And it is 32.0 and 24.1 times higher than benchmark materials of DFB-CDP (β-cyclodextrin (β-CD)-based polymer network) and activated carbon under the same conditions. Furthermore, PAF-1-NDMB exhibits the highest k2 value of 24,000 g mg−1 h−1 among all reported PFOA sorbents. And it can remove 99.99% PFOA from 1000 ppb to <70 ppt within 2 min, which is lower than the advisory level of Environmental Protection Agency of United States. This work thus not only provides a generic approach for constructing PFOA adsorbents, but also develops POPs as a platform for PFOA capture.
Controlling forward and backward rotary molecular motion on demand
Authors: Pfeifer L. , Crespi S. , van der Meulen P. , Kemmink J. , Scheek R. M. , Hilbers M. F. , Buma W. J. , Feringa B. L. 
Published: April 2022

AbstractSynthetic molecular machines hold tremendous potential to revolutionize chemical and materials sciences. Their autonomous motion controlled by external stimuli allows to develop smart materials whose properties can be adapted on command. For the realisation of more complex molecular machines, it is crucial to design building blocks whose properties can be controlled by multiple orthogonal stimuli. A major challenge is to reversibly switch from forward to backward and again forward light-driven rotary motion using external stimuli. Here we report a push-pull substituted photo-responsive overcrowded alkene whose function can be toggled between that of a unidirectional 2nd generation rotary motor and a molecular switch depending on its protonation and the polarity of its environment. With its simplicity in design, easy preparation, outstanding stability and orthogonal control of distinct forward and backward motions, we believe that the present concept paves the way for creating more advanced molecular machines.