bluuebunny/crossref_metadata_2025_split huggingface dataset:
The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression
Authors: Xia Xiaohong , Huang Chuyi , Liao Yuning , Liu Yuan , He Jinchan , Shao Zhenlong , Hu Tumei , Yu Cuifu , Jiang Lili , Liu Jinbao , Huang Hongbiao 
Published: March 2021

AbstractBreast cancer has the highest incidence and mortality in women worldwide. There are 70% of breast cancers considered as estrogen receptor α (ERα) positive. Therefore, the ERα-targeted therapy has become one of the most effective solution for patients with breast cancer. Whereas a better understanding of ERα regulation is critical to shape evolutional treatments for breast cancer. By exploring the regulatory mechanisms of ERα at levels of post-translational modifications, we identified the deubiquitinase USP15 as a novel protector for preventing ERα degradation and a critical driver for breast cancer progression. Specifically, we demonstrated that USP15 promoted the proliferation of ERα+, but not ERα- breast cancer, in vivo and in vitro. Meanwhile, USP15 knockdown notably enhanced the antitumor activities of tamoxifen on breast cancer cells. Importantly, USP15 knockdown induced the downregulation of ERα protein via promoting its K48-linked ubiquitination, which is required for proliferative inhibition of breast cancer cells. These findings not only provide a novel treatment for overcoming resistance to endocrine therapy, but also represent a therapeutic strategy on ERα degradation by targeting USP15-ERα axis.
Elevated TEFM expression promotes growth and metastasis through activation of ROS/ERK signaling in hepatocellular carcinoma
Authors: Wan Lixin , Wang Yang , Zhang Zijie , Wang Jiaxin , Niu Menglan , Wu Yuanyuan , Yang Yating , Dang Yongxia , Hui Shuang , Ni Meng , Wan Bo , Bao Dengke 
Published: March 2021

AbstractTEFM (transcription elongation factor of mitochondria) has been identified as a novel nuclear-encoded transcription elongation factor in the transcription of mitochondrial genome. Our bioinformatics analysis of TCGA data revealed an aberrant over-expression of TEFM in hepatocellular carcinoma (HCC). We analyzed its biological effects and clinical significance in this malignancy. TEFM expression was analyzed by quantitative real-time PCR, western blot, and immunohistochemistry analysis in HCC tissues and cell lines. The effects of TEFM on HCC cell growth and metastasis were determined by cell proliferation, colony formation, flow cytometric cell cycle and apoptosis, migration, and invasion assays. TEFM expression was significantly increased in HCC tissues mainly caused by down-regulation of miR-194-5p. Its increased expression is correlated with poor prognosis of HCC patients. TEFM promoted HCC growth and metastasis both in vitro and in vivo by promoting G1–S cell transition, epithelial-to-mesenchymal transition (EMT), and suppressing cell apoptosis. Mechanistically, TEFM exerts its tumor growth and metastasis promoting effects at least partly through increasing ROS production and subsequently by activation of ERK signaling. Our study suggests that TEFM functions as a vital oncogene in promoting growth and metastasis in HCC and may contribute to the targeted therapy of HCC.
Neuromodulation of BAG co-chaperones by HIV-1 viral proteins and H2O2: implications for HIV-associated neurological disorders
Authors: Duggan Michael R. , Mohseni Ahooyi Taha , Parikh Vinay , Khalili Kamel 
Published: March 2021

AbstractDespite increasing numbers of aged individuals living with HIV, the mechanisms underlying HIV-associated neurological disorders (HANDs) remain elusive. As HIV-1 pathogenesis and aging are characterized by oxidative stress as well as altered protein quality control (PQC), reactive oxygen species (ROS) themselves might constitute a molecular mediator of neuronal PQC by modulating BCL-2 associated athanogene (BAG) family members. Present results reveal H2O2 replicated and exacerbated a reduction in neuronal BAG3 induced by the expression of HIV-1 viral proteins (i.e., Tat and Nef), while also causing an upregulation of BAG1. Such a reciprocal regulation of BAG3 and BAG1 levels was also indicated in two animal models of HIV, the doxycycline-inducible Tat (iTat) and the Tg26 mouse. Inhibiting oxidative stress via antioxidants in primary culture was capable of partially preserving neuronal BAG3 levels as well as electrophysiological functioning otherwise altered by HIV-1 viral proteins. Current findings indicate HIV-1 viral proteins and H2O2 may mediate neuronal PQC by exerting synergistic effects on complementary BAG family members, and suggest novel therapeutic targets for the aging HIV-1 population.
Linear and nonlinear chromatic integration in the mouse retina
Authors: Khani Mohammad Hossein , Gollisch Tim 
Published: March 2021

AbstractThe computations performed by a neural circuit depend on how it integrates its input signals into an output of its own. In the retina, ganglion cells integrate visual information over time, space, and chromatic channels. Unlike the former two, chromatic integration is largely unexplored. Analogous to classical studies of spatial integration, we here study chromatic integration in mouse retina by identifying chromatic stimuli for which activation from the green or UV color channel is maximally balanced by deactivation through the other color channel. This reveals nonlinear chromatic integration in subsets of On, Off, and On–Off ganglion cells. Unlike the latter two, nonlinear On cells display response suppression rather than activation under balanced chromatic stimulation. Furthermore, nonlinear chromatic integration occurs independently of nonlinear spatial integration, depends on contributions from the rod pathway and on surround inhibition, and may provide information about chromatic boundaries, such as the skyline in natural scenes.
Observation of novel charge ordering and spin reorientation in perovskite oxide PbFeO3
Authors: Ye Xubin , Zhao Jianfa , Das Hena , Sheptyakov Denis , Yang Junye , Sakai Yuki , Hojo Hajime , Liu Zhehong , Zhou Long , Cao Lipeng , Nishikubo Takumi , Wakazaki Shogo , Dong Cheng , Wang Xiao , Hu Zhiwei , Lin Hong-Ji , Chen Chien-Te , Sahle Christoph , Efiminko Anna , Cao Huibo , Calder Stuart , Mibu Ko , Kenzelmann Michel , Tjeng Liu Hao , Yu Runze , Azuma Masaki , Jin Changqing , Long Youwen 
Published: March 2021

AbstractPbMO3 (M = 3d transition metals) family shows systematic variations in charge distribution and intriguing physical properties due to its delicate energy balance between Pb 6s and transition metal 3d orbitals. However, the detailed structure and physical properties of PbFeO3 remain unclear. Herein, we reveal that PbFeO3 crystallizes into an unusual 2ap × 6ap × 2ap orthorhombic perovskite super unit cell with space group Cmcm. The distinctive crystal construction and valence distribution of Pb2+0.5Pb4+0.5FeO3 lead to a long range charge ordering of the -A-B-B- type of the layers with two different oxidation states of Pb (Pb2+ and Pb4+) in them. A weak ferromagnetic transition with canted antiferromagnetic spins along the a-axis is found to occur at 600 K. In addition, decreasing the temperature causes a spin reorientation transition towards a collinear antiferromagnetic structure with spin moments along the b-axis near 418 K. Our theoretical investigations reveal that the peculiar charge ordering of Pb generates two Fe3+ magnetic sublattices with competing anisotropic energies, giving rise to the spin reorientation at such a high critical temperature.
Stochastic sampling effects favor manual over digital contact tracing
Authors: Mancastroppa Marco , Castellano Claudio , Vezzani Alessandro , Burioni Raffaella 
Published: March 2021

AbstractIsolation of symptomatic individuals, tracing and testing of their nonsymptomatic contacts are fundamental strategies for mitigating the current COVID-19 pandemic. The breaking of contagion chains relies on two complementary strategies: manual reconstruction of contacts based on interviews and a digital (app-based) privacy-preserving contact tracing. We compare their effectiveness using model parameters tailored to describe SARS-CoV-2 diffusion within the activity-driven model, a general empirically validated framework for network dynamics. We show that, even for equal probability of tracing a contact, manual tracing robustly performs better than the digital protocol, also taking into account the intrinsic delay and limited scalability of the manual procedure. This result is explained in terms of the stochastic sampling occurring during the case-by-case manual reconstruction of contacts, contrasted with the intrinsically prearranged nature of digital tracing, determined by the decision to adopt the app or not by each individual. The better performance of manual tracing is enhanced by heterogeneity in agent behavior: superspreaders not adopting the app are completely invisible to digital contact tracing, while they can be easily traced manually, due to their multiple contacts. We show that this intrinsic difference makes the manual procedure dominant in realistic hybrid protocols.
A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons
Authors: Gordon Patricia M. , Hamid Fursham , Makeyev Eugene V. , Houart Corinne 
Published: March 2021

AbstractThe RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease. Here, we report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs). These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. We show that one such peptide encoded by the CLE-containing epha4b mRNA isoform is responsible for neurodevelopmental defects in the sfpq mutant. The uncovered CLE-repressive activity of SFPQ is conserved in mouse and human, and SFPQ-inhibited CLEs are found expressed across ALS iPSC-derived neurons. These results greatly expand our understanding of SFPQ function and uncover a gene regulation mechanism with wide relevance to human neuropathologies.
Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy
Authors: Kottke Timothy , Tonne Jason , Evgin Laura , Driscoll Christopher B. , van Vloten Jacob , Jennings Victoria A. , Huff Amanda L. , Zell Brady , Thompson Jill M. , Wongthida Phonphimon , Pulido Jose , Schuelke Matthew R. , Samson Adel , Selby Peter , Ilett Elizabeth , McNiven Mark , Roberts Lewis R. , Borad Mitesh J. , Pandha Hardev , Harrington Kevin , Melcher Alan , Vile Richard G. 
Published: March 2021

AbstractIn our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance.
Unc13A and Unc13B contribute to the decoding of distinct sensory information in Drosophila
Authors: Pooryasin Atefeh , Maglione Marta , Schubert Marco , Matkovic-Rachid Tanja , Hasheminasab Sayed-mohammad , Pech Ulrike , Fiala André , Mielke Thorsten , Sigrist Stephan J. 
Published: March 2021

AbstractThe physical distance between presynaptic Ca2+ channels and the Ca2+ sensors triggering the release of neurotransmitter-containing vesicles regulates short-term plasticity (STP). While STP is highly diversified across synapse types, the computational and behavioral relevance of this diversity remains unclear. In the Drosophila brain, at nanoscale level, we can distinguish distinct coupling distances between Ca2+ channels and the (m)unc13 family priming factors, Unc13A and Unc13B. Importantly, coupling distance defines release components with distinct STP characteristics. Here, we show that while Unc13A and Unc13B both contribute to synaptic signalling, they play distinct roles in neural decoding of olfactory information at excitatory projection neuron (ePN) output synapses. Unc13A clusters closer to Ca2+ channels than Unc13B, specifically promoting fast phasic signal transfer. Reduction of Unc13A in ePNs attenuates responses to both aversive and appetitive stimuli, while reduction of Unc13B provokes a general shift towards appetitive values. Collectively, we provide direct genetic evidence that release components of distinct nanoscopic coupling distances differentially control STP to play distinct roles in neural decoding of sensory information.
P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression
Authors: Yeini Eilam , Ofek Paula , Pozzi Sabina , Albeck Nitzan , Ben-Shushan Dikla , Tiram Galia , Golan Sapir , Kleiner Ron , Sheinin Ron , Israeli Dangoor Sahar , Reich-Zeliger Shlomit , Grossman Rachel , Ram Zvi , Brem Henry , Hyde Thomas M. , Magod Prerna , Friedmann-Morvinski Dinorah , Madi Asaf , Satchi-Fainaro Ronit 
Published: March 2021

AbstractGlioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.
Sub-thermionic, ultra-high-gain organic transistors and circuits
Authors: Luo Zhongzhong , Peng Boyu , Zeng Junpeng , Yu Zhihao , Zhao Ying , Xie Jun , Lan Rongfang , Ma Zhong , Pan Lijia , Cao Ke , Lu Yang , He Daowei , Ning Hongkai , Meng Wanqing , Yang Yang , Chen Xiaoqing , Li Weisheng , Wang Jiawei , Pan Danfeng , Tu Xuecou , Huo Wenxing , Huang Xian , Shi Dongquan , Li Ling , Liu Ming , Shi Yi , Feng Xue , Chan Paddy K. L. , Wang Xinran 
Published: March 2021

AbstractThe development of organic thin-film transistors (OTFTs) with low power consumption and high gain will advance many flexible electronics. Here, by combining solution-processed monolayer organic crystal, ferroelectric HfZrOx gating and van der Waals fabrication, we realize flexible OTFTs that simultaneously deliver high transconductance and sub-60 mV/dec switching, under one-volt operating voltage. The overall optimization of transconductance, subthreshold swing and output resistance leads to transistor intrinsic gain and amplifier voltage gain over 5.3 × 104 and 1.1 × 104, respectively, which outperform existing technologies using organics, oxides and low-dimensional nanomaterials. We further demonstrate battery-powered, integrated wearable electrocardiogram (ECG) and pulse sensors that can amplify human physiological signal by 900 times with high fidelity. The sensors are capable of detecting weak ECG waves (undetectable even by clinical equipment) and diagnosing arrhythmia and atrial fibrillation. Our sub-thermionic OTFT is promising for battery/wireless powered yet performance demanding applications such as electronic skins and radio-frequency identification tags, among many others.
DNA replication origins retain mobile licensing proteins
Authors: Sánchez Humberto , McCluskey Kaley , van Laar Theo , van Veen Edo , Asscher Filip M. , Solano Belén , Diffley John F. X. , Dekker Nynke H. 
Published: March 2021

AbstractDNA replication in eukaryotes initiates at many origins distributed across each chromosome. Origins are bound by the origin recognition complex (ORC), which, with Cdc6 and Cdt1, recruits and loads the Mcm2-7 (MCM) helicase as an inactive double hexamer during G1 phase. The replisome assembles at the activated helicase in S phase. Although the outline of replisome assembly is understood, little is known about the dynamics of individual proteins on DNA and how these contribute to proper complex formation. Here we show, using single-molecule optical trapping and confocal microscopy, that yeast ORC is a mobile protein that diffuses rapidly along DNA. Origin recognition halts this search process. Recruitment of MCM molecules in an ORC- and Cdc6-dependent fashion results in slow-moving ORC-MCM intermediates and MCMs that rapidly scan the DNA. Following ATP hydrolysis, salt-stable loading of MCM single and double hexamers was seen, both of which exhibit salt-dependent mobility. Our results demonstrate that effective helicase loading relies on an interplay between protein diffusion and origin recognition, and suggest that MCM is stably loaded onto DNA in multiple forms.
Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination
Authors: Saraswat Darpan , Shayya Hani J. , Polanco Jessie J. , Tripathi Ajai , Welliver R. Ross , Pol Suyog U. , Seidman Richard A. , Broome Jacqueline E. , O’Bara Melanie A. , van Kuppervelt Toin H. , Phillips Joanna J. , Dutta Ranjan , Sim Fraser J. 
Published: March 2021

AbstractChronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.
Cargo sorting zones in the trans-Golgi network visualized by super-resolution confocal live imaging microscopy in plants
Authors: Shimizu Yutaro , Takagi Junpei , Ito Emi , Ito Yoko , Ebine Kazuo , Komatsu Yamato , Goto Yumi , Sato Mayuko , Toyooka Kiminori , Ueda Takashi , Kurokawa Kazuo , Uemura Tomohiro , Nakano Akihiko 
Published: March 2021

AbstractThe trans-Golgi network (TGN) has been known as a key platform to sort and transport proteins to their final destinations in post-Golgi membrane trafficking. However, how the TGN sorts proteins with different destinies still remains elusive. Here, we examined 3D localization and 4D dynamics of TGN-localized proteins of Arabidopsis thaliana that are involved in either secretory or vacuolar trafficking from the TGN, by a multicolor high-speed and high-resolution spinning-disk confocal microscopy approach that we developed. We demonstrate that TGN-localized proteins exhibit spatially and temporally distinct distribution. VAMP721 (R-SNARE), AP (adaptor protein complex)−1, and clathrin which are involved in secretory trafficking compose an exclusive subregion, whereas VAMP727 (R-SNARE) and AP-4 involved in vacuolar trafficking compose another subregion on the same TGN. Based on these findings, we propose that the single TGN has at least two subregions, or “zones”, responsible for distinct cargo sorting: the secretory-trafficking zone and the vacuolar-trafficking zone.
Enzymatic enhancing of triplet–triplet annihilation upconversion by breaking oxygen quenching for background-free biological sensing
Authors: Huang Ling , Le Timmy , Huang Kai , Han Gang 
Published: March 2021

AbstractTriplet-triplet annihilation upconversion nanoparticles have attracted considerable interest due to their promises in organic chemistry, solar energy harvesting and several biological applications. However, triplet-triplet annihilation upconversion in aqueous solutions is challenging due to sensitivity to oxygen, hindering its biological applications under ambient atmosphere. Herein, we report a simple enzymatic strategy to overcome oxygen-induced triplet-triplet annihilation upconversion quenching. This strategy stems from a glucose oxidase catalyzed glucose oxidation reaction, which enables rapid oxygen depletion to turn on upconversion in the aqueous solution. Furthermore, self-standing upconversion biological sensors of such nanoparticles are developed to detect glucose and measure the activity of enzymes related to glucose metabolism in a highly specific, sensitive and background-free manner. This study not only overcomes the key roadblock for applications of triplet-triplet annihilation upconversion nanoparticles in aqueous solutions, it also establishes the proof-of-concept to develop triplet-triplet annihilation upconversion nanoparticles as background free self-standing biological sensors.
Long-lasting, monovalent-selective capacitive deionization electrodes
Authors: Guyes Eric N. , Shocron Amit N. , Chen Yinke , Diesendruck Charles E. , Suss Matthew E. 
Published: March 2021

AbstractEmerging water purification applications often require tunable and ion-selective technologies. For example, when treating water for direct use in irrigation, often monovalent Na+must be removed preferentially over divalent minerals, such as Ca2+, to reduce both ionic conductivity and sodium adsorption ratio (SAR). Conventional membrane-based water treatment technologies are either largely non-selective or not dynamically tunable. Capacitive deionization (CDI) is an emerging membraneless technology that employs inexpensive and widely available activated carbon electrodes as the active element. We here show that a CDI cell leveraging sulfonated cathodes can deliver long-lasting, tunable monovalent ion selectivity. For feedwaters containing Na+and Ca2+, our cell achieves a Na+/Ca2+separation factor of up to 1.6. To demonstrate the cell longevity, we show that monovalent selectivity is retained over 1000 charge–discharge cycles, the highest cycle life achieved for a membraneless CDI cell with porous carbon electrodes to our knowledge, while requiring an energy consumption of ~0.38 kWh/m3of treated water. Furthermore, we show substantial and simultaneous reductions of ionic conductivity and SAR, such as from 1.75 to 0.69 mS/cm and 19.8 to 13.3, respectively, demonstrating the potential of such a system towards single-step water treatment of brackish and wastewaters for direct use in irrigation.