bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular model system to dissect the isoform-selectivity of Akt inhibitors
Authors: Quambusch Lena , Depta Laura , Landel Ina , Lubeck Melissa , Kirschner Tonia , Nabert Jonas , Uhlenbrock Niklas , Weisner Jörn , Kostka Michael , Levy Laura M. , Schultz-Fademrecht Carsten , Glanemann Franziska , Althoff Kristina , Müller Matthias P. , Siveke Jens T. , Rauh Daniel 
Published: September 2021

AbstractThe protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms’ distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level. Our cellular model system complemented by protein X-ray crystallography and structure-based ligand design results in covalent-allosteric Akt inhibitors with unique selectivity profiles. In a first proof-of-concept, the developed molecules allow studies on isoform-selective effects of Akt inhibition in cancer cells. Thus, this study will pave the way to resolve isoform-selective roles in health and disease and foster the development of next-generation therapeutics with superior on-target properties.
Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis
Authors: Zhang Xiannian , Peng Linna , Luo Yingying , Zhang Shaosen , Pu Yang , Chen Yamei , Guo Wenjia , Yao Jiacheng , Shao Mingming , Fan Wenyi , Cui Qionghua , Xi Yiyi , Sun Yanxia , Niu Xiangjie , Zhao Xuan , Chen Liping , Wang Yuqian , Liu Yachen , Yang Xinyu , Wang Chengcheng , Zhong Ce , Tan Wen , Wang Jianbin , Wu Chen , Lin Dongxin 
Published: September 2021

AbstractEsophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we investigate the composition of ESCC tumors based on 208,659 single-cell transcriptomes derived from 60 individuals. We identify 8 common expression programs from malignant epithelial cells and discover 42 cell types, including 26 immune cell and 16 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and analyse the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we link the cancer cell transcriptomes to the somatic mutations and identify several markers significantly associated with patients’ survival, which may be relevant to precision care of ESCC patients. These results reveal the immunosuppressive status in the ESCC TME and further our understanding of ESCC.
Moisture-induced autonomous surface potential oscillations for energy harvesting
Authors: Long Yu , He Peisheng , Shao Zhichun , Li Zhaoyang , Kim Han , Yao Archie Mingze , Peng Yande , Xu Renxiao , Ahn Christine Heera , Lee Seung-Wuk , Zhong Junwen , Lin Liwei 
Published: September 2021

AbstractA variety of autonomous oscillations in nature such as heartbeats and some biochemical reactions have been widely studied and utilized for applications in the fields of bioscience and engineering. Here, we report a unique phenomenon of moisture-induced electrical potential oscillations on polymers, poly([2-(methacryloyloxy)ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide-co-acrylic acid), during the diffusion of water molecules. Chemical reactions are modeled by kinetic simulations while system dynamic equations and the stability matrix are analyzed to show the chaotic nature of the system which oscillates with hidden attractors to induce the autonomous surface potential oscillation. Using moisture in the ambient environment as the activation source, this self-excited chemoelectrical reaction could have broad influences and usages in surface-reaction based devices and systems. As a proof-of-concept demonstration, an energy harvester is constructed and achieved the continuous energy production for more than 15,000 seconds with an energy density of 16.8 mJ/cm2. A 2-Volts output voltage has been produced to power a liquid crystal display toward practical applications with five energy harvesters connected in series.
C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers
Authors: Nanaura Hitoki , Kawamukai Honoka , Fujiwara Ayano , Uehara Takeru , Aiba Yuichiro , Nakanishi Mari , Shiota Tomo , Hibino Masaki , Wiriyasermkul Pattama , Kikuchi Sotaro , Nagata Riko , Matsubayashi Masaya , Shinkai Yoichi , Niwa Tatsuya , Mannen Taro , Morikawa Naritaka , Iguchi Naohiko , Kiriyama Takao , Morishima Ken , Inoue Rintaro , Sugiyama Masaaki , Oda Takashi , Kodera Noriyuki , Toma-Fukai Sachiko , Sato Mamoru , Taguchi Hideki , Nagamori Shushi , Shoji Osami , Ishimori Koichiro , Matsumura Hiroyoshi , Sugie Kazuma , Saio Tomohide , Yoshizawa Takuya , Mori Eiichiro 
Published: September 2021

AbstractNuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-β2 (Kapβ2) at 1:1 ratio. The nuclear magnetic resonances of Kapβ2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapβ2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration.
Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism
Authors: Maben Zachary , Arya Richa , Georgiadis Dimitris , Stratikos Efstratios , Stern Lawrence J. 
Published: September 2021

AbstractThe endoplasmic-reticulum aminopeptidase ERAP1 processes antigenic peptides for loading on MHC-I proteins and recognition by CD8 T cells as they survey the body for infection and malignancy. Crystal structures have revealed ERAP1 in either open or closed conformations, but whether these occur in solution and are involved in catalysis is not clear. Here, we assess ERAP1 conformational states in solution in the presence of substrates, allosteric activators, and inhibitors by small-angle X-ray scattering. We also characterize changes in protein conformation by X-ray crystallography, and we localize alternate C-terminal binding sites by chemical crosslinking. Structural and enzymatic data suggest that the structural reconfigurations of ERAP1 active site are physically linked to domain closure and are promoted by binding of long peptide substrates. These results clarify steps required for ERAP1 catalysis, demonstrate the importance of conformational dynamics within the catalytic cycle, and provide a mechanism for the observed allosteric regulation and Lys/Arg528 polymorphism disease association.
Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens
Authors: Hwang Michael S. , Miller Michelle S. , Thirawatananond Puchong , Douglass Jacqueline , Wright Katharine M. , Hsiue Emily Han-Chung , Mog Brian J. , Aytenfisu Tihitina Y. , Murphy Michael B. , Aitana Azurmendi P. , Skora Andrew D. , Pearlman Alexander H. , Paul Suman , DiNapoli Sarah R. , Konig Maximilian F. , Bettegowda Chetan , Pardoll Drew M. , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Zhou Shibin , Gabelli Sandra B. 
Published: September 2021

AbstractChimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2R140Q-HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means.
Colossal thermo-hydro-electrochemical voltage generation for self-sustainable operation of electronics
Authors: Zhang Yufan , Sohn Ahrum , Chakraborty Anirban , Yu Choongho 
Published: September 2021

AbstractThermoelectrics are suited to converting dissipated heat into electricity for operating electronics, but the small voltage (~0.1 mV K−1) from the Seebeck effect has been one of the major hurdles in practical implementation. Here an approach with thermo-hydro-electrochemical effects can generate a large thermal-to-electrical energy conversion factor (TtoE factor), −87 mV K−1 with low-cost carbon steel electrodes and a solid-state polyelectrolyte made of polyaniline and polystyrene sulfonate (PANI:PSS). We discovered that the thermo-diffusion of water in PANI:PSS under a temperature gradient induced less (or more) water on the hotter (or colder) side, raising (or lowering) the corrosion overpotential in the hotter (or colder) side and thereby generating output power between the electrodes. Our findings are expected to facilitate subsequent research for further increasing the TtoE factor and utilizing dissipated thermal energy.
A functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci
Authors: Joslin Amelia C. , Sobreira Débora R. , Hansen Grace T. , Sakabe Noboru J. , Aneas Ivy , Montefiori Lindsey E. , Farris Kathryn M. , Gu Jing , Lehman Donna M. , Ober Carole , He Xin , Nóbrega Marcelo A. 
Published: September 2021

AbstractGenome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.
Brown adipose tissue monocytes support tissue expansion
Authors: Gallerand Alexandre , Stunault Marion I. , Merlin Johanna , Luehmann Hannah P. , Sultan Deborah H. , Firulyova Maria M. , Magnone Virginie , Khedher Narges , Jalil Antoine , Dolfi Bastien , Castiglione Alexia , Dumont Adelie , Ayrault Marion , Vaillant Nathalie , Gilleron Jérôme , Barbry Pascal , Dombrowicz David , Mack Matthias , Masson David , Bertero Thomas , Becher Burkhard , Williams Jesse W. , Zaitsev Konstantin , Liu Yongjian , Guinamard Rodolphe R. , Yvan-Charvet Laurent , Ivanov Stoyan 
Published: September 2021

AbstractMonocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.
Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma
Authors: Sun Guangxi , Chen Junru , Liang Jiayu , Yin Xiaoxue , Zhang Mengni , Yao Jin , He Ning , Armstrong Cameron M. , Zheng Linmao , Zhang Xingming , Zhu Sha , Sun Xiaomeng , Yang Xiaoxia , Zhao Wanbin , Liao Banghua , Pan Xiuyi , Nie Ling , Yang Ling , Chen Yuntian , Zhao Jinge , Zhang Haoran , Dai Jindong , Shen Yali , Liu Jiyan , Huang Rui , Liu Jiandong , Wang Zhipeng , Ni Yuchao , Wei Qiang , Li Xiang , Zhou Qiao , Huang Haojie , Liu Zhenhua , Shen Pengfei , Chen Ni , Zeng Hao 
Published: September 2021

AbstractTFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.
The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling
Authors: Shen Chen , Nayak Anmada , Neitzel Leif R. , Adams Amber A. , Silver-Isenstadt Maya , Sawyer Leah M. , Benchabane Hassina , Wang Huilan , Bunnag Nawat , Li Bin , Wynn Daniel T. , Yang Fan , Garcia-Contreras Marta , Williams Charles H. , Dakshanamurthy Sivanesan , Hong Charles C. , Ayad Nagi G. , Capobianco Anthony J. , Ahmed Yashi , Lee Ethan , Robbins David J. 
Published: September 2021

AbstractImmunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the β-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease.
Polymerized small molecular acceptor based all-polymer solar cells with an efficiency of 16.16% via tuning polymer blend morphology by molecular design
Authors: Du Jiaqi , Hu Ke , Zhang Jinyuan , Meng Lei , Yue Jiling , Angunawela Indunil , Yan Hongping , Qin Shucheng , Kong Xiaolei , Zhang Zhanjun , Guan Bo , Ade Harald , Li Yongfang 
Published: September 2021

AbstractAll-polymer solar cells (all-PSCs) based on polymerized small molecular acceptors (PSMAs) have made significant progress recently. Here, we synthesize two A-DA’D-A small molecule acceptor based PSMAs of PS-Se with benzo[c][1,2,5]thiadiazole A’-core and PN-Se with benzotriazole A’-core, for the studies of the effect of molecular structure on the photovoltaic performance of the PSMAs. The two PSMAs possess broad absorption with PN-Se showing more red-shifted absorption than PS-Se and suitable electronic energy levels for the application as polymer acceptors in the all-PSCs with PBDB-T as polymer donor. Cryogenic transmission electron microscopy visualizes the aggregation behavior of the PBDB-T donor and the PSMA in their solutions. In addition, a bicontinuous-interpenetrating network in the PBDB-T:PN-Se blend film with aggregation size of 10~20 nm is clearly observed by the photoinduced force microscopy. The desirable morphology of the PBDB-T:PN-Se active layer leads its all-PSC showing higher power conversion efficiency of 16.16%.
Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells
Authors: Jergović Mladen , Coplen Christopher P. , Uhrlaub Jennifer L. , Besselsen David G. , Cheng Shu , Smithey Megan J. , Nikolich-Žugich Janko 
Published: September 2021

AbstractNaïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.
Determination of X-ray detection limit and applications in perovskite X-ray detectors
Authors: Pan Lei , Shrestha Shreetu , Taylor Neil , Nie Wanyi , Cao Lei R. 
Published: September 2021

AbstractX-ray detection limit and sensitivity are important figure of merits for perovskite X-ray detectors, but literatures lack a valid mathematic expression for determining the lower limit of detection for a perovskite X-ray detector. In this work, we present a thorough analysis and new method for X-ray detection limit determination based on a statistical model that correlates the dark current and the X-ray induced photocurrent with the detection limit. The detection limit can be calculated through the measurement of dark current and sensitivity with an easy-to-follow practice. Alternatively, the detection limit may also be obtained by the measurement of dark current and photocurrent when repeatedly lowering the X-ray dose rate. While the material quality is critical, we show that the device architecture and working mode also have a significant influence on the sensitivity and the detection limit. Our work establishes a fair comparison metrics for material and detector development.
Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease
Authors: Hu Di , Sun Xiaoyan , Magpusao Anniefer , Fedorov Yuriy , Thompson Matthew , Wang Benlian , Lundberg Kathleen , Adams Drew J. , Qi Xin 
Published: September 2021

AbstractMitochondrial dysfunction is a common hallmark of neurological disorders, and reducing mitochondrial damage is considered a promising neuroprotective therapeutic strategy. Here, we used high-throughput small molecule screening to identify CHIR99021 as a potent enhancer of mitochondrial function. CHIR99021 improved mitochondrial phenotypes and enhanced cell viability in several models of Huntington’s disease (HD), a fatal inherited neurodegenerative disorder. Notably, CHIR99201 treatment reduced HD-associated neuropathology and behavioral defects in HD mice and improved mitochondrial function and cell survival in HD patient-derived neurons. Independent of its known inhibitory activity against glycogen synthase kinase 3 (GSK3), CHIR99021 treatment in HD models suppressed the proteasomal degradation of calpastatin (CAST), and subsequently inhibited calpain activation, a well-established effector of neural death, and Drp1, a driver of mitochondrial fragmentation. Our results established CAST-Drp1 as a druggable signaling axis in HD pathogenesis and highlighted CHIR99021 as a mitochondrial function enhancer and a potential lead for developing HD therapies.