bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer
Authors: Gu Yayun , Gao Huanyao , Zhang Huan , John August , Zhu Xiujuan , Shivaram Suganti , Yu Jia , Weinshilboum Richard M. , Wang Liewei 
Published: July 2022

AbstractThe HER2 receptor modulates downstream signaling by forming homodimers and heterodimers with other members of the HER family. For patients with HER2-positive breast cancer, Trastuzumab, an anti-HER2 monoclonal antibody as first-line therapy has shown significant survival benefits. However, the development of acquired resistance to Trastuzumab continues to be a significant obstacle. TNF receptor-associated factor 4 (TRAF4) upregulation was discovered to be associated with a worse clinical outcome. Here we identified TRAF4 overexpression as one of the putative mechanisms for HER2-positive breast cancer cells to maintain HER2 signaling during Trastuzumab treatment, while TRAF4 knockdown reduced HER2 stability and improved Trastuzumab sensitivity. Mechanistically, TRAF4 regulates HER2 level through its impact on SMAD specific E3 ubiquitin protein ligase protein 2 (SMURF2). The development of a membrane-associated protein complex containing HER2, TRAF4, and SMURF2 has been observed. SMURF2 bound to the HER2 cytoplasmic domain, and directly ubiquitinated it leading to HER2 degradation, whereas TRAF4 stabilized HER2 by degrading SMURF2 and inhibiting the binding of SMURF2 to HER2. Moreover, downregulation of TRAF4 has decreased the AKT/mTOR signaling. In conclusion, we discovered a new HER2 signaling regulation that involves the TRAF4-SMURF2 complex, a possible mechanism that might contribute to anti-HER2 resistance, making TRAF4 a viable target for treating HER2 + breast cancer.
Epitope detection in monocytes (EDIM) for liquid biopsy including identification of GD2 in childhood neuroblastoma—a pilot study
Authors: Stagno Matias J. , Schmidt Andreas , Bochem Jonas , Urla Cristian , Handgretinger Rupert , Cabanillas Stanchi Karin M. , Saup Rafael , Queudeville Manon , Fuchs Jörg , Warmann Steven W. , Schmid Evi 
Published: July 2022

Abstract
Background
Neuroblastoma (NB) is the most common paediatric extracranial solid malignancy. We analysed the role of the epitope detection in monocytes (EDIM) technique for liquid biopsy in NB patients.

Methods
Tumour epitopes transketolase-like 1 (TKTL1), Apo10 (DNaseX) and GD2 were assessed: expression levels in seven NB tumour samples and five NB cell lines were analysed using RT-PCR and flow cytometry. LAN-1 cells were co-cultured with blood and assessed using EDIM. Peripheral blood macrophages of patients with neuroblastoma (n = 38) and healthy individuals (control group, n = 37) were labelled (CD14+/CD16+) and assessed for TKTL1, Apo10 and GD2 using the EDIM technology.

Results
mRNA expression of TKTL1 and DNaseX/Apo10 was elevated in 6/7 NB samples. Spike experiments showed upregulation of TKTL1, Apo10 and GD2 in LAN-1 cells following co-culturing with blood. TKTL1 and Apo10 were present in macrophages of 36/38 patients, and GD2 in 15/19 patients. The 37 control samples were all negative. EDIM expression scores of the three epitopes allowed differentiation between NB patients and healthy individuals.

Conclusions
The EDIM test might serve as a non-invasive tool for liquid biopsy in children suffering from NB. Future studies are necessary for assessing risk stratification, tumour biology, treatment monitoring, and early detection of tumour relapses.
Modular scaffolding by lncRNA HOXA10-AS promotes oral cancer progression
Authors: Chen Yi-Tung , Kan Chia-Hua , Liu Hsuan , Liu Yu-Hao , Wu Chih-Ching , Kuo Yu-Ping , Chang Ian Yi-Feng , Chang Kai-Ping , Yu Jau-Song , Tan Bertrand Chin-Ming 
Published: July 2022

AbstractRecent findings have implicated long noncoding RNAs (lncRNAs) as pivotal gene regulators for diverse biological processes, despite their lack of protein-coding capabilities. Accumulating evidence suggests the significance of lncRNAs in mediating cell signaling pathways, especially those associated with tumorigenesis. Consequently, lncRNAs have emerged as novel functional regulators and indicators of cancer development and malignancy. Recent transcriptomic profiling has recognized a tumor-biased expressed lncRNA, the HOXA10-AS transcript, whose expression is associated with patient survival. Functional cell-based assays show that the HOXA10-AS transcript is essential in the regulation of oral cancer growth and metastasis. LncRNA expression is also associated with drug sensitivity. In this study, we identify that HOXA10-AS serves as a modular scaffold for TP63 mRNA processing and that such involvement regulates cancer growth. These findings provide a functional interpretation of lncRNA-mediated molecular regulation, highlighting the significance of the lncRNA transcriptome in cancer biology.
Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer
Authors: Zhou Xiaoshu , Zhou Rui , Rao Xinrui , Hong Jiaxin , Li Qianwen , Jie Xiaohua , Wang Jian , Xu Yingzhuo , Zhu Kuikui , Li Zhenyu , Wu Gang 
Published: July 2022

AbstractThe efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
Authors: Liu Ruxia , Xu Chunling , Zhang Weilin , Cao Yangpo , Ye Jingjing , Li Bo , Jia Shi , Weng Lin , Liu Yingying , Liu Lei , Zheng Ming 
Published: July 2022

AbstractHypoxic pulmonary hypertension (PH) is a progressive disease characterized by hyper-proliferation of pulmonary vascular cells including pulmonary artery smooth muscle cells (PASMCs) and can lead to right heart failure and early death. Selective degradation of mitochondria by mitophagy during hypoxia regulates mitochondrial functions in many cells, however, it is not clear if mitophagy is involved in the pathogenesis of hypoxic PH. By employing the hypoxic mitophagy receptor Fundc1 knockout (KO) and transgenic (TG) mouse models, combined hypoxic PH models, the current study found that mitophagy is actively involved in hypoxic PH through regulating PASMC proliferation. In the pulmonary artery medium from hypoxic PH mice, mitophagy was upregulated, accompanied with the increased active form of FUNDC1 protein and the enhanced binding affinity of FUNDC1 with LC3B. In PASMCs, overexpression of FUNDC1 increased mitophagy and cell proliferation while knockdown of FUNDC1 inhibited hypoxia-induced mitophagy and PASMC proliferation. Stimulation of mitophagy by FUNDC1 in PASMCs elevated ROS production and inhibited ubiquitination of hypoxia inducible factor 1α (HIF1α), and inhibition of mitophagy by FUNDC1 knockdown or knockout abolished hypoxia-induced ROS-HIF1α upregulation. Moreover, Fundc1 TG mice developed severe hemodynamics changes and pulmonary vascular remodeling, and Fundc1 KO mice were much resistant to hypoxic PH. In addition, intraperitoneal injection of a specific FUNDC1 peptide inhibitor to block mitophagy ameliorated hypoxic PH. Our results reveal that during hypoxic PH, FUNDC1-mediated mitophagy is upregulated which activates ROS-HIF1α pathway and promotes PASMC proliferation, ultimately leads to pulmonary vascular remodeling and PH.
A phase I/II study of triple-mutated oncolytic herpes virus G47∆ in patients with progressive glioblastoma
Authors: Todo Tomoki , Ino Yasushi , Ohtsu Hiroshi , Shibahara Junji , Tanaka Minoru 
Published: July 2022

AbstractHere, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 108 pfu (low dose) or 1 × 109 pfu (set dose), twice to identical coordinates within 5–14 days. Thirteen patients completed treatment (low dose, n = 3; set dose, n = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7–34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for “immunoprogression” characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development.
A metagenomic DNA sequencing assay that is robust against environmental DNA contamination
Authors: Mzava Omary , Cheng Alexandre Pellan , Chang Adrienne , Smalling Sami , Djomnang Liz-Audrey Kounatse , Lenz Joan Sesing , Longman Randy , Steadman Amy , Gómez-Escobar Luis G. , Schenck Edward J. , Salvatore Mirella , Satlin Michael J. , Suthanthiran Manikkam , Lee John R. , Mason Christopher E. , Dadhania Darshana , De Vlaminck Iwijn 
Published: July 2022

AbstractMetagenomic DNA sequencing is a powerful tool to characterize microbial communities but is sensitive to environmental DNA contamination, in particular when applied to samples with low microbial biomass. Here, we present Sample-Intrinsic microbial DNA Found by Tagging and sequencing (SIFT-seq) a metagenomic sequencing assay that is robust against environmental DNA contamination introduced during sample preparation. The core idea of SIFT-seq is to tag the DNA in the sample prior to DNA isolation and library preparation with a label that can be recorded by DNA sequencing. Any contaminating DNA that is introduced in the sample after tagging can then be bioinformatically identified and removed. We applied SIFT-seq to screen for infections from microorganisms with low burden in blood and urine, to identify COVID-19 co-infection, to characterize the urinary microbiome, and to identify microbial DNA signatures of sepsis and inflammatory bowel disease in blood.
Subsurface ocean warming preceded Heinrich Events
Authors: Max Lars , Nürnberg Dirk , Chiessi Cristiano M. , Lenz Marlene M. , Mulitza Stefan 
Published: July 2022

AbstractAlthough the global environmental impact of Laurentide Ice-Sheet destabilizations on glacial climate during Heinrich Events is well-documented, the mechanism driving these ice-sheet instabilities remains elusive. Here we report foraminifera-based subsurface (~150 m water depth) ocean temperature and salinity reconstructions from a sediment core collected in the western subpolar North Atlantic, showing a consistent pattern of rapid subsurface ocean warming preceding the transition into each Heinrich Event identified in the same core of the last 27,000 years. These results provide the first solid evidence for the massive accumulation of ocean heat near the critical depth to trigger melting of marine-terminating portions of the Laurentide Ice Sheet around Labrador Sea followed by Heinrich Events. The repeated build-up of a subsurface heat reservoir in the subpolar Atlantic closely corresponds to times of weakened Atlantic Meridional Overturning Circulation, indicating a precursor role of ocean circulation changes for initiating abrupt ice-sheet instabilities during Heinrich Events. We infer that a weaker ocean circulation in future may result in accelerated interior-ocean warming of the subpolar Atlantic, which could be critical for the stability of modern, marine-terminating Arctic glaciers and the freshwater budget of the North Atlantic.
Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
Authors: Gomez-Sintes Raquel , Xin Qisheng , Jimenez-Loygorri Juan Ignacio , McCabe Mericka , Diaz Antonio , Garner Thomas P. , Cotto-Rios Xiomaris M. , Wu Yang , Dong Shuxian , Reynolds Cara A. , Patel Bindi , de la Villa Pedro , Macian Fernando , Boya Patricia , Gavathiotis Evripidis , Cuervo Ana Maria 
Published: July 2022

AbstractChaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.
Surrogate- and invariance-boosted contrastive learning for data-scarce applications in science
Authors: Loh Charlotte , Christensen Thomas , Dangovski Rumen , Kim Samuel , Soljačić Marin 
Published: July 2022

AbstractDeep learning techniques have been increasingly applied to the natural sciences, e.g., for property prediction and optimization or material discovery. A fundamental ingredient of such approaches is the vast quantity of labeled data needed to train the model. This poses severe challenges in data-scarce settings where obtaining labels requires substantial computational or labor resources. Noting that problems in natural sciences often benefit from easily obtainable auxiliary information sources, we introduce surrogate- and invariance-boosted contrastive learning (SIB-CL), a deep learning framework which incorporates three inexpensive and easily obtainable auxiliary information sources to overcome data scarcity. Specifically, these are: abundant unlabeled data, prior knowledge of symmetries or invariances, and surrogate data obtained at near-zero cost. We demonstrate SIB-CL’s effectiveness and generality on various scientific problems, e.g., predicting the density-of-states of 2D photonic crystals and solving the 3D time-independent Schrödinger equation. SIB-CL consistently results in orders of magnitude reduction in the number of labels needed to achieve the same network accuracies.
Biallelic and gene-wide genomic substitution for endogenous intron and retroelement mutagenesis in human cells
Authors: Ohno Tomoyuki , Akase Taichi , Kono Shunya , Kurasawa Hikaru , Takashima Takuto , Kaneko Shinya , Aizawa Yasunori 
Published: July 2022

AbstractFunctional annotation of the vast noncoding landscape of the diploid human genome still remains a major challenge of genomic research. An efficient, scarless, biallelic, and gene-wide mutagenesis approach is needed for direct investigation of the functional significance of endogenous long introns in gene regulation. Here we establish a genome substitution platform, the Universal Knock-in System or UKiS, that meets these requirements. For proof of concept, we first used UKiS on the longest intron of TP53 in the pseudo-diploid cell line HCT116. Complete deletion of the intron, its substitution with mouse and zebrafish syntenic introns, and specific removal of retrotransposon-derived elements (retroelements) were all efficiently and accurately achieved in both alleles, revealing a suppressive role of intronic Alu elements in TP53 expression. We also used UKiS for TP53 intron deletion in human induced pluripotent stem cells without losing their stemness. Furthermore, UKiS enabled biallelic removal of all introns from three human gene loci of ~100 kb and longer to demonstrate that intron requirements for transcriptional activities vary among genes. UKiS is a standard platform with which to pursue the design of noncoding regions for genome writing in human cells.
Biodegradable germanium electronics for integrated biosensing of physiological signals
Authors: Zhao Haonan , Xue Zhongying , Wu Xiaozhong , Wei Zhihuan , Guo Qiuyu , Xu Miao , Qu Chunyan , You Chunyu , Mei Yongfeng , Zhang Miao , Di Zengfeng , Guo Qinglei 
Published: July 2022

AbstractTransient electronics that can disappear or degrade via physical disintegration or chemical reaction over a pre-defined operational period provide essential for their applications in implantable bioelectronics due to the complete elimination of the second surgical extraction. However, the dissolution of commonly utilized bioresorbable materials often accompanies hydrogen production, which may cause potential or irreparable harm to the human body. This paper introduces germanium nanomembrane-based bioresorbable electronic sensors, where the chemical dissolution of all utilized materials in biofluidic theoretically have no gaseous products. In particular, the superior electronic transport of germanium enables the demonstrated bioresorbable electronic sensors to successfully distinguish the crosstalk of different physiological signals, such as temperature and strain, suggesting the significant prospect for the construction of dual or multi-parameter biosensors. Systematical studies reveal the gauge factor and temperature coefficient of resistance comparable to otherwise similar devices with gaseous products during their dissolution.
A general design of caging-group-free photoactivatable fluorophores for live-cell nanoscopy
Authors: Lincoln Richard , Bossi Mariano L. , Remmel Michael , D’Este Elisa , Butkevich Alexey N. , Hell Stefan W. 
Published: July 2022

AbstractThe controlled switching of fluorophores between non-fluorescent and fluorescent states is central to every super-resolution fluorescence microscopy (nanoscopy) technique, and the exploration of radically new switching mechanisms remains critical to boosting the performance of established, as well as emerging super-resolution methods. Photoactivatable dyes offer substantial improvements to many of these techniques, but often rely on photolabile protecting groups that limit their applications. Here we describe a general method to transform 3,6-diaminoxanthones into caging-group-free photoactivatable fluorophores. These photoactivatable xanthones (PaX) assemble rapidly and cleanly into highly fluorescent, photo- and chemically stable pyronine dyes upon irradiation with light. The strategy is extendable to carbon- and silicon-bridged xanthone analogues, yielding a family of photoactivatable labels spanning much of the visible spectrum. Our results demonstrate the versatility and utility of PaX dyes in fixed and live-cell labelling for conventional microscopy, as well as the coordinate-stochastic and deterministic nanoscopies STED, PALM and MINFLUX.
Unveiling microscopic carrier loss mechanisms in 12% efficient Cu2ZnSnSe4 solar cells
Authors: Li Jianjun , Huang Jialiang , Ma Fajun , Sun Heng , Cong Jialin , Privat Karen , Webster Richard F. , Cheong Soshan , Yao Yin , Chin Robert Lee , Yuan Xiaojie , He Mingrui , Sun Kaiwen , Li Hui , Mai Yaohua , Hameiri Ziv , Ekins-Daukes Nicholas J. , Tilley Richard D. , Unold Thomas , Green Martin A. , Hao Xiaojing 
Published: July 2022

AbstractUnderstanding carrier loss mechanisms at microscopic regions is imperative for the development of high-performance polycrystalline inorganic thin-film solar cells. Despite the progress achieved for kesterite, a promising environmentally benign and earth-abundant thin-film photovoltaic material, the microscopic carrier loss mechanisms and their impact on device performance remain largely unknown. Herein, we unveil these mechanisms in state-of-the-art Cu2ZnSnSe4 (CZTSe) solar cells using a framework that integrates multiple microscopic and macroscopic characterizations with three-dimensional device simulations. The results indicate the CZTSe films have a relatively long intragrain electron lifetime of 10–30 ns and small recombination losses through bandgap and/or electrostatic potential fluctuations. We identify that the effective minority carrier lifetime of CZTSe is dominated by a large grain boundary recombination velocity (~104 cm s−1), which is the major limiting factor of present device performance. These findings and the framework can greatly advance the research of kesterite and other emerging photovoltaic materials.
Systematic discovery of biomolecular condensate-specific protein phosphorylation
Authors: Sridharan Sindhuja , Hernandez-Armendariz Alberto , Kurzawa Nils , Potel Clement M. , Memon Danish , Beltrao Pedro , Bantscheff Marcus , Huber Wolfgang , Cuylen-Haering Sara , Savitski Mikhail M. 
Published: July 2022

AbstractReversible protein phosphorylation is an important mechanism for regulating (dis)assembly of biomolecular condensates. However, condensate-specific phosphosites remain largely unknown, thereby limiting our understanding of the underlying mechanisms. Here, we combine solubility proteome profiling with phosphoproteomics to quantitatively map several hundred phosphosites enriched in either soluble or condensate-bound protein subpopulations, including a subset of phosphosites modulating protein–RNA interactions. We show that multi-phosphorylation of the C-terminal disordered segment of heteronuclear ribonucleoprotein A1 (HNRNPA1), a key RNA-splicing factor, reduces its ability to locate to nuclear clusters. For nucleophosmin 1 (NPM1), an essential nucleolar protein, we show that phosphorylation of S254 and S260 is crucial for lowering its partitioning to the nucleolus and additional phosphorylation of distal sites enhances its retention in the nucleoplasm. These phosphorylation events decrease RNA and protein interactions of NPM1 to regulate its condensation. Our dataset is a rich resource for systematically uncovering the phosphoregulation of biomolecular condensates.