bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational evidence for lithium-induced brain plasticity and neuroprotection in the treatment of neuropsychiatric disorders
Authors: Puglisi-Allegra Stefano , Ruggieri Stefano , Fornai Francesco 
Published: July 2021

AbstractIncreasing evidence indicates lithium (Li+) efficacy in neuropsychiatry, pointing to overlapping mechanisms that occur within distinct neuronal populations. In fact, the same pathway depending on which circuitry operates may fall in the psychiatric and/or neurological domains. Li+ restores both neurotransmission and brain structure unveiling that psychiatric and neurological disorders share common dysfunctional molecular and morphological mechanisms, which may involve distinct brain circuitries. Here an overview is provided concerning the therapeutic/neuroprotective effects of Li+ in different neuropsychiatric disorders to highlight common molecular mechanisms through which Li+ produces its mood-stabilizing effects and to what extent these overlap with plasticity in distinct brain circuitries. Li+ mood-stabilizing effects are evident in typical bipolar disorder (BD) characterized by a cyclic course of mania or hypomania followed by depressive episodes, while its efficacy is weaker in the opposite pattern. We focus here on neural adaptations that may underlie psychostimulant-induced psychotic development and to dissect, through the sensitization process, which features are shared in BD and other psychiatric disorders, including schizophrenia. The multiple functions of Li+ highlighted here prove its exceptional pharmacology, which may help to elucidate its mechanisms of action. These may serve as a guide toward a multi-drug strategy. We propose that the onset of sensitization in a specific BD subtype may predict the therapeutic efficacy of Li+. This model may help to infer in BD which molecular mechanisms are relevant to the therapeutic efficacy of Li+.
MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer
Authors: Lampis Andrea , Hahne Jens C. , Gasparini Pierluigi , Cascione Luciano , Hedayat Somaieh , Vlachogiannis Georgios , Murgia Claudio , Fontana Elisa , Edwards Joanne , Horgan Paul G. , Terracciano Luigi , Sansom Owen J. , Martins Carlos D. , Kramer-Marek Gabriela , Croce Carlo M. , Braconi Chiara , Fassan Matteo , Valeri Nicola 
Published: July 2021

AbstractJunctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.
SKP-SCs transplantation alleviates 6-OHDA-induced dopaminergic neuronal injury by modulating autophagy
Authors: Ma Chengxiao , Zhang Wen , Wang Wengcong , Shen Jiabing , Cai Kefu , Liu Mei , Cao Maohong 
Published: July 2021

AbstractParkinson’s disease is a common neurodegenerative disease. Cell transplantation is a promising therapeutic option for improving the survival and function of dopaminergic neurons, but the mechanisms underlying the interaction between the transplanted cells and the recipient neurons remain to be studied. In this study, we investigated the effects of skin precursor cell-derived Schwann cells (SKP-SCs) directly cocultured with 6-OHDA-injured dopaminergic neurons in vitro and of SKP-SCs transplanted into the brains of 6-OHDA-induced PD mice in vivo. In vitro and in vivo studies revealed that SKP-SCs could reduce the damage to dopaminergic neurons by enhancing self-autophagy and modulating neuronal autophagy. Thus, the present study provides the first evidence that cell transplantation mitigates 6-OHDA-induced damage to dopaminergic neurons by enhancing self-autophagy, suggesting that earlier transplantation of Schwann cells might help alleviate the loss of dopaminergic neurons.
The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression
Authors: Gao Long , Liu Yuan , Du Xiaohong , Ma Sai , Ge Minmin , Tang Haijun , Han Chenfeng , Zhao Xin , Liu Yanbin , Shao Yun , Wu Zhao , Zhang Lianjun , Meng Fang , Xiao-Feng Qin F. 
Published: July 2021

AbstractIt has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.
The proteolytic landscape of cells exposed to non-lethal stresses is shaped by executioner caspases
Authors: Conde-Rubio María del Carmen , Mylonas Roman , Widmann Christian 
Published: July 2021

AbstractCells are in constant adaptation to environmental changes to insure their proper functioning. When exposed to stresses, cells activate specific pathways to elicit adaptive modifications. Those changes can be mediated by selective modulation of gene and protein expression as well as by post-translational modifications, such as phosphorylation and proteolytic processing. Protein cleavage, as a controlled and limited post-translational modification, is involved in diverse physiological processes such as the maintenance of protein homeostasis, activation of repair pathways, apoptosis and the regulation of proliferation. Here we assessed by quantitative proteomics the proteolytic landscape in two cell lines subjected to low cisplatin concentrations used as a mild non-lethal stress paradigm. This landscape was compared to the one obtained in the same cells stimulated with cisplatin concentrations inducing apoptosis. These analyses were performed in wild-type cells and in cells lacking the two main executioner caspases: caspase-3 and caspase-7. Ninety-two proteins were found to be cleaved at one or a few sites (discrete cleavage) in low stress conditions compared to four hundred and fifty-three in apoptotic cells. Many of the cleaved proteins in stressed cells were also found to be cleaved in apoptotic conditions. As expected, ~90% of the cleavage events were dependent on caspase-3/caspase-7 in apoptotic cells. Strikingly, upon exposure to non-lethal stresses, no discrete cleavage was detected in cells lacking caspase-3 and caspase-7. This indicates that the proteolytic landscape in stressed viable cells fully depends on the activity of executioner caspases. These results suggest that the so-called executioner caspases fulfill important stress adaptive responses distinct from their role in apoptosis. Mass spectrometry data are available via ProteomeXchange with identifier PXD023488.
OASIS/CREB3L1 is a factor that responds to nuclear envelope stress
Authors: Kamikawa Yasunao , Saito Atsushi , Matsuhisa Koji , Kaneko Masayuki , Asada Rie , Horikoshi Yasunori , Tashiro Satoshi , Imaizumi Kazunori 
Published: July 2021

AbstractThe nuclear envelope (NE) safeguards the genome and is pivotal for regulating genome activity as the structural scaffold of higher-order chromatin organization. NE had been thought as the stable during the interphase of cell cycle. However, recent studies have revealed that the NE can be damaged by various stresses such as mechanical stress and cellular senescence. These types of stresses are called NE stress. It has been proposed that NE stress is closely related to cellular dysfunctions such as genome instability and cell death. Here, we found that an endoplasmic reticulum (ER)-resident transmembrane transcription factor, OASIS, accumulates at damaged NE. Notably, the major components of nuclear lamina, Lamin proteins were depleted at the NE where OASIS accumulates. We previously demonstrated that OASIS is cleaved at the membrane domain in response to ER stress. In contrast, OASIS accumulates as the full-length form to damaged NE in response to NE stress. The accumulation to damaged NE is specific for OASIS among OASIS family members. Intriguingly, OASIS colocalizes with the components of linker of nucleoskeleton and cytoskeleton complexes, SUN2 and Nesprin-2 at the damaged NE. OASIS partially colocalizes with BAF, LEM domain proteins, and a component of ESCRT III, which are involved in the repair of ruptured NE. Furthermore, OASIS suppresses DNA damage induced by NE stress and restores nuclear deformation under NE stress conditions. Our findings reveal a novel NE stress response pathway mediated by OASIS.
Circ_0030998 promotes tumor proliferation and angiogenesis by sponging miR-567 to regulate VEGFA in colorectal cancer
Authors: Jin Longyang , Han Chao , Zhai Tianyu , Zhang Xiaoyu , Chen Chun , Lian Lei 
Published: July 2021

AbstractColorectal cancer (CRC) is one of the most common malignancies worldwide. Circular RNAs (circRNAs) are involved in pathological processes, especially in the development of cancers, but the roles of circRNAs in CRC are largely unknown. In this study, we investigated the role and underlying mechanisms of Circ_0030998 in CRC cell proliferation and angiogenesis. We found that Circ_0030998 was upregulated in CRC tissues and cells, and its upregulation was related to poor prognosis in CRC patients. Circ_0030998 promoted CRC cell proliferation in vitro and in vivo, and facilitated the angiogenesis of HUVECs. Mechanistic studies demonstrated that Circ_0030998 acted as a miR-567 sponge to relieve its inhibitory effect on VEGFA. Rescue assays validated that Circ_0030998 functioned in CRC cell proliferation and angiogenesis relying on VEGFA. Our findings clarified the Circ_0030998/miR-567/VEGFA regulation axis and indicated that Circ_0030998 could be a potential therapeutic target for CRC.
Impairment of neuronal mitochondrial function by l-DOPA in the absence of oxygen-dependent auto-oxidation and oxidative cell damage
Authors: Hörmann Philipp , Delcambre Sylvie , Hanke Jasmin , Geffers Robert , Leist Marcel , Hiller Karsten 
Published: July 2021

AbstractL-3,4-Dihydroxyphenylalanin (l-DOPA or levodopa) is currently the most used drug to treat symptoms of Parkinson’s disease (PD). After crossing the blood–brain barrier, it is enzymatically converted to dopamine by neuronal cells and restores depleted endogenous neurotransmitter levels. l-DOPA is prone to auto-oxidation and reactive intermediates of its degradation including reactive oxygen species (ROS) have been implicated in cellular damage. In this study, we investigated how oxygen tension effects l-DOPA stability. We applied oxygen tensions comparable to those in the mammalian brain and demonstrated that 2% oxygen almost completely stopped its auto-oxidation. l-DOPA even exerted a ROS scavenging function. Further mechanistic analysis indicated that l-DOPA reprogrammed mitochondrial metabolism and reduced oxidative phosphorylation, depolarized the mitochondrial membrane, induced reductive glutamine metabolism, and depleted the NADH pool. These results shed new light on the cellular effects of l-DOPA and its neuro-toxicity under physiological oxygen levels that are very distinct to normoxic in vitro conditions.
Current insights into the expression and functions of tumor-derived immunoglobulins
Authors: Zhao Jing , Peng Hui , Gao Jie , Nong Anna , Hua Haoming , Yang Shulin , Chen Liying , Wu Xiangsheng , Zhang Hao , Wang Juping 
Published: July 2021

AbstractNumerous studies have reported expressions of immunoglobulins (Igs) in many human tumor tissues and cells. Tumor-derived Igs have displayed multiple significant functions which are different from classical Igs produced by B lymphocytes and plasma cells. This review will concentrate on major progress in expressions, functions, and mechanisms of tumor-derived Igs, similarities and differences between tumor-derived Igs and B-cell-derived Igs. We also discuss the future research directions of tumor-derived Igs, including their structural characteristics, physicochemical properties, mechanisms for rearrangement and expression regulation, signaling pathways involved, and clinical applications.
Identification of the pyroptosis‑related prognostic gene signature and the associated regulation axis in lung adenocarcinoma
Authors: Lin Wanli , Chen Ying , Wu Bomeng , chen Ying , Li Zuwei 
Published: July 2021

AbstractLung adenocarcinoma (LUAD) remains the most common deadly disease and has a poor prognosis. Pyroptosis could regulate tumour cell proliferation, invasion, and metastasis, thereby affecting the prognosis of cancer patients. However, the role of pyroptosis-related genes (PRGs) in LUAD remains unclear. In our study, comprehensive bioinformatics analysis was performed to construct a prognostic gene model and ceRNA network. The correlations between PRGs and tumour-immune infiltration, tumour mutation burden, and microsatellite instability were evaluated using Pearson’s correlation analysis. A total of 23 PRGs were upregulated or downregulated in LUAD. The genetic mutation variation landscape of PRG in LUAD was also summarised. Functional enrichment analysis revealed that these 33 PRGs were mainly involved in pyroptosis, the NOD-like receptor signalling pathway, and the Toll-like receptor signalling pathway. Prognosis analysis indicated a poor survival rate in LUAD patients with low expression of NLRP7, NLRP1, NLRP2, and NOD1 and high CASP6 expression. A prognostic PRG model constructed using the above five prognostic genes could predict the overall survival of LUAD patients with medium-to-high accuracy. Significant correlation was observed between prognostic PRGs and immune-cell infiltration, tumour mutation burden, and microsatellite instability. A ceRNA network was constructed to identify a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis in LUAD. In conclusion, we performed a comprehensive bioinformatics analysis and identified a prognostic PRG signature containing five genes (NLRP7, NLRP1, NLRP2, NOD1, and CASP6) for LUAD patients. Our results also identified a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis, which may also play an important role in the progression of LUAD. Further study needs to be conducted to verify this result.
Structural basis of ethnic-specific variants of PAX4 associated with type 2 diabetes
Authors: Hosoe Jun , Suzuki Ken , Miya Fuyuki , Kato Takashi , Tsunoda Tatsuhiko , Okada Yukinori , Horikoshi Momoko , Shojima Nobuhiro , Yamauchi Toshimasa , Kadowaki Takashi 
Published: July 2021

AbstractRecently, we conducted genome-wide association studies of type 2 diabetes (T2D) in a Japanese population, which identified 20 novel T2D loci that were not associated with T2D in Europeans. Moreover, nine novel missense risk variants, such as those of PAX4, were not rare in the Japanese population, but rare in Europeans. We report in silico structural analysis of ethnic-specific variants of PAX4, which suggests the pathogenic effect of these variants.
Predicting trends in the quality of state-of-the-art neural networks without access to training or testing data
Authors: Martin Charles H. , Peng Tongsu , Mahoney Michael W. 
Published: July 2021

AbstractIn many applications, one works with neural network models trained by someone else. For such pretrained models, one may not have access to training data or test data. Moreover, one may not know details about the model, e.g., the specifics of the training data, the loss function, the hyperparameter values, etc. Given one or many pretrained models, it is a challenge to say anything about the expected performance or quality of the models. Here, we address this challenge by providing a detailed meta-analysis of hundreds of publicly available pretrained models. We examine norm-based capacity control metrics as well as power law based metrics from the recently-developed Theory of Heavy-Tailed Self Regularization. We find that norm based metrics correlate well with reported test accuracies for well-trained models, but that they often cannot distinguish well-trained versus poorly trained models. We also find that power law based metrics can do much better—quantitatively better at discriminating among series of well-trained models with a given architecture; and qualitatively better at discriminating well-trained versus poorly trained models. These methods can be used to identify when a pretrained neural network has problems that cannot be detected simply by examining training/test accuracies.
Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles
Authors: Kucharz Krzysztof , Kristensen Kasper , Johnsen Kasper Bendix , Lund Mette Aagaard , Lønstrup Micael , Moos Torben , Andresen Thomas Lars , Lauritzen Martin Johannes 
Published: July 2021

AbstractEffective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain.
DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination
Authors: Chakraborty Prasun , Hiom Kevin 
Published: July 2021

AbstractDouble stranded DNA Breaks (DSB) that occur in highly transcribed regions of the genome are preferentially repaired by homologous recombination repair (HR). However, the mechanisms that link transcription with HR are unknown. Here we identify a critical role for DHX9, a RNA helicase involved in the processing of pre-mRNA during transcription, in the initiation of HR. Cells that are deficient in DHX9 are impaired in the recruitment of RPA and RAD51 to sites of DNA damage and fail to repair DSB by HR. Consequently, these cells are hypersensitive to treatment with agents such as camptothecin and Olaparib that block transcription and generate DSB that specifically require HR for their repair. We show that DHX9 plays a critical role in HR by promoting the recruitment of BRCA1 to RNA as part of the RNA Polymerase II transcription complex, where it facilitates the resection of DSB. Moreover, defects in DHX9 also lead to impaired ATR-mediated damage signalling and an inability to restart DNA replication at camptothecin-induced DSB. Together, our data reveal a previously unknown role for DHX9 in the DNA Damage Response that provides a critical link between RNA, RNA Pol II and the repair of DNA damage by homologous recombination.
Ultralow-threshold laser using super-bound states in the continuum
Authors: Hwang Min-Soo , Lee Hoo-Cheol , Kim Kyoung-Ho , Jeong Kwang-Yong , Kwon Soon-Hong , Koshelev Kirill , Kivshar Yuri , Park Hong-Gyu 
Published: July 2021

AbstractWavelength-scale lasers provide promising applications through low power consumption requiring for optical cavities with increased quality factors. Cavity radiative losses can be suppressed strongly in the regime of optical bound states in the continuum; however, a finite size of the resonator limits the performance of bound states in the continuum as cavity modes for active nanophotonic devices. Here, we employ the concept of a supercavity mode created by merging symmetry-protected and accidental bound states in the continuum in the momentum space, and realize an efficient laser based on a finite-size cavity with a small footprint. We trace the evolution of lasing properties before and after the merging point by varying the lattice spacing, and we reveal this laser demonstrates the significantly reduced threshold, substantially increased quality factor, and shrunken far-field images. Our results provide a route for nanolasers with reduced out-of-plane losses in finite-size active nanodevices and improved lasing characteristics.