bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways
Authors: Shang Chaowei , Zhou Hongyu , Liu Wang , Shen Tao , Luo Yan , Huang Shile 
Published: June 2020

AbstractThe mammalian target of rapamycin (mTOR) functions as two complexes (mTORC1 and mTORC2), regulating cell growth and metabolism. Aberrant mTOR signaling occurs frequently in cancers, so mTOR has become an attractive target for cancer therapy. Iron chelators have emerged as promising anticancer agents. However, the mechanisms underlying the anticancer action of iron chelation are not fully understood. Particularly, reports on the effects of iron chelation on mTOR complexes are inconsistent or controversial. Here, we found that iron chelators consistently inhibited mTORC1 signaling, which was blocked by pretreatment with ferrous sulfate. Mechanistically, iron chelation-induced mTORC1 inhibition was not related to ROS induction, copper chelation, or PP2A activation. Instead, activation of AMPK pathway mainly and activation of both HIF-1/REDD1 and Bnip3 pathways partially contribute to iron chelation-induced mTORC1 inhibition. Our findings indicate that iron chelation inhibits mTORC1 via multiple pathways and iron is essential for mTORC1 activation.
Multimodal network dynamics underpinning working memory
Authors: Murphy Andrew C. , Bertolero Maxwell A. , Papadopoulos Lia , Lydon-Staley David M. , Bassett Danielle S. 
Published: June 2020

AbstractComplex human cognition arises from the integrated processing of multiple brain systems. However, little is known about how brain systems and their interactions might relate to, or perhaps even explain, human cognitive capacities. Here, we address this gap in knowledge by proposing a mechanistic framework linking frontoparietal system activity, default mode system activity, and the interactions between them, with individual differences in working memory capacity. We show that working memory performance depends on the strength of functional interactions between the frontoparietal and default mode systems. We find that this strength is modulated by the activation of two newly described brain regions, and demonstrate that the functional role of these systems is underpinned by structural white matter. Broadly, our study presents a holistic account of how regional activity, functional connections, and structural linkages together support integrative processing across brain systems in order for the brain to execute a complex cognitive process.
Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
Authors: Ciudad Sonia , Puig Eduard , Botzanowski Thomas , Meigooni Moeen , Arango Andres S. , Do Jimmy , Mayzel Maxim , Bayoumi Mariam , Chaignepain Stéphane , Maglia Giovanni , Cianferani Sarah , Orekhov Vladislav , Tajkhorshid Emad , Bardiaux Benjamin , Carulla Natàlia 
Published: June 2020

AbstractFormation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimerʼs disease (AD). Here, we present the three-dimensional structure of an Aβ oligomer formed in a membrane mimicking environment, namely an Aβ(1-42) tetramer, which comprises a six stranded β-sheet core. The two faces of the β-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Aβ(1-42) in the sample, Aβ(1-42) octamers are also formed, made by two Aβ(1-42) tetramers facing each other forming a β-sandwich structure. Notably, Aβ(1-42) tetramers and octamers inserted into lipid bilayers as well-defined pores. To establish oligomer structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed a mechanism of membrane disruption in which water permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core β-sheets edges of the oligomers.
Early stratification of radiotherapy response by activatable inflammation magnetic resonance imaging
Authors: Zhou Zijian , Deng Hongzhang , Yang Weijing , Wang Zhantong , Lin Lisen , Munasinghe Jeeva , Jacobson Orit , Liu Yijing , Tang Longguang , Ni Qianqian , Kang Fei , Liu Yuan , Niu Gang , Bai Ruiliang , Qian Chunqi , Song Jibin , Chen Xiaoyuan 
Published: June 2020

AbstractTumor heterogeneity is one major reason for unpredictable therapeutic outcomes, while stratifying therapeutic responses at an early time may greatly benefit the better control of cancer. Here, we developed a hybrid nanovesicle to stratify radiotherapy response by activatable inflammation magnetic resonance imaging (aiMRI) approach. The high Pearson’s correlation coefficient R values are obtained from the correlations between the T1 relaxation time changes at 24–48 h and the ensuing adaptive immunity (R = 0.9831) at day 5 and the tumor inhibition ratios (R = 0.9308) at day 18 after different treatments, respectively. These results underscore the role of acute inflammatory oxidative response in bridging the innate and adaptive immunity in tumor radiotherapy. Furthermore, the aiMRI approach provides a non-invasive imaging strategy for early prediction of the therapeutic outcomes in cancer radiotherapy, which may contribute to the future of precision medicine in terms of prognostic stratification and therapeutic planning.
Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity
Authors: Zheng Lifeng , Yu Mei , Lin Rui , Wang Yunxuan , Zhuo Zhan , Cheng Ning , Wang Mengzhen , Tang Yongqiang , Wang Liping , Hou Sheng-Tao 
Published: June 2020

AbstractThe complex relationship between specific hippocampal oscillation frequency deficit and cognitive dysfunction in the ischemic brain is unclear. Here, using a mouse two-vessel occlusion (2VO) cerebral ischemia model, we show that visual stimulation with a 40 Hz light flicker drove hippocampal CA1 slow gamma and restored 2VO-induced reduction in CA1 slow gamma power and theta-low gamma phase-amplitude coupling, but not those of the high gamma. Low gamma frequency lights at 30 Hz, 40 Hz, and 50 Hz, but not 10 Hz, 80 Hz, and arrhythmic frequency light, were protective against degenerating CA1 neurons after 2VO, demonstrating the importance of slow gamma in cognitive functions after cerebral ischemia. Mechanistically, 40 Hz light flicker enhanced RGS12-regulated CA3-CA1 presynaptic N-type calcium channel-dependent short-term synaptic plasticity and associated postsynaptic long term potentiation (LTP) after 2VO. These results support a causal relationship between CA1 slow gamma and cognitive dysfunctions in the ischemic brain.
Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia
Authors: Vu Therese , Straube Jasmin , Porter Amy H. , Bywater Megan , Song Axia , Ling Victoria , Cooper Leanne , Pali Gabor , Bruedigam Claudia , Jacquelin Sebastien , Green Joanne , Magor Graham , Perkins Andrew , Chalk Alistair M. , Walkley Carl R. , Heidel Florian H. , Mukhopadhyay Pamela , Cloonan Nicole , Gröschel Stefan , Mallm Jan-Philipp , Fröhling Stefan , Scholl Claudia , Lane Steven W. 
Published: June 2020

AbstractThe caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.
Spectral cross-cumulants for multicolor super-resolved SOFI imaging
Authors: Grußmayer K. S. , Geissbuehler S. , Descloux A. , Lukes T. , Leutenegger M. , Radenovic A. , Lasser T. 
Published: June 2020

AbstractSuper-resolution optical fluctuation imaging provides a resolution beyond the diffraction limit by analysing stochastic fluorescence fluctuations with higher-order statistics. Using nth order spatio-temporal cross-cumulants the spatial resolution and the sampling can be increased up to n-fold in all spatial dimensions. In this study, we extend the cumulant analysis into the spectral domain and propose a multicolor super-resolution scheme. The simultaneous acquisition of two spectral channels followed by spectral cross-cumulant analysis and unmixing increases the spectral sampling. The number of discriminable fluorophore species is thus not limited to the number of physical detection channels. Using two color channels, we demonstrate spectral unmixing of three fluorophore species in simulations and experiments in fixed and live cells. Based on an eigenvalue/vector analysis, we propose a scheme for an optimized spectral filter choice. Overall, our methodology provides a route for easy-to-implement multicolor sub-diffraction imaging using standard microscopes while conserving the spatial super-resolution property.
A constricted opening in Kir channels does not impede potassium conduction
Authors: Black Katrina A. , He Sitong , Jin Ruitao , Miller David M. , Bolla Jani R. , Clarke Oliver B. , Johnson Paul , Windley Monique , Burns Christopher J. , Hill Adam P. , Laver Derek , Robinson Carol V. , Smith Brian J. , Gulbis Jacqueline M. 
Published: June 2020

AbstractThe canonical mechanistic model explaining potassium channel gating is of a conformational change that alternately dilates and constricts a collar-like intracellular entrance to the pore. It is based on the premise that K+ ions maintain a complete hydration shell while passing between the transmembrane cavity and cytosol, which must be accommodated. To put the canonical model to the test, we locked the conformation of a Kir K+ channel to prevent widening of the narrow collar. Unexpectedly, conduction was unimpaired in the locked channels. In parallel, we employed all-atom molecular dynamics to simulate K+ ions moving along the conduction pathway between the lower cavity and cytosol. During simulations, the constriction did not significantly widen. Instead, transient loss of some water molecules facilitated K+ permeation through the collar. The low free energy barrier to partial dehydration in the absence of conformational change indicates Kir channels are not gated by the canonical mechanism.
Social training reconfigures prediction errors to shape Self-Other boundaries
Authors: Ereira Sam , Hauser Tobias U. , Moran Rani , Story Giles W. , Dolan Raymond J. , Kurth-Nelson Zeb 
Published: June 2020

AbstractSelectively attributing beliefs to specific agents is core to reasoning about other people and imagining oneself in different states. Evidence suggests humans might achieve this by simulating each other’s computations in agent-specific neural circuits, but it is not known how circuits become agent-specific. Here we investigate whether agent-specificity adapts to social context. We train subjects on social learning tasks, manipulating the frequency with which self and other see the same information. Training alters the agent-specificity of prediction error (PE) circuits for at least 24 h, modulating the extent to which another agent’s PE is experienced as one’s own and influencing perspective-taking in an independent task. Ventromedial prefrontal myelin density, indexed by magnetisation transfer, correlates with the strength of this adaptation. We describe a frontotemporal learning network, which exploits relationships between different agents’ computations. Our findings suggest that Self-Other boundaries are learnable variables, shaped by the statistical structure of social experience.
Vault changes after cyclopentolate instillation in eyes with posterior chamber phakic intraocular lens
Authors: Gargallo-Martinez Beatriz , Garcia-Medina Jose Javier , Rubio-Velazquez Elena , Fernandes Paulo , Villa-Collar César , Gonzalez-Meijome José M. , Gutierrez-Ortega Ramón 
Published: June 2020

AbstractPosterior chamber phakic intraocular lens (pIOL) implantation is a common option for correcting moderate-to-high ocular refractive defects. Because this pIOL is implanted on ciliary sulcus, the distance between the back surface of the pIOL and the anterior surface of the crystalline lens, that it is known as vault, should be measured in different conditions to ensure the technique’s safety. Cyclopentolate is a drug that dilates the pupil and relaxes accommodation (cycloplegia). It is often used for different ocular examinations and for other medical purposes. However, there is no evidence of the effect of this drug on vault. This study quantified central vault changes associated with cyclopentolate instillation. We measured the vault under normal conditions (pre-cycloplegic instillation) and after instilling cyclopentolate on 39 eyes of 39 patients with implanted pIOL. Our results suggest that cyclopentolate instillation may induce changes to vault in eyes with implanted pIOL. These changes seem safe and are mainly associated with vault under normal conditions, but also with anterior chamber depth, pupillary diameter and pIOL size.
3D Magnetic Resonance Spirometry
Authors: Boucneau Tanguy , Fernandez Brice , Larson Peder , Darrasse Luc , Maître Xavier 
Published: June 2020

AbstractSpirometry is today the gold standard technique for assessing pulmonary ventilatory function in humans. From the shape of a flow-volume loop measured while the patient is performing forced respiratory cycles, the Forced Vital Capacity (FVC) and the Forced Expiratory Volume in one second (FEV1) can be inferred, and the pulmonologist is able to detect and characterize common respiratory afflictions. This technique is non-invasive, simple, widely available, robust, repeatable and reproducible. Yet, its outcomes rely on the patient’s cooperation and provide only global information over the lung. With 3D Magnetic Resonance (MR) Spirometry, local ventilation can be assessed by MRI anywhere in the lung while the patient is freely breathing. The larger dimensionality of 3D MR Spirometry advantageously allows the extraction of original metrics that characterize the anisotropic and hysteretic regional mechanical behavior of the lung. Here, we demonstrated the potential of this technique on a healthy human volunteer breathing along different respiratory patterns during the MR acquisition. These new results are discussed with lung physiology and recent pulmonary CT data. As respiratory mechanics inherently support lung ventilation, 3D MR Spirometry may open a new way to non-invasively explore lung function while providing improved diagnosis of localized pulmonary diseases.
Diverging Trends in Age at First Myocardial Infarction: Evidence from Two German Population-Based Studies
Authors: Beller Johannes , Bauersachs Johann , Schäfer Andreas , Schwettmann Lars , Heier Margit , Peters Annette , Meisinger Christa , Geyer Siegfried 
Published: June 2020

AbstractLittle is known about trends in the age of onset of first myocardial infarction. Thus, we examined trends in the age of onset distribution of first myocardial infarction using two population-based datasets from Germany. First, we used German claims data based on an annual case number of approximately 2 million women and men covering the period from 2006 to 2016. Second, we used data from the KORA (Cooperative Health Research in the Region of Augsburg) Myocardial Infarction Registry covering the period from 2000–2016. Analyses were performed by means of quantile regression to estimate trends across the whole distribution of age of onset. Overall, NSample 1 = 69627 and NSample 2 = 9954 first myocardial infarctions were observed. In both samples, we found highly heterogeneous trends in age of onset. In men, we consistently found that age of onset increased before 50 and after 70 but decreased within this age bracket. For women, on the other hand, we consistently found that age of onset decreased for first myocardial infarctions before 70 but increased slightly or remained relatively stable thereafter. Therefore, late myocardial infarctions tended to occur later in life, while regular myocardial infarctions tended to occur earlier. These results suggest that in myocardial infarction, both morbidity compression and morbidity expansion might have occurred at the same time but for different parts of the age at onset distribution.
Characterization of starvation-induced autophagy in cerebellar Purkinje cells of pHluorin-mKate2-human LC3B transgenic mice
Authors: Oliva Trejo Juan Alejandro , Tanida Isei , Suzuki Chigure , Kakuta Soichiro , Tada Norihiro , Uchiyama Yasuo 
Published: June 2020

AbstractWe generated a new transgenic mouse model that expresses a pHluorin-mKate2 fluorescent protein fused with human LC3B (PK-LC3 mice) for monitoring autophagy activity in neurons of the central nervous system. Histological analysis revealed fluorescent puncta in neurons of the cerebral cortex, hippocampus, cerebellar Purkinje cells, and anterior spinal regions. Using CLEM analysis, we confirmed that PK-LC3-positive puncta in the perikarya of Purkinje cells correspond to autophagic structures. To validate the usability of PK-LC3 mice, we quantified PK-LC3 puncta in Purkinje cells of mice kept in normal feeding conditions and of mice starved for 24 hours. Our results showed a significant increase in autophagosome number and in individual puncta areal size following starvation. To confirm these results, we used morphometry at the electron microscopic level to analyze the volume densities of autophagosomes and lysosomes/autolysosomes in Purkinje cells of PK-LC3 mice. The results revealed that the volume densities of autophagic structures increase significantly after starvation. Together, our data show that PK-LC3 mice are suitable for monitoring autophagy flux in Purkinje cells of the cerebellum, and potentially other areas in the central nervous system.
Inhaled nitric oxide therapy in acute bronchiolitis: A multicenter randomized clinical trial
Authors: Goldbart Aviv , Golan-Tripto Inbal , Pillar Giora , Livnat-Levanon Galit , Efrati Ori , Spiegel Ronen , Lubetzky Ronit , Lavie Moran , Carmon Lior , Ghaffari Abdi , Nahum Amit 
Published: June 2020

AbstractCurrently, there are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and thus the recommended approach is supportive. Inhaled Nitric oxide (iNO), possesses anti-viral properties, improves oxygenation, and was shown to be safe in infants with respiratory conditions. Hospitalized infants with acute bronchiolitis were therefore recruited to a prospective double-blinded, multi-center, randomized controlled pilot study. They received intermittent high dose iNO (160 ppm) plus oxygen/air for 30 min or oxygen/air alone (control), five times/day, up to 5 days. Sixty-nine infants were enrolled. No difference was observed in frequencies of subjects with at least one Adverse Event (AE) in iNO (44.1%) vs. control (55.9%); neither was Methemoglobin >7% safety threshold. No drug-related serious AEs (SAEs) were reported. Analysis of Per-Protocol population revealed that length of stay (LOS), time to SpO2 ≥92%, and time to mTal clinical score ≤5 improved by 26.7 ± 12.7 (Welch’s t-test p = 0.04), 20.8 ± 8.9 (p = 0.023), and 14.6 ± 9.1 (p = 0.118) hours, respectively, in the iNO group compared to the control. Overall, high dose iNO (160ppm) was safe, well-tolerated, reduced LOS and showed rapid improvement of oxygen saturation, compared to the standard therapy. Further investigation in larger cohorts is warranted to validate these encouraging efficacy outcomes. (Trial registration: NCT03053388)
Improvement in Detection Limit for Lateral Flow Assay of Biomacromolecules by Test-Zone Pre-enrichment
Authors: Zhang Yi , Liu Xiao , Wang Lingling , Yang Hanjie , Zhang Xiaoxiao , Zhu Chenglong , Wang Wenlong , Yan Lijing , Li Bowei 
Published: June 2020

AbstractLateral flow assay (LFA) is one of the most prevalent commercially available techniques for point-of-care tests due to its simplicity, celerity, low cost and robust operation. However, conventional colorimetric LFAs have inferior limits of detection (LODs) compared to sophisticated laboratory-based assays. Here, we report a simple strategy of test-zone pre-enrichment to improve the LOD of LFA by loading samples before the conjugate pad assembly. The developed method enables visual LODs of miR-210 mimic and human chorionic gonadotropin protein, to be improved by 10–100 fold compared with a conventional LFA setup without introducing any additional instrument and reagent except for phosphate running buffer, while no obvious difference occurred for Aflatoxin B1 (AFB1). It takes about 6–8 min to enrich every 50 μL of sample diluted with phosphate running buffer, therefore we can get visual results within 20 min. We identified a parameter by modeling the entire process, the concentration of probe-analyte conjugate at test zone when signaling unit being loaded, to be important for the improvement of visual limit of detection. In addition, the test-zone pre-enrichment did not impair the selectivity when miR-210 mimic was adopted as target. Integrated with other optimization, amplification and modification of LFAs, the developed test-zone pre-enrichment method can be applied to further improve LOD of LFAs.
Density functional theory studies on cytosine analogues for inducing double-proton transfer with guanine
Authors: Xue Jinjie , Guo Xingping , Wang Xingbao , Xiao Yafeng 
Published: June 2020

AbstractTo induce double-proton transfer (DPT) with guanine in a biological environment, 12 cytosine analogues (Ca) were formed by atomic substitution. The DPT reactions in the Watson–Crick cytosine–guanine model complex (Ca0G) and 12 modified cytosine–guanine complexes (Ca1-12G) were investigated using density functional theory methods at the M06-2X/def2svp level. The intramolecular proton transfers within the analogues are not facile due to high energy barriers. The hydrogen bond lengths of the Ca1-12G complexes are shorter than those in the Ca0G complex, which are conducive to DPT reactions. The DPT energy barriers of Ca1-12G complexes are also lower than that of the Ca0G complex, in particular, the barriers in the Ca7G and Ca11G complexes were reduced to −1.33 and −2.02 kcal/mol, respectively, indicating they are significantly more prone to DPT reactions. The DPT equilibrium constants of Ca1-12G complexes range from 1.60 × 100 to 1.28 × 107, among which the equilibrium constants of Ca7G and Ca11G are over 1.0 × 105, so their DPT reactions may be adequate. The results demonstrate that those cytosine analogues, especially Ca7 and Ca11, are capable of inducing DPT with guanine, and then the guanine tautomer will form mismatches with thymine during DNA replication, which may provide new strategies for gene therapy.