bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia
Authors: Gianni’ Maurizio , Goracci Laura , Schlaefli Anna , Di Veroli Alessandra , Kurosaki Mami , Guarrera Luca , Bolis Marco , Foglia Marika , Lupi Monica , Tschan Mario P. , Cruciani Gabriele , Terao Mineko , Garattini Enrico 
Published: January 2022

AbstractThe role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and LPCAT1 levels requires activation of the autophagic process, as down-regulation of the two proteins is blocked in ATG5-silenced NB4-shATG5 cells.
RNF12 is regulated by AKT phosphorylation and promotes TGF-β driven breast cancer metastasis
Authors: Huang Yongsheng , Liu Sijia , Shan Mengjie , Hagenaars Sophie C. , Mesker Wilma E. , Cohen Danielle , Wang Lin , Zheng Zhi , Devilee Peter , Tollenaar Rob A. E. M. , Li Zhangfu , Song Yongmei , Zhang Long , Li Dan , ten Dijke Peter 
Published: January 2022

AbstractTransforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.
Total energy expenditure is repeatable in adults but not associated with short-term changes in body composition
Authors: Rimbach Rebecca , Yamada Yosuke , Sagayama Hiroyuki , Ainslie Philip N. , Anderson Lene F. , Anderson Liam J. , Arab Lenore , Baddou Issaad , Bedu-Addo Kweku , Blaak Ellen E. , Blanc Stephane , Bonomi Alberto G. , Bouten Carlijn V. C. , Bovet Pascal , Buchowski Maciej S. , Butte Nancy F. , Camps Stefan G. J. A. , Close Graeme L. , Cooper Jamie A. , Das Sai Krupa , Dugas Lara R. , Ekelund Ulf , Entringer Sonja , Forrester Terrence , Fudge Barry W. , Goris Annelies H. , Gurven Michael , Hambly Catherine , El Hamdouchi Asmaa , Hoos Marije B. , Hu Sumei , Joonas Noorjehan , Joosen Annemiek M. , Katzmarzyk Peter , Kempen Kitty P. , Kimura Misaka , Kraus William E. , Kushner Robert F. , Lambert Estelle V. , Leonard William R. , Lessan Nader , Martin Corby K. , Medin Anine C. , Meijer Erwin P. , Morehen James C. , Morton James P. , Neuhouser Marian L. , Nicklas Theresa A. , Ojiambo Robert M. , Pietiläinen Kirsi H. , Pitsiladis Yannis P. , Plange-Rhule Jacob , Plasqui Guy , Prentice Ross L. , Rabinovich Roberto A. , Racette Susan B. , Raichlen David A. , Ravussin Eric , Reynolds Rebecca M. , Roberts Susan B. , Schuit Albertine J. , Sjödin Anders M. , Stice Eric , Urlacher Samuel S. , Valenti Giulio , Van Etten Ludo M. , Van Mil Edgar A. , Wells Jonathan C. K. , Wilson George , Wood Brian M. , Yanovski Jack , Yoshida Tsukasa , Zhang Xueying , Murphy-Alford Alexia J. , Loechl Cornelia U. , Luke Amy H. , Rood Jennifer , Schoeller Dale A. , Westerterp Klaas R. , Wong William W. , Speakman John R. , Pontzer Herman ,   The IAEA DLW Database Consortium, Speakman John R. 
Published: January 2022

AbstractLow total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20–60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested.
A method to construct the dynamic landscape of a bio-membrane with experiment and simulation
Authors: Smith Albert A. , Vogel Alexander , Engberg Oskar , Hildebrand Peter W. , Huster Daniel 
Published: January 2022

AbstractBiomolecular function is based on a complex hierarchy of molecular motions. While biophysical methods can reveal details of specific motions, a concept for the comprehensive description of molecular dynamics over a wide range of correlation times has been unattainable. Here, we report an approach to construct the dynamic landscape of biomolecules, which describes the aggregate influence of multiple motions acting on various timescales and on multiple positions in the molecule. To this end, we use 13C NMR relaxation and molecular dynamics simulation data for the characterization of fully hydrated palmitoyl-oleoyl-phosphatidylcholine bilayers. We combine dynamics detector methodology with a new frame analysis of motion that yields site-specific amplitudes of motion, separated both by type and timescale of motion. In this study, we show that this separation allows the detailed description of the dynamic landscape, which yields vast differences in motional amplitudes and correlation times depending on molecular position.
Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease
Authors: Yang Yun , Tapias Victor , Acosta Diana , Xu Hui , Chen Huanlian , Bhawal Ruchika , Anderson Elizabeth T. , Ivanova Elena , Lin Hening , Sagdullaev Botir T. , Chen Jianer , Klein William L. , Viola Kirsten L. , Gandy Sam , Haroutunian Vahram , Beal M. Flint , Eliezer David , Zhang Sheng , Gibson Gary E. 
Published: January 2022

AbstractAbnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.
The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1
Authors: Singh Jai Prakash , Li Yang , Chen Yi-Yun , Hsu Shang-Te Danny , Page Rebecca , Peti Wolfgang , Meng Tzu-Ching 
Published: January 2022

AbstractT-Cell Protein Tyrosine Phosphatase (TCPTP, PTPN2) is a non-receptor type protein tyrosine phosphatase that is ubiquitously expressed in human cells. TCPTP is a critical component of a variety of key signaling pathways that are directly associated with the formation of cancer and inflammation. Thus, understanding the molecular mechanism of TCPTP activation and regulation is essential for the development of TCPTP therapeutics. Under basal conditions, TCPTP is largely inactive, although how this is achieved is poorly understood. By combining biomolecular nuclear magnetic resonance spectroscopy, small-angle X-ray scattering, and chemical cross-linking coupled with mass spectrometry, we show that the C-terminal intrinsically disordered tail of TCPTP functions as an intramolecular autoinhibitory element that controls the TCPTP catalytic activity. Activation of TCPTP is achieved by cellular competition, i.e., the intrinsically disordered cytosolic tail of Integrin-α1 displaces the TCPTP autoinhibitory tail, allowing for the full activation of TCPTP. This work not only defines the mechanism by which TCPTP is regulated but also reveals that the intrinsically disordered tails of two of the most closely related PTPs (PTP1B and TCPTP) autoregulate the activity of their cognate PTPs via completely different mechanisms.
Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF
Authors: Tao Hui , Mori Takahiro , Chen Heping , Lyu Shuang , Nonoyama Akihito , Lee Shoukou , Abe Ikuro 
Published: January 2022

AbstractNon-heme iron and α-ketoglutarate-dependent (Fe/αKG) oxygenases catalyze various oxidative biotransformations. Due to their catalytic flexibility and high efficiency, Fe/αKG oxygenases have attracted keen attention for their application as biocatalysts. Here, we report the biochemical and structural characterizations of the unusually promiscuous and catalytically versatile Fe/αKG oxygenase SptF, involved in the biosynthesis of fungal meroterpenoid emervaridones. The in vitro analysis revealed that SptF catalyzes several continuous oxidation reactions, including hydroxylation, desaturation, epoxidation, and skeletal rearrangement. SptF exhibits extremely broad substrate specificity toward various meroterpenoids, and efficiently produced unique cyclopropane-ring-fused 5/3/5/5/6/6 and 5/3/6/6/6 scaffolds from terretonins. Moreover, SptF also hydroxylates steroids, including androsterone, testosterone, and progesterone, with different regiospecificities. Crystallographic and structure-based mutagenesis studies of SptF revealed the molecular basis of the enzyme reactions, and suggested that the malleability of the loop region contributes to the remarkable substrate promiscuity. SptF exhibits great potential as a promising biocatalyst for oxidation reactions.
Imaging moiré deformation and dynamics in twisted bilayer graphene
Authors: de Jong Tobias A. , Benschop Tjerk , Chen Xingchen , Krasovskii Eugene E. , de Dood Michiel J. A. , Tromp Rudolf M. , Allan Milan P. , van der Molen Sense Jan 
Published: January 2022

AbstractIn ‘magic angle’ twisted bilayer graphene (TBG) a flat band forms, yielding correlated insulator behavior and superconductivity. In general, the moiré structure in TBG varies spatially, influencing the overall conductance properties of devices. Hence, to understand the wide variety of phase diagrams observed, a detailed understanding of local variations is needed. Here, we study spatial and temporal variations of the moiré pattern in TBG using aberration-corrected Low Energy Electron Microscopy (AC-LEEM). We find a smaller spatial variation than reported previously. Furthermore, we observe thermal fluctuations corresponding to collective atomic displacements over 70 pm on a timescale of seconds. Remarkably, no untwisting is found up to 600 ∘C. We conclude that thermal annealing can be used to decrease local disorder. Finally, we observe edge dislocations in the underlying atomic lattice, the moiré structure acting as a magnifying glass. These topological defects are anticipated to exhibit unique local electronic properties.
A mass spectrometric method for in-depth profiling of phosphoinositide regioisomers and their disease-associated regulation
Authors: Morioka Shin , Nakanishi Hiroki , Yamamoto Toshiyoshi , Hasegawa Junya , Tokuda Emi , Hikita Tomoya , Sakihara Tomoko , Kugii Yuuki , Oneyama Chitose , Yamazaki Masakazu , Suzuki Akira , Sasaki Junko , Sasaki Takehiko 
Published: January 2022

AbstractPhosphoinositides are a family of membrane lipids essential for many biological and pathological processes. Due to the existence of multiple phosphoinositide regioisomers and their low intracellular concentrations, profiling these lipids and linking a specific acyl variant to a change in biological state have been difficult. To enable the comprehensive analysis of phosphoinositide phosphorylation status and acyl chain identity, we develop PRMC-MS (Phosphoinositide Regioisomer Measurement by Chiral column chromatography and Mass Spectrometry). Using this method, we reveal a severe skewing in acyl chains in phosphoinositides in Pten-deficient prostate cancer tissues, extracellular mobilization of phosphoinositides upon expression of oncogenic PIK3CA, and a unique profile for exosomal phosphoinositides. Thus, our approach allows characterizing the dynamics of phosphoinositide acyl variants in intracellular and extracellular milieus.
Prediction of biomarkers and therapeutic combinations for anti-PD-1 immunotherapy using the global gene network association
Authors: Wu Chia-Chin , Wang Y. Alan , Livingston J. Andrew , Zhang Jianhua , Futreal P. Andrew 
Published: January 2022

AbstractOwing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.
Assessing the energy transition in China towards carbon neutrality with a probabilistic framework
Authors: Zhang Shu , Chen Wenying 
Published: January 2022

AbstractA profound transformation of China’s energy system is required to achieve carbon neutrality. Here, we couple Monte Carlo analysis with a bottom-up energy-environment-economy model to generate 3,000 cases with different carbon peak times, technological evolution pathways and cumulative carbon budgets. The results show that if emissions peak in 2025, the carbon neutrality goal calls for a 45–62% electrification rate, 47–78% renewable energy in primary energy supply, 5.2–7.9 TW of solar and wind power, 1.5–2.7 PWh of energy storage usage and 64–1,649 MtCO2 of negative emissions, and synergistically reducing approximately 80% of local air pollutants compared to the present level in 2050. The emission peak time and cumulative carbon budget have significant impacts on the decarbonization pathways, technology choices, and transition costs. Early peaking reduces welfare losses and prevents overreliance on carbon removal technologies. Technology breakthroughs, production and consumption pattern changes, and policy enhancement are urgently required to achieve carbon neutrality.
Vacuum laser acceleration of super-ponderomotive electrons using relativistic transparency injection
Authors: Singh P. K. , Li F.-Y. , Huang C.-K. , Moreau A. , Hollinger R. , Junghans A. , Favalli A. , Calvi C. , Wang S. , Wang Y. , Song H. , Rocca J. J. , Reinovsky R. E. , Palaniyappan S. 
Published: January 2022

AbstractIntense lasers can accelerate electrons to very high energy over a short distance. Such compact accelerators have several potential applications including fast ignition, high energy physics, and radiography. Among the various schemes of laser-based electron acceleration, vacuum laser acceleration has the merits of super-high acceleration gradient and great simplicity. Yet its realization has been difficult because injecting free electrons into the fast-oscillating laser field is not trivial. Here we demonstrate free-electron injection and subsequent vacuum laser acceleration of electrons up to 20 MeV using the relativistic transparency effect. When a high-contrast intense laser drives a thin solid foil, electrons from the dense opaque plasma are first accelerated to near-light speed by the standing laser wave in front of the solid foil and subsequently injected into the transmitted laser field as the opaque plasma becomes relativistically transparent. It is possible to further optimize the electron injection/acceleration by manipulating the laser polarization, incident angle, and temporal pulse shaping. Our result also sheds light on the fundamental relativistic transparency process, crucial for producing secondary particle and light sources.
Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Authors: Jiwaji Zoeb , Tiwari Sachin S. , Avilés-Reyes Rolando X. , Hooley Monique , Hampton David , Torvell Megan , Johnson Delinda A. , McQueen Jamie , Baxter Paul , Sabari-Sankar Kayalvizhi , Qiu Jing , He Xin , Fowler Jill , Febery James , Gregory Jenna , Rose Jamie , Tulloch Jane , Loan Jamie , Story David , McDade Karina , Smith Amy M. , Greer Peta , Ball Matthew , Kind Peter C. , Matthews Paul M. , Smith Colin , Dando Owen , Spires-Jones Tara L. , Johnson Jeffrey A. , Chandran Siddharthan , Hardingham Giles E. 
Published: January 2022

AbstractAlzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPTP301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.
Resonator nanophotonic standing-wave array trap for single-molecule manipulation and measurement
Authors: Ye Fan , Inman James T. , Hong Yifeng , Hall Porter M. , Wang Michelle D. 
Published: January 2022

AbstractNanophotonic tweezers represent emerging platforms with significant potential for parallel manipulation and measurements of single biological molecules on-chip. However, trapping force generation represents a substantial obstacle for their broader utility. Here, we present a resonator nanophotonic standing-wave array trap (resonator-nSWAT) that demonstrates significant force enhancement. This platform integrates a critically-coupled resonator design to the nSWAT and incorporates a novel trap reset scheme. The nSWAT can now perform standard single-molecule experiments, including stretching DNA molecules to measure their force-extension relations, unzipping DNA molecules, and disrupting and mapping protein-DNA interactions. These experiments have realized trapping forces on the order of 20 pN while demonstrating base-pair resolution with measurements performed on multiple molecules in parallel. Thus, the resonator-nSWAT platform now meets the benchmarks of a table-top precision optical trapping instrument in terms of force generation and resolution. This represents the first demonstration of a nanophotonic platform for such single-molecule experiments.