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In the presence of a large perpendicular electric field, Bernal-stacked bilayer graphene (BLG) features several broken-symmetry metallic phases1-3 as well as magnetic-field-induced superconductivity1. The superconducting state is quite fragile, however, appearing only in a narrow window of density and with a maximum critical temperature Tc ≈ 30 mK. Here we show that placing monolayer tungsten diselenide (WSe2) on BLG promotes Cooper pairing to an extraordinary degree: superconductivity appears at zero magnetic field, exhibits an order of magnitude enhancement in Tc and occurs over a density range that is wider by a factor of eight. By mapping quantum oscillations in BLG-WSe2 as a function of electric field and doping, we establish that superconductivity emerges throughout a region for which the normal state is polarized, with two out of four spin-valley flavours predominantly populated. In-plane magnetic field measurements further reveal that superconductivity in BLG-WSe2 can exhibit striking dependence of the critical field on doping, with the Chandrasekhar-Clogston (Pauli) limit roughly obeyed on one end of the superconducting dome, yet sharply violated on the other. Moreover, the superconductivity arises only for perpendicular electric fields that push BLG hole wavefunctions towards WSe2, indicating that proximity-induced (Ising) spin-orbit coupling plays a key role in stabilizing the pairing. Our results pave the way for engineering robust, highly tunable and ultra-clean graphene-based superconductors.
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Magic-angle twisted trilayer graphene (MATTG) exhibits a range of strongly correlated electronic phases that spontaneously break its underlying symmetries1,2. Here we investigate the correlated phases of MATTG using scanning tunnelling microscopy and identify marked signatures of interaction-driven spatial symmetry breaking. In low-strain samples, over a filling range of about two to three electrons or holes per moiré unit cell, we observe atomic-scale reconstruction of the graphene lattice that accompanies a correlated gap in the tunnelling spectrum. This short-scale restructuring appears as a Kekulé supercell-implying spontaneous inter-valley coherence between electrons-and persists in a wide range of magnetic fields and temperatures that coincide with the development of the gap. Large-scale maps covering several moiré unit cells further reveal a slow evolution of the Kekulé pattern, indicating that atomic-scale reconstruction coexists with translation symmetry breaking at a much longer moiré scale. We use auto-correlation and Fourier analyses to extract the intrinsic periodicity of these phases and find that they are consistent with the theoretically proposed incommensurate Kekulé spiral order3,4. Moreover, we find that the wavelength characterizing moiré-scale modulations monotonically decreases with hole doping away from half-filling of the bands and depends weakly on the magnetic field. Our results provide essential insights into the nature of the correlated phases of MATTG in the presence of strain and indicate that superconductivity can emerge from an inter-valley coherent parent state.
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Magic-angle twisted trilayer graphene (MATTG) has emerged as a moiré material that exhibits strong electronic correlations and unconventional superconductivity1,2. However, local spectroscopic studies of this system are still lacking. Here we perform high-resolution scanning tunnelling microscopy and spectroscopy of MATTG that reveal extensive regions of atomic reconstruction favouring mirror-symmetric stacking. In these regions, we observe symmetry-breaking electronic transitions and doping-dependent band-structure deformations similar to those in magic-angle bilayers, as expected theoretically given the commonality of flat bands3,4. Most notably in a density window spanning two to three holes per moiré unit cell, the spectroscopic signatures of superconductivity are manifest as pronounced dips in the tunnelling conductance at the Fermi level accompanied by coherence peaks that become gradually suppressed at elevated temperatures and magnetic fields. The observed evolution of the conductance with doping is consistent with a gate-tunable transition from a gapped superconductor to a nodal superconductor, which is theoretically compatible with a sharp transition from a Bardeen-Cooper-Schrieffer superconductor to a Bose-Einstein-condensation superconductor with a nodal order parameter. Within this doping window, we also detect peak-dip-hump structures that suggest that superconductivity is driven by strong coupling to bosonic modes of MATTG. Our results will enable further understanding of superconductivity and correlated states in graphene-based moiré structures beyond twisted bilayers5.
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Magic-angle twisted bilayer graphene (MATBG) exhibits a range of correlated phenomena that originate from strong electron-electron interactions. These interactions make the Fermi surface highly susceptible to reconstruction when ±1, ±2 and ±3 electrons occupy each moiré unit cell, and lead to the formation of various correlated phases1-4. Although some phases have been shown to have a non-zero Chern number5,6, the local microscopic properties and topological character of many other phases have not yet been determined. Here we introduce a set of techniques that use scanning tunnelling microscopy to map the topological phases that emerge in MATBG in a finite magnetic field. By following the evolution of the local density of states at the Fermi level with electrostatic doping and magnetic field, we create a local Landau fan diagram that enables us to assign Chern numbers directly to all observed phases. We uncover the existence of six topological phases that arise from integer fillings in finite fields and that originate from a cascade of symmetry-breaking transitions driven by correlations7,8. These topological phases can form only for a small range of twist angles around the magic angle, which further differentiates them from the Landau levels observed near charge neutrality. Moreover, we observe that even the charge-neutrality Landau spectrum taken at low fields is considerably modified by interactions, exhibits prominent electron-hole asymmetry, and features an unexpectedly large splitting between zero Landau levels (about 3 to 5 millielectronvolts). Our results show how strong electronic interactions affect the MATBG band structure and lead to correlation-enabled topological phases.
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Targeted knock-in of fluorescent reporters enables powerful gene and protein analyses in a physiological context. However, precise integration of long sequences remains challenging in vivo. Here, we demonstrate cloning-free and precise reporter knock-in into zebrafish genes, using PCR-generated templates for homology-directed repair with short homology arms (PCR tagging). Our novel knock-in reporter lines of vesicle-associated membrane protein (vamp) zebrafish homologues reveal subcellular complexity in this protein family. Our approach enables fast and efficient reporter integration in the zebrafish genome (in 10-40% of injected embryos) and rapid generation of stable germline-transmitting lines.
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Sistemas CRISPR-Cas , Pez Cebra , Animales , Sistemas CRISPR-Cas/genética , Pez Cebra/genética , Técnicas de Sustitución del Gen , Genoma , Edición GénicaRESUMEN
Magic-angle twisted bilayer graphene (TBG), with rotational misalignment close to 1.1 degrees, features isolated flat electronic bands that host a rich phase diagram of correlated insulating, superconducting, ferromagnetic and topological phases1-6. Correlated insulators and superconductivity have been previously observed only for angles within 0.1 degree of the magic angle and occur in adjacent or overlapping electron-density ranges; nevertheless, the origins of these states and the relation between them remain unclear, owing to their sensitivity to microscopic details. Beyond twist angle and strain, the dependence of the TBG phase diagram on the alignment4,6 and thickness of the insulating hexagonal boron nitride (hBN)7,8 used to encapsulate the graphene sheets indicates the importance of the microscopic dielectric environment. Here we show that adding an insulating tungsten diselenide (WSe2) monolayer between the hBN and the TBG stabilizes superconductivity at twist angles much smaller than the magic angle. For the smallest twist angle of 0.79 degrees, superconductivity is still observed despite the TBG exhibiting metallic behaviour across the whole range of electron densities. Finite-magnetic-field measurements further reveal weak antilocalization signatures as well as breaking of fourfold spin-valley symmetry, consistent with spin-orbit coupling induced in the TBG via its proximity to WSe2. Our results constrain theoretical explanations for the emergence of superconductivity in TBG and open up avenues towards engineering quantum phases in moiré systems.
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Activity of the vascular cambium gives rise to secondary xylem for wood formation in trees. The transcription factor WUSCHEL-related HOMEOBOX4 (WOX4) is a central regulator downstream of the hormone and peptide signaling pathways that maintain cambial activity. However, the genetic regulatory network underlying WOX4-mediated wood formation at the post-transcriptional level remains to be elucidated. In this study, we identified the ubiquitin receptor PagDA1 in hybrid poplar (Populus alba × Populus glandulosa clone 84K) as a negative regulator of wood formation, which restricts cambial activity during secondary growth. Overexpression of PagDA1 in poplar resulted in a relatively reduced xylem due to decreased cambial cell division. By contrast, mutation of PagDA1 by CRISPR/Cas9 resulted in an increased cambial cell activity and promoted xylem formation. Genetic analysis demonstrated that PagDA1 functions antagonistically in a common pathway as PagWOX4 to regulate cambial activity. We propose that PagDA1 physically associates with PagWOX4 and modulates the degradation of PagWOX4 by the 26S proteasome. Moreover, genetic analysis revealed that PagDA1 exerts its negative effect on cambial development by modulating the stability of PagWOX4 in a ubiquitin-dependent manner mediated by the E3 ubiquitin ligase PagDA2. In sum, we have identified a cambial regulatory protein complex, PagDA1-PagWOX4, as a potential target for wood biomass improvement.
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Cámbium , Populus , Redes Reguladoras de Genes , Factores de Transcripción , Ubiquitinas , Madera , XilemaRESUMEN
Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA+ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.
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Glomerulonefritis por IGA , Ratones , Animales , Ácido gamma-Aminobutírico/metabolismo , Inmunoglobulina A/metabolismo , Centro Germinal/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Diferenciación Celular , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , MamíferosRESUMEN
OBJECTIVES: Homopolymer (HP) sequencing is error-prone in next-generation sequencing (NGS) assays, and may induce false insertion/deletions and substitutions. This study aimed to evaluate the performance of dichromatic and tetrachromatic fluorogenic NGS platforms when sequencing homopolymeric regions. RESULTS: A HP-containing plasmid was constructed and diluted to serial frequencies (3%, 10%, 30%, 60%) to determine the performance of an MGISEQ-2000, MGISEQ-200, and NextSeq 2000 in HP sequencing. An evident negative correlation was observed between the detected frequencies of four nucleotide HPs and the HP length. Significantly decreased rates (P < 0.01) were found in all 8-mer HPs in all three NGS systems at all four expected frequencies, except in the NextSeq 2000 at 3%. With the application of a unique molecular identifier (UMI) pipeline, there were no differences between the detected frequencies of any HPs and the expected frequencies, except for poly-G 8-mers using the MGI 200 platform. UMIs improved the performance of all three NGS platforms in HP sequencing. CONCLUSIONS: We first constructed an HP-containing plasmid based on an EGFR gene backbone to evaluate the performance of NGS platforms when sequencing homopolymeric regions. A highly comparable performance was observed between the MGISEQ-2000 and NextSeq 2000, and introducing UMIs is a promising approach to improve the performance of NGS platforms in sequencing homopolymeric regions.
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Secuenciación de Nucleótidos de Alto Rendimiento , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Plásmidos/genética , Humanos , Análisis de Secuencia de ADN/métodosRESUMEN
BACKGROUND: Hybridization capture-based targeted next generation sequencing (NGS) is gaining importance in routine cancer clinical practice. DNA library preparation is a fundamental step to produce high-quality sequencing data. Numerous unexpected, low variant allele frequency calls were observed in libraries using sonication fragmentation and enzymatic fragmentation. In this study, we investigated the characteristics of the artifact reads induced by sonication and enzymatic fragmentation. We also developed a bioinformatic algorithm to filter these sequencing errors. RESULTS: We used pairwise comparisons of somatic single nucleotide variants (SNVs) and insertions and deletions (indels) of the same tumor DNA samples prepared using both ultrasonic and enzymatic fragmentation protocols. Our analysis revealed that the number of artifact variants was significantly greater in the samples generated using enzymatic fragmentation than using sonication. Most of the artifacts derived from the sonication-treated libraries were chimeric artifact reads containing both cis- and trans-inverted repeat sequences of the genomic DNA. In contrast, chimeric artifact reads of endonuclease-treated libraries contained palindromic sequences with mismatched bases. Based on these distinctive features, we proposed a mechanistic hypothesis model, PDSM (pairing of partial single strands derived from a similar molecule), by which these sequencing errors derive from ultrasonication and enzymatic fragmentation library preparation. We developed a bioinformatic algorithm to generate a custom mutation "blacklist" in the BED region to reduce errors in downstream analyses. CONCLUSIONS: We first proposed a mechanistic hypothesis model (PDSM) of sequencing errors caused by specific structures of inverted repeat sequences and palindromic sequences in the natural genome. This new hypothesis predicts the existence of chimeric reads that could not be explained by previous models, and provides a new direction for further improving NGS analysis accuracy. A bioinformatic algorithm, ArtifactsFinder, was developed and used to reduce the sequencing errors in libraries produced using sonication and enzymatic fragmentation.
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Artefactos , Genoma Humano , Humanos , Biblioteca de Genes , Análisis de Secuencia de ADN/métodos , ADN de Neoplasias , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
In light of the intensifying global energy crisis and the mounting demand for environmental protection, it is of vital importance to develop advanced hydrogen energy conversion systems. Electrolysis cells for hydrogen production and fuel cell devices for hydrogen utilization are indispensable in hydrogen energy conversion. As one of the electrolysis cells, water splitting involves two electrochemical reactions, hydrogen evolution reaction and oxygen evolution reaction. And oxygen reduction reaction coupled with hydrogen oxidation reaction, represent the core electrocatalytic reactions in fuel cell devices. However, the inherent complexity and the lack of a clear understanding of the structure-performance relationship of these electrocatalytic reactions, have posed significant challenges to the advancement of research in this field. In this work, the recent development in revealing the mechanism of electrocatalytic reactions in hydrogen energy conversion systems is reviewed, including in situ characterization and theoretical calculation. First, the working principles and applications of operando measurements in unveiling the reaction mechanism are systematically introduced. Then the application of theoretical calculations in the design of catalysts and the investigation of the reaction mechanism are discussed. Furthermore, the challenges and opportunities are also summarized and discussed for paving the development of hydrogen energy conversion systems.
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BACKGROUND: Left ventricular (LV) systolic dysfunction worsens outcomes in patients undergoing percutaneous coronary intervention (PCI). The objective of this study, therefore, was to evaluate outcomes of pLVAD-supported high-risk PCI (HRPCI) patients according to LV ejection fraction (LVEF). METHODS: Patients from the PROTECT III study undergoing pLVAD-supported HRPCI were stratified according to baseline LVEF: severe LV dysfunction (LVEF <30%), mild and moderate LV dysfunction (LVEF ≥30% to <50%), or preserved LV function (LVEF ≥50%). Major adverse cardiovascular and cerebrovascular events (MACCE: composite of all-cause death, myocardial infarction, stroke/transient ischemic attack, and repeat revascularization), and PCI-related complications were assessed at 90 days and mortality was assessed at 1-year. RESULTS: From March 2017 to March 2020, 940 patients had evaluable baseline LVEF recorded in the study database. Patients with preserved LV function were older, more frequently presented with myocardial infarction, and underwent more left main PCI and atherectomy. Immediate PCI-related coronary complications were infrequent (2.7%, overall), similar between groups (P = 0.98), and not associated with LVEF. Unadjusted 90-day MACCE rates were similar among LVEF groups; however, as a continuous variable, LVEF was associated with both 90-day MACCE (adj.HR per 5% 0.89, 95% CI [0.80, 0.98], P = 0.018) and 1-year mortality (adj.HR per 5% 0.84 [0.78, 0.90], P <0.0001). CONCLUSIONS: Patients who underwent pLVAD-supported HRPCI exhibited low incidence of PCI-related complications, regardless of baseline LVEF. However, LVEF was associated with 90-day MACCE and 1-year mortality.
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Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Intervención Coronaria Percutánea , Disfunción Ventricular Izquierda , Humanos , Volumen Sistólico , Función Ventricular Izquierda , Resultado del Tratamiento , Infarto del Miocardio/complicaciones , Enfermedad de la Arteria Coronaria/complicacionesRESUMEN
Mixed potential ammonia (NH3) sensors with the Fe- and Mo-codoped BiVO4 sensing electrode and Ag reference electrode based on the yttria-stabilized zirconia solid electrolyte were developed. Fe- and Mo-doped BiVO4 sensing materials were prepared using solution combustion synthesis and then characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS). It was observed that Fe doping could greatly improve the response rate, while Mo doping could enhance the response signal (ΔU) and sensitivity. Based on the optimal doping ratio of Fe and Mo each, the synergistic enhancement of the performance by Fe and Mo codoping was investigated. The sensor coated by BiV0.75Fe0.2Mo0.05Oδ materials exhibited a prominent sensing performance to a low concentration of 10-50 ppm of NH3 at 525 °C with the outstanding sensitivity of -148.988 mV/decade. Fe and Mo doping also improved the selectivity of the sensor to NH3, with the relative deviations less than ±8% of other typical gases' interference including NO, NO2, CO, CO2, and CH4. Besides, the sensor showed good resistance to fluctuations in the oxygen concentration and favorable stability against changes in the water vapor concentration. In addition, the sensor also exhibited good long-term stability. The mixed potential response mechanism was further discussed and analyzed through polarization curves as well as through gas chromatography and infrared absorption spectroscopy.
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A Gram-negative, motile, rod-shaped aerobic and alkalogenic bacterium, designated as strain YLCF04T, was isolated from chicken faeces. Its growth was optimal at 28â°C (range, 10-40â°C), pH 8 (range, pH 6-9) and in 1â% (w/v) NaCl (range, 0-10â%). It was classified to the genus Paenalcaligenes and was most closely related to Paenalcaligenes hominis CCUG 53761AT (97.5 % similarity) based on 16S rRNA gene sequence analysis. Average nucleotide identity and digital DNA-DNA hybridization values between YLCF04T and P. hominis CCUG 53761AT were 76.3 and 18.2â%, respectively. Strain YLCF04T has a genome size of 2.7 Mb with DNA G+C content of 46.3 mol%. Based on its phylogenetic, genomic, phenotypic and biochemical characteristics, strain YLCF04T represents a novel species of the genus Paenalcaligenes, for which the name Paenalcaligenes faecalis sp. nov. is proposed. The type strain is YLCF04T (=CCTCC AB 2022359T= KCTC 92789T).
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Alcaligenaceae , Técnicas de Tipificación Bacteriana , Composición de Base , Pollos , ADN Bacteriano , Heces , Hibridación de Ácido Nucleico , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Animales , ARN Ribosómico 16S/genética , Pollos/microbiología , Heces/microbiología , ADN Bacteriano/genética , Alcaligenaceae/genética , Alcaligenaceae/clasificación , Alcaligenaceae/aislamiento & purificación , Ácidos Grasos , Genoma BacterianoRESUMEN
Freshly formed soap films, soap bubbles, or foam films display iridescent colors due to thin film interference that changes as squeeze flow drives drainage and a progressive decrease in film thickness. Ultrathin (thickness <100 nm) freestanding films of soft matter containing micelles, particles, polyelectrolyte-surfactant complexes, or other supramolecular structures or liquid crystalline phases display drainage via stratification. A fascinating array of thickness variations and transitions, including stepwise thinning and coexistence of thick-thin flat regions, arise in micellar foam films that undergo drainage via stratification. In this tutorial, we describe the IDIOM (interferometry digital imaging optical microscopy) protocols that combine the conventional interferometry principle with digital filtration and image analysis to obtain nanometer accuracy for thickness determination while having high spatial and temporal resolution. We provide fully executable image analysis codes and algorithms for the analysis of nanotopography and summarize some of the unique insights obtained for stratified micellar foam films.
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Cross-sample contamination is one of the major issues in next-generation sequencing (NGS)-based molecular assays. This type of contamination, even at very low levels, can significantly impact the results of an analysis, especially in the detection of somatic alterations in tumor samples. Several contamination identification tools have been developed and implemented as a crucial quality-control step in the routine NGS bioinformatic pipeline. However, no study has been published to comprehensively and systematically investigate, evaluate, and compare these computational methods in the cancer NGS analysis. In this study, we comprehensively investigated nine state-of-the-art computational methods for detecting cross-sample contamination. To explore their application in cancer NGS analysis, we further compared the performance of five representative tools by qualitative and quantitative analyses using in silico and simulated experimental NGS data. The results showed that Conpair achieved the best performance for identifying contamination and predicting the level of contamination in solid tumors NGS analysis. Moreover, based on Conpair, we developed a Python script, Contamination Source Predictor (ConSPr), to identify the source of contamination. We anticipate that this comprehensive survey and the proposed tool for predicting the source of contamination will assist researchers in selecting appropriate cross-contamination detection tools in cancer NGS analysis and inspire the development of computational methods for detecting sample cross-contamination and identifying its source in the future.
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Biología Computacional , Neoplasias , Humanos , Biología Computacional/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias/diagnóstico , Neoplasias/genética , Control de CalidadRESUMEN
The impact of drought on terrestrial ecosystems is increasing, and the spatiotemporal heterogeneity of drought changes exacerbates the difficulty of determining ecosystem responses, especially in arid regions far from oceans. Tree rings have been widely used to understand how forest ecosystems respond to drought. However, the link between local hydroclimate variations related to tree rings and large-scale climate changes is not clear in the Qilian Mountains. Here, we used the tree ring width index to analyze the trend of Picea crassifolia growth and its relationship with climate in the middle Qilian Mountains. The results showed that the radial growth trend of Picea crassifolia is synchronized in the middle Qilian Mountains by calculating the Gleichläufigkeit index (GLK). Our analyses indicated that tree radial growth is positively correlated with drought during the growing season. Tree growth responds stably to drought (scPDSI and SPEI) and precipitation but unstably to temperature during 1950-2019. We further traced the meteorological factors that cause regional drought changes associated with radial growth. An increased total precipitation and decreased evaporation contribute to drought alleviation, favoring an increased tree radial growth. The increased total precipitation is mainly due to increased large-scale precipitation, which is related to water vapor transport changes. This study attempts to explore the influence of large-scale meteorology on regional drought change and its related tree radial growth response, which helps us to better understand the changes in forest ecosystems under climate change.
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Cambio Climático , Sequías , Árboles , Árboles/crecimiento & desarrollo , Lluvia , Picea/crecimiento & desarrollo , China , Clima Desértico , BosquesRESUMEN
Increasing pressures on aquatic ecosystems because of pollutants, nutrient enrichment, and global warming have severely depleted oxygen concentrations. This sudden and significant lack of oxygen has resulted in persistent increases in fish mortality rates. Revealing the molecular mechanism of fish hypoxia adaptation will help researchers to find markers for hypoxia induced by environmental stress. Here, we used a multiomics approach to identify several hypoxia-associated miRNAs, mRNAs, proteins, and metabolites involved in diverse biological pathways in the muscles of Pelteobagrus vachelli. Our findings revealed significant hypoxia-associated changes in muscles over 4 h of hypoxia exposure and discrete tissue-specific patterns. We have previously reported that P. vachelli livers exhibit increased anaerobic glycolysis, heme synthesis, erythropoiesis, and inhibit apoptosis when exposed to hypoxia for 4 h. However, the opposite was observed in muscles. According to our comprehensive analysis, fishes show an acute response to hypoxia, including activation of catabolic pathways to generate more energy, reduction of biosynthesis to decrease energy consumption, and shifting from aerobic to anaerobic metabolic contributions. Also, we found that hypoxia induced muscle dysfunction by impairing mitochondrial function, activating inflammasomes, and apoptosis. The hypoxia-induced mitochondrial dysfunction enhanced oxidative stress, apoptosis, and further triggered interleukin-1ß production via inflammasome activation. In turn, interleukin-1ß further impaired mitochondrial function or apoptosis by suppressing downstream mitochondrial biosynthesis-related proteins, thus resulting in a vicious cycle of inflammasome activation and mitochondrial dysfunction. Our findings contribute meaningful insights into the molecular mechanisms of hypoxia, and the methods and study design can be utilized across different fish species.
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Bagres , Ecosistema , Animales , Bagres/metabolismo , Hipoxia/metabolismo , Músculos/metabolismo , Oxígeno/metabolismoRESUMEN
INTRODUCTION: Aging is one of the risk factors for the early onset of Alzheimer's disease (AD). We previously discovered that the age-dependent increase in Ubiquitin Conjugating Enzyme E2 N (UBE2N) plays a role in the accumulation of misfolded proteins through K63 ubiquitination, which has been linked to AD pathogenesis. However, the impact of UBE2N on amyloid pathology and clearance has remained unknown. RESULTS: We observed the elevated UBE2N during the amyloid beta (Aß) generation in the brains of 5×FAD, APP/PS1 mice, and patients with AD, in comparison to healthy individuals. UBE2N overexpression exacerbated amyloid deposition in 5×FAD mice and senescent monkeys, whereas knocking down UBE2N via CRISPR/Cas9 reduced Aß generation and cognitive deficiency. Moreover, pharmacological inhibition of UBE2N ameliorated Aß pathology and subsequent transcript defects in 5×FAD mice. DISCUSSION: We have discovered that age-dependent expression of UBE2N is a critical regulator of AD pathology. Our findings suggest that UBE2N could serve as a potential pharmacological target for the advancement of AD therapeutics. HIGHLIGHTS: Ubiquitin Conjugating Enzyme E2 N (UBE2N) level was elevated during amyloid beta (Aß) deposition in AD mouse and patients' brains. UBE2N exacerbated Aß generation in the AD mouse and senescent monkey. Drug inhibition of UBE2N ameliorated Aß pathology and cognitive deficiency.
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Lung aging triggers the onset of various chronic lung diseases, with alveolar repair being a key focus for alleviating pulmonary conditions. The regeneration of epithelial structures, particularly the differentiation from type II alveolar epithelial (AT2) cells to type I alveolar epithelial (AT1) cells, serves as a prominent indicator of alveolar repair. Nonetheless, the precise role of aging in impeding alveolar regeneration and its underlying mechanism remain to be fully elucidated. Our study employed histological methods to examine lung aging effects on structural integrity and pathology. Lung aging led to alveolar collapse, disrupted epithelial structures, and inflammation. Additionally, a relative quantification analysis revealed age-related decline in AT1 and AT2 cells, along with reduced proliferation and differentiation capacities of AT2 cells. To elucidate the mechanisms underlying AT2 cell functional decline, we employed transcriptomic techniques and revealed a correlation between inflammatory factors and genes regulating proliferation and differentiation. Furthermore, a D-galactose-induced senescence model in A549 cells corroborated our omics experiments and confirmed inflammation-induced cell cycle arrest and a >30% reduction in proliferation/differentiation. Physiological aging-induced chronic inflammation impairs AT2 cell functions, hindering tissue repair and promoting lung disease progression. This study offers novel insights into chronic inflammation's impact on stem cell-mediated alveolar regeneration.