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Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.
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Alérgenos , Interleucina-33 , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Animais , Caspase 1/metabolismo , Inflamação , Interleucina-1beta/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Peptídeo Hidrolases/metabolismo , Grânulos de EstresseRESUMO
High cholesterol is a major risk factor for cardiovascular disease1. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.
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Receptor de Asialoglicoproteína , Colesterol , Metabolismo dos Lipídeos , Proteínas Quinases Ativadas por AMP/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Receptor de Asialoglicoproteína/antagonistas & inibidores , Receptor de Asialoglicoproteína/deficiência , Receptor de Asialoglicoproteína/genética , Receptor de Asialoglicoproteína/metabolismo , Assialoglicoproteínas/metabolismo , Atorvastatina/farmacologia , Proteína BRCA1 , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Sinergismo Farmacológico , Endocitose , Ezetimiba/farmacologia , Humanos , Lipídeos/análise , Lipídeos/sangue , Fígado/metabolismo , Receptores X do Fígado/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1 , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).
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Isquemia Encefálica , AVC Isquêmico , Imagem de Perfusão , Tenecteplase , Trombectomia , Ativador de Plasminogênio Tecidual , Humanos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/mortalidade , Isquemia Encefálica/cirurgia , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/diagnóstico por imagem , Perfusão , Imagem de Perfusão/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/cirurgia , Tenecteplase/administração & dosagem , Tenecteplase/efeitos adversos , Tenecteplase/uso terapêutico , Trombectomia/efeitos adversos , Trombectomia/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/mortalidade , AVC Isquêmico/cirurgia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/cirurgia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/cirurgia , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Tempo para o TratamentoRESUMO
Cholesterol is an essential lipid and its synthesis is nutritionally and energetically costly1,2. In mammals, cholesterol biosynthesis increases after feeding and is inhibited under fasting conditions3. However, the regulatory mechanisms of cholesterol biosynthesis at the fasting-feeding transition remain poorly understood. Here we show that the deubiquitylase ubiquitin-specific peptidase 20 (USP20) stabilizes HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway, in the feeding state. The post-prandial increase in insulin and glucose concentration stimulates mTORC1 to phosphorylate USP20 at S132 and S134; USP20 is recruited to the HMGCR complex and antagonizes its degradation. The feeding-induced stabilization of HMGCR is abolished in mice with liver-specific Usp20 deletion and in USP20(S132A/S134A) knock-in mice. Genetic deletion or pharmacological inhibition of USP20 markedly decreases diet-induced body weight gain, reduces lipid levels in the serum and liver, improves insulin sensitivity and increases energy expenditure. These metabolic changes are reversed by expression of the constitutively stable HMGCR(K248R). This study reveals an unexpected regulatory axis from mTORC1 to HMGCR via USP20 phosphorylation and suggests that inhibitors of USP20 could be used to lower cholesterol levels to treat metabolic diseases including hyperlipidaemia, liver steatosis, obesity and diabetes.
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Colesterol/biossíntese , Ingestão de Alimentos/fisiologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Linhagem Celular , Glucose/metabolismo , Humanos , Insulina/metabolismo , Fígado/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Metabolismo/genética , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/deficiência , Ubiquitinação , Aumento de PesoRESUMO
Aberrant transcripts expression of the m6A methyltransferase complex (MTC) is widely found across human cancers, suggesting a dysregulated signaling cascade which integrates m6A epitranscriptome to drive tumorigenesis. However, the responsible transcriptional machinery directing the expression of distinct MTC subunits remains unclear. Here, we identified an unappreciated interplay between the histone acetyl-lysine reader BRD4 and the m6A writer complex across human cancers. BRD4 directly stimulates transcripts expression of seven MTC subunits, allowing the maintenance of the nuclear writer complex integrity. Upon BET inhibition, this BRD4-MTC signaling cascade accounts for global m6A reduction and the subsequent dynamic alteration of BRD4-dependent transcriptome, resulting in impaired DNA damage response that involves activation of homologous recombination (HR) repair and repression of apoptosis. We further demonstrated that the combined synergy upon BET/PARP inhibition largely relies on disrupted m6A modification of HR and apoptotic genes, counteracting PARP inhibitor (PARPi) resistance in patient-derived xenograft models. Our study revealed a widespread active cross-talk between BRD4-dependent epigenetic and MTC-mediated epitranscriptomic networks, which provides a unique therapeutic vulnerability that can be leveraged in combined DNA repair-targeted therapy.
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Antineoplásicos , Proteínas que Contêm Bromodomínio , Proteínas Nucleares , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Reparo do DNA , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Epigênese Genética , Proteínas que Contêm Bromodomínio/genética , Proteínas que Contêm Bromodomínio/metabolismo , AnimaisRESUMO
Heat waves and air pollution extremes exert compounding effects on human health and food security and may worsen under future climate change. On the basis of reconstructed daily O3 levels in China and meteorological reanalysis, we found that the interannual variability of the frequency of summertime co-occurrence of heat wave and O3 pollution in China is regulated mainly by a combination of springtime warming in the western Pacific Ocean, western Indian Ocean, and Ross Sea. These sea surface temperature anomalies impose influences on precipitation, radiation, etc., to modulate the co-occurrence, which were also confirmed with coupled chemistry-climate numerical experiments. We thus built a multivariable regression model to predict co-occurrence a season in advance, and correlation coefficient could reach 0.81 (P < 0.01) for the North China Plain. Our results provide useful information for the government to take actions in advance to mitigate damage from these synergistic costressors.
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The United States is the world's largest oil/gas methane emitter according to current national reports. Reducing these emissions is a top priority in the US government's climate action plan. Here, we use a 2010 to 2019 high-resolution inversion of surface and satellite observations of atmospheric methane to quantify emission trends for individual oil/gas production regions in North America and relate them to production and infrastructure. We estimate a mean US oil/gas methane emission of 14.8 (12.4 to 16.5) Tg a-1 for 2010 to 2019, 70% higher than reported by the US Environmental Protection Agency. While emissions in Canada and Mexico decreased over the period, US emissions increased from 2010 to 2014, decreased until 2017, and rose again afterward. Increases were driven by the largest production regions (Permian, Anadarko, Marcellus), while emissions in the smaller production regions generally decreased. Much of the year-to-year emission variability can be explained by oil/gas production rates, active well counts, and new wells drilled, with the 2014 to 2017 decrease driven by reduction in new wells and the 2017 to 2019 surge driven by upswing of production. We find a steady decrease in the oil/gas methane intensity (emission per unit methane gas production) for almost all major US production regions. The mean US methane intensity decreased from 3.7% in 2010 to 2.5% in 2019. If the methane intensity for the oil/gas supply chain continues to decrease at this pace, we may expect a 32% decrease in US oil/gas emissions by 2030 despite projected increases in production.
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Growing population and consumption pose unprecedented demands on food production. However, ammonia emissions mainly from food systems increase oceanic nitrogen deposition contributing to eutrophication. Here, we developed a long-term oceanic nitrogen deposition dataset (1970 to 2018) with updated ammonia emissions from food systems, evaluated the impact of ammonia emissions on oceanic nitrogen deposition patterns, and discussed the potential impact of nitrogen fertilizer overuse. Based on the chemical transport modeling approach, oceanic ammonia-related nitrogen deposition increased by 89% globally between 1970 and 2018, and now, it exceeds oxidized nitrogen deposition by over 20% in coastal regions including China Sea, India Coastal, and Northeastern Atlantic Shelves. Approximately 38% of agricultural nitrogen fertilizer was excessive, which corresponds to 15% of global oceanic ammonia-related nitrogen deposition. Policymakers and water quality managers need to pay increasingly more attention to ammonia associated with food production if the goal of reducing coastal nitrogen pollution is to be achieved for Sustainable Development Goals.
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Amônia , Nitrogênio , Nitrogênio/análise , Amônia/análise , Fertilizantes/análise , Agricultura , China , Qualidade da Água , SoloRESUMO
Incorporating sulfur (S) atoms into polymer main chains endows these materials with many attractive features, including a high refractive index, mechanical properties, electrochemical properties, and adhesive ability to heavy metal ions. The copolymerization involving S-containing monomers constitutes a facile method for effectively constructing S-containing polymers with diverse structures, readily tunable sequences, and topological structures. In this review, we describe the recent advances in the synthesis of S-containing polymers via copolymerization or multicomponent polymerization techniques concerning a variety of S-containing monomers, such as dithiols, carbon disulfide, carbonyl sulfide, cyclic thioanhydrides, episulfides and elemental sulfur (S8). Particularly, significant focus is paid to precise control of the main-chain sequence, stereochemistry, and topological structure for achieving high-value applications.
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Reputable evidence from multiple studies suggests that excessive and uncontrolled inflammation plays an indispensable role in mediating, amplifying, and protracting acute lung injury (ALI). Traditionally, immunity and energy metabolism are regarded as separate functions regulated by distinct mechanisms, but recently, more and more evidence show that immunity and energy metabolism exhibit a strong interaction which has given rise to an emerging field of immunometabolism. Mammalian lungs are organs with active fatty acid metabolism, however, during ALI, inflammation and oxidative stress lead to a series metabolic reprogramming such as impaired fatty acid oxidation, increased expression of proteins involved in fatty acid uptake and transport, enhanced synthesis of fatty acids, and accumulation of lipid droplets. In addition, obesity represents a significant risk factor for ALI/ARDS. Thus, we have further elucidated the mechanisms of obesity exacerbating ALI from the perspective of fatty acid metabolism. To sum up, this paper presents a systematical review of the relationship between extensive fatty acid metabolic pathways and acute lung injury and summarizes recent advances in understanding the involvement of fatty acid metabolism-related pathways in ALI. We hold an optimistic believe that targeting fatty acid metabolism pathway is a promising lung protection strategy, but the specific regulatory mechanisms are way too complex, necessitating further extensive and in-depth investigations in future studies.
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Lesão Pulmonar Aguda , Ácidos Graxos , Animais , Ácidos Graxos/metabolismo , Inflamação , Lipopolissacarídeos , Pulmão/metabolismo , Obesidade/metabolismo , HumanosRESUMO
SignificanceAgricultural systems are already major forces of ammonia pollution and environmental degradation. How agricultural ammonia emissions affect the spatio-temporal patterns of nitrogen deposition and where to target future mitigation efforts, remains poorly understood. We develop a substantially complete and coherent agricultural ammonia emissions dataset in nearly recent four decades, and evaluate the relative role of reduced nitrogen in total nitrogen deposition in a spatially explicit way. Global reduced nitrogen deposition has grown rapidly, and will occupy a greater dominant position in total nitrogen deposition without future ammonia regulations. Recognition of agricultural ammonia emissions on nitrogen deposition is critical to formulate effective policies to address ammonia related environmental challenges and protect ecosystems from excessive nitrogen inputs.
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Poluentes Atmosféricos , Amônia , Agricultura , Poluentes Atmosféricos/análise , Amônia/análise , Ecossistema , Monitoramento Ambiental , Poluição Ambiental , Nitrogênio/análiseRESUMO
China is set to actively reduce its methane emissions in the coming decade. A comprehensive evaluation of the current situation can provide a reference point for tracking the country's future progress. Here, using satellite and surface observations, we quantify China's methane emissions during 2010-2017. Including newly available data from a surface network across China greatly improves our ability to constrain emissions at subnational and sectoral levels. Our results show that recent changes in China's methane emissions are linked to energy, agricultural, and environmental policies. We find contrasting methane emission trends in different regions attributed to coal mining, reflecting region-dependent responses to China's energy policy of closing small coal mines (decreases in Southwest) and consolidating large coal mines (increases in North). Coordinated production of coalbed methane and coal in southern Shanxi effectively decreases methane emissions, despite increased coal production there. We also detect unexpected increases from rice cultivation over East and Central China, which is contributed by enhanced rates of crop-residue application, a factor not accounted for in current inventories. Our work identifies policy drivers of recent changes in China's methane emissions, providing input to formulating methane policy toward its climate goal.
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Carvão Mineral , Metano , Agricultura , China , Metano/análise , PolíticasRESUMO
Background Large language models (LLMs) hold substantial promise for medical imaging interpretation. However, there is a lack of studies on their feasibility in handling reasoning questions associated with medical diagnosis. Purpose To investigate the viability of leveraging three publicly available LLMs to enhance consistency and diagnostic accuracy in medical imaging based on standardized reporting, with pathology as the reference standard. Materials and Methods US images of thyroid nodules with pathologic results were retrospectively collected from a tertiary referral hospital between July 2022 and December 2022 and used to evaluate malignancy diagnoses generated by three LLMs-OpenAI's ChatGPT 3.5, ChatGPT 4.0, and Google's Bard. Inter- and intra-LLM agreement of diagnosis were evaluated. Then, diagnostic performance, including accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC), was evaluated and compared for the LLMs and three interactive approaches: human reader combined with LLMs, image-to-text model combined with LLMs, and an end-to-end convolutional neural network model. Results A total of 1161 US images of thyroid nodules (498 benign, 663 malignant) from 725 patients (mean age, 42.2 years ± 14.1 [SD]; 516 women) were evaluated. ChatGPT 4.0 and Bard displayed substantial to almost perfect intra-LLM agreement (κ range, 0.65-0.86 [95% CI: 0.64, 0.86]), while ChatGPT 3.5 showed fair to substantial agreement (κ range, 0.36-0.68 [95% CI: 0.36, 0.68]). ChatGPT 4.0 had an accuracy of 78%-86% (95% CI: 76%, 88%) and sensitivity of 86%-95% (95% CI: 83%, 96%), compared with 74%-86% (95% CI: 71%, 88%) and 74%-91% (95% CI: 71%, 93%), respectively, for Bard. Moreover, with ChatGPT 4.0, the image-to-text-LLM strategy exhibited an AUC (0.83 [95% CI: 0.80, 0.85]) and accuracy (84% [95% CI: 82%, 86%]) comparable to those of the human-LLM interaction strategy with two senior readers and one junior reader and exceeding those of the human-LLM interaction strategy with one junior reader. Conclusion LLMs, particularly integrated with image-to-text approaches, show potential in enhancing diagnostic medical imaging. ChatGPT 4.0 was optimal for consistency and diagnostic accuracy when compared with Bard and ChatGPT 3.5. © RSNA, 2024 Supplemental material is available for this article.
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Nódulo da Glândula Tireoide , Humanos , Feminino , Adulto , Nódulo da Glândula Tireoide/diagnóstico por imagem , Estudos Retrospectivos , Idioma , Redes Neurais de Computação , Curva ROCRESUMO
Background Noninvasive tests can be used to screen patients with chronic liver disease for advanced liver fibrosis; however, the use of single tests may not be adequate. Purpose To construct sequential clinical algorithms that include a US deep learning (DL) model and compare their ability to predict advanced liver fibrosis with that of other noninvasive tests. Materials and Methods This retrospective study included adult patients with a history of chronic liver disease or unexplained abnormal liver function test results who underwent B-mode US of the liver between January 2014 and September 2022 at three health care facilities. A US-based DL network (FIB-Net) was trained on US images to predict whether the shear-wave elastography (SWE) value was 8.7 kPa or higher, indicative of advanced fibrosis. In the internal and external test sets, a two-step algorithm (Two-step#1) using the Fibrosis-4 Index (FIB-4) followed by FIB-Net and a three-step algorithm (Three-step#1) using FIB-4 followed by FIB-Net and SWE were used to simulate screening scenarios where liver stiffness measurements were not or were available, respectively. Measures of diagnostic accuracy were calculated using liver biopsy as the reference standard and compared between FIB-4, SWE, FIB-Net, and European Association for the Study of the Liver guidelines (ie, FIB-4 followed by SWE), along with sequential algorithms. Results The training, validation, and test data sets included 3067 (median age, 42 years [IQR, 33-53 years]; 2083 male), 1599 (median age, 41 years [IQR, 33-51 years]; 1124 male), and 1228 (median age, 44 years [IQR, 33-55 years]; 741 male) patients, respectively. FIB-Net obtained a noninferior specificity with a margin of 5% (P < .001) compared with SWE (80% vs 82%). The Two-step#1 algorithm showed higher specificity and positive predictive value (PPV) than FIB-4 (specificity, 79% vs 57%; PPV, 44% vs 32%) while reducing unnecessary referrals by 42%. The Three-step#1 algorithm had higher specificity and PPV compared with European Association for the Study of the Liver guidelines (specificity, 94% vs 88%; PPV, 73% vs 64%) while reducing unnecessary referrals by 35%. Conclusion A sequential algorithm combining FIB-4 and a US DL model showed higher diagnostic accuracy and improved referral management for all-cause advanced liver fibrosis compared with FIB-4 or the DL model alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ghosh in this issue.
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Algoritmos , Técnicas de Imagem por Elasticidade , Cirrose Hepática , Humanos , Masculino , Cirrose Hepática/diagnóstico por imagem , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Técnicas de Imagem por Elasticidade/métodos , Adulto , Aprendizado Profundo , Fígado/diagnóstico por imagem , Fígado/patologia , Idoso , Ultrassonografia/métodosRESUMO
Although TiNb2O7 (TNO) with comparable operating potential and ideal theoretical capacity is considered to be the most ideal replacement for negative Li4Ti5O12 (LTO), the low ionic and electronic conductivity still limit its practical application as satisfactory anode for lithium-ion batteries (LIBs) with high-power density. Herein, TNO nanoparticles modified by Cerium (Ce) with outstanding electrochemical performance are synthesized. The successful introduction of Ce3+ in the lattice leads to increased interplanar spacing, refined grain size, more oxygen vacancy, and a smaller lithium diffusion barrier, which are conducive to improve conductivity of both Li+ and electrons. As a result, the modified TNO reaches high reversible capacity of 256.0 mA h g-1 at 100 mA g-1 after 100 cycles, and 183.0 mA h g-1 even under 3200 mA g-1. In particular, when the temperature drops to -20 °C, the cell undergoing 1500 cycles at a high current density of 500 mA g-1 can still reach 89.7 mA h g-1, corresponding to a capacity decay rate per cycle of only 0.033%. This work provides a new way to improve the electrochemical properties of alternative anodes for LIBs at extreme temperature.
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PURPOSE: Diabetic Retinopathy Clinical Research Network Protocol T suggests that the response to treatment among patients with diabetic macular edema (DME) may vary depending on baseline best-corrected visual acuity (BCVA). We evaluated the efficacy of faricimab 6 mg versus aflibercept 2 mg over 2 years in patients with DME and baseline BCVA of 20/50 or worse enrolled in faricimab phase III trials. DESIGN: YOSEMITE and RHINE were identically designed, multicenter, randomized, double-masked, active comparator-controlled, noninferiority trials. PARTICIPANTS: Adults ≥18 years of age with center-involving macular edema secondary to type 1 or 2 diabetes. METHODS: Patients were randomized to faricimab every 8 weeks (Q8W), faricimab personalized treat-and-extend (T&E) regimen, or aflibercept Q8W. Post hoc subgroup analyses were conducted using the intention-to-treat population with baseline BCVA of 20/50 or worse. MAIN OUTCOME MEASURES: Changes in ETDRS BCVA and central subfield thickness (CST) from baseline to years 1 and 2 were compared between treatment arms using mixed-model repeated measures analyses. RESULTS: In YOSEMITE and RHINE, respectively, 220 and 217 patients in the faricimab Q8W arm, 220 and 219 patients in the faricimab T&E arm, and 219 and 214 patients in the aflibercept Q8W arm showed baseline BCVA of 20/50 or worse. In both trials, mean change in ETDRS BCVA was comparable between treatments across trials at years 1 and 2. In YOSEMITE, adjusted mean change from baseline in CST (µm) at year 1 was greater with faricimab Q8W (-232.8; P < 0.0001) and faricimab T&E (-217.4; P = 0.0004) ) versus aflibercept Q8W (-190.4). In RHINE, this was faricimab Q8W (-214.2; P = 0.0006) and faricimab T&E (-206.6; P = 0.0116) versus aflibercept Q8W (-186.6). In both trials, change from baseline in CST at year 2 was greater with faricimab Q8W versus aflibercept. The median time to first CST of <325 µm and first absence of intraretinal fluid was shorter in the faricimab arms versus the aflibercept arm, with fewer injections on average. CONCLUSIONS: In patients with DME and baseline ETDRS BCVA of 20/50 or worse, faricimab treatment resulted in comparable visual acuity, greater reduction in retinal thickness, and fewer injections compared with aflibercept. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Fruit colour is a critical determinant for the appearance quality and commercial value of apple fruits. Viroid-induced dapple symptom severely affects the fruit coloration, however, the underlying mechanism remains unknown. In this study, we identified an apple dimple fruit viroid (ADFVd)-derived small interfering RNA, named vsiR693, which targeted the mRNA coding for a bHLH transcription factor MdPIF1 (PHYTOCHROME-INTERACTING FACTOR 1) to regulate anthocyanin biosynthesis in apple. 5' RLM-RACE and artificial microRNA transient expression system proved that vsiR693 directly targeted the mRNA of MdPIF1 for cleavage. MdPIF1 positively regulated anthocyanin biosynthesis in both apple calli and fruits, and it directly bound to G-box element in the promoter of MdPAL and MdF3H, two anthocyanin biosynthetic genes, to promote their transcription. Expression of vsiR693 negatively regulated anthocyanin biosynthesis in both apple calli and fruits. Furthermore, co-expression of vsiR693 and MdPIF1 suppressed MdPIF1-promoted anthocyanin biosynthesis in apple fruits. Infiltration of ADFVd infectious clone suppressed coloration surrounding the injection sites in apple fruits, while a mutated version of ADFVd, in which the vsiR693 producing region was mutated, failed to repress fruit coloration around the injection sites. These data provide evidence that a viroid-derived small interfering RNA targets host transcription factor to regulate anthocyanin biosynthesis in apple.
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Drought stress is one of the main environmental factors limiting plant growth and development. Plants adapt to changing soil moisture by modifying root architecture, inducing stomatal closure, and inhibiting shoot growth. The AP2/ERF transcription factor DREB2A plays a key role in maintaining plant growth in response to drought stress, but the molecular mechanism underlying this process remains to be elucidated. Here, it was found that overexpression of MdDREB2A positively regulated nitrogen utilisation by interacting with DRE cis-elements of the MdNIR1 promoter. Meanwhile, MdDREB2A could also directly bind to the promoter of MdSWEET12, which may enhance root development and nitrogen assimilation, ultimately promoting plant growth. Overall, this regulatory mechanism provides an idea for plants in coordinating with drought tolerance and nitrogen assimilation to maintain optimal plant growth and development under drought stress.
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Secas , Proteínas de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Regiões Promotoras Genéticas , Sacarose/metabolismo , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/genéticaRESUMO
Toolpath generation techniques have become increasingly critical in ultra-precision diamond turning for optical microstructures due to the dramatically enhanced geometrical complexity of the machined region. However, the conventionally used spiral toolpath is required for interpolation from the structural models, leading to random instability of the feeding axis and additional profile error between the toolpath and designed structures, which means an enlarged effect on the machining quality in ultra-precision machining. In this paper, a rotary-coordinate and shuttling-element cutting strategy based on integrated geometrical modelling and spiral toolpath generation is presented for ultra-precision turning of optical microstructures. Using the innovative rotary-coordinate and shuttling-element cutting method, the point clouds for the micro-structured modelling can be scattered along the spiral shape which can be directly fitted as the final toolpath. A series of simulation and cutting experiments have been carried out to realize the effectiveness of this method, and it is found that the preparation time in diamond turning can be significantly reduced along with ameliorating the machining quality.
RESUMO
Perfluorinated acrylate polymer materials exhibit low absorption loss at 1310 and 1550â nm, but molecular oxygen inhibits their photocuring. We propose a novel, to our knowledge, UV photolithography method incorporating a pre-exposure process for fabricating low-loss perfluorinated acrylate polymer waveguides. During the pre-exposure process, a partially cured thin layer forms on the core layer, effectively overcoming oxygen inhibition in subsequent lithography. Furthermore, the functional group contents of the polymerized materials were characterized by a Raman spectrometer to analyze the development reaction under the pre-exposure layer. Utilizing this improved method, we fabricated a straight waveguide with a length of 21â cm. The experiments showed that the propagation losses are 0.14â dB/cm at 1310â nm and 0.51â dB/cm at 1550â nm. The inter-channel cross talk for a core pitch of 250â µm was measured as low as -49â dB at 1310â nm. Error-free NRZ data transmission over this waveguide at 25â Gb/s was achieved, showcasing the potential in optical interconnect and communication applications.