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1.
Nature ; 605(7909): 340-348, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35344983

RESUMEN

The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern1,2. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern3,4. Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs) such as TMPRSS2; these proteases cleave the viral spike protein to expose the fusion peptide for cell entry, and thus have an essential role in the virus lifecycle5,6. Here we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of higher than 106 in inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids7. In Calu-3 cells it inhibits the entry of the SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Notably, in the K18-human ACE2 transgenic mouse model of severe COVID-19, we found that N-0385 affords a high level of prophylactic and therapeutic benefit after multiple administrations or even after a single administration. Together, our findings show that TTSP-mediated proteolytic maturation of the spike protein is critical for SARS-CoV-2 infection in vivo, and suggest that N-0385 provides an effective early treatment option against COVID-19 and emerging SARS-CoV-2 variants of concern.


Asunto(s)
COVID-19 , SARS-CoV-2 , Inhibidores de Serina Proteinasa , Animales , COVID-19/prevención & control , COVID-19/virología , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , SARS-CoV-2/efectos de los fármacos , Serina Endopeptidasas , Inhibidores de Serina Proteinasa/farmacología , Inhibidores de Serina Proteinasa/uso terapéutico , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacos
2.
Nature ; 606(7915): 797-803, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35705814

RESUMEN

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.


Asunto(s)
Antagonistas de Receptores Androgénicos , Melanoma , Quinasas de Proteína Quinasa Activadas por Mitógenos , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas B-raf , Receptores Androgénicos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Receptores Androgénicos/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Análisis de Supervivencia
3.
Glob Chang Biol ; 30(1): e17018, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37937464

RESUMEN

Blooms of microalgal red tides and macroalgae (e.g., green and golden tides caused by Ulva and Sargassum) have caused widespread problems around China in recent years, but there is uncertainty around what triggers these blooms and how they interact. Here, we use 30 years of monitoring data to help answer these questions, focusing on the four main species of microalgae Prorocentrum donghaiense, Karenia mikimotoi, Noctiluca scintillans, and Skeletonema costatum) associated with red tides in the region. The frequency of red tides increased from 1991 to 2003 and then decreased until 2020, with S. costatum red tides exhibiting the highest rate of decrease. Green tides started to occur around China in 1999 and the frequency of green tides has since been on the increase. Golden tides were first reported to occur around China in 2012. The frequency of macroalgal blooms has a negative linear relationship with the frequency and coverage of red tides around China, and a positive correlation with total nitrogen and phosphorus loads as well as with atmospheric CO2 and sea surface temperature (SST). Increased outbreaks of macroalgal blooms are very likely due to worsening levels of eutrophication, combined with rising CO2 and SST, which contribute to the reduced frequency of red tides. The increasing grazing rate of microzooplankton also results in the decline in areas affected by red tides. This study shows a clear shift of algal blooms from microalgae to macroalgae around China over the past 30 years driven by the combination of eutrophication, climate change, and grazing stress, indicating a fundamental change in coastal systems in the region.


Asunto(s)
Dinoflagelados , Microalgas , Algas Marinas , Cambio Climático , Dióxido de Carbono , Eutrofización , China
4.
Microb Ecol ; 87(1): 68, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38722447

RESUMEN

It is necessary to predict the critical transition of lake ecosystems due to their abrupt, non-linear effects on social-economic systems. Given the promising application of paleolimnological archives to tracking the historical changes of lake ecosystems, it is speculated that they can also record the lake's critical transition. We studied Lake Dali-Nor in the arid region of Inner Mongolia because of the profound shrinking the lake experienced between the 1300 s and the 1600 s. We reconstructed the succession of bacterial communities from a 140-cm-long sediment core at 4-cm intervals and detected the critical transition. Our results showed that the historical trajectory of bacterial communities from the 1200 s to the 2010s was divided into two alternative states: state1 from 1200 to 1300 s and state2 from 1400 to 2010s. Furthermore, in the late 1300 s, the appearance of a tipping point and critical slowing down implied the existence of a critical transition. By using a multi-decadal time series from the sedimentary core, with general Lotka-Volterra model simulations, local stability analysis found that bacterial communities were the most unstable as they approached the critical transition, suggesting that the collapse of stability triggers the community shift from an equilibrium state to another state. Furthermore, the most unstable community harbored the strongest antagonistic and mutualistic interactions, which may imply the detrimental role of interaction strength on community stability. Collectively, our study showed that sediment DNA can be used to detect the critical transition of lake ecosystems.


Asunto(s)
Bacterias , ADN Bacteriano , Sedimentos Geológicos , Lagos , Lagos/microbiología , Lagos/química , Sedimentos Geológicos/microbiología , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , China , ADN Bacteriano/genética , Ecosistema , ARN Ribosómico 16S/genética , Microbiota
6.
Environ Res ; 257: 119084, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38823617

RESUMEN

Ocean acidification (OA) is known to influence biological and ecological processes, mainly focusing on its impacts on single species, but little has been documented on how OA may alter plankton community interactions. Here, we conducted a mesocosm experiment with ambient (∼410 ppmv) and high (1000 ppmv) CO2 concentrations in a subtropical eutrophic region of the East China Sea and examined the community dynamics of microeukaryotes, bacterioplankton and microeukaryote-attached bacteria in the enclosed coastal seawater. The OA treatment with elevated CO2 affected taxa as the phytoplankton bloom stages progressed, with a 72.89% decrease in relative abundance of the protist Cercozoa on day 10 and a 322% increase in relative abundance of Stramenopile dominated by diatoms, accompanied by a 29.54% decrease in relative abundance of attached Alphaproteobacteria on day 28. Our study revealed that protozoans with different prey preferences had differing sensitivity to high CO2, and attached bacteria were more significantly affected by high CO2 compared to bacterioplankton. Our findings indicate that high CO2 changed the co-occurrence network complexity and stability of microeukaryotes more than those of bacteria. Furthermore, high CO2 was found to alter the proportions of potential interactions between phytoplankton and their predators, as well as microeukaryotes and their attached bacteria in the networks. The changes in the relative abundances and interactions of microeukaryotes between their predators in response to high CO2 revealed in our study suggest that high CO2 may have profound impacts on marine food webs.

7.
J Environ Manage ; 352: 120119, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38244411

RESUMEN

Eutrophication is a growing environmental concern in lake ecosystems globally, significantly impacting the structures and ecological functions of bacterioplankton communities and posing a substantial threat to the stability of lake ecosystems. However, the patterns of functional dissimilarity, network complexity, and stability within bacterioplankton communities across different trophic states, along with the underlying mechanisms through which eutrophication influences these aspects, are not well-understood. To bridge this knowledge gap, we collected 88 samples from 34 lakes spanning trophic gradients and investigated bacterioplankton communities using network analysis and multiple statistical methods. Our results reveal that eutrophication, progressing from mesotrophic to hyper-eutrophic states, reduces the putative functional dissimilarity of bacterioplankton, particularly affecting the relative proportions of functional groups such as oxygenic photoautotrophy, phototrophy, and photoautotrophy. Network complexity exhibited a unimodal pattern across increasing trophic states, peaking at mesotrophic states and then decreasing towards hyper-eutrophic conditions, while stability exhibited the opposite pattern (U-shaped), indicating a variation in response to trophic state changes. In essence, eutrophication diminishes network complexity but enhances network stability. Collectively, these findings shed light on the ecological impact of eutrophication on bacterioplankton communities and elucidate the potential mechanisms by which eutrophication drives functional dissimilarity, network complexity and stability within bacterioplankton communities. These insights carry significant implications for the ecological management of eutrophic lakes.


Asunto(s)
Ecosistema , Lagos , Lagos/química , Eutrofización , Organismos Acuáticos , China
8.
BMC Microbiol ; 23(1): 47, 2023 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-36823577

RESUMEN

Sediment bacterial communities play a critical role in biogeochemical cycling in alpine lake ecosystems. However, little is known about the sediment microbial communities in these lakes. In this study, the bacterial community composition (BCC) and their relationships with environmental factors of the sediment in Sayram Lake, the largest alpine and cold-water inland lake, China was analyzed using Illumina MiSeq sequencing. In total, we obtained 618,271 high quality sequences. The results showed that the bacterial communities with 30 phyla and 546 genera, were spread out among the 5 furface sediment samples, respectively. The communities were dominated by Proteobacteria, Acidobacteria, Planctomycetes, Gemmatimonadetes, Chloroflexi, Actinobacteria, Verrucomicrobia and Bacteroidetes, accounting for 48.15 ± 8.10%, 11.23 ± 3.10%, 8.42 ± 2.15%, 8.37 ± 2.26%, 7.40 ± 3.05%, 5.62 ± 1.25%, 4.18 ± 2.12% and 2.24 ± 1.10% of the total reads, respectively. At the genus level, the communities were dominated by Aquabacterium, Pseudomonas, Woeseia, MND1, Ignavibacterium and Truepera, accounting for 7.89% ± 8.24%, 2.32% ± 1.05%, 2.14% ± 0.94%, 2% ± 1.22%, 0.94% ± 0.14% and 0.80% ± 0.14% of the total reads, respectively. Statistical analyses showed the similarity of the sediment bacterial communities at our field sites was considerably low, far below 35%, and total organic carbon (TOC) was the dominant environmental factor affecting the spatial changes of BCC in the sediment. Thus, this study greatly improving our understanding of the microbial ecology of alpine lake in the arid and semi-arid ecosystems today so seriously threatened.


Asunto(s)
Lagos , Microbiota , Lagos/microbiología , Sedimentos Geológicos/microbiología , Bacterias/genética , China , ARN Ribosómico 16S/genética
9.
Biomacromolecules ; 24(1): 367-376, 2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36479984

RESUMEN

Here, we describe the all-aqueous bicontinuous emulsions with cholesteric liquid crystal domains through hierarchical colloidal self-assembly of nanoparticles. This is achieved by homogenization of a rod-like cellulose nanocrystal (CNC) with two immiscible, phase separating polyethylene glycol (PEG) and dextran polymer solutions. The dispersed CNCs exhibit unequal affinity for the binary polymer mixtures that depends on the balance of osmotic and chemical potential between the two phases. Once at the critical concentration, CNC particles are constrained within one component of the polymer phases and self-assemble into a cholesteric organization. The obtained liquid crystal emulsion demonstrates a confined three-dimensional percolating bicontinuous network with cholesteric self-assembly of CNC within the PEG phase; meanwhile, the nanoparticles in the dextran phase remain isotropic instead. Our results provide an alternative way to arrest bicontinuous structures through intraphase trapping and assembling of nanoparticles, which is a viable and flexible route to extend for a wide range of colloidal systems.


Asunto(s)
Cristales Líquidos , Nanopartículas , Celulosa/química , Emulsiones/química , Cristales Líquidos/química , Dextranos , Polímeros/química , Nanopartículas/química , Polietilenglicoles , Agua/química
10.
J Org Chem ; 88(8): 5059-5068, 2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-36343284

RESUMEN

Phosphine-containing porous organic polymers (phosphine-POPs) are a kind of potential catalyst support for alkene hydroformylation. However, the synthesis of phosphine-POPs with strong π-acceptor is still a challenge. Herein, we report the synthesis of phosphine-POPs with different π-acceptor properties [POL-P(Pyr)3, CPOL-BPa&PPh3-15, and CPOL-BP&PPh3-15] and evaluated their performances as ligands to coordinate with Rh(acac)(CO)2 for hydroformylation of alkenes. We found that the Rh center with stronger π-acceptor phosphine-POPs showed better catalytic performance. Rh/CPOL-BPa&PPh3-15 with strong π-acceptor bidentate phosphoramidites showed obviously higher activity and regioselectivity (TON = 7.5 × 103, l/b = 26.1) than Rh/CPOL-BP&PPh3-15 (TON = 5.3 × 103, l/b = 5.0) with weaker π-acceptor bidentate phosphonites. Particularly, the TON of the hydroformylation reached 27.7 × 103 upon using Rh/POL-P(Pyr)3 which possessed tris(1-pyrrolyl)phosphane coordination sites. Overall, our study provides an orientation to design phosphine-POPs for hydroformylation reactions.

11.
Environ Res ; 238(Pt 2): 117235, 2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-37775010

RESUMEN

Unraveling how climate warming affects microorganisms and the underlying mechanisms has been a hot topic in climate change and microbial ecology. To date, many studies have reported microbial responses to climate warming, especially in soil ecosystems, however, knowledge of how warming influences microeukaryotic diversity, network complexity and stability in lake ecosystems, in particular the possible underlying mechanisms, is largely unknown. To address this gap, we conducted 20 mesocosms spanning five temperature scenarios (26 °C, 27.5 °C, 29 °C, 30.5 °C, and 32 °C) in Lake Bosten, a hotspot for studying climate change, and investigated microeukaryotic communities using 18S rRNA gene sequencing. Our results demonstrated that warming, time, and their interactions significantly reduced microeukaryotic α-diversity (two-way ANOVA: P<0.01). Although warming did not significantly affect microeukaryotic community structure (ANOSIM: P>0.05), it enhanced species turnover. Microeukaryotic networks exhibited distinct co-occurrence patterns and topological properties across temperature scenarios. Warming reduced network complexity and stability, as well as altered species interactions. Collectively, these findings are likely to have implications for ecological management of lake ecosystems, in particular semi-arid and arid regions, and for predicting ecological consequences of climate change.


Asunto(s)
Cambio Climático , Ecosistema , Análisis de Varianza , Temperatura
12.
Cell Mol Life Sci ; 79(11): 565, 2022 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-36284011

RESUMEN

Mitochondria are major sources of cytotoxic reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, that when uncontrolled contribute to cancer progression. Maintaining a finely tuned, healthy mitochondrial population is essential for cellular homeostasis and survival. Mitophagy, the selective elimination of mitochondria by autophagy, monitors and maintains mitochondrial health and integrity, eliminating damaged ROS-producing mitochondria. However, mechanisms underlying mitophagic control of mitochondrial homeostasis under basal conditions remain poorly understood. E3 ubiquitin ligase Gp78 is an endoplasmic reticulum membrane protein that induces mitochondrial fission and mitophagy of depolarized mitochondria. Here, we report that CRISPR/Cas9 knockout of Gp78 in HT-1080 fibrosarcoma cells increased mitochondrial volume, elevated ROS production and rendered cells resistant to carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitophagy. These effects were phenocopied by knockdown of the essential autophagy protein ATG5 in wild-type HT-1080 cells. Use of the mito-Keima mitophagy probe confirmed that Gp78 promoted both basal and damage-induced mitophagy. Application of a spot detection algorithm (SPECHT) to GFP-mRFP tandem fluorescent-tagged LC3 (tfLC3)-positive autophagosomes reported elevated autophagosomal maturation in wild-type HT-1080 cells relative to Gp78 knockout cells, predominantly in proximity to mitochondria. Mitophagy inhibition by either Gp78 knockout or ATG5 knockdown reduced mitochondrial potential and increased mitochondrial ROS. Live cell analysis of tfLC3 in HT-1080 cells showed the preferential association of autophagosomes with mitochondria of reduced potential. Xenograft tumors of HT-1080 knockout cells show increased labeling for mitochondria and the cell proliferation marker Ki67 and reduced labeling for the TUNEL cell death reporter. Basal Gp78-dependent mitophagic flux is, therefore, selectively associated with reduced potential mitochondria promoting maintenance of a healthy mitochondrial population, limiting ROS production and tumor cell proliferation.


Asunto(s)
Mitofagia , Superóxidos , Humanos , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Especies Reactivas de Oxígeno/metabolismo , Antígeno Ki-67/metabolismo , Superóxidos/metabolismo , Peróxido de Hidrógeno/farmacología , Mitocondrias/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Autofagia/genética
13.
Angew Chem Int Ed Engl ; 62(42): e202311335, 2023 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-37646093

RESUMEN

Ni-based catalysts have been widely studied in the hydrogenation of CO2 to CH4 , but selective and efficient synthesis of higher alcohols (C2+ OH) from CO2 hydrogenation over Ni-based catalyst is still challenging due to successive hydrogenation of C1 intermediates leading to methanation. Herein, we report an unprecedented synthesis of C2+ OH from CO2 hydrogenation over K-modified Ni-Zn bimetal catalyst with promising activity and selectivity. Systematic experiments (including XRD, in situ spectroscopic characterization) and computational studies reveal the in situ generation of an active K-modified Ni-Zn carbide (K-Ni3 Zn1 C0.7 ) by carburization of Zn-incorporated Ni0 , which can significantly enhance CO2 adsorption and the surface coverage of alkyl intermediates, and boost the C-C coupling to C2+ OH rather than conventional CH4 . This work opens a new catalytic avenue toward CO2 hydrogenation to C2+ OH, and also provides an insightful example for the rational design of selective and efficient Ni-based catalysts for CO2 hydrogenation to multiple carbon products.

14.
Angew Chem Int Ed Engl ; 62(32): e202307678, 2023 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-37366267

RESUMEN

The propulsion of photocatalytic hydrogen (H2 ) production is limited by the rational design and regulation of catalysts with precise structures and excellent activities. In this work, the [MoOS3 ]2- unit is introduced into the CuI clusters to form a series of atomically-precise MoVI -CuI bimetallic clusters of [Cu6 (MoOS3 )2 (C6 H5 (CH2 )S)2 (P(C6 H4 -R)3 )4 ] ⋅ xCH3 CN (R=H, CH3 , or F), which show high photocatalytic H2 evolution activities and excellent stability. By electron push-pull effects of the surface ligand, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) levels of these MoVI -CuI clusters can be finely tuned, promoting the resultant visible-light-driven H2 evolution performance. Furthermore, MoVI -CuI clusters loaded onto the surface of magnetic Fe3 O4 carriers significantly reduced the loss of catalysts in the collection process, efficiently addressing the recycling issues of such small cluster-based catalyst. This work not only highlights a competitively universal approach on the design of high-efficiency cluster photocatalysts for energy conversion, but also makes it feasible to manipulate the catalytic performance of clusters through a rational substituent strategy.

15.
Breast Cancer Res Treat ; 196(1): 45-56, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36056297

RESUMEN

INTRODUCTION: Triple-negative breast cancer (TNBC) is known for its aggressive behaviors and lacking of effective treatment. Programmed cell death ligand-1 (PD-L1) inhibitor has just been approved for using in the management of advanced TNBC. To accurately screen TNBC sensitive to anti-PD-L1 treatment and to explore the feasibility of the ataxia-telangiectasia mutation protein (ATM) inhibitor combined with PD-L1 inhibitor, radiotherapy and chemotherapy, we focus on whether ATM participates in the regulation of PD-L1 and affects the prognosis of patients through c-Src, signal transducer and activator of transcription 1&3 (STAT1 and STAT3). MATERIALS AND METHODS: We used immunohistochemical staining to explore the relationship of ATM with c-Src, STAT1, STAT3, PD-1/PD-L1, Tumor-infiltrating lymphocytes (TILs), as well as other clinicopathologic features in 86 pathological stage III TNBCs. Their impact on prognosis was also explored. RESULTS: We found ATM expression was negatively correlated with STAT1, STAT3, PD-L1, TILs and CD8 + cells in TNBC. STAT1 positively correlated the expression of PD-L1. In TNBC with ATM low expression, STAT3 was an independent factor for improved prognosis, while PD-L1 was an independent negative prognostic factor. Furthermore, in low ATM group, the phosphorylation of tyrosine at position 419 of c-Src (p-c-src Y419) was correlated with the overexpression of STAT3. CONCLUSION: Locally advanced TNBC with low ATM expression may be more likely to benefit from anti-PD-L1 inhibitors. The feasibility of ATM functional inhibitor combined with immune checkpoint blockade therapies in the treatment of TNBC is also worthy of further exploration. Our study suggests that STAT3 has different impacts on tumor progression in different tumors.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico , Ligandos , Linfocitos Infiltrantes de Tumor , Mutación , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/terapia , Tirosina/metabolismo
16.
PLoS Biol ; 17(8): e3000355, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31469817

RESUMEN

The endoplasmic reticulum (ER) is an expansive, membrane-enclosed organelle composed of smooth peripheral tubules and rough, ribosome-studded central ER sheets whose morphology is determined, in part, by the ER-shaping proteins, reticulon (RTN) and cytoskeleton-linking membrane protein 63 (CLIMP-63), respectively. Here, stimulated emission depletion (STED) super-resolution microscopy shows that reticulon4a (RTN4a) and CLIMP-63 also regulate the organization and dynamics of peripheral ER tubule nanodomains. STED imaging shows that lumenal ER monomeric oxidizing environment-optimized green fluorescent protein (ERmoxGFP), membrane Sec61ßGFP, knock-in calreticulin-GFP, and antibody-labeled ER-resident proteins calnexin and derlin-1 are all localized to periodic puncta along the length of peripheral ER tubules that are not readily observable by diffraction limited confocal microscopy. RTN4a segregates away from and restricts lumenal blob length, while CLIMP-63 associates with and increases lumenal blob length. RTN4a and CLIMP-63 also regulate the nanodomain distribution of ER-resident proteins, being required for the preferential segregation of calnexin and derlin-1 puncta away from lumenal ERmoxGFP blobs. High-speed (40 ms/frame) live cell STED imaging shows that RTN4a and CLIMP-63 regulate dynamic nanoscale lumenal compartmentalization along peripheral ER tubules. RTN4a enhances and CLIMP-63 disrupts the local accumulation of lumenal ERmoxGFP at spatially defined sites along ER tubules. The ER-shaping proteins RTN and CLIMP-63 therefore regulate lumenal ER nanodomain heterogeneity, interaction with ER-resident proteins, and dynamics in peripheral ER tubules.


Asunto(s)
Retículo Endoplásmico/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Nogo/metabolismo , Animales , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Citoesqueleto/metabolismo , Humanos , Membranas/metabolismo , Microtúbulos/metabolismo , Microscopía Óptica no Lineal/métodos
17.
Org Biomol Chem ; 20(25): 5035-5044, 2022 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-35661854

RESUMEN

In recent years, gold-catalyzed cycloadditions of allenes, especially those involving a gold carbene intermediate, have received significant interest, as they avoid the utilization of potentially hazardous and inaccessible diazo compounds as starting materials for carbene generation. Cycloaddition reactions consisting of the uncomplicated addition of two or more unsaturated functional groups are one of the most efficient synthetic methodologies for the rapid assembly of carbo- and heterocyclic structures from simple acyclic precursors. In this review, we introduce an overview of the advances in the gold-catalyzed cycloaddition of allenes via a metal carbene intermediate and categorize these reactions according to the reaction types of the cycloadditions.

18.
Age Ageing ; 51(1)2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34673897

RESUMEN

BACKGROUND: Multiple myeloma is a disease of the older people, whose prognoses are highly heterogeneous. The International Myeloma Working Group (IMWG) proposed a geriatric assessment (GA) based on age, functional status and comorbidities to discriminate between fit and frail patients. Given the multidimensional nature of frailty and the relatively recent exploration of frailty in the field of MM, reaching a consensus on the measurement of frailty in MM patients remains challenging. OBJECTIVE: We sought to assess the feasibility of performing a comprehensive GA (CGA) in older MM patients in a real-world and multicentre setting and to evaluate their baseline CGA profiles. RESULTS: We studied 349 older patients with newly diagnosed MM (age range, 65-86 years). Our results showed that a CGA is feasible for older MM patients. Using the IMWG-GA criteria, we identified significantly more frail patients in our cohort comparing to in the IMWG cohort (43% vs 30%, P = 0.002). In the IMWG-GA 'fit' group, risk of malnutrition, depression and cognitive impairment remains. The median follow-up time was 26 months (range 1-38). The median overall survival (OS) was 34.7 months, and the estimated 3-year OS rate was 50%. A high MNA-SF score (MNA-SF ≥ 12), low GDS score (GDS ≤ 5) and high CCI score (CCI ≥ 2) can be used to predict the OS of older patients with newly diagnosed MM. This study is registered at www.clinicaltrials.gov (NCT03122327). CONCLUSIONS: Our study justifies the need for a CGA in older patients with newly diagnosed MM.


Asunto(s)
Fragilidad , Mieloma Múltiple , Anciano , Anciano de 80 o más Años , Anciano Frágil , Fragilidad/diagnóstico , Fragilidad/epidemiología , Evaluación Geriátrica , Humanos , Mieloma Múltiple/diagnóstico , Estudios Prospectivos
19.
J Fish Biol ; 101(4): 1084-1091, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35833517

RESUMEN

This study provides a novel record of the reproductive behaviour of the Kong skate (Okamejei kenojei) in captivity. These skates were found to mate and deposit eggs at a temperature of 16.5 ± 0.5°C. The results showed that 76.13% of the eggs possessed one yolk, 0.77% of the eggs possessed two yolks and 23.11% of the eggs had no yolk (N = 1043). The deposition of non-yolk and double-yolk eggs was random. A total of 100 eggs were collected. After nearly 92 ± 5 days of incubation, 28 eggs failed to hatch, and 72 skates were successfully hatched with a female-to-male ratio of 1:1 (P > 0.05). The results enrich our knowledge of the reproduction in cartilaginous fishes and can inform management and conservation strategies for this species.


Asunto(s)
Reproducción , Rajidae , Femenino , Masculino , Animales , Embarazo , Oviposición , Temperatura , Parto , Yema de Huevo
20.
J Environ Manage ; 319: 115764, 2022 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-35982565

RESUMEN

Arid and semiarid regions account for âˆ¼ 40% of the world's land area. Rivers and lakes in these regions provide sparse, but valuable, water resources for the fragile environments, and play a vital role in the development and sustainability of local societies. During the late 1980s, the climate of arid and semiarid northwest China dramatically changed from "warm-dry" to "warm-wet". Understanding how these environmental changes and anthropogenic activities affect water quantity and quality is critically important for protecting aquatic ecosystems and determining the best use of freshwater resources. Lake Bosten is the largest inland freshwater lake in NW China and has experienced inter-conversion between freshwater and brackish status. Herein, we explored the long-term water level and salinity trends in Lake Bosten from 1958 to 2019. During the past 62 years, the water level and salinity of Lake Bosten exhibited inverse "W-shaped" and "M-shaped" patterns, respectively. Partial least squares path modeling (PLS-PM) suggested that the decreasing water level and salinization during 1958-1986 were mainly caused by anthropogenic activities, while the variations in water level and salinity during 1987-2019 were mainly affected by climate change. The transformation of anthropogenic activities and climate change is beneficial for sustainable freshwater management in the Lake Bosten Catchment. Our findings highlight the benefit of monitoring aquatic environmental changes in arid and semi-arid regions over the long-term for the purpose of fostering a balance between socioeconomic development and ecological protection of the lake environment.


Asunto(s)
Cambio Climático , Ecosistema , Efectos Antropogénicos , China , Monitoreo del Ambiente , Lagos , Agua
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