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1.
Nat Immunol ; 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39223350

RESUMEN

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.

2.
Mar Environ Res ; 201: 106687, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39173207

RESUMEN

In the coastal waters around Shandong peninsula, an unprecedented winter bloom of dinoflagellates Gonyaulax polygramma and Akashiwo sanguinea occurred in 2021 from late November to early December. The bloom affected a wide area of coastal waters extending from west to east along the northern Shandong peninsula and had a devastating blow to the kelp cultivation industry. Based on the remote-sensing data, the initiation of the bloom was traced back to the region adjacent to the mouth of the Yellow River in Laizhou Bay, where enhanced freshwater discharge from the Yellow River was recorded from September to November. It's proposed that the increased precipitation in the Yellow River basin associated with northward extension of the precipitation band in China could be an important reason for this winter bloom. This unusual winter bloom around Shandong peninsula highlights the potential risks of harmful algal blooms and their impacts on coastal ecosystems under the background of climate change.


Asunto(s)
Acuicultura , Dinoflagelados , Floraciones de Algas Nocivas , Algas Marinas , Algas Marinas/crecimiento & desarrollo , Estaciones del Año , Agua de Mar/química , China , Cambio Climático , Ecosistema , Fitoplancton
3.
Cell Rep ; 43(8): 114518, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39028623

RESUMEN

Soluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature between gp120 and gp41 constrains intersubunit mobility and may alter antigenicity. Here, we report an alternative strategy to generate stabilized soluble Env trimers free of covalent gp120-gp41 bonds. Stabilization was achieved by introducing an intrasubunit disulfide bond between the inner and outer domains of gp120, defined as interdomain lock (IDL). Correctly folded IDL trimers displaying a native-like antigenic profile were produced for HIV-1 Envs of different clades. Importantly, the IDL design abrogated CD4 binding while not affecting recognition by potent neutralizing antibodies to the CD4-binding site. By cryoelectron microscopy, IDL trimers were shown to adopt a closed prefusion configuration, while single-molecule fluorescence resonance energy transfer documented a high prevalence of native-like conformation. Thus, IDL trimers may be promising candidates as vaccine immunogens.


Asunto(s)
Proteína gp120 de Envoltorio del VIH , Proteína gp41 de Envoltorio del VIH , VIH-1 , Multimerización de Proteína , Solubilidad , Proteína gp120 de Envoltorio del VIH/metabolismo , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp41 de Envoltorio del VIH/metabolismo , Proteína gp41 de Envoltorio del VIH/química , Proteína gp41 de Envoltorio del VIH/inmunología , Humanos , VIH-1/metabolismo , VIH-1/inmunología , Anticuerpos Neutralizantes/inmunología , Antígenos CD4/metabolismo , Conformación Proteica , Unión Proteica
4.
Medicine (Baltimore) ; 103(29): e38815, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39029086

RESUMEN

To evaluate the efficacy of erythrocyte apheresis on the treatment of secondary erythrocytosis. Patients with secondary erythrocytosis who had visited the Department of Hematology at the Qinghai University Affiliated Hospital between January 2021 and May 2022 were enrolled. Based on the treatment method used, the patients were divided into erythrocytapheresis group and bloodletting group. In total, 50 patients were treated using a hemocyte separator and 36 patients were treated with bloodletting. The outcomes of 2 groups were compared. Compared with the bloodletting group, the clinical symptoms improved, blood routine indicators such as RBC, Hb, and HCT significantly reduced, and the progression rate was lower in the erythrocytapheresis group. Erythrocytic apheresis is effective and safe for the treatment of secondary erythrocytosis.


Asunto(s)
Eliminación de Componentes Sanguíneos , Policitemia , Humanos , Policitemia/terapia , Policitemia/sangre , Femenino , Masculino , Persona de Mediana Edad , Eliminación de Componentes Sanguíneos/métodos , Adulto , Resultado del Tratamiento , Venodisección/métodos , Eritrocitos , Anciano
5.
Water Res ; 261: 122022, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39002417

RESUMEN

Controllable and recyclable magnetic porous microspheres (MPMs) have been proposed as a means for enhancing the anaerobic digestion (AD) of sludge, as they do not require continuous replenishment and can serve as carriers for anaerobes. However, the effects of MPMs on the interfacial thermodynamics of sludge and the biological responses triggered by abiotic effects in AD systems remain to be clarified. Herein, the underlying mechanisms by which MPMs alter the solid-liquid interface of sludge to drive methanogenesis were investigated. A significant increase in the contents of 13C and 2H (D) in methane molecules was observed in the presence of MPMs, suggesting that MPMs might enhance the CO2-reduction methanogenesis and participation of water in methane generation. Experimental results demonstrated that the addition of MPMs did not promote the anaerobic bioconversion of soluble organics for methanogenesis, suggesting that the enhanced methanogenesis and water participation were not achieved through promotion of the bioconversion of original liquid-state organics in sludge. Analyses of the capillary force, surface adhesion force, and interfacial proton-coupled electron transfer (PCET) of MPMs revealed that MPMs can enhance mass transfer, effective contact, and electron-proton transfer with sludge. These outcomes were confirmed by the statistical analyses of variations in the interfacial thermodynamics and PCET of sludge with and without MPMs during AD. It was thus proposed that the MPMs enhanced the PCET of sludge and PCET-driven release of protons from water by promoting the interfacial Lewis acid-base interactions of sludge, thereby resulting in the enrichment of free and attached methanogenic consortia and the high energy-conserving metabolic cooperation. This proposition was further confirmed by identifying the predominant syntrophic partners, suggesting that PCET-based efficient methanogenesis was attributable to the enrichment of genomes harbouring CO2-reducing pathway and genes encoding water-mediated proton transfer. These findings offer new insights into how substrate properties can be altered by exogenous materials to enable highly efficient methanogenesis.


Asunto(s)
Metano , Microesferas , Aguas del Alcantarillado , Termodinámica , Metano/metabolismo , Porosidad , Anaerobiosis
6.
Water Res ; 257: 121746, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38733966

RESUMEN

Sewage sludge is promising for the recovery and utilisation of nutrient components, but its complex nature hinders the release of these components. The combination of pH and thermal modifications shows promise for the release of nutrient components from sludge. However, comprehensive studies on the full spectrum of pH levels and corresponding mechanisms of pH-varying thermal modification are lacking. In this study, the main nutrient components, physicochemical properties, molecular structure, and noncovalent interactions of sludge were comprehensively investigated through pH-varying thermal modification (within a pH range of 2.0 to 12.0 under the same thermal condition). The experimental results showed that the release of main organics, particularly nitrogen (N)-containing organics, was well-fitted, with a tick-like function (R2: 0.74-0.96). The thermal protons exhibited a notable accumulative mutagenic effect on the N-containing organics release, while the thermal hydroxyl ions had a more direct effect, as revealed by the changes in multivalent metals and molecular structures with the protonation-deprotonation of carboxyl groups. The driving force for the release of N-containing organics was identified as the fluctuation of electrostatic interactions at the solid-liquid interface of the sludge. However, the release of phosphorus (P)-containing substances exhibited a contrasting response to that of N-containing substances with varying pH, likely because the reaction sites of thermal protons and thermal hydroxyl ions for P-containing substances were different. Moreover, high concentrations of thermal protons and hydroxyl ions collapsed the Lifshitz-van der Waals interactions of sludge, resulting in a decrease in viscoelasticity and binding strength. These propositions were further confirmed through statistical analyses of the main indicators of the main nutrient components, physicochemical properties, and noncovalent interactions of sludge. These findings can provide a basis for optimising characteristic-specific methods to recovery nutrient components (N/P) from sludge.


Asunto(s)
Nitrógeno , Fósforo , Aguas del Alcantarillado , Aguas del Alcantarillado/química , Fósforo/química , Nitrógeno/química , Concentración de Iones de Hidrógeno , Eliminación de Residuos Líquidos/métodos
7.
Acta Pharmacol Sin ; 45(6): 1160-1174, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38438581

RESUMEN

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.


Asunto(s)
Neuronas GABAérgicas , Hiperalgesia , Ratones Endogámicos C57BL , Receptores Nicotínicos , Animales , Receptores Nicotínicos/metabolismo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Masculino , Hiperalgesia/metabolismo , Hiperalgesia/tratamiento farmacológico , Ratones , Porción Reticular de la Sustancia Negra/metabolismo , Porción Reticular de la Sustancia Negra/efectos de los fármacos , Nicotina/farmacología , Analgésicos/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Capsaicina/farmacología , Acetilcolina/metabolismo , Optogenética , Umbral del Dolor/efectos de los fármacos
8.
Chem Sci ; 15(11): 3996-4004, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38487224

RESUMEN

A multi-component carbonylation reaction is an efficient strategy for the synthesis of valuable carbonyl compounds from simple and readily available substrates. However, there remain challenges in carbonylation reactions where two CO molecules are converted to different groups in the target product. Considering the merit of complex amides, we reported here a copper-catalyzed multi-component borylamidation for the synthesis of γ-boryl amides. This method provides access to a wide range of functional γ-boryl amides from alkenes, amines, B2pin2, and CO with good yields and excellent diastereomeric ratios. Notably, two CO molecules were converted to methylene and carbonyl groups in the target amides. A series of amines were successfully involved in the transformation, including arylamines, aliphatic amines, and hydrochloride salts of secondary aliphatic amines.

9.
Water Res ; 254: 121393, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38428236

RESUMEN

The addition of exogenous materials is a commonly reported method for promoting the anaerobic digestion (AD) of sludge. However, most exogenous materials are nano-sized and their use encounters problems relating to a need for continuous replenishment, uncontrollability and non-recyclability. Here, magnetic porous microspheres (MPMs), which can be controlled by magnetic forces, were prepared and used to enhance the methanogenesis of sludge. It was observed that the MPMs were spherical particles with diameters of approximately 100 µm and had a stable macroporous hybrid structure of magnetic cores and polymeric shells. Furthermore, the MPMs had good magnetic properties and a strong solid-liquid interfacial electron transfer ability, suggesting that MPMs are excellent carriers for methanogenic consortia. Experimental results showed that the addition of MPMs increased methane production and the proportion of methane in biogas from AD by 100.0 % and 21.2 %, respectively, indicating the MPMs notably enhanced the methanogenesis of sludge. Analyses of variations in key enzyme activities and electron transfer in sludge samples with and without MPMs in AD revealed that the MPMs significantly enhanced the activities of key enzymes involved in hydrolysis, acidification and methanation. This was achieved mainly by enhancing the extracellular electron transfer to strengthen the proton motive force on the cell membrane, which provides more energy generation for methanogenic metabolism. A careful examination of the variations in the morphology, pore structure and magnetism of the MPMs before and after AD revealed that the MPMs increased the prevalence of many highly active anaerobes, and that this did not weaken the magnetic performance. The microbial community structure and metatranscriptomic analysis further indicated that the acetotrophic methanogens (i.e., Methanosaeta) were mainly in a free state and that CO2-reducing methanogens (i.e., Methanolinea and Methanobacterium) mainly adhered to the MPMs. The above synergistic metabolism led to efficient methanogenesis, which indicates that the MPMs optimised the spatial ecological niche of methanogenic consortia. These findings provide an important reference for the development of magnetic porous materials promoting AD.


Asunto(s)
Metano , Aguas del Alcantarillado , Aguas del Alcantarillado/química , Anaerobiosis , Microesferas , Porosidad , Metano/metabolismo , Fenómenos Magnéticos
10.
J Hazard Mater ; 469: 133896, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38428300

RESUMEN

Paralytic shellfish toxins (PSTs) produced by some marine dinoflagellates can cause severe human intoxication via vectors like bivalves. Toxic dinoflagellate Gymnodinium catenatum produce a novel group of hydroxybenzoate PSTs named GC toxins, but their biokinetics in bivalves haven't been well examined. In this experiment, we analyzed PSTs in bay scallops Argopecten irradians exposed to G. catenatum (strain MEL11) to determine their accumulation, elimination, anatomical distribution, and biotransformation. To our surprise, up to 30% of the PSTs were accumulated in the adductor muscle of scallops at the end of the experiment, and the toxicity of adductor muscle exceeded the regulatory limit of 800 µg STXeq/kg in only 6 days. High concentration of toxins in the adductor muscle are likely linked to the rapid transfer of GC toxins from viscera to other tissues. Moreover, most GC toxins in scallops were found rapidly transformed to decarbamoyl toxins through enzyme-mediated hydrolysis, which was further supported by the in vitro incubation experiments. Our study demonstrates that GC toxins actively participate in toxin distribution and transformation in scallops, which may increase the risks of food poisoning associated with the consumption of scallop adductor muscle. ENVIRONMENTAL IMPLICATION: The negative impacts of harmful algal blooms (HABs) have become a global environmental concern under the joint effects of cultural eutrophication and climate change. Our study, targeted on the biokinetics of paralytic shellfish toxins in scallops exposed to Gymnodinium catenatum producing unique GC toxins, aims to elucidate potential risks of seafood poisoning associated with GC toxins. The findings of this study will help us to understand the roles of GC toxins in seafood poisoning, and to develop effective management strategies against toxic algal blooms and phycotoxins.


Asunto(s)
Bivalvos , Dinoflagelados , Pectinidae , Intoxicación por Mariscos , Animales , Humanos , Toxinas Marinas/toxicidad , Intoxicación por Mariscos/etiología , Pectinidae/metabolismo , Bivalvos/metabolismo , Hidroxibenzoatos/metabolismo , Alimentos Marinos , Mariscos
11.
Water Res ; 254: 121422, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38460225

RESUMEN

Methanogenesis of waste biomass (WB) is a promising method for global sustainable development, reduction of pollution and carbon emission levels, and recovering bioenergy. Unlike in the methanogenesis of organic wastewater, in which microbial cells come into direct contact with the dissolved substrate, the 'solid-liquid-solid' modes in WB and between WB and microbial cells, which involve numerous solid-liquid interfaces, greatly hinder the methanogenesis efficiency of WB. Amongst all WB, waste activated sludge is the most complex, poorly biodegradable and representative. Herein, we highlight the role of water evaporation-driven solid-liquid interfacial restructuring of sludge in determining its methanogenesis efficiency. Non-free water evaporation increased surface roughness and adhesion, and compressed pore structure with numerous capillaries in sludge, resulting in a new solid-liquid interface of sludge with great capillary force and highly ordered interfacial water molecules, which provides an extremely favourable condition for high mass transfer and proton-coupled electron transfer (PCET) in sludge. This restructuring was confirmed to induce the enhancement of solid-liquid interfacial noncovalent interactions and electron transfer efficiency in the subsequent methanogenesis process (P < 0.05), promoting the effective contact between the sludge substrate and microbial cells, thereby enriching the methanogenic consortia (i.e., Clostridia and Methanosarcina were increased by 290.0 % and 239.7 %, respectively) and improving the activities of key enzymes. Stable isotope tracing and metagenomic analysis further reveal that this restructuring promoted the participation of water molecules in the methane formation by PCET-driven release of protons from water, and enhanced main methanogenesis metabolic pathways, especially the metabolic pathway of CO2-reduction methanogenesis (+65.2 %), thereby resulting in a great advance in methane generation (+147 %, P < 0.001). The findings can provide a reference for regulating directional anaerobic biotransformation of water-rich multiphase complex substrates by interfacial restructuring inducement.


Asunto(s)
Reactores Biológicos , Aguas del Alcantarillado , Aguas del Alcantarillado/química , Anaerobiosis , Biomasa , Metano , Agua
12.
Radiol Oncol ; 58(1): 67-77, 2024 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-38378037

RESUMEN

BACKGROUND: Gastric cancer is an epidemic malignancy that is commonly diagnosed at the late stage. Evidence has elucidated that RAD54B exerts a crucial role in the progress of various tumors, but its specific role and mechanism in gastric cancer remain gloomy. MATERIALS AND METHODS: The level of RAD54B was detected by western blot. RAD54B expression was downregulated or upregulated in both MKN45 and AGS cells by the transfection of shRAD54B or overexpression plasmid, respectively. The role of RAD54B in the growth, migration, invasion and tube formation of gastric cancer was evaluated by Edu, colony formation, transwell and tube formation assays. In addition, the molecular mechanism of RAD54B in gastric cancer was also determined by western blot. Moreover, in vivo experiment was conducted in xenografted mice. RESULTS: The expression of RAD54B was discovered to be upregulated in gastric cancer based on the ATGC and GEPIA databases, which was also confirmed in gastric cancer cell lines. Moreover, overexpression of RAD54B enhanced the growth, migration, invasion, tube formation and Wnt/ß-catenin signaling axis in AGS and MKN45 cells. As expected, knockdown of RAD54B in AGS and MKN45 cells reversed these promotions. More importantly, in vivo assay also verified that RAD54B accelerated the growth of gastric cancer and Wnt/ß-catenin signaling pathway. CONCLUSIONS: Both loss-of-function and gain-of-function assays demonstrated that RAD54B facilitated gastric cancer cell progress and angiogenesis through the Wnt/ß-catenin axis.


Asunto(s)
Neoplasias Gástricas , Animales , Ratones , Angiogénesis , beta Catenina/metabolismo , Línea Celular Tumoral , Movimiento Celular , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Vía de Señalización Wnt , Humanos
13.
iScience ; 27(2): 108877, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38318357

RESUMEN

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth. Here, we demonstrate that long trimer-boosting intervals, but not long FP immunization intervals, reduce the anti-base response. Additionally, we identify that FP priming before trimer immunization enhances antibody avidity to the Env trimer. We also establish that adjuvants Matrix M and Adjuplex further reduce anti-base responses and increase neutralizing titers. FP priming, long trimer-immunization interval, and an appropriate adjuvant can thus reduce anti-base antibody responses and improve Env-directed vaccine outcomes.

14.
PLoS One ; 19(1): e0296314, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38180957

RESUMEN

The development of automated grading equipment requires achieving high throughput and precise detection of disease spots on jujubes. However, the current algorithms are inadequate in accomplishing these objectives due to their high density, varying sizes and shapes, and limited location information regarding disease spots on jujubes. This paper proposes a method called JujubeSSD, to boost the precision of identifying disease spots in jujubes based on a single shot multi-box detector (SSD) network. In this study, a diverse dataset comprising disease spots of varied sizes and shapes, varying densities, and multiple location details on jujubes was created through artificial collection and data augmentation. The parameter information obtained from transfer learning into the backbone feature extraction network of the SSD model, which reduced the time of spot detection to 0.14 s. To enhance the learning of target detail features and improve the recognition of weak information, the traditional convolution layer was replaced with deformable convolutional networks (DCNs). Furthermore, to address the challenge of varying sizes and shapes of disease spot regions on jujubes, the path aggregation feature pyramid network (PAFPN) and balanced feature pyramid (BFP) were integrated into the SSD network. Experimental results demonstrate that the mean average precision at the IoU (intersection over union) threshold of 0.5 (mAP@0.5) of JujubeSSD reached 97.1%, representing an improvement of approximately 6.35% compared to the original algorithm. When compared to existing algorithms, such as YOLOv5 and Faster R-CNN, the improvements in mAP@0.5 were 16.84% and 8.61%, respectively. Therefore, the proposed method for detecting jujube disease spot achieves superior performance in jujube surface disease detection and meets the requirements for practical application in agricultural production.


Asunto(s)
Ziziphus , Agricultura , Algoritmos , Movimiento Celular , Aprendizaje
15.
J Clin Invest ; 134(1)2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-37917239

RESUMEN

ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1-mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.


Asunto(s)
Histonas , Neoplasias , Humanos , Ratones , Animales , Histonas/metabolismo , Lisina , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo
16.
Chemosphere ; 350: 141068, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38160955

RESUMEN

Aerobic composting is eco-friendly and sustainable practice for kitchen waste (KW) disposal to restore soil fertility and reduce environmental risks. However, KW compact structure, perishable nature, acidification by anaerobic acidogens, inhibits the metabolism of aerobic microbes, insufficient breakdown of organic matters, and prolong the composting duration. This study, co-composted coal fly ash (FA), to regulate bacterial dynamics, co-occurrence patterns and nutrients transformation in KW composting. Our results indicated, FA created suitable environment by increasing pH and temperature, which facilitated the proliferation and reshaping of microbial community. FA fostered the relative abundances of phlya (Proteobacteria, Chloroflexi and Actinobacteriota) and genera (Bacillus, Paenibacillus and Lysinibacillus), which promoted the nutrients transformation (phosphorus and nitrogen) in KW compost. FA enhanced the mutualistic correlations between bacterial communities, promoted the network complexity (nodes & edges) and contains more positive connections, which reflect the FA amendment effects. KW mature compost seed germination index reached >85% of FA treatment, indicated the final products fully met the Chinese national standard for organic fertilizer. These findings might provide opportunity to advance the KW composting and collaborative management of multiple waste to curb the current environmental challenges.


Asunto(s)
Compostaje , Microbiota , Ceniza del Carbón , Carbón Mineral , Bacterias , Suelo
17.
Sci Total Environ ; 912: 169313, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38123094

RESUMEN

Anaerobic digestion (AD) is a promising technique for sludge treatment and resource recovery. Metals are very important components of sludge and can have substantial effects on its complex nature and microbial activity. However, systematic reviews have not addressed how metals in sludge affect AD and how they can be regulated to improve AD. This paper comprehensively reviews the effects of metals on the AD of sludge from both abiotic and biotic perspectives. First, we introduce the contents and basic characteristics (e.g., chemical forms) of intrinsic metals in sewage sludge. Then, we summarise the main mechanism by which metals influence sludge properties and the methods for removing metals and thus improving AD. Next, we analyze the effects of both intrinsic and exogenous metals on the enzymes and microbial communities involved in anaerobic bioconversion, focusing on the types, critical concentrations and valence states of the metals. Finally, we propose ideas for future research on the roles of metals in the AD of sludge. In summary, this review systematically clarifies the roles of metals in the AD of sludge and provides a reference for improving AD by regulating these metals.


Asunto(s)
Aguas del Alcantarillado , Eliminación de Residuos Líquidos , Aguas del Alcantarillado/química , Anaerobiosis , Eliminación de Residuos Líquidos/métodos , Metano , Metales , Reactores Biológicos
18.
Phytochemistry ; 218: 113951, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38096962

RESUMEN

Inubritanolides C and D (1 and 2), two exo sesquiterpenoid [4 + 2] adducts with unprecedented interconverting conformations of twist-chair and chair, together with two previously undescribed endo [4 + 2] dimers (3 and 4) were discovered from Inula britannica flowers. Dimers 1 and 2 have an undescribed carbon skeleton comprising of eudesmanolide and guaianolide units with the linkage mode of C-11/C-1' and C-13/C-3' via a Diels-Alder cycloaddition reaction. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, ECD, and variable-temperature NMR experiments. Dimer 2 displayed a strong inhibitory effect on breast cancer cells by promoting lipid ROS production, showing its potential as ferroptosis inducer.


Asunto(s)
Asteraceae , Ferroptosis , Inula , Sesquiterpenos , Inula/química , Conformación Molecular , Sesquiterpenos/farmacología , Sesquiterpenos/química , Estructura Molecular
19.
Nat Commun ; 14(1): 7900, 2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38036550

RESUMEN

Left ventricular regional wall thickness (LVRWT) is an independent predictor of morbidity and mortality in cardiovascular diseases (CVDs). To identify specific genetic influences on individual LVRWT, we established a novel deep learning algorithm to calculate 12 LVRWTs accurately in 42,194 individuals from the UK Biobank with cardiac magnetic resonance (CMR) imaging. Genome-wide association studies of CMR-derived 12 LVRWTs identified 72 significant genetic loci associated with at least one LVRWT phenotype (P < 5 × 10-8), which were revealed to actively participate in heart development and contraction pathways. Significant causal relationships were observed between the LVRWT traits and hypertrophic cardiomyopathy (HCM) using genetic correlation and Mendelian randomization analyses (P < 0.01). The polygenic risk score of inferoseptal LVRWT at end systole exhibited a notable association with incident HCM, facilitating the identification of high-risk individuals. The findings yield insights into the genetic determinants of LVRWT phenotypes and shed light on the biological basis for HCM etiology.


Asunto(s)
Cardiomiopatía Hipertrófica , Estudio de Asociación del Genoma Completo , Humanos , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/genética , Corazón , Ventrículos Cardíacos/patología , Fenotipo
20.
Thromb J ; 21(1): 105, 2023 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-37794471

RESUMEN

BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.

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