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1.
ACS Omega ; 9(21): 22903-22922, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38826535

ABSTRACT

The intense collision between marine and terrestrial agents results in the dual-source (marine and terrigenous) characteristics of marine source rocks. Our research quantitatively assessed terrestrial organic matter and revealed the crucial role of terrestrial organic materials in the organic matter enrichment of lower Miocene to upper Oligocene marine source rocks in the Qiongdognnan Basin. The quantitative assessment was achieved using partial least-squares analysis with eight biomarker parameters associated with n-alkanes, isoprenoids, bicadinanes, taraxerane, tricyclic terpanes, and gammacerane. Differential unloading of terrestrial organic materials based on sedimentary facies of the delta-marginal sea system were observed through oleanane and bicadinane contents. It should be noted that the diagnostic ratio of oleanane was excluded from the quantitative analysis due to the dual influence from differential unloading and contact with seawater of the terrestrial organic materials. Calculation results show that the terrestrial organic matter was highest in the delta front at 70%, followed by prodelta at 59% and inner shallow marine at 57%. From the late Oligocene to the early Miocene, the proportion of terrestrial organic matter in marine source rocks continuously increased, with the highest average value observed in the second member of the Sanya Formation at 69% and the lowest occurring in the third member of the Lingshui Formation at 46%. Increasing terrestrial organic material inputs and preservation driven by the East Asian summer monsoon provided first-order control of the accumulation of organic carbon in the Qiongdongnan Basin during late Oligocene to early Miocene, rather than the bioproductivity of marine algae. The redox conditions of the water column determine the enrichment extent of organic matter.

2.
Appl Opt ; 63(12): 3130-3137, 2024 Apr 20.
Article in English | MEDLINE | ID: mdl-38856457

ABSTRACT

Numerous applications at the photon-starved regime require a free-space coupling single-photon detector with a large active area, low dark count rate (DCR), and superior time resolutions. Here, we developed a superconducting microstrip single-photon detector (SMSPD), with a large active area of 260 µm in diameter, a DCR of ∼5k c p s, and a low time jitter of ∼171p s, operated at a near-infrared of 1550 nm and a temperature of ∼2.0K. As a demonstration, we applied the detector to a single-pixel galvanometer scanning system and successfully reconstructed the object information in depth and intensity using a time-correlated photon counting technology.

4.
Arch Toxicol ; 2024 May 15.
Article in English | MEDLINE | ID: mdl-38744709

ABSTRACT

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated ß-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of ß-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate ß-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1ß secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.

5.
Phys Rev Lett ; 132(16): 160801, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38701444

ABSTRACT

A solid-state approach for quantum networks is advantageous, as it allows the integration of nanophotonics to enhance the photon emission and the utilization of weakly coupled nuclear spins for long-lived storage. Silicon carbide, specifically point defects within it, shows great promise in this regard due to the easy of availability and well-established nanofabrication techniques. Despite of remarkable progresses made, achieving spin-photon entanglement remains a crucial aspect to be realized. In this Letter, we experimentally generate entanglement between a silicon vacancy defect in silicon carbide and a scattered single photon in the zero-phonon line. The spin state is measured by detecting photons scattered in the phonon sideband. The photonic qubit is encoded in the time-bin degree of freedom and measured using an unbalanced Mach-Zehnder interferometer. Photonic correlations not only reveal the quality of the entanglement but also verify the deterministic nature of the entanglement creation process. By harnessing two pairs of such spin-photon entanglement, it becomes straightforward to entangle remote quantum nodes at long distance.

6.
Yi Chuan ; 46(5): 373-386, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38763772

ABSTRACT

Cardioembolic stroke, characterized by severe illness, poor prognosis, and high recurrence rate, is one of the important causes of ischemic stroke. In the field of genetic research, numerous genes associated with cardioembolic stroke have been identified, and their potential in predicting disease risk and evaluating risk factors has been progressively explored. Here, we provide an overview of the latest advancements in genetics for cardioembolic stroke, including genome-wide association studies, copy number variation studies, whole-genome sequencing studies. Furthermore, we also summarize the application of genetic datasets in polygenic risk score and Mendelian randomization. The aim of this overview is to provide insights and references from multiple perspectives for future investigations on the genetic information for cardioembolic stroke.


Subject(s)
DNA Copy Number Variations , Embolic Stroke , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Embolic Stroke/genetics , Embolic Stroke/etiology , Risk Factors
7.
Water Res ; 257: 121712, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38728776

ABSTRACT

In this study, a conjunctive water management model based on interval stochastic bi-level programming method (CM-ISBP) is proposed for planning water trading program as well as quantifying mutual effects of water trading and systematic water saving. CM-ISBP incorporates water resources assessment with soil and water assessment tool (SWAT), systematic water-saving simulation combined with water trading, and interval stochastic bi-level programming (ISBP) within a general framework. Systematic water saving involves irrigation water-saving technologies (sprinkler irrigation, micro-irrigation, low-pressure pipe irrigation), enterprise water-saving potential and water-saving subsidy. The CM-ISBP is applied to a real case of a water-scarce watershed (i.e. Dagu River watershed, China). Mutual effects of water trading and water-saving activities are simulated with model establishment and quantified through mechanism analysis. The fate of saved water under the systematic water saving is also revealed. The coexistence of the two systems would increase system benefits by [11.89, 12.19]%, and increase the water use efficiency by [40.04, 40.46]%. Thus mechanism that couples water trading and water saving is optimal and recommended according to system performance.


Subject(s)
Conservation of Water Resources , Water Supply , China , Conservation of Water Resources/methods , Models, Theoretical , Rivers , Agricultural Irrigation , Water Resources , Conservation of Natural Resources
8.
Phys Rev Lett ; 132(18): 180803, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38759186

ABSTRACT

Solid-state qubits with a photonic interface is very promising for quantum networks. Color centers in silicon carbide have shown excellent optical and spin coherence, even when integrated with membranes and nanostructures. Additionally, nuclear spins coupled with electron spins can serve as long-lived quantum memories. Pioneering work previously has realized the initialization of a single nuclear spin and demonstrated its entanglement with an electron spin. In this Letter, we report the first realization of single-shot readout for a nuclear spin in SiC. We obtain a deterministic nuclear spin initialization and readout fidelity of 94.95% with a measurement duration of 1 ms. With a dual-step readout scheme, we obtain a readout fidelity as high as 99.03% within 0.28 ms by sacrificing the success efficiency. Our Letter complements the experimental toolbox of harnessing both electron and nuclear spins in SiC for future quantum networks.

9.
Crit Rev Biotechnol ; : 1-19, 2024 May 26.
Article in English | MEDLINE | ID: mdl-38797672

ABSTRACT

Astaxanthin, a ketone carotenoid known for its high antioxidant activity, holds significant potential for application in nutraceuticals, aquaculture, and cosmetics. The increasing market demand necessitates a higher production of astaxanthin using Phaffia rhodozyma. Despite extensive research efforts focused on optimizing fermentation conditions, employing mutagenesis treatments, and utilizing genetic engineering technologies to enhance astaxanthin yield in P. rhodozyma, progress in this area remains limited. This review provides a comprehensive summary of the current understanding of rough metabolic pathways, regulatory mechanisms, and preliminary strategies for enhancing astaxanthin yield. However, further investigation is required to fully comprehend the intricate and essential metabolic regulation mechanism underlying astaxanthin synthesis. Specifically, the specific functions of key genes, such as crtYB, crtS, and crtI, need to be explored in detail. Additionally, a thorough understanding of the action mechanism of bifunctional enzymes and alternative splicing products is imperative. Lastly, the regulation of metabolic flux must be thoroughly investigated to reveal the complete pathway of astaxanthin synthesis. To obtain an in-depth mechanism and improve the yield of astaxanthin, this review proposes some frontier methods, including: omics, genome editing, protein structure-activity analysis, and synthetic biology. Moreover, it further elucidates the feasibility of new strategies using these advanced methods in various effectively combined ways to resolve these problems mentioned above. This review provides theory and method for studying the metabolic pathway of astaxanthin in P. rhodozyma and the industrial improvement of astaxanthin, and provides new insights into the flexible combined use of multiple modern advanced biotechnologies.

10.
Article in English | MEDLINE | ID: mdl-38587855

ABSTRACT

BACKGROUND: Inflammation is crucial in the development of AKI and subsequent CKD following renal ischemia-reperfusion (IR) injury. Gut microbiota metabolites trigger inflammation and affect IR-induced renal damage. Yet, the driving factors and mechanisms are unclear. Trimethylamine N-oxide (TMAO), a gut-derived choline metabolite, is a strong pro-inflammatory factor that increases in patients with AKI and CKD. We hypothesized that TMAO can promote renal injury caused by IR. METHODS: Mice subjected to unilateral renal IR to induce AKI and CKD were fed a high-choline diet to observe the effects of TMAO on kidney inflammation, fibrosis, and macrophage dynamics. RESULTS: A choline-rich diet altered the gut microbiota and elevated TMAO levels, which exacerbated IR-induced AKI and subsequent CKD. Single-cell analysis identified a distinct subset of CCR2+ macrophages derived from monocytes as key responders to TMAO, intensifying immune cell interactions and worsening renal injury. TMAO promoted sustained CCR2 expression after IR, increasing macrophage infiltration. CCR2 deletion and antagonist RS-102895 improved TMAO-induced inflammation and fibrosis, alleviated renal injury induced by IR. CONCLUSIONS: Our study provides valuable insights into the link between TMAO and IR-incited renal inflammation and fibrosis, emphasizing the critical role of TMAO-mediated macrophage infiltration via CCR2 as a key therapeutic target in the acute and chronic phase after IR.

11.
Phys Rev Lett ; 132(13): 133603, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38613308

ABSTRACT

An integrated quantum light source is increasingly desirable in large-scale quantum information processing. Despite recent remarkable advances, a new material platform is constantly being explored for the fully on-chip integration of quantum light generation, active and passive manipulation, and detection. Here, for the first time, we demonstrate a gallium nitride (GaN) microring based quantum light generation in the telecom C-band, which has potential toward the monolithic integration of quantum light source. In our demonstration, the GaN microring has a free spectral range of 330 GHz and a near-zero anomalous dispersion region of over 100 nm. The generation of energy-time entangled photon pair is demonstrated with a typical raw two-photon interference visibility of 95.5±6.5%, which is further configured to generate a heralded single photon with a typical heralded second-order autocorrelation g_{H}^{(2)}(0) of 0.045±0.001. Our results pave the way for developing a chip-scale quantum photonic circuit.

12.
Biomaterials ; 308: 122551, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38593710

ABSTRACT

Sarcopenia, a prevalent muscle disease characterized by muscle mass and strength reduction, is associated with impaired skeletal muscle regeneration. However, the influence of the biomechanical properties of sarcopenic skeletal muscle on the efficiency of the myogenic program remains unclear. Herein, we established a mouse model of sarcopenia and observed a reduction in stiffness within the sarcopenic skeletal muscle in vivo. To investigate whether the biomechanical properties of skeletal muscle directly impact the myogenic program, we established an in vitro system to explore the intrinsic mechanism involving matrix stiffness control of myogenic differentiation. Our findings identify the microtubule motor protein, kinesin-1, as a mechano-transduction hub that senses and responds to matrix stiffness, crucial for myogenic differentiation and muscle regeneration. Specifically, kinesin-1 activity is positively regulated by stiff matrices, facilitating its role in transporting mitochondria and enhancing translocation of the glucose transporter GLUT4 to the cell surface for glucose uptake. Conversely, the softer matrices significantly suppress kinesin-1 activity, leading to the accumulation of mitochondria around nuclei and hindering glucose uptake by inhibiting GLUT4 membrane translocation, consequently impairing myogenic differentiation. The insights gained from the in-vitro system highlight the mechano-transduction significance of kinesin-1 motor proteins in myogenic differentiation. Furthermore, our study confirms that enhancing kinesin-1 activity in the sarcopenic mouse model restores satellite cell expansion, myogenic differentiation, and muscle regeneration. Taken together, our findings provide a potential target for improving muscle regeneration in sarcopenia.


Subject(s)
Kinesins , Regeneration , Sarcopenia , Animals , Kinesins/metabolism , Mice , Sarcopenia/metabolism , Sarcopenia/pathology , Muscle, Skeletal/metabolism , Mice, Inbred C57BL , Cell Differentiation , Muscle Development , Male , Glucose Transporter Type 4/metabolism , Extracellular Matrix/metabolism , Mitochondria/metabolism , Biomechanical Phenomena , Glucose/metabolism
13.
mSystems ; 9(4): e0020624, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38514462

ABSTRACT

Helicobacter pylori is a highly successful pathogen that poses a substantial threat to human health. However, the dynamic interaction between H. pylori and the human gastric epithelium has not been fully investigated. In this study, using dual RNA sequencing technology, we characterized a cytotoxin-associated gene A (cagA)-modulated bacterial adaption strategy by enhancing the expression of ATP-binding cassette transporter-related genes, metQ and HP_0888, upon coculturing with human gastric epithelial cells. We observed a general repression of electron transport-associated genes by cagA, leading to the activation of oxidative phosphorylation. Temporal profiling of host mRNA signatures revealed the downregulation of multiple splicing regulators due to bacterial infection, resulting in aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. Moreover, we demonstrated a protective effect of gastric H. pylori colonization against chronic dextran sulfate sodium (DSS)-induced colitis. Mechanistically, we identified a cluster of propionic and butyric acid-producing bacteria, Muribaculaceae, selectively enriched in the colons of H. pylori-pre-colonized mice, which may contribute to the restoration of intestinal barrier function damaged by DSS treatment. Collectively, this study presents the first dual-transcriptome analysis of H. pylori during its dynamic interaction with gastric epithelial cells and provides new insights into strategies through which H. pylori promotes infection and pathogenesis in the human gastric epithelium. IMPORTANCE: Simultaneous profiling of the dynamic interaction between Helicobacter pylori and the human gastric epithelium represents a novel strategy for identifying regulatory responses that drive pathogenesis. This study presents the first dual-transcriptome analysis of H. pylori when cocultured with gastric epithelial cells, revealing a bacterial adaptation strategy and a general repression of electron transportation-associated genes, both of which were modulated by cytotoxin-associated gene A (cagA). Temporal profiling of host mRNA signatures dissected the aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. We demonstrated a protective effect of gastric H. pylori colonization against chronic DSS-induced colitis through both in vitro and in vivo experiments. These findings significantly enhance our understanding of how H. pylori promotes infection and pathogenesis in the human gastric epithelium and provide evidence to identify targets for antimicrobial therapies.


Subject(s)
Colitis , Helicobacter pylori , Animals , Humans , Mice , Bacterial Proteins/genetics , Antigens, Bacterial/genetics , Helicobacter pylori/genetics , Transcriptome/genetics , RNA Precursors/metabolism , Host-Pathogen Interactions/genetics , Sequence Analysis, RNA , RNA, Messenger/metabolism , Cytotoxins/metabolism
14.
Nat Commun ; 15(1): 2252, 2024 Mar 13.
Article in English | MEDLINE | ID: mdl-38480744

ABSTRACT

Zero thermal expansion (ZTE) alloys with high mechanical response are crucial for their practical usage. Yet, unifying the ZTE behavior and mechanical response in one material is a grand obstacle, especially in multicomponent ZTE alloys. Herein, we report a near isotropic zero thermal expansion (αl = 1.10 × 10-6 K-1, 260-310 K) in the natural heterogeneous LaFe54Co3.5Si3.35 alloy, which exhibits a super-high toughness of 277.8 ± 14.7 J cm-3. Chemical partition, in the dual-phase structure, assumes the role of not only modulating thermal expansion through magnetic interaction but also enhancing mechanical properties via interface bonding. The comprehensive analysis reveals that the hierarchically synergistic enhancement among lattice, phase interface, and heterogeneous structure is significant for strong toughness. Our findings pave the way to tailor thermal expansion and obtain prominent mechanical properties in multicomponent alloys, which is essential to ultra-stable functional materials.

15.
Int J Mol Sci ; 25(3)2024 Jan 25.
Article in English | MEDLINE | ID: mdl-38338776

ABSTRACT

Rice effective panicle is a major trait for grain yield and is affected by both the genetic tiller numbers and the early tillering vigor (ETV) traits to survive environmental adversities. The mechanism behind tiller bud formation has been well described, while the genes and the molecular mechanism underlying rice-regulating ETV traits are unclear. In this study, the candidate genes in regulating ETV traits have been sought by quantitative trait locus (QTL) mapping and bulk-segregation analysis by resequencing method (BSA-seq) conjoint analysis using rice backcross inbred line (BIL) populations, which were cultivated as late-season rice of double-cropping rice systems. By QTL mapping, seven QTLs were detected on chromosomes 1, 3, 4, and 9, with the logarithm of the odds (LOD) values ranging from 3.52 to 7.57 and explained 3.23% to 12.98% of the observed phenotypic variance. By BSA-seq analysis, seven QTLs on chromosomes 1, 2, 4, 5, 7, and 9 were identified using single-nucleotide polymorphism (SNP) and insertions/deletions (InDel) index algorithm and Euclidean distance (ED) algorithm. The overlapping QTL resulting from QTL mapping and BSA-seq analysis was shown in a 1.39 Mb interval on chromosome 4. In the overlap interval, six genes, including the functional unknown genes Os04g0455650, Os04g0470901, Os04g0500600, and ethylene-insensitive 3 (Os04g0456900), sialyltransferase family domain containing protein (Os04g0506800), and ATOZI1 (Os04g0497300), showed the differential expression between ETV rice lines and late tillering vigor (LTV) rice lines and have a missense base mutation in the genomic DNA sequences of the parents. We speculate that the six genes are the candidate genes regulating the ETV trait in rice, which provides a research basis for revealing the molecular mechanism behind the ETV traits in rice.


Subject(s)
Oryza , Quantitative Trait Loci , Oryza/genetics , Seasons , Chromosome Mapping/methods , Phenotype
16.
Sci Rep ; 14(1): 2944, 2024 02 05.
Article in English | MEDLINE | ID: mdl-38316801

ABSTRACT

Optimum irrigation scheduling is important for ensuring high yield and water productivity in substrate-cultivated vegetables and is determined based on information such as substrate water content, meteorological parameters, and crop growth. The aim of this study was to determine a precise irrigation schedule for coconut coir culture in a solar greenhouse by comparing the irrigation, evapotranspiration (ET), substrate water content (VWC), as well as the crop growth indices and yield of cucumber, and irrigation water productivity (IWP) under three irrigation schedules: the soil moisture sensor-based method (T-VWC), the accumulated radiation combined with soil moisture sensor-based method (Rn-VWC), and the crop evapotranspiration estimated method using the hourly PM-ETo equation with an improved calculation of Kc (T-ETc). The results showed that the daily irrigation and evapotranspiration amount were the highest under T-VWC treatment, while the lowest under T-ETc treatment. In different meteorological environments, the change in irrigation amount was more consistent with the ET,and the VWC was relatively stable in T-ETc treatment compared with that under T-VWC or Rn-VWC treatments. The plant height, leaves number, leaf area, and stem diameter of T-VWC and Rn-VWC treatments were higher than those of the T-ETc treatments, but there was no significant difference in cucumber yield. Compared with the T-VWC treatment, total irrigation amount under Rn-VWC and T-ETc treatments significantly decreased by 25.75% and 34.04%, respectively ([Formula: see text]). The highest IWP values of 25.07 kg m[Formula: see text] was achieved from T-ETc treatment with significantly increasing by 44.33% compared to the T-VWC treatment (17.37 kg m[Formula: see text]). In summary, the T-ETc treatment allowed more reasonable irrigation management and was appropriate for growing cucumber in coconut coir culture.


Subject(s)
Cucumis sativus , Lignin/analogs & derivatives , Agricultural Irrigation/methods , Cocos , Soil/chemistry , Water/analysis
17.
Environ Res ; 249: 118377, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38331150

ABSTRACT

Nexus approach provides an effective perspective for implementing synergetic management of water resources. In this study, an interval two-stage chance-constrained water rights trading planning model under water-ecology-food nexus perspective (ITCWR-WEF) is proposed to analyze the interaction between water trading and water-ecology-food (WEF) nexus, which fills in the water resources management gaps from a novel nexus perspective. ITCWR-WEF incorporates hydrological simulation with soil and water assessment tool (SWAT), water rights configuration with interval two-stage chance-constrained programming (ITCP), and multi-criterion analysis with Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS). The developed ITCWR-WEF is applied to a real case of Daguhe watershed, which has characteristics of water scarcity, food producing areas and fragile ecosystem. Initial water rights allocation is addressed before the trading. Mechanisms analysis is designed to reveal mutual effect of water rights trading and WEF nexus. Optimal water management scenario is identified through multi-criterion analysis. Results reveal that the mechanism of water rights trading with WEF nexus under low constraint-violation risk level of water availability and environment capacity is recommended to promote the rational water resources allocation to balance the economic goals, water environment and water supply security, as well as ecological and food water demand guarantees.


Subject(s)
Conservation of Water Resources , Water Resources , Water Supply , Water Resources/supply & distribution , Water Supply/statistics & numerical data , Conservation of Water Resources/methods , Conservation of Water Resources/statistics & numerical data , Agriculture/methods , Agriculture/statistics & numerical data
18.
Int J Biol Macromol ; 263(Pt 1): 130275, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38373563

ABSTRACT

Polysaccharides from natural products play multiple roles and have extensive bioactivities in life process. Bioactivities of polysaccharides (e.g., Lentinan, Schizophyllan, Scleroglucan, Curdlan, Cinerean) have a close relation to their chain conformation. Compared to other types of polysaccharides, the conformation of ß-glucan has been studied more. The major research methods of conformation of polysaccharides from natural products (Congo red experiment, circular dichroism spectrum, viscosity method, light scattering method, size exclusion chromatography, atomic force microscope), corresponding experimental schemes, and the external factors affecting polysaccharide conformation were reviewed in this paper. These research methods of conformation have been widely used, among which Congo red experiment and viscosity method are the most convenient ones to study the morphological changes of polysaccharide chains.


Subject(s)
Biological Products , Congo Red , Molecular Conformation , Lentinan/chemistry , Polysaccharides/chemistry , Carbohydrate Conformation
19.
Drug Des Devel Ther ; 18: 1-12, 2024.
Article in English | MEDLINE | ID: mdl-38205395

ABSTRACT

Purpose: Adagrasib is a selective and reversible inhibitor of KRAS G12C, which significantly delays the progression of solid tumors. However, the absorption, distribution, metabolism, and excretion of adagrasib in vivo are unclear. This study explores the absorption and distribution of adagrasib in vivo. Methods: An ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method was established for the determination of adagrasib in the rat plasma and tissue. Sprague-Dawley rats were intravenous administrated (5 mg/kg) and oral administrated (30 mg/kg) with adagrasib, and the plasma concentration of adagrasib was determined. After single oral administration of adagrasib (30 mg/kg), the heart, liver, spleen, lung, kidney, intestine, and pancreas were excised. The organs were homogenized with saline solution, and the concentration of adagrasib in tissues was determined. Results: The intra- and inter-day accuracy were from 84.90% to 113.47%, and the precision was within ±15%. The matrix effect and recovery were within ±15%. The maximum plasma concentration (Cmax) of adagrasib was 677.45 ± 58.72 ng/mL. The elimination half-life time (t1/2) was 3.50 ± 0.21 h after oral administration and 2.08 ± 0.54 h after intravenous administration. The oral bioavailability was 50.72%. The highest concentrations of adagrasib in liver was 5047.80 ± 676.48 ng/g at 2 h after administration, and it was still detectable at 24 hours after administration. Conclusion: Adagrasib was slowly absorbed and cleared rapidly, and it was also widely distributed in vivo. This study provides a potential reference for adagrasib in clinical studies.


Subject(s)
Acetonitriles , Liquid Chromatography-Mass Spectrometry , Piperazines , Proto-Oncogene Proteins p21(ras) , Pyrimidines , Rats , Animals , Rats, Sprague-Dawley , Biological Availability , Tissue Distribution , Chromatography, Liquid , Tandem Mass Spectrometry
20.
Ren Fail ; 46(1): 2296612, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38178566

ABSTRACT

Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD), but there is no consensus on its definition. In 2015, Flythe proposed a definition of IDH (Definition 1 in this study): nadir systolic blood pressure (SBP) <90 mmHg during hemodialysis for patients with pre-dialysis SBP <159 mmHg, and nadir SBP <100 mmHg during hemodialysis for patients with pre-dialysis SBP ≥160 mmHg. This prospective observational cohort study investigated the association of frequent IDH based on Definition 1 with clinical outcomes and compared Definition 1 with a commonly used definition (nadir SBP <90 mmHg during hemodialysis, Definition 2). The incidence of IDH was observed over a 3-month exposure assessment period. Patients with IDH events ≥30% were classified as 'frequent IDH'; the others were 'infrequent IDH'. All-cause mortality, cardiovascular mortality, and all-cause hospitalization events were followed up for 36 months. This study enrolled 163 HD patients. The incidence of IDH was 11.1% according to Definition 1 and 10.5% according to Definition 2. The Kaplan-Meier curves showed that frequent IDH patients had higher risks of all-cause mortality (p = 0.009, Definition 1; p = 0.002, Definition 2) and cardiovascular mortality (p = 0.021, Definition 1). Multivariable Cox regression analysis indicated that frequent IDH was independently associated with a higher risk of all-cause mortality (Model 1: HR = 2.553, 95%CI 1.334-4.886, p = 0.005; Model 2: HR = 2.406, 95%CI 1.253-4.621, p = 0.008). In conclusion, HD patients classified as frequent IDH are at a greater risk of all-cause mortality. This highlights the significance of acknowledging and proactively managing frequent IDH within the HD patients.


Subject(s)
Hypotension , Kidney Failure, Chronic , Humans , Prospective Studies , Kidney Failure, Chronic/complications , Renal Dialysis/adverse effects , Hypotension/epidemiology , Hypotension/etiology , Blood Pressure
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