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1.
Front Plant Sci ; 15: 1417504, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38947951

RESUMO

Improving the nutrient content of red soils in southern China is a priority for efficient rice production there. To assess the effectiveness of oilseed rape as green manure for the improvement of soil phosphorus nutrient supply and rice yield in red soil areas, a long-term field plot experiment was conducted comparing two species of rape, Brassica napus (BN) and Brassica juncea (BJ). The effects of returning oilseed rape on soil phosphorus availability, phosphorus absorption, and yield of subsequent rice under rice-green manure rotation mode were analyzed, using data from the seasons of 2020 to 2021. The study found that compared with winter fallow treatment (WT) and no-tillage treatment (NT), the soil available phosphorus content of BN was increased, and that of BJ was significantly increased. The content of water-soluble inorganic phosphorus of BJ increased, and that of BN increased substantially. Compared with the WT, the soil organic matter content and soil total phosphorus content of BN significantly increased, as did the soil available potassium content of BJ, and the soil total phosphorus content of BJ was significantly increased compared with NT. The soil particulate phosphorus content of BJ and BN was significantly increased by 14.00% and 16.00%, respectively. Compared with the WT, the phosphorus activation coefficient of BJ was significantly increased by 11.41%. The rice plant tiller number under the green manure returning treatment was significantly increased by 43.16% compared with the winter fallow treatment. The green manure returning measures increased rice grain yield by promoting rice tiller numbers; BN increased rice grain yield by 9.91% and BJ by 11.68%. Based on these results, returning oilseed rape green manure could augment the phosphorus nutrients of red soil and promote phosphorus availability. Rice-oilseed rape green manure rotation could increase rice grain yield.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38963606

RESUMO

PURPOSE: To identify novel variants in ACTL9 and new phenotypes responsible for male infertility. METHODS: Genomic DNA was extracted from peripheral blood samples for whole-exome sequencing (WES). Computer-assisted sperm analysis (CASA) was used to test the motility of spermatozoa. The ultrastructure of flagella and the mitochondrial sheath were assessed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Immunostaining was used to validate the localization and expression of ACTL9 and ACTL7A. An Actl9-mutated mouse model was used to validate the phenotypes by CASA and TEM. RESULTS: We identified novel homozygous variants in ACTL9 in two independent Chinese families. Spermatozoa with ACTL9 mutations showed decreased CASA parameters and a higher proportion of spermatozoa with abnormal morphology, exhibiting coiled flagella and a thickened midpiece. The spermatozoa were characterized by chaotic or irregular '9+2' structures and irregular mitochondrial sheath arrangements in the flagellum. Actl9 knock-in mice also showed abnormal CASA parameters and irregular '9+2' structures in flagella. CONCLUSIONS: Our study expands the mutation spectrum and phenotypic spectrum of ACTL9.

3.
Vet Microbiol ; 296: 110171, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38981202

RESUMO

Intestinal pathogenic Escherichia coli (InPEC) is one of the most common causes of bacterial diarrhea in farm animals, including profuse neonatal diarrhea and post weaning diarrhea (PWD) in piglets. In this study, we investigated the prevalence of InPEC and associated primary virulence factors among 543 non-duplicate E. coli isolates from diarrheal pigs from 15 swine farms in southern China. Six major virulence genes associated with InPEC were identified among 69 (12.71 %) E. coli isolates and included est (6.62 %), K88 (4.79 %), elt (3.68 %), eae (1.47 %), stx2 (0.92 %) and F18 (0.55 %). Three pathotypes of InPEC were identified including ETEC (8.10 %), EPEC (1.29 %) and STEC/ETEC (0.92 %). In particular, K88 was only found in ETEC from breeding farms, whereas F18 was only present in STEC/ETEC hybrid from finishing farms. Whole genome sequence analysis of 37 E. coli isolates revealed that InPEC strains frequently co-carried multiple antibiotic resistance gene (ARG). est, elt and F18 were also found to co-locate with ARGs on a single IncFIB/IncFII plasmid. InPEC isolates from different pathotypes also possessed different profiles of virulence genes and antimicrobial resistance genes. Population structure analysis demonstrated that InPEC isolates from different pathotypes were highly heterogeneous whereas those of the same pathotype were extremely similar. Plasmid analysis revealed that K88 and/or est/elt were found on pGX18-2-like/pGX203-2-like and pGX203-1-like IncFII plasmids, while F18 and elt/est, as well as diverse ARGs were found to co-locate on IncFII/IncFIB plasmids with a non-typical backbone. Moreover, these key virulence genes were flanked by or adjacent to IS elements. Our findings indicated that both clonal expansion and horizontal spread of epidemic IncFII plasmids contributed to the prevalence of InPEC and the specific virulence genes (F4, F18, elt and est) in the tested swine farms.

5.
Int J Mol Sci ; 25(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-39000546

RESUMO

Plants are often exposed to biotic or abiotic stress, which can seriously impede their growth and development. In recent years, researchers have focused especially on the study of plant responses to biotic and abiotic stress. As one of the most widely planted grapevine rootstocks, 'Beta' has been extensively proven to be highly resistant to stress. However, further research is needed to understand the mechanisms of abiotic stress in 'Beta' rootstocks. In this study, we isolated and cloned a novel WRKY transcription factor, VhWRKY44, from the 'Beta' rootstock. Subcellular localization analysis revealed that VhWRKY44 was a nuclear-localized protein. Tissue-specific expression analysis indicated that VhWRKY44 had higher expression levels in grape roots and mature leaves. Further research demonstrated that the expression level of VhWRKY44 in grape roots and mature leaves was highly induced by salt and cold treatment. Compared with the control, Arabidopsis plants overexpressing VhWRKY44 showed stronger resistance to salt and cold stress. The activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were significantly increased, and the contents of proline, malondialdehyde (MDA) and chlorophyll were changed considerably. In addition, significantly higher levels of stress-related genes were detected in the transgenic lines. The results indicated that VhWRKY44 was an important transcription factor in 'Beta' with excellent salt and cold tolerance, providing a new foundation for abiotic stress research.


Assuntos
Arabidopsis , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Plantas Geneticamente Modificadas , Fatores de Transcrição , Vitis , Arabidopsis/genética , Arabidopsis/metabolismo , Vitis/genética , Vitis/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Estresse Fisiológico/genética , Temperatura Baixa , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Tolerância ao Sal/genética , Folhas de Planta/metabolismo , Folhas de Planta/genética
6.
Shanghai Kou Qiang Yi Xue ; 33(2): 123-129, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-39005086

RESUMO

PURPOSE: To investigate the effect of Morinda officinalis polysaccharides(MOP) on the expression of fibronectin(FN) and fibronectin containing extra domain A(FN-EDA) in inflammatory periodontal ligament fibroblasts. METHODS: Thirty six rats were randomly divided into a control group(n=12) and a model group (n=24). The model group used orthodontic wire ligation to establish periodontitis. After three weeks, 6 rats from each group were selected and confirmed by Micro-CT to complete the modeling. The remaining rats in the model group were randomly divided into periodontitis group, normal saline(NS) group, and MOP group. In the MOP group, MOP (200 mg/kg for 3 d, 50 µL for 4 weeks) was injected into the palatal side of the left maxillary first molar of the rats. In the NS group, same volume of NS was injected, and no treatment was performed in the periodontitis group. The left maxillary tissue of rats were taken and the pathological changes of periodontal tissue were observed by H-E staining. The expression of FN and FN-EDA was detected by immunohistochemistry. Periodontal ligament fibroblasts were cultured in vitro, the effect of MOP on cell activity detected by CCK-8. The fourth generation cells were divided into control group, inflammation group (10 mg/mL lipopolysaccharide), and experimental group (12.5 µg/mL MOP, 12.5 µg/mL MOP+10 mg/mL lipopolysaccharide). The expression of FN and FN-EDA was detected by qRT-PCR and Western blot. The data were statistically analyzed using Prism 8.0 software package. RESULTS: In vivo experiments, the expression of FN-EDA in the MOP group was significantly lower than that in the periodontitis group and NS group(P<0.05), and the infiltration of inflammatory cells was reduced. However, there was no significant difference in the expression of FN in each group. In vitro experiments, compared with the control group, the expression of FN-EDA mRNA and protein in the inflammation group was significantly increased(P<0.000 1). MOP significantly reduced the expression of FN-EDA in inflammatory cells, but had no significant effect on FN expression. CONCLUSIONS: With increased expression of FN-EDA in inflammatory periodontal ligament tissues and cells, MOP may play a role in inhibiting inflammation by down-regulating FN-EDA.


Assuntos
Fibroblastos , Fibronectinas , Morinda , Ligamento Periodontal , Polissacarídeos , Animais , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Polissacarídeos/farmacologia , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Ligamento Periodontal/citologia , Ratos , Morinda/química , Fibronectinas/metabolismo , Fibronectinas/genética , Periodontite/tratamento farmacológico , Periodontite/metabolismo , Inflamação/tratamento farmacológico , Ratos Sprague-Dawley
7.
Reproduction ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-39042720

RESUMO

Oocyte activation failure, one of the main factors of total fertilization failure (TFF) after ICSI, could be induced by abnormal calcium oscillations. Phospholipase C zeta (PLCζ), a sperm factor, was associated with Ca2+ oscillations in oocytes of mammals. To date, only a limited number of mutations in PLCZ1 (the gene encodes PLCζ) have been linked to TFF demonstrated by the observed reduction in protein levels or activity. In this study, males with normozoospermic sperm suffering TFF after ICSI and their families were recruited. Firstly, mutations in the PLCZ1 sequence were identified by Whole exome sequencing and validated by Sanger sequencing. Then the transcript and protein levels and locations of PLCZ1/PLCζ in sperms of patients were studied followed by in vitro function analysis and in silico analysis to investigate the function-structure correlation of mutations identified in PLCZ1 through Western blotting, Immunofluorescence, RT-qPCR and Molecular Simulation. Ca2+ oscillations were detected after cRNA microinjection with MⅡ mouse oocyte to investigate the calcium oscillations of abnormal PLCζ. Five variants in compound heterozygosity were identified including five new mutations and three-reported mutations which were located across the main domains of PLCζ, except the EF hands domain. The transcript and protein levels were decreased among all the mutations identified in PLCZ1 at different degrees when transfected with HEK293T cells. Among these mutations, M138V and R391* of PLCζ could not trigger normal Ca2+ oscillations. In case 5, an abnormal location in the head of sperm and a higher expression of PLCζ in the sperm were found.

8.
Clin Transl Sci ; 17(7): e13852, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38988035

RESUMO

N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8-118 h, and the median time to reach maximum plasma concentration was 4-7 h. Exposures were dose-proportional after single dose (6-46 ng/mL) and more than dose-proportional after multiple doses (6-41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.


Assuntos
Relação Dose-Resposta a Droga , Doença de Huntington , Receptores de N-Metil-D-Aspartato , Humanos , Masculino , Adulto , Doença de Huntington/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Adulto Jovem , Voluntários Saudáveis , Adolescente , Cognição/efeitos dos fármacos , Idoso
9.
Food Chem ; 459: 140445, 2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39024887

RESUMO

The misuse of antibiotics has caused serious impacts on food safety and human health, making it crucial to develop rapidly and highly sensitive methods for detecting trace nitrofuran antibiotics (NFs). In this study, phosphorus, nitride-doped carbon nanosheets (PN/CNs) were synthesized using a simple hydrothermal method based on graphitic carbon nitride. This prepared material showed excellent water solubility and stable optical properties. A new fluorescence sensing platform based on PN/CNs was constructed for the highly sensitive detection of four NFs. This sensitivity was mainly attributed to the fluorescence resonance energy transfer (FRET) mechanism. The limits of detection for nitrofurazone, nitrofurantoin, furazolidone and furaltadone were determined to be 13.41, 15.24, 16.37 and 19.94 nM, respectively. The high sensitivity and selectivity of PN/CNs for these four NFs were thoroughly evaluated by the Stern-Volmer equation and FRET quenching efficiency. This proposed method exhibited high sensitivity and can be successfully applied to detect NFs in fish.

10.
Thromb Haemost ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38914130

RESUMO

BACKGROUND: Venous thromboembolism (VTE) is predisposed by thrombotic mutations in patients with hereditary thrombophilia. Although prothrombin deficiencies caused by homozygous or compound heterozygous mutations are associated with bleeding diathesis, rare cases have shown a correlation between heterozygous prothrombin mutations and thrombosis. MATERIALS AND METHODS: We surveyed genetic variants involved in thrombosis and hemostasis in 347 patients with unprovoked VTE or having a positive family history of thrombosis. For patients identified with heterozygous prothrombin mutations, we conducted family investigations and performed a thrombin generation test (TGT) to elucidate the thrombotic risk. Novel mutants were expressed and subjected to functional assays to clarify the underlying thrombotic mechanisms. RESULTS: Heterozygous prothrombin mutations were identified in 3.5% of patients (12/347), including three novel mutations Phe382Ser, Phe382Leu, and Asp597Tyr found in one patient each, as well as previously reported Arg541Trp mutation in four patients and Arg596Gln mutation in five patients. A total of 42 mutation carriers were identified within the 12 pedigrees, among whom 64.3% (27/42) had experienced thrombotic events. TGT results demonstrated hypercoagulability for carriers of the five mutations, with Arg596Gln showing the highest thrombin generation potential followed by Arg541Trp. The Phe382-associated mutations severely impaired thrombomodulin-binding ability of thrombin, resulting in obviously reduced protein C (PC) activation. The Asp597Tyr mutation exhibited a mild reduction in both inactivation by antithrombin and PC activation reactions. CONCLUSION: The presence of heterozygous prothrombin mutations represents a potential genetic predisposition for VTE. All thrombosis-associated mutations potentiate coagulation activity by either conferring antithrombin resistance and/or impairing PC pathway activity.

11.
ACS Nano ; 18(26): 16853-16866, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38896491

RESUMO

The precise modulation of electrical activity in specific neuronal populations is paramount for rectifying abnormal neurological functions and is a critical element in the therapeutic arsenal for neurological disorders. However, achieving a balance between minimal invasiveness and robust neuroprotection poses a considerable challenge. Herein, we present a nanoneuromodulation strategy integrating neuroprotective features to effectively address epilepsy with minimal invasiveness and enable wireless functionality. Strategically engineered nanotransducer, adorned with platinum (Pt) decoration with titanium disulfide (TiS2) (TiS2/Pt), enables precise modulation of neuronal electrical activity in vitro and in vivo, ensuring exceptional temporal fidelity under millisecond-precision near-infrared (NIR) light pulses irradiation. Concurrently, TiS2/Pt showcase a pronounced enhancement in enzyme-mimicking activity, offering a robust defense against oxidative neurological injury in vitro. Nanotransducer-enabled wireless neuromodulation with biocatalytic neuroprotective capacity is highly effective in alleviating epileptic high-frequency neural activity and diminishing oxidative stress levels, thereby restoring redox equilibrium. This integrated therapeutic approach reduces the severity of epilepsy, demonstrating minimal invasiveness and obviating the requirements for genetic manipulation and optical fiber implantation, while providing an alternative avenue for neurological disorder treatment.


Assuntos
Epilepsia , Epilepsia/terapia , Animais , Titânio/química , Titânio/farmacologia , Platina/química , Platina/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Neuroproteção/efeitos dos fármacos , Camundongos , Dissulfetos/química , Dissulfetos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Raios Infravermelhos , Ratos
12.
Thromb Res ; 240: 109044, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38824799

RESUMO

Protein C (PC), a vitamin K-dependent serine protease zymogen in plasma, can be activated by thrombin-thrombomodulin(TM) complex, resulting in the formation of activated protein C (APC). APC functions to downregulate thrombin generation by inactivating active coagulation factors V(FVa) and VIII(FVIIIa). Deficiency in PC increases the risk of venous thromboembolism (VTE). We have identified two unrelated VTE patients with the same heterozygous mutation (c.1384 T > C, p.Ter462GlnextTer17) in PROC. To comprehend the role of this mutation in VTE development, we expressed recombinant PC-Ter462GlnextTer17 in mammalian cells and evaluated its characteristics using established coagulation assay systems. Functional studies revealed a significant impairment in the activation of the mutant by thrombin or thrombin-TM complex. Furthermore, APC-Ter462GlnextTer17 demonstrated diminished hydrolytic activity towards the chromogenic substrate S2366. APTT and FVa degradation assays showed that both the anticoagulant activity of the mutant protein was markedly impaired, regardless of whether protein S was present or absent. These results were further supported by a thrombin generation assay conducted using purified and plasma-based systems. In conclusion, the Ter462GlnextTer17 mutation introduces a novel tail at the C-terminus of PC, leading to impaired activity in both PC zymogen activation and APC's anticoagulant function. This impairment contributes to thrombosis in individuals carrying this heterozygous mutation and represents a genetic risk factor for VTE.


Assuntos
Mutação , Proteína C , Trombose Venosa , Proteína C/metabolismo , Proteína C/genética , Humanos , Trombose Venosa/genética , Masculino , Feminino , Pessoa de Meia-Idade , Adulto
13.
IEEE Trans Cybern ; PP2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865225

RESUMO

This article addresses the solution of continuous-time linear Itô stochastic systems with Markovian jumps using an online policy iteration (PI) approach grounded in Q -learning. Initially, a model-dependent offline algorithm, structured according to traditional optimal control strategies, is designed to solve the algebraic Riccati equation (ARE). Employing Lyapunov theory, we rigorously derive the convergence of the offline PI algorithm and the admissibility of the iterative control law through mathematical analysis. This article represents the first attempt to tackle these technical challenges. Subsequently, to address the limitations inherent in the offline algorithm, we introduce a novel online Q -learning algorithm tailored for Itô stochastic systems with Markovian jumps. The proposed Q -learning algorithm obviates the need for transition probabilities and system matrices. We provide a thorough stability analysis of the closed-loop system. Finally, the effectiveness and applicability of the proposed algorithms are demonstrated through a simulation example, underpinned by the theorems established herein.

14.
Sci Rep ; 14(1): 12765, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834645

RESUMO

Blood flow infections (BSIs) is common occurrences in intensive care units (ICUs) and are associated with poor prognosis. The study aims to identify risk factors and assess mortality among BSI patients admitted to the ICU at Shanghai Ruijin hospital north from January 2022 to June 2023. Additionally, it seeks to present the latest microbiological isolates and their antimicrobial susceptibility. Independent risk factors for BSI and mortality were determined using the multivariable logistic regression model. The study found that the latest incidence rate of BSI was 10.11%, the mortality rate was 35.21% and the mean age of patients with BSI was 74 years old. Klebsiella pneumoniae was the predominant bacterial isolate. Logistic multiple regression revealed that tracheotomy, tigecycline, gastrointestinal bleeding, shock, length of hospital stay, age and laboratory indicators (such as procalcitonine and hemoglobin) were independent risk factors for BSI. Given the elevated risk associated with use of tracheotomy and tigecycline, it underscores the importance of the importance of cautious application of tracheostomy and empirical antibiotic management strategies. Meanwhile, the independent risk factors of mortality included cardiovascular disease, length of hospital stay, mean platelet volume (MPV), uric acid levels and ventilator. BSI patients exhibited a significant decrease in platelet count, and MPV emerged as an independent factor of mortality among them. Therefore, continuous monitoring of platelet-related parameters may aid in promptly identifying high-risk patients and assessing prognosis. Moreover, monitoring changes in uric acid levels may serve as an additional tool for prognostic evaluation in BSI patients.


Assuntos
Bacteriemia , Unidades de Terapia Intensiva , Centros de Atenção Terciária , Humanos , China/epidemiologia , Masculino , Idoso , Fatores de Risco , Feminino , Pessoa de Meia-Idade , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Tempo de Internação , Incidência , Klebsiella pneumoniae/isolamento & purificação , Klebsiella pneumoniae/patogenicidade , Adulto
15.
J Thromb Haemost ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38788977

RESUMO

BACKGROUND: Protein C (PC) pathway serves as a major defense mechanism against thrombosis by the activation of PC through the thrombin-thrombomodulin complex and subsequent inactivation of the activated factor (F)V (FVa) and FVIII (FVIIIa) with the assistance of protein S, thereby contributing to hemostatic balance. We identified 2 unrelated patients who suffered from recurrent thrombosis and carried the same heterozygous mutation c.1153A>G, p.Met343Val (M343V), in PROC gene. This mutation had not been previously reported. OBJECTIVES: To explore the molecular basis underlying the anticoagulant defect in patients carrying the M343V mutation in PROC. METHODS: We expressed PC-M343V variant in mammalian cells and characterized its properties through coagulation assays. RESULTS: Our findings demonstrated that while activation of mutant zymogen by thrombin-thrombomodulin complex was slightly affected, cleavage of chromogenic substrate by APC-M343V was significantly impaired. However, Ca2+ increased the cleavage efficiency by approximately 50%. Additionally, there was a severe reduction in affinity between APC-M343V and Na+. Furthermore, the inhibitory ability of APC-M343V toward FVa was markedly impaired. Structural and simulation analyses suggested that Val343 might disrupt the potential hydrogen bonds with Trp380 and cause Trp380 to orient closer to His211, potentially interfering with substrate binding and destabilizing the catalytic triad of APC. CONCLUSION: The M343V mutation in patients adversely affects the reactivity and/or folding of the active site as well as the binding of the physiological substrate to the protease, resulting in impaired protein C anticoagulant activity and ultimately leading to thrombosis.

16.
mSystems ; 9(6): e0116423, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38747582

RESUMO

Salmonella 4,[5],12:i:-, a monophasic variant of Salmonella Typhimurium, has emerged as a global cause of multidrug-resistant salmonellosis and has become endemic in many developing and developed countries, especially in China. Here, we have sequenced 352 clinical isolates in Guangdong, China, during 2009-2019 and performed a large-scale collection of Salmonella 4,[5],12:i:- with whole genome sequencing (WGS) data across the globe, to better understand the population structure, antimicrobial resistance (AMR) genomic characterization, and transmission routes of Salmonella 4,[5],12:i:- across Guangdong. Salmonella 4,[5],12:i:- strains showed broad genetic diversity; Guangdong isolates were found to be widely distributed among the global lineages. Of note, we identified the formation of a novel Guangdong clade (Bayesian analysis of population structure lineage 1 [BAPS1]) genetically diversified from the global isolates and likely emerged around 1990s. BAPS1 exhibits unique genomic features, including large pan-genome, decreased ciprofloxacin susceptibility due to mutation in gyrA and carriage of plasmid-mediated quinolone resistance (PMQR) genes, and the multidrug-resistant IncHI2 plasmid. Furthermore, high genetic similarity was found between strains collected from Guangdong, Europe, and North America, indicating the association with multiple introductions from overseas. These results suggested that global dissemination and local clonal expansion simultaneously occurred in Guangdong, China, and horizontally acquired resistance to first-line and last-line antimicrobials at local level, underlying emergences of extensive drug and pan-drug resistance. Our findings have increased the knowledge of global and local epidemics of Salmonella 4,[5],12:i:- in Guangdong, China, and provided a comprehensive baseline data set essential for future molecular surveillance.IMPORTANCESalmonella 4,[5],12:i:- has been regarded as the predominant pandemic serotype causing diarrheal diseases globally, while multidrug resistance (MDR) constitutes great public health concerns. This study provided a detailed and comprehensive genome-scale analysis of this important Salmonella serovar in the past decade in Guangdong, China. Our results revealed the complexity of two distinct transmission modes, namely global transmission and local expansion, circulating in Guangdong over a decade. Using phylogeography models, the origin of Salmonella 4,[5],12:i:- was predicted from two aspects, year and country, that is, Salmonella 4,[5],12:i:- emerged in 1983, and was introduced from the UK, and subsequently differentiated into the local endemic lineage circa 1991. Additionally, based on the pan-genome analysis, it was found that the gene accumulation rate in local endemic BAPS 1 lineage was higher than in other lineages, and the horizontal transmission of MDR IncHI2 plasmid associated with high resistance played a major role, which showed the potential threat to public health.


Assuntos
Farmacorresistência Bacteriana Múltipla , Infecções por Salmonella , Sequenciamento Completo do Genoma , China/epidemiologia , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Infecções por Salmonella/microbiologia , Infecções por Salmonella/epidemiologia , Infecções por Salmonella/transmissão , Infecções por Salmonella/tratamento farmacológico , Antibacterianos/farmacologia , Genoma Bacteriano/genética , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Testes de Sensibilidade Microbiana , Filogenia , Genômica , Plasmídeos/genética
17.
J Hazard Mater ; 472: 134530, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38718514

RESUMO

Constructing green and sustainable advanced oxidation processes (AOPs) for the degradation of organic contaminants is of great importance but still remains big challenge. In this work, an effective AOP (MnFe2O4-activated periodate, MnFe2O4/PI) was established and investigated for the oxidation of organic contaminants. To avoid the severe aggregation of MnFe2O4 nanoparticles, a hybrid MnFe2O4-biochar catalyst (MnFe2O4-BC) was further synthesized by anchoring MnFe2O4 nanoparticles on chemically inert biochar substrate. Intriguingly, MnFe2O4-BC/PI exhibited different selectivity towards organic contaminants compared with MnFe2O4/PI, revealing that biochar not only served as the substrate, but also directly participated into the oxidation process. Electron-transfer mechanism was comprehensively elucidated to be responsible for the abatement of pollutants in both MnFe2O4/PI and MnFe2O4-BC/PI. The surface oxygen vacancies (OVs) of MnFe2O4 were identified as the active sites for the formation of high potential complexes MnFe2O4-PI*, which could directly and indirectly degrade the organic pollutants. For the hybrid MnFe2O4-BC catalyst, biochar played multiple roles: (i) substrate, (ii) provided massive adsorption sites, (iii) electron-transfer mediator. The differences in selectivity of MnFe2O4/PI and MnFe2O4-BC/PI were determined by the adsorption affinity between biochar substrate and organics. Overall, the findings of this study expand the knowledge on the selectivity of PI-triggered AOPs.


Assuntos
Carvão Vegetal , Compostos Férricos , Compostos de Manganês , Oxirredução , Carvão Vegetal/química , Compostos de Manganês/química , Compostos Férricos/química , Catálise , Transporte de Elétrons , Poluentes Químicos da Água/química
18.
Cell Biol Toxicol ; 40(1): 37, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38777957

RESUMO

Bisphenol A (BPA) is a common component in the manufacture of daily plastic consumer goods. Recent studies have suggested that prenatal exposure to BPA can increase the susceptibility of offspring to mental illness, although the underlying mechanisms remain unclear. In this study, we performed transcriptomic and epigenomic profiling in the adult mouse brain following prenatal exposure to low-dose BPA. We observed a sex-specific transcriptional dysregulation in the cortex, with more significant differentially expressed genes was observed in adult cortex from male offspring. Moreover, the upregulated genes primarily influenced neuronal functions, while the downregulated genes were significantly associated with energy metabolism pathways. More evidence supporting impaired mitochondrial function included a decreased ATP level and a reduced number of mitochondria in the cortical neuron of the BPA group. We further investigated the higher-order chromatin regulatory patterns of DEGs by incorporating published Hi-C data. Interestingly, we found that upregulated genes exhibited more distal interactions with multiple enhancers, while downregulated genes displayed relatively short-range interactions among adjacent genes. Our data further revealed decreased H3K9me3 signal on the distal enhancers of upregulated genes, whereas increased DNA methylation and H3K27me3 signals on the promoters of downregulated genes. In summary, our study provides compelling evidence for the potential health risks associated with prenatal exposure to BPA, and uncovers sex-specific transcriptional changes with a complex interplay of multiple epigenetic mechanisms.


Assuntos
Compostos Benzidrílicos , Encéfalo , Metilação de DNA , Epigênese Genética , Fenóis , Efeitos Tardios da Exposição Pré-Natal , Animais , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Epigênese Genética/efeitos dos fármacos , Masculino , Camundongos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Camundongos Endogâmicos C57BL
19.
Int J Pharm ; 658: 124225, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38750982

RESUMO

High-altitude sleep disturbance is a common symptom of acute mountain sickness, which can be alleviated via modulation of the gut-brain axis. Quercetin (Que) is used to modulate gut microbiota and serves as a potential drug to regulate the gut-brain axis, but the poor solubility and bioavailability affect its biological functions. Here, Que nanoparticles (QNPs) were prepared with zein using an antisolvent method, and QNP-loaded calcium alginate hydrogel microspheres (QNP@HMs) were prepared using electrospinning technology to improve the gastrointestinal stability and intestinal adhesion of QNPs. In the mouse model of high-altitude sleep disturbance, oral administration of QNP@HMs before the mice entering high altitude prolonged sleep duration, improved blood cell recovery, spontaneous behavior and short-term memory, and reduced such inflammation factors as TNF-α and iNOS. Moreover, QNP@HMs enhanced the abundance of probiotics in the gut, including Lactobacillus and Lachnospira, and reduced intestinal inflammation. However, in the mice after gut sterilization by long-term oral antibiotics, QNP@HMs showed no therapeutic effect. QNP@HMs are a promising medication for the prevention of high-altitude sleep disturbance based on the gut-brain axis.


Assuntos
Encéfalo , Microbioma Gastrointestinal , Hidrogéis , Microesferas , Nanopartículas , Quercetina , Animais , Quercetina/administração & dosagem , Quercetina/farmacologia , Quercetina/química , Nanopartículas/administração & dosagem , Hidrogéis/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Administração Oral , Masculino , Camundongos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Alginatos/química , Alginatos/administração & dosagem , Probióticos/administração & dosagem
20.
Org Lett ; 26(21): 4548-4553, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38757610

RESUMO

gem-Difluoroalkenes and monofluorinated cycloalkenes have emerged as basic structural units in a variety of bioactive molecules and natural products. Thus, developing straightforward and efficient methods for synthesizing fluorinated alkene compounds is of considerable significance. Herein, we disclose a visible-light-induced defluorination of 2-trifluoromethyl-1-alkene via a 1,5-HAT process using N-alkoxyphtalimides as both radical precursor and potential nucleophile. The mild and stepwise reaction leads to a variety of structurally diverse gem-difluoroalkenes and monofluorinated cyclooctenes with high efficiency, respectively.

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