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1.
Lancet Neurol ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38614108

RESUMO

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

3.
Materials (Basel) ; 17(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38591570

RESUMO

Hydration plays a crucial role in cement composites, but the traditional methods for measuring hydration heat face several limitations. In this study, we propose a machine learning-based approach to predict hydration heat at specific time points for three types of cement composites: ordinary Portland cement pastes, fly ash cement pastes, and fly ash-metakaolin cement composites. By adjusting the model architecture and analyzing the datasets, we demonstrate that the optimized artificial neural network model not only performs well during the learning process but also accurately predicts hydration heat for various cement composites from an extra dataset. This approach offers a more efficient way to measure hydration heat for cement composites, reducing the need for labor- and time-intensive sample preparation and testing. Furthermore, it opens up possibilities for applying similar machine learning approaches to predict other properties of cement composites, contributing to efficient cement research and production.

4.
Water Res ; 256: 121591, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38615606

RESUMO

Risk assessment and adaptation have become key focuses in the examination of urban flooding risk. In recent decades, global climate change has resulted in a high incidence of extreme weather events, notably flooding. This study introduces a spatial multi-indicator model developed for assessing flood risk at the urban agglomeration scale. A crucial addition to the model is the incorporation of an adaptive capacity within the IPCC risk framework. The model systematically considers various flood risk indicators related to the economic, social, and geographic environments of the central and southern Liaoning urban agglomeration (CSLN). It generates a spatial distribution map of integrated flood risk for multiple scenario combinations. Furthermore, the intricate relationship between different risk indicators and flood risk was analyzed using correlation analysis and the Light Gradient Boosting Machine model (Light GBM). The findings reveal notable variations in flood risk under different scenarios. The inclusion of vulnerability indicators increased flood risk by 33 %, while the subsequent inclusion of adaptive indicators decreased flood risk by 45 %. Dense populations and assets contribute to high flood risk, while adaptive capacity significantly mitigates urban flood risk. The framework adopted in this paper can be applied to other areas where urban agglomeration-scale flood risk assessment is needed, and can contribute to advancing scientific research on flood forecasting and mitigation.

5.
J Colloid Interface Sci ; 665: 888-897, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38564953

RESUMO

Piezoelectric catalysis, which converts mechanical energy into chemical activity, has important applications in environmental remediation. However, the piezo-catalytic activity of various piezoelectric materials is limited by the weak piezoelectricity as well as the mismatched band-gap, leading to inefficient electron-hole pair generation and difficult carrier migration. Here, a simple strategy combining phase boundary and energy band structure modulation was innovatively proposed to enhance the piezo-catalytic activity of BaTiO3 ferroelectric by Ce ions selecting different doping sites. Thanks to the coexistence of tetragonal (P4mm) and orthorhombic (Amm2) phases effectively flattened the Gibbs free-energy and thus enhanced the piezoelectric activity, as well as suitable energy bandwidth facilitating the carrier migration were realized in the B-sites doped Ba(Ti0.95Ce0.05)O3. The degradation rate constant k of tetracycline (TC) was high to 30.56 × 10-3 min-1, which was 2.03 times higher than that of pure BaTiO3 and superior to most representative lead-free perovskite piezoelectric materials. Theoretical calculations validated that the charge density and high O2 and OH- adsorption energy on the Ba(Ti0.95Ce0.05)O3 surface promoted more efficient •O2- and •OH radicals conversion and bettered response to piezo-catalytic reaction. This work is important to design high-performance piezo-catalysts by synergistic regulation of phase boundary and energy band structure in perovskite materials for long-term antibiotic tetracycline removal.

6.
Nat Commun ; 15(1): 3124, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600164

RESUMO

Crop wild relatives offer natural variations of disease resistance for crop improvement. Here, we report the isolation of broad-spectrum powdery mildew resistance gene Pm36, originated from wild emmer wheat, that encodes a tandem kinase with a transmembrane domain (WTK7-TM) through the combination of map-based cloning, PacBio SMRT long-read genome sequencing, mutagenesis, and transformation. Mutagenesis assay reveals that the two kinase domains and the transmembrane domain of WTK7-TM are critical for the powdery mildew resistance function. Consistently, in vitro phosphorylation assay shows that two kinase domains are indispensable for the kinase activity of WTK7-TM. Haplotype analysis uncovers that Pm36 is an orphan gene only present in a few wild emmer wheat, indicating its single ancient origin and potential contribution to the current wheat gene pool. Overall, our findings not only provide a powdery mildew resistance gene with great potential in wheat breeding but also sheds light into the mechanism underlying broad-spectrum resistance.


Assuntos
Ascomicetos , Triticum , Triticum/genética , Melhoramento Vegetal , Genes de Plantas , Ascomicetos/genética , Mapeamento Cromossômico , Resistência à Doença/genética , Doenças das Plantas/genética
7.
Ear Nose Throat J ; : 1455613231206287, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38577914

RESUMO

Objective: To provide the experience of diagnosis and treatment of second branchial cleft fistula in children. Methods: The clinical data of 76 children with second branchial cleft fistulas admitted to Beijing Children's Hospital affiliated with Capital Medical University from January 2016 to December 2020 were retrospectively analyzed. All patients underwent cervical ultrasonography and resection of the second branchial cleft fistula, and their clinical manifestations, surgical methods, complications, recurrence condition, and lesion appearance of the patients were analyzed. Results: Among the 76 cases, the lesions of 43 cases were on the right side, 20 were on the left side, and 13 were bilateral, for a total of 89 lesions. There were 49 type I lesions, 28 type II lesions, 8 type III lesions, and 4 type IV lesions. Type I and type II cases underwent complete excision of the fistula through a small incision in the neck; 2 cases of type III branchial cleft fistulas were treated with trapezoidal incision; 2 cases of type III branchial cleft fistulas underwent single transverse incisions; single small incision-assisted endoscopic resection was adopted in 4 cases of type III and 4 cases of type IV branchial cleft fistulas. During the follow-up period of 6 to 60 months, only 3 cases developed postoperative infection, the others had no postoperative complications, and no cases had recurrence during postoperative follow-up. Conclusion: The incision of the second branchial fistula should be selected according to imaging examination to achieve removal of the fistula while maintaining esthetics.

8.
Phytomedicine ; 127: 155461, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38452697

RESUMO

BACKGROUND: The active ingredients of the Chinese medical herb Paris polyphylla, P. polyphylla ethanol extract (PPE) and polyphyllin I (PPI), potentially inhibit epithelial-mesenchymal transition (EMT) in tumors. However, the roles of these ingredients in inhibiting EMT in adenomyosis (AM) remain to be explored. PURPOSE: The primary goal of the study was to uncover the underlying molecular processes through which PPE and PPI suppress EMT in AM, alongside assessing the safety profiles of these substances. METHODS: To assess the suppressive impact of PPE on adenomyosis-derived cells (AMDCs), we employed Transwell and wound healing assays. The polyphyllins (PPI, PPII, PPVII) contained in PPE were characterized using high-performance liquid chromatography (HPLC). Then, bioinformatics techniques were performed to pinpoint potential PPI targets that could be effective in treating AM. Immunoblotting was used to verify the key proteins and pathways identified via bioinformatics. Furthermore, we examined the efficacy of PPE and PPI in treating Institute of Cancer Research (ICR) mice with AM by observing the morphological and pathological features of the uterus and performing immunohistochemistry. In addition, we assessed safety by evaluating liver, kidney and spleen pathologic features and serum test results. RESULTS: Three major polyphyllins of PPE were revealed by HPLC, and PPI had the highest concentration. In vitro experiments indicated that PPE and PPI effectively prevent AMDCs invasion and migration. Bioinformatics revealed that the primary targets E-cadherin, N-cadherin and TGFß1, as well as the EMT biological process, were enriched in PPI-treated AM. Immunoblotting assays corroborated the hypothesis that PPE and PPI suppress the TGFß1/Smad2/3 pathway in AMDCs to prevent EMT from progressing. Additionally, in vivo studies showed that PPE (3 mg/kg and 6 mg/kg) and PPI (3 mg/kg and 6 mg/kg), successfully suppressed the EMT process through targeting the TGFß1/Smad2/3 signaling pathway. Besides, it was observed that lower doses of PPE (3 mg/kg) and PPI (3 mg/kg) exerted minimal effects on the liver, kidneys, and spleen. CONCLUSIONS: PPE and PPI efficiently impede the development of EMT by inhibiting the TGFß1/Smad2/3 pathway, revealing an alternative pathway for the pharmacological treatment of AM.


Assuntos
Adenomiose , Antineoplásicos , Diosgenina/análogos & derivados , Liliaceae , Humanos , Feminino , Animais , Camundongos , Adenomiose/tratamento farmacológico , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal
9.
Molecules ; 29(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38474537

RESUMO

Spider silk protein, renowned for its excellent mechanical properties, biodegradability, chemical stability, and low immune and inflammatory response activation, consists of a core domain with a repeat sequence and non-repeating sequences at the N-terminal and C-terminal. In this review, we focus on the relationship between the silk structure and its mechanical properties, exploring the potential applications of spider silk materials in the detection of energetic materials.


Assuntos
Seda , Aranhas , Sequências Repetitivas de Ácido Nucleico , Seda/química , Animais
10.
BMC Pediatr ; 24(1): 215, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528506

RESUMO

BACKGROUND: Neonatal respiratory distress syndrome (NRDS) is a prevalent cause of respiratory failure and death among newborns, and prompt diagnosis is imperative. Historically, diagnosis of NRDS relied mostly on typical clinical manifestations, chest X-rays, and CT scans. However, recently, ultrasound has emerged as a valuable and preferred tool for aiding NRDS diagnosis. Nevertheless, evaluating lung ultrasound imagery necessitates rigorous training and may be subject to operator-dependent bias, limiting its widespread use. As a result, it is essential to investigate a new, reliable, and operator-independent diagnostic approach that does not require subjective factors or operator expertise. This article aims to explore the diagnostic potential of ultrasound-based radiomics in differentiating NRDS from other non-NRDS lung disease. METHODS: A total of 150 neonatal lung disease cases were consecutively collected from the department of neonatal intensive care unit of the Quanzhou Maternity and Children's Hospital, Fujian Province, from September 2021 to October 2022. Of these patients, 60 were diagnosed with NRDS, whereas 30 were diagnosed with neonatal pneumonia, meconium aspiration syndrome (MAS), and transient tachypnea (TTN). Two ultrasound images with characteristic manifestations of each lung disease were acquired and divided into training (n = 120) and validation cohorts (n = 30) based on the examination date using an 8:2 ratio. The imaging texture features were extracted using PyRadiomics and, after the screening, machine learning models such as random forest (RF), logistic regression (LR), K-nearest neighbors (KNN), support vector machine (SVM), and multilayer perceptron (MLP) were developed to construct an imaging-based diagnostic model. The diagnostic efficacy of each model was analyzed. Lastly, we randomly selected 282 lung ultrasound images and evaluated the diagnostic efficacy disparities between the optimal model and doctors across differing levels of expertise. RESULTS: Twenty-two imaging-based features with the highest weights were selected to construct a predictive model for neonatal respiratory distress syndrome. All models exhibited favorable diagnostic performances. Analysis of the Youden index demonstrated that the RF model had the highest score in both the training (0.99) and validation (0.90) cohorts. Additionally, the calibration curve indicated that the RF model had the best calibration (P = 0.98). When compared to the diagnostic performance of experienced and junior physicians, the RF model had an area under the curve (AUC) of 0.99; however, the values for experienced and junior physicians were 0.98 and 0.85, respectively. The difference in diagnostic efficacy between the RF model and experienced physicians was not statistically significant (P = 0.24), whereas that between the RF model and junior physicians was statistically significant (P < 0.0001). CONCLUSION: The RF model exhibited excellent diagnostic performance in the analysis of texture features based on ultrasound radiomics for diagnosing NRDS.


Assuntos
Síndrome do Desconforto Respiratório do Recém-Nascido , Humanos , Recém-Nascido , Área Sob a Curva , Síndrome de Aspiração de Mecônio , 60570 , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico por imagem , Ultrassonografia
11.
Sci Total Environ ; 926: 172066, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38556022

RESUMO

The interactions and collective impacts of different types of hazards within a compound hazard system, along with the influence of geographical covariates on flooding are presently unclear. Understanding these relationships is crucial for comprehending the formation and dynamic processes of the hazard chain and improving the ability to identify flood warning signals in complex hazard scenarios. In this study, we presented a multivariate spatial extreme value hierarchical (MSEVH) framework to assess the spatial extreme water levels (EWL) at different return levels under the influence of a hazard chain and geographical covariates. The Pearl River Delta (PRD) was selected as a research example to assess the effectiveness of the MSEVH framework. Firstly, we identified a hazard chain (extreme streamflow from the Xijiang River (XR) - extreme streamflow from the Beijiang River (BR) - extreme sea level) and three geographical covariates influencing EWL in the PRD. Then, we compared four hazard scenarios in the MSEVH framework to evaluate the spatial EWL at different return levels under the influence of the hazard chain in the PRD. The final step involves assessing spatial EWL with the effect of the hazard chain and geographical covariates. The results indicate that when extreme streamflow from XR and BR occurs concurrently, the extreme streamflow from BR weakens the influence of extreme streamflow from XR on EWL in the PRD. However, it cannot fully offset the overall impact of extreme streamflow from XR on EWL. In addition, when extreme streamflow from XR, extreme streamflow from BR, and extreme sea level occur simultaneously, the extreme sea level enhances the influence of concurrent extreme streamflow from XR and BR on EWL in the PRD. The proposed MSEVH is not only applicable to the PRD but also shows promising potential for evaluating extreme hydrometeorological variables under the influence of other hazard chains.

12.
JMIR Aging ; 7: e50880, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38533782

RESUMO

Background: The potential benefits of IT for the well-being of older adults have been widely anticipated. However, findings regarding the impact of internet use on depressive symptoms are inconsistent. As a result of IT's exponential growth, internet skills have supplanted internet access as the source of the digital divide. Objective: This study evaluates the effect of internet skills on depressive symptoms through an instrumental variables (IV) approach. Methods: Data from the China Health and Retirement Longitudinal Study's wave 4 (2018) were used. This included 16,949 community residents aged 45 years and older. To overcome the endogeneity issue, we used an IV approach. Results: Our results reveal the emergence of a second-level digital divide, the disparity in internet skills, among Chinese middle-aged and older adults. Liner regression suggests that a 1% increase in internet skills is associated with a 0.037% decrease in depressive symptoms (ß=-.037, SE 0.009), which underestimates the causal effect. As expected, internet skills are an endogenous variable (F test P value <.001). IV regressions indicate that a 1% increase in internet skills reduces 1.135% (SE 0.471) to 1.741% (SE 0.297) of depressive symptoms. These 2 IV are neither weak (F-1=16.7 and 28.5; both >10) nor endogenous (Wu-Hausman test P value of .10; >.05 or >.01). Conclusions: Better mental health is predicted through improved and higher internet skills. Consequently, residents and policy makers in China should focus on bridging the digital divide in internet skills among middle-aged and older adults.


Assuntos
Depressão , Internet , Pessoa de Meia-Idade , Humanos , Idoso , Depressão/psicologia , Estudos Longitudinais , Estudos Transversais , China
13.
ACS Infect Dis ; 10(4): 1201-1211, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38457660

RESUMO

Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis and the second-most contagious killer after COVID-19. The emergence of drug-resistant TB has caused a great need to identify and develop new anti-TB drugs with novel targets. Indole propionic acid (IPA), a structural analog of tryptophan (Trp), is active against M. tuberculosis in vitro and in vivo. It has been verified that IPA exerts its antimicrobial effect by mimicking Trp as an allosteric inhibitor of TrpE, which is the first enzyme in the Trp synthesis pathway of M. tuberculosis. However, other Trp structural analogs, such as indolmycin, also target tryptophanyl-tRNA synthetase (TrpRS), which has two functions in bacteria: synthesis of tryptophanyl-AMP by catalyzing ATP + Trp and producing Trp-tRNATrp by transferring Trp to tRNATrp. So, we speculate that IPA may also target TrpRS. In this study, we found that IPA can dock into the Trp binding pocket of M. tuberculosis TrpRS (TrpRSMtb), which was further confirmed by isothermal titration calorimetry (ITC) assay. The biochemical analysis proved that TrpRS can catalyze the reaction between IPA and ATP to generate pyrophosphate (PPi) without Trp as a substrate. Overexpression of wild-type trpS in M. tuberculosis increased the MIC of IPA to 32-fold, and knock-down trpS in Mycolicibacterium smegmatis made it more sensitive to IPA. The supplementation of Trp in the medium abrogated the inhibition of M. tuberculosis by IPA. We demonstrated that IPA can interfere with the function of TrpRS by mimicking Trp, thereby impeding protein synthesis and exerting its anti-TB effect.


Assuntos
Mycobacterium tuberculosis , Propionatos , Triptofano-tRNA Ligase , Tuberculose , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Triptofano-tRNA Ligase/genética , Triptofano-tRNA Ligase/química , Triptofano-tRNA Ligase/metabolismo , RNA de Transferência de Triptofano/metabolismo , Indóis/farmacologia , Trifosfato de Adenosina
14.
Macromol Biosci ; : e2300528, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38444237

RESUMO

Hydrogel wound dressing can accelerate angiogenesis to achieve rapid wound healing, but traditional hydrogel dressings are difficult to meet the repair of joint sites due to their low mechanical strength. Therefore, we constructed the gel system by designing the chemical-physical interpenetrating network structure to achieve high strength and high toughness of the hydrogel. The high-strength double-network hydrogels were synthesized by simple free radical polymerization and low-temperature physicochemical cross-linking in our experiments. The suspension was obtained by green reduction of graphene oxide with carboxymethyl chitosan, followed by the introduction of acrylamide (AM) to form a covalent cross-linked network, which was immersed in ferric chloride solution to form metal ligand bonds, and finally the chemical-physical dual cross-linked network hydrogel wound dressing was prepared. Here, reduced graphene oxide can enhance electrical conductivity and excellent near-infrared photothermal effect to the hydrogel. The cell viability of this novel wound dressing was above 90.0%, its hemolysis rate was below 2.0%, and the electrical conductivity could reach (6.89 ± 0.07 (mS/cm)). In addition, the stress-strain curve demonstrated that the double cross-linked network hydrogel could reach a stress of more than 0.8 MPa at 82.0% strain, and the cyclic compression experiment shows that it can still recover its original shape after five times of repeated compression. This work can provide a reference for the exploitation of high mechanical strength hydrogel wound dressings with good electrical conductivity and near-infrared photothermal effect. This article is protected by copyright. All rights reserved.

15.
Elife ; 122024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38483314

RESUMO

Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms that maintain HC survival is crucial for preventing hearing impairment. Intriguingly, Pou4f3-/- or Gfi1-/- HCs form initially but then rapidly degenerate, whereas Rbm24-/- HCs degenerate considerably later. However, the transcriptional cascades involving Pou4f3, Gfi1, and Rbm24 remain undescribed. Here, we demonstrate that Rbm24 expression is completely repressed in Pou4f3-/- HCs but unaltered in Gfi1-/- HCs, and further that the expression of both POU4F3 and GFI1 is intact in Rbm24-/- HCs. Moreover, by using in vivo mouse transgenic reporter assays, we identify three Rbm24 enhancers to which POU4F3 binds. Lastly, through in vivo genetic testing of whether Rbm24 restoration alleviates the degeneration of Pou4f3-/- HCs, we show that ectopic Rbm24 alone cannot prevent Pou4f3-/- HCs from degenerating. Collectively, our findings provide new molecular and genetic insights into how HC survival is regulated.


Assuntos
Terapia Genética , Fatores de Transcrição , Animais , Camundongos , Animais Geneticamente Modificados , Fatores de Transcrição/genética , Células Ciliadas Auditivas , Som , Mamíferos , Proteínas de Homeodomínio , Fator de Transcrição Brn-3C/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA
16.
Int J Mol Sci ; 25(5)2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38474177

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) can cause a variety of malignancies. Ganciclovir (GCV) is one of the most efficient drugs against KSHV, but its non-specificity can cause other side effects in patients. Nucleic acid miR-34a-5p can inhibit the transcription of KSHV RNA and has great potential in anti-KSHV therapy, but there are still problems such as easy degradation and low delivery efficiency. Here, we constructed a co-loaded dual-drug nanocomplex (GCV@ZIF-8/PEI-FA+miR-34a-5p) that contains GCV internally and adsorbs miR-34a-5p externally. The folic acid (FA)-coupled polyethyleneimine (PEI) coating layer (PEI-FA) was shown to increase the cellular uptake of the nanocomplex, which is conducive to the enrichment of drugs at the KSHV infection site. GCV and miR-34a-5p are released at the site of the KSHV infection through the acid hydrolysis characteristics of ZIF-8 and the "proton sponge effect" of PEI. The co-loaded dual-drug nanocomplex not only inhibits the proliferation and migration of KSHV-positive cells but also decreases the mRNA expression level of KSHV lytic and latent genes. In conclusion, this co-loaded dual-drug nanocomplex may provide an attractive strategy for antiviral drug delivery and anti-KSHV therapy.


Assuntos
Herpesvirus Humano 8 , MicroRNAs , Sarcoma de Kaposi , Humanos , Herpesvirus Humano 8/genética , Ganciclovir/farmacologia , MicroRNAs/genética , Sarcoma de Kaposi/genética
17.
Theor Appl Genet ; 137(3): 63, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427048

RESUMO

KEY MESSAGE: The gene BrABCG26 responsible for male sterility of Chinese cabbage was confirmed by two allelic mutants. Male-sterile lines are an important way of heterosis utilization in Chinese cabbage. In this study, two allelic male-sterile mutants msm3-1 and msm3-2 were obtained from a Chinese cabbage double haploid (DH) line 'FT' by using EMS-mutagenesis. Compared to the wild-type 'FT,' the stamens of mutants were completely degenerated and had no pollen, and other characters had no obvious differences. Cytological observation revealed that the failure of vacuolation of the mononuclear microspore, accompanied by abnormal tapetal degradation, resulted in anther abortion in mutants. Genetic analysis showed that a recessive gene controlled the mutant trait. MutMap combined with kompetitive allele specific PCR genotyping analyses showed that BraA01g038270.3C, encoding a transporter ABCG26 that played a vital role in pollen wall formation, was the candidate gene for msm3-1, named BrABCG26. Compared with wild-type 'FT,' the mutations existed on the second exon (C to T) and the sixth exon (C to T) of BrABCG26 gene in mutants msm3-1 and msm3-2, leading to the loss-of-function truncated protein, which verified the BrABCG26 function in stamen development. Subcellular localization and expression pattern analysis indicated that BrABCG26 was localized in the nucleus and was expressed in all organs, with the highest expression in flower buds. Compared to the wild-type 'FT,' the expressions of BrABCG26 were significantly reduced in flower buds and anthers of mutants. Promoter activity analysis showed that a strong GUS signal was detected in flower buds. These results indicated that BrABCG26 is responsible for the male sterility of msm3 mutants in Chinese cabbage.


Assuntos
Brassica rapa , Brassica , Infertilidade Masculina , Masculino , Humanos , Brassica rapa/genética , Perfilação da Expressão Gênica/métodos , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Plantas/genética , Brassica/genética , Mutação , Regulação da Expressão Gênica de Plantas , Infertilidade das Plantas/genética
18.
Heliyon ; 10(2): e24388, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38298688

RESUMO

To examine the impact of ginger volatile oil (GVO) on the growth of MDA-MB-231 breast cancer cells in the presence of bisphenol A (BPA) by modulating the diversity of gut microbiota. METHODS: MDA-MB-231 breast cancer cells were injected subcutaneously into the right armpit of female BALB/c Nude (nu/nu) mice to create a triple negative breast cancer model. Thirty nude mice were randomly divided into 5 groups: control group (distilled water every day), BPA control group (distilled PEG-400+ DMSO + cyclodextrin every day), BPA + GVO (0.25 mL/kg) group, BPA + GVO (0.5 mL/kg) group, BPA + GVO (1 mL/kg) group, 6 mice in each group; The drug was given by gavage once a day for 4 weeks. At the end of the experiment, the changes of tumor mass and tumor volume were observed and compared in 5 groups of tumor-bearing mice. High-throughput sequencing (16S rRNA) was used to detect the changes of gut microflora in each group. RESULTS: The volume and weight of breast cancer decreased in the low, medium and high dose groups of GVO. Among them, the difference between the high-dose group and the BPA group reached a significant level (P < 0.05). The species and abundance of gut flora decreased following BPA treatment, but increased after combined treatment of BPA with GVO. In the tumor control group, the ratio of Firmicutes(F) and Bacteroidea(B) respectively was 0.10:0.79 at the phylum level, while the ratio of BPA group further decreased (0.04:0.88). After feeding GVO, the number of Firmicutes and Bacteroidea increased, the F/B ratio increased, and the level of Lactobacillus and alistipes increased. In the BPA and GVO treatment group, the predominant gut microflora functions are cell membrane biogenesis, carbohydrate transport and metabolism. This is followed by amino acid transport and metabolism, and transcription function. After GVO administration, the Gram-positive bacteria (G+) ratio had an increasing trend and the Gram-negative bacteria (G-)ratio had a decreasing trend. CONCLUSION: The species and abundance of gut flora decreased following BPA treatment, but increased after combined treatment of BPA with GVO.

19.
Front Med (Lausanne) ; 11: 1321599, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38384419

RESUMO

Introduction: Critically ill patients are more susceptible to malnutrition due to their severe illness. Moreover, elderly patients who are critically ill lack specific nutrition recommendations, with nutritional care in the intensive care units (ICUs) deplorable for the elderly. This study aims to investigate nutrition treatment and its correlation to mortality in elderly patients who are critically ill in intensive care units. Method: A multiple-center prospective cohort study was conducted in China from 128 intensive care units (ICUs). A total of 1,238 elderly patients were included in the study from 26 April 2017. We analyzed the nutrition characteristics of elderly patients who are critically ill, including initiated timing, route, ways of enteral nutrition (EN), and feeding complications, including the adverse aspects of feeding, acute gastrointestinal injury (AGI), and feeding interruption. Multivariate logistic regression analysis was used to screen out the impact of nutrition treatment on a 28-day survival prognosis of elderly patients in the ICU. Result: A total of 1,238 patients with a median age of 76 (IQR 70-83) were enrolled in the study. The Sequential Organ Failure (SOFA) median score was 7 (interquartile range: IQR 5-10) and the median Acute Physiology and Chronic Health Evaluation (APACHE) II was 21 (IQR 16-25). The all-cause mortality score was 11.6%. The percentage of nutritional treatment initiated 24 h after ICU admission was 58%, with an EN of 34.2% and a parenteral nutrition (PN) of 16.0% in elderly patients who are critically ill. Patients who had gastrointestinal dysfunction with AGI stage from 2 to 4 were 25.2%. Compared to the survivors' group, the non-survivors group had a lower ratio of EN delivery (57% vs. 71%; p = 0.015), a higher ratio of post-pyloric feeding (9% vs. 2%; p = 0.027), and higher frequency of feeding interrupt (24% vs. 17%, p = 0.048). Multivariable logistics regression analysis showed that patients above 76 years old with OR (odds ratio) 2.576 (95% CI, 1.127-5.889), respiratory rate > 22 beats/min, and ICU admission for 24 h were independent risk predictors of the 28-day mortality study in elderly patients who are critically ill. Similarly, other independent risk predictors of the 28-day mortality study were those with an OR of 2.385 (95%CI, 1.101-5.168), lactate >1.5 mmol/L, and ICU admission for 24 h, those with an OR of 7.004 (95%CI, 2.395-20.717) and early PN delivery within 24 h of ICU admission, and finally those with an OR of 5.401 (95%CI, 1.175-24.821) with EN delivery as reference. Conclusion: This multi-center prospective study describes clinical characteristics, the mode and timing of nutrition treatment, frequency of AGI, and adverse effects of nutrition in elderly ICU patients. According to this survey, ICU patients with early PN delivery, older age, faster respiratory rate, and higher lactate level may experience poor prognosis.

20.
Adv Healthc Mater ; : e2303683, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38386961

RESUMO

Employing tumor whole cells for tumor immunotherapy is a promising tumor therapy proposed in the early stage, but its therapeutic efficacy is weakened by the methods of eliminating pathogenicity and the mass ratio of the effective antigen carried by itself. Here, by adding gold ion to live cancer cells in the microfluidic droplets, w e obtain dead tumor whole cells with NIR-controlled catalytic ability whose pathogenicity is removed while plenary tumor antigens, major structure, and homing ability are reserved. The engineered tumor cell (Cell-Au) with the addition of prodrug provides 1 O2 in an O2 -free Russell mechanism, which serves better in a hypoxic tumor microenvironment. This tumor whole-cell catalytic vaccine (TWCV) promotes the activation of dendritic cells and the transformation of macrophages into tumor suppressor phenotype. In 4T1 tumor-bearing mice, the Cell-Au-based vaccine supports the polarization of cytotoxicity T cells, resulting in tumor eradication and long-term animal survival. Compared with antigen vaccines or adoptive cell therapy which takes months to obtain, this TWCV can be prepared in just a few days with satisfactory immune activation and tumor therapeutic efficacy, which provides an alternative way for the preparation of personalized tumor vaccines across tumor types and gives immunotherapy a new path. This article is protected by copyright. All rights reserved.

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