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1.
Bioorg Chem ; 153: 107757, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39226649

RESUMEN

Diseases caused by plant viruses and pathogens pose a serious threat to crop yield and quality. Traditional pesticides have gradually developed drug resistance and brought certain environmental safety issues during long-term overuse. There is an urgent need to discover new candidate compounds to address these issues. In this study, we achieved the efficient synthesis of iheyamine A and its derivatives, and discovered their excellent antiviral activities against tobacco mosaic virus (TMV). Most compounds displayed higher antiviral activities against TMV than commercial ribavirin at 500 µg/mL, with compounds 3a (Inactive effect IC50: 162 µg/mL), 3d (Inactive effect IC50: 249 µg/mL), 6p (Inactive effect IC50: 254 µg/mL), and 7a (Inactive effect IC50: 234 µg/mL) exhibiting better antiviral activities than ningnanmycin at 500 µg/mL (Inactive effect IC50: 269 µg/mL). Meanwhile, the structure-activity relationships of this type of compounds were systematically studied. We chose 3a for further antiviral mechanism research and found that it can directly act on viral coat protein (CP). The interaction of 3a and CP was further verified via molecular docking. These compounds also showed broad-spectrum fungicidal activities against 8 plant pathogenic fungi, especially for P. piricola. This study provides a reference for the role of iheyamine alkaloids in combating plant pathogenic diseases.

2.
Support Care Cancer ; 32(10): 630, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39225814

RESUMEN

BACKGROUND: Detection of precachexia is important for the prevention and treatment of cachexia. However, how to identify precachexia is still a challenge. OBJECTIVE: This study aimed to detect cancer precachexia using a simple method and distinguish the different characteristics of precachexia and cachexia. METHODS: We included 3896 participants in this study. We used all baseline characteristics as input variables and trained machine learning (ML) models to calculate the importance of the variables. After filtering the variables based on their importance, the models were retrained. The best model was selected based on the receiver operating characteristic value. Subsequently, we used the same method and process to identify patients with precachexia in a noncachexia population using the same method and process. RESULTS: Participants in this study included 2228 men (57.2%) and 1668 women (42.8%), of whom 471 were diagnosed with precachexia, 1178 with cachexia, and the remainder with noncachexia. The most important characteristics of cachexia were eating changes, arm circumference, high-density lipoprotein (HDL) level, and C-reactive protein albumin ratio (CAR). The most important features distinguishing precachexia were eating changes, serum creatinine, HDL, handgrip strength, and CAR. The two logistic regression models for screening for cachexia and diagnosing precachexia had the highest area under the curve values of 0.830 and 0.701, respectively. Calibration and decision curves showed that the models had good accuracy. CONCLUSION: We developed two models for identifying precachexia and cachexia, which will help clinicians detect and diagnose precachexia.


Asunto(s)
Caquexia , Aprendizaje Automático , Neoplasias , Humanos , Caquexia/etiología , Caquexia/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias/complicaciones , Anciano , Estudios de Cohortes , Proteína C-Reactiva/análisis , Adulto
3.
Nutr J ; 23(1): 96, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39160526

RESUMEN

BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.


Asunto(s)
Envejecimiento , Menarquia , Menopausia , Encuestas Nutricionales , Fenotipo , Humanos , Femenino , Adulto , Envejecimiento/fisiología , Persona de Mediana Edad , Encuestas Nutricionales/estadística & datos numéricos , Encuestas Nutricionales/métodos , Menopausia/fisiología , Menarquia/fisiología , Embarazo , Anciano , Reproducción/fisiología , Historia Reproductiva , Estilo de Vida
4.
Int J Mol Sci ; 25(15)2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39125754

RESUMEN

The Dlk1-Dio3 domain is important for normal embryonic growth and development. The heart is the earliest developing and functioning organ of the embryo. In this study, we constructed a transcriptional termination model by inserting termination sequences and clarified that the lack of long non-coding RNA (lncRNA) expression in the Dlk1-Dio3 domain caused the death of maternal insertion mutant (MKI) and homozygous mutant (HOMO) mice starting from E13.5. Parental insertion mutants (PKI) can be born and grow normally. Macroscopically, dying MKI and HOMO embryos showed phenomena such as embryonic edema and reduced heart rate. Hematoxylin and eosin (H.E.) staining showed thinning of the myocardium in MKI and HOMO embryos. In situ hybridization (IHC) and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) showed downregulation of lncGtl2, Rian, and Mirg expression in MKI and HOMO hearts. The results of single-cell RNA sequencing (scRNA-Seq) analysis indicated that the lack of lncRNA expression in the Dlk1-Dio3 domain led to reduced proliferation of epicardial cells and may be an important cause of cardiac dysplasia. In conclusion, this study demonstrates that Dlk1-Dio3 domain lncRNAs play an integral role in ventricular development.


Asunto(s)
Proteínas de Unión al Calcio , Regulación del Desarrollo de la Expresión Génica , Corazón , Yoduro Peroxidasa , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , Ratones , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Corazón/embriología , Corazón/crecimiento & desarrollo , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Femenino , Desarrollo Embrionario/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proliferación Celular/genética , Embrión de Mamíferos/metabolismo , Proteínas Nucleares
5.
Biology (Basel) ; 13(8)2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39194532

RESUMEN

The global focus on fostering harmonious interactions and promoting rational coexistence among wildlife species to uphold or reinstate biodiversity remains a prominent area of interest. We conducted a study on the sable and yellow-throated marten in Taipinggou National Nature Reserve, Heilongjiang, China, using the line transect method and infrared camera traps from 2022 to 2023. We then analyzed the overlap of their suitable habitats and niches with the aim of gaining insight into the interspecific competition between these two species. We found that the suitable habitat areas for the sable and yellow-throated marten were 55.20 km2 and 23.28 km2, accounting for 24.86% and 10.48% of the total area of this study, respectively. The overlap between the suitable habitats for the sable and yellow-throated marten was 15.73 km2, accounting for 28.5% and 67.6% of their suitable habitat, supporting our Hypothesis 1. The first principal component (Dim1) of the niche explained 35.4% of the overall variability, which is mainly related to the environmental variables "Distance from Settlements" and "Distance from Roads". Overall, 25.5% of the total variability was explained by the second principal component (Dim2), associated with "Slope" and "Distance from Coniferous and Broadleaved Mixed Forest". The niches occupied by the sable and yellow-throated marten were both off-center of the environmental background space, with the niches of the sable being larger than those of the yellow-throated marten. Schoener's D index was 0.56, indicating a high degree of niche overlap between the sable and yellow-throated marten, supporting our Hypothesis 2. Our study is helpful in terms of formulating conservation and management policies for the sable and yellow-throated marten.

6.
Bioorg Chem ; 151: 107708, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39133973

RESUMEN

Pesticides play an important role in the development of agriculture, as they can prevent and control crop diseases and pests, improve crop yield and quality. However, the abuse and improper use of pesticides can lead to negative impacts such as environmental pollution and pest resistance issues. There is an urgent need to develop green, safe, and efficient pesticides. In this work, natural product arecoline was selected as parent structure, a series of arecoline derivatives were designed, synthesized, and systematically investigated antiviral activities against tobacco mosaic virus (TMV). These compounds were found to have good to excellent anti-TMV activities for the first time. The antiviral activities of 4a, 4 h, 4 l, 4p, 6a, 6c, and 6f are higher than that of ningnanmycin. Compounds 4 h (EC50 value 146 µg/mL) and 4p (EC50 value 161 µg/mL) with simple structures and excellent activities emerged as new antiviral candidates. We chose 4 h to further investigate the antiviral mechanism, which revealed that it can cause virus fragmentation by acting on the viral coat protein (CP). We further validated this result through molecular docking. These compounds also displayed broad-spectrum fungicidal activities against 8 plant pathogenic fungi. This work lays the theoretical foundation for the application of arecoline derivatives in the agricultural field.


Asunto(s)
Antivirales , Arecolina , Diseño de Fármacos , Oxadiazoles , Virus del Mosaico del Tabaco , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Oxadiazoles/química , Oxadiazoles/farmacología , Oxadiazoles/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Arecolina/farmacología , Arecolina/síntesis química , Arecolina/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular
7.
Enzyme Microb Technol ; 180: 110501, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39197217

RESUMEN

L-phosphinothricin (L-PPT) is the most popular broad-spectrum and highly effective herbicide. Transaminases (TAs) play a pivotal role in asymmetric synthesis of L-PPT, yet encounter the challenge of unfavorable reaction equilibrium. In this study, the novel dual transaminases cascade system (DTCS) was introduced to facilitate the synthesis of L-PPT. The specific amine transaminase BdATA, originating from Bradyrhizobium diazoefficiens ZJY088, was screened and identified. It exhibited remarkable activity, good stability, and required only 2.5 equivalents of isopropylamine to transform pyruvate effectively. By coupling BdATA with previously reported SeTA to construct the DTCS for pyruvate removal in situ, the L-PPT yield escalated from 37.37 % to 85.35 %. Three advantages of the DTCS were presented: the removal of pyruvate alleviated by-product inhibition, the use of isopropylamine reduced reliance on excess L-alanine, and no demand for expensive cofactors like NAD(P)H. It demonstrated an innovative idea for addressing the challenges associated with transaminase-mediated synthesis of L-PPT.


Asunto(s)
Aminobutiratos , Ácido Pirúvico , Transaminasas , Transaminasas/metabolismo , Aminobutiratos/metabolismo , Ácido Pirúvico/metabolismo , Bradyrhizobium/enzimología , Herbicidas , Proteínas Bacterianas/metabolismo , Aminas/metabolismo , Propilaminas/química
8.
Cell Death Dis ; 15(8): 566, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39107271

RESUMEN

Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.


Asunto(s)
Proliferación Celular , Progresión de la Enfermedad , Péptidos y Proteínas de Señalización Intercelular , Neoplasias Pancreáticas , Factor de Transcripción AP-1 , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Animales , Factor de Transcripción AP-1/metabolismo , Línea Celular Tumoral , Ratones , Regulación Neoplásica de la Expresión Génica , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular/genética , Microambiente Tumoral , Masculino , Ratones Desnudos , Elementos de Facilitación Genéticos/genética , Femenino
9.
Cancer Res ; 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39037758

RESUMEN

Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer.

10.
Polymers (Basel) ; 16(13)2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-39000707

RESUMEN

In this work, a kind of side chain liquid crystalline poly(urethane-acrylate)s was synthesized by free polymerization based on self-made liquid crystalline monomers, and a series of liquid crystalline polyurethane/shape memory polyurethane composite membranes were prepared by electrospinning. The synthesized liquid crystalline poly(urethane-acrylate)s have excellent thermal stability. Due to the regular arrangement of azobenzene on the side chains, polymers can rapidly undergo a photoinduced transition from trans-isomerism to cis-isomerism in THF solution and restore reversible configurational changes under visible light. The composite membranes prepared by electrospinning can also undergo photoinduced deformation within 6 s, and the deformation slowly returns under visible light. Meanwhile, the composites have shape memory, and after deformation caused by stretching, the membranes can quickly recover their original shape under thermal stimulation. These results indicate that the composites have triple response performances of photoinduced deformation, photo-, and thermal recovery.

11.
Quant Imaging Med Surg ; 14(7): 4936-4949, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-39022281

RESUMEN

Background: Malignant cerebral edema (MCE), a potential complication following endovascular thrombectomy (EVT) in the treatment of acute ischemic stroke (AIS), can result in significant disability and mortality. This study aimed to develop a nomogram model based on the hyperattenuated imaging marker (HIM), characterized by hyperattenuation on head noncontrast computed tomography (CT) immediately after thrombectomy, to predict MCE in patients receiving EVT. Methods: In this retrospective cohort study, we selected 151 patients with anterior circulation large-vessel occlusion who received endovascular treatment. The patients were randomly allocated into training (n=121) and test (n=30) cohorts. HIM was used to extract radiomics characteristics. Conventional clinical and radiological features associated with MCE were also extracted. A model based on extreme gradient boosting (XGBoost) machine learning using fivefold cross-validation was employed to acquire radiomics and clinical features. Based on HIM, clinical and radiological signatures were used to construct a prediction nomogram for MCE. Subsequently, the signatures were merged through logistic regression (LR) analysis in order to create a comprehensive clinical radiomics nomogram. Results: A total of 28 patients out of 151 (18.54%) developed MCE. The analysis of the receiver operating characteristic curve indicated an area under the curve (AUC) of 0.999 for the prediction of MCE in the training group and an AUC of 0.938 in the test group. The clinical and radiomics nomogram together showed the highest accuracy in predicting outcomes in both the training and test groups. Conclusions: The novel nomogram, which combines clinical manifestations and imaging findings based on postinterventional HIM, may serve as a predictor for MCE in patients experiencing AIS after EVT.

12.
Bioresour Bioprocess ; 11(1): 73, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39052177

RESUMEN

Human immortal keratinocyte cells (HaCaT) are induced with UVB to establish an injury model. This model is utilized to investigate whether oat bran fermentation broth (OBF) has a reparative effect on skin inflammation and damage to the skin barrier caused by UVB irradiation. The results show that compared with unfermented oat bran (OB), OBF exhibits higher structural homogeneity, increased molecular weight size, active substances content, and in vitro antioxidant activity. OBF has a scavenging effect on excess reactive oxygen species (ROS) and increases the intracellular levels of antioxidant enzymes. It was found that OBF has a stronger inhibitory effect on the release of inflammatory factors than OB. It increases the synthesis of AQP3 and FLG proteins while decreasing the secretion of KLK-7. OBF can inhibit the transcription level of inflammatory factors by suppressing the JAK/STAT signaling pathway. Safety experiments demonstrate that OBF has a high safety profile.

13.
J Colloid Interface Sci ; 675: 218-225, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38968638

RESUMEN

Converting plastics into organic matter by photoreforming is an emerging way to deal with plastic pollution and produce valuable organic matter. Water shortage can be alleviated by using seawater resources. To solve these problems, we synthesize a ternary heterostructure composite g-C3N4/CdS/NiS. Heterojunctions are formed between graphitized carbon nitride (g-C3N4), cadmium sulfide (CdS) and nickel sulfide (NiS), which effectively improve the problem of fast charge recombination of pure g-C3N4 and CdS. The results of the g-C3N4/CdS/NiS photocatalytic tests show that the hydrogen production rates in seawater and pure water for 5 h are 30.44 and 25.79 mmol/g/h, respectively. In stability test, the hydrogen production rate of the g-C3N4/CdS/NiS in seawater and pure water is similar. This suggests that seawater can replace pure water as a source of hydrogen. While H2 is generated, the lactate obtained by polylactic acid (PLA) hydrolysis is oxidized to form small organic compounds such as formate, acetate and pyruvate. Our study shows that g-C3N4/CdS/NiS can not only use seawater as a hydrogen source to produce H2, but also photoreformate plastics dissolved in seawater into valuable small organic molecules. This has a positive impact on the production and use of clean energy, as well as on plastic pollution and water scarcity.

14.
Photodiagnosis Photodyn Ther ; 48: 104237, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38871017

RESUMEN

PURPOSE: To report the use of anterior segment optical coherence tomography (AS-OCT) for superficial keratectomy (SK) in anterior corneal opacity. METHODS: The characteristics of 43 eyes (39 patients) with various lesions responsible for anterior corneal opacity were included in this retrospective non-comparative study. AS-OCT was performed on all eyes before surgery. The thickness of corneal opacity and the underlying healthy stroma were measured. SK was performed on each individual. RESULTS: Four types of anterior corneal opacity were evaluated, including corneal degeneration (26/43), Reis-Bücklers corneal dystrophy (8/43), alkali burn (1/43) and corneal tumors (8/43). Based on AS-OCT images, all eyes showed abnormal hyper-reflective signals in the superficial cornea to less than one-third of the normal corneal thickness in the deepest corneal opacity. All 43 eyes underwent an SK procedure. In addition, 1 eye with alkali burns and 7 eyes with corneal tumors were combined with amniotic membrane transplantation. All eyes restored transparency without significant complications. CONCLUSION: AS-OCT is a valuable method for objective preoperative and noninvasive assessments of anterior corneal opacities and is useful for guiding SK.


Asunto(s)
Opacidad de la Córnea , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Estudios Retrospectivos , Queratectomía/métodos , Adolescente , Anciano de 80 o más Años , Segmento Anterior del Ojo/diagnóstico por imagen , Adulto Joven , Cirugía Asistida por Computador/métodos , Resultado del Tratamiento
15.
Microbiol Res ; 286: 127796, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38870618

RESUMEN

The contribution of commensal microbes to human health and disease is unknown. Bacteroides fragilis (B. fragilis) is an opportunistic pathogen and a common colonizer of the human gut. Nontoxigenic B. fragilis (NTBF) and enterotoxigenic B. fragilis (ETBF) are two kinds of B. fragilis. NTBF has been shown to affect the host immune system and interact with gut microbes and pathogenic microbes. Previous studies indicated that certain strains of B. fragilis have the potential to serve as probiotics, based on their observed relationship with the immune system. However, several recent studies have shown detrimental effects on the host when beneficial gut bacteria are found in the digestive system or elsewhere. In some pathological conditions, NTBF may have adverse reactions. This paper presents a comprehensive analysis of NTBF ecology from the host-microbe perspective, encompassing molecular disease mechanisms analysis, bacteria-bacteria interaction, bacteria-host interaction, and the intricate ecological context of the gut. Our review provides much-needed insights into the precise application of NTBF.


Asunto(s)
Infecciones por Bacteroides , Bacteroides fragilis , Microbioma Gastrointestinal , Bacteroides fragilis/genética , Bacteroides fragilis/patogenicidad , Humanos , Infecciones por Bacteroides/microbiología , Probióticos , Animales , Interacciones Microbiota-Huesped , Interacciones Huésped-Patógeno , Tracto Gastrointestinal/microbiología , Simbiosis , Interacciones Microbianas
16.
Sci Bull (Beijing) ; 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38910106

RESUMEN

Many clustered regularly interspaced short palindromic repeat and CRISPR-associated protein 12b (CRISPR-Cas12b) nucleases have been computationally identified, yet their potential for genome editing remains largely unexplored. In this study, we conducted a GFP-activation assay screening 13 Cas12b nucleases for mammalian genome editing, identifying five active candidates. Candidatus hydrogenedentes Cas12b (ChCas12b) was found to recognize a straightforward WTN (W = T or A) proto-spacer adjacent motif (PAM), thereby dramatically expanding the targeting scope. Upon optimization of the single guide RNA (sgRNA) scaffold, ChCas12b exhibited activity comparable to SpCas9 across a panel of nine endogenous loci. Additionally, we identified nine mutations enhancing ChCas12b specificity. More importantly, we demonstrated that both ChCas12b and its high-fidelity variant, ChCas12b-D496A, enabled allele-specific disruption of genes harboring single nucleotide polymorphisms (SNPs). These data position ChCas12b and its high-fidelity counterparts as promising tools for both fundamental research and therapeutic applications.

17.
ACS Appl Mater Interfaces ; 16(25): 32554-32565, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38865698

RESUMEN

The assembly of two-dimensional (2D) nanomaterials into a three-dimensional (3D) aerogel can effectively prevent the problem of restacking. Here, nanofiber-reinforced MXene/reduced graphene oxide (rGO) conductive aerogel is prepared via the hydrothermal reduction of GO using pyrrole and in situ composite with MXene. Combined with low-content 2D conductive nanosheets (MXene and rGO) as "brick", conductive polypyrrole as "mortar", and one-dimensional (1D) nanofiber as "rebar", a strong interfacial cross-linking of MXene and rGO nanosheets is realized through covalent and noncovalent bonds to synergistically improve its mechanical performance. Based on the prepared MXene/rGO aerogel, a high-performance piezoresistive sensor with a sensitivity of up to 20.80 kPa-1 in a wide pressure range of 15.6 kPa is obtained, and it can withstand more than 5000 cyclic compressions. Besides, the sensor shows a stable output and can be applied to monitor various human motion signals. In addition, an all-solid-state supercapacitor electrode is also fabricated, which shows a high area-specific capacitance of up to 274 mF/cm2 at a current density of 1 mA/cm2.

18.
Front Nutr ; 11: 1292834, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38860158

RESUMEN

Background: The causal association of sarcopenia with the incidence risk of hepatocellular carcinoma (HCC) in the European population, and the potential mediating role of C-reactive protein (CRP), remains unclear. This study employed a bidirectional two-sample, two-step Mendelian randomization (MR) analysis to investigate the causality and identify the mediator. Methods: Summary statistics for HCC, CRP, and sarcopenia-related traits, including appendicular lean mass (ALM), hand grip strength (HGS), and walking pace (WP), were acquired from publicly available databases. We conducted bidirectional MR and Steiger tests of directionality to check the presence of reverse causality. Additionally, a two-step MR analysis was used to assess the mediating effect of CRP in the causality between sarcopenia and HCC. Tests for heterogeneity and horizontal pleiotropy were performed. Results: As ALM increases, the risk of HCC occurrence decreases [odds ratio (OR), 95% confidence interval (CI): 0.703, 0.524-0.943; P = 0.019]. And, genetically predicted low-HGS (OR, 95%CI: 2.287, 1.013-5.164; P = 0.047) was associated with an increased incidence risk of HCC, with no reverse causality. However, we found no evidence supporting a causality between WP and HCC. CRP was identified as the mediator of the causal effect of ALM and low-HGS on HCC, with corresponding mediating effects of 9.1% and 7.4%. Conclusions: This MR study effectively demonstrates that lower ALM and low-HGS are linked to an elevated risk of HCC within the European population, and the causality was not bidirectional. Furthermore, CRP serves as a mediator in the associations. These findings may help mitigate HCC risk among individuals with sarcopenia.

19.
PLoS Biol ; 22(6): e3002680, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38865309

RESUMEN

CRISPR-Cas12a, often regarded as a precise genome editor, still requires improvements in specificity. In this study, we used a GFP-activation assay to screen 14 new Cas12a nucleases for mammalian genome editing, successfully identifying 9 active ones. Notably, these Cas12a nucleases prefer pyrimidine-rich PAMs. Among these nucleases, we extensively characterized Mb4Cas12a obtained from Moraxella bovis CCUG 2133, which recognizes a YYN PAM (Y = C or T). Our biochemical analysis demonstrates that Mb4Cas12a can cleave double-strand DNA across a wide temperature range. To improve specificity, we constructed a SWISS-MODEL of Mb4Cas12a based on the FnCas12a crystal structure and identified 8 amino acids potentially forming hydrogen bonds at the target DNA-crRNA interface. By replacing these amino acids with alanine to disrupt the hydrogen bond, we tested the influence of each mutation on Mb4Cas12a specificity. Interestingly, the F370A mutation improved specificity with minimal influence on activity. Further study showed that Mb4Cas12a-F370A is capable of discriminating single-nucleotide polymorphisms. These new Cas12a orthologs and high-fidelity variants hold substantial promise for therapeutic applications.


Asunto(s)
Alelos , Proteínas Asociadas a CRISPR , Sistemas CRISPR-Cas , Edición Génica , Edición Génica/métodos , Proteínas Asociadas a CRISPR/metabolismo , Proteínas Asociadas a CRISPR/genética , Humanos , Endodesoxirribonucleasas/metabolismo , Endodesoxirribonucleasas/genética , Endodesoxirribonucleasas/química , Animales , Ingeniería de Proteínas/métodos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Polimorfismo de Nucleótido Simple , Mutación , ADN/metabolismo , ADN/genética , Células HEK293
20.
Foods ; 13(10)2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38790770

RESUMEN

Houttuynia cordata Thunb is rich in active substances and has excellent antioxidant and anti-inflammatory activity. Scanning electron microscopy and gel permeation chromatography were used to analyze the molecular characteristics of the fermentation broth of Houttuynia cordata Thunb obtained through fermentation with Clavispora lusitaniae (HCT-f). The molecular weight of HCT-f was 2.64265 × 105 Da, and the polydispersity coefficient was 183.10, which were higher than that of unfermented broth of Houttuynia cordata Thunb (HCT). By investigating the active substance content and in vitro antioxidant activity of HCT-f and HCT, the results indicated that HCT-f had a higher active substance content and exhibited a superior scavenging effect on 2,2-diphenyl-1-picrylhydrazyl radicals and hydroxyl radicals, with IC50 values of 11.85% and 9.01%, respectively. Our results showed that HCT-f could effectively alleviate the increase in the secretion of inflammatory factors and apoptotic factors caused by lipopolysaccharide (LPS) stimulation, and had a certain effect on repairing skin barrier damage. HCT-f could exert an anti-inflammatory effect by down-regulating signaling in the MAPK/NF-κB pathway. The results of erythrocyte hemolysis and chicken embryo experiments showed that HCT-f had a high safety profile. Therefore, this study provides a theoretical basis for the application of HCT-f as an effective ingredient in food and cosmetics.

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