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1.
Transl Cancer Res ; 13(3): 1290-1313, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38617504

RESUMO

Background: Chromatin regulators (CRs) are implicated in the development of cancer, but a comprehensive investigation of their role in colon adenocarcinoma (COAD) is inadequate. The purpose of this study is to find CRs that can provide recommendations for clinical diagnosis and treatment, and to explore the reasons why they serve as critical CRs. Methods: We obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted Gene Co-Expression Network Analysis (WGCNA) screened tumor-associated CRs. LASSO-Cox regression was used to construct the model and to screen key CRs together with support vector machine (SVM), the univariate Cox regression. We used single-cell data to explore the expression of CRs in cells and their communication. Immune infiltration, immune checkpoints, mutation, methylation, and drug sensitivity analyses were performed. Gene expression was verified by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Pan-cancer analysis was used to explore the importance of hub CRs. Results: We finally obtained 32 tumor-associated CRs. The prognostic model was constructed based on RCOR2, PPARGC1A, PKM, RAC3, PHF19, MYBBP1A, ORC1, and EYA2 by the LASSO-Cox regression. Single-cell data revealed that the model was immune-related. Combined with immune infiltration analysis, immune checkpoint analysis, and tumor immune dysfunction and exclusion (TIDE) analysis, the low-score risk group had more immune cell infiltration and better immune response. Mutation and methylation analysis showed that multiple CRs may be mutated and methylated in colon cancer. Drug sensitivity analysis revealed that the low-risk group may be more sensitive to several drugs and PKM was associated with multiple drugs. Combined with machine learning, PKM is perhaps the most critical gene in CRs. Pan-cancer analysis showed that PKM plays a role in the prognosis of cancers. Conclusions: We developed a prognostic model for COAD based on CRs. Increased expression of the core gene PKM is linked with a poor prognosis in several malignancies.

2.
Ecotoxicol Environ Saf ; 276: 116315, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38614001

RESUMO

This study explores the role of endogenous indole-3-acetic acid (IAA) in modulating plant responses to pollution stress and its effect on pollutant accumulation, with a focus on fluoranthene (Flu) in ryegrass. To elucidate the mechanism, we employed an IAA promoter (α-aminobutyric acid [α-AB]) and an IAA inhibitor (naphthylphthalamic acid [NPA]) to regulate IAA levels and analyze Flu uptake characteristics. The experimental setup included a Flu treatment group (ryegrass with Flu addition) and a control group (ryegrass without Flu). Our findings demonstrate that Flu treatment enhanced IAA content and plant growth in ryegrass compared to the control. The Flu+AB treatment further enhanced these effects, while the Flu+NPA treatment exhibited a contrasting trend. Moreover, Flu+AB treatment led to increased Flu accumulation, in contrast to the inhibitory effect observed with Flu+NPA treatment. Flu treatment also enhanced the activities of key antioxidant enzymes (SOD, POD, CAT) and increased soluble sugar and protein levels, indicative of enzymatic and nonenzymatic defense responses, respectively. The Flu+AB treatment amplified these responses, whereas the Flu+NPA treatment attenuated them. Significantly, Flu treatment raised H+-ATPase activity compared to the control, an effect further elevated by Flu+AB treatment and diminished by Flu+NPA treatment. A random forest analysis suggested that Flu accumulation dependency varied under different treatments: it relied more on H+-ATPase activity under Flu+AB treatment and more on SOD activity under Flu+NPA treatment. Additionally, Flu+AB treatment boosted the transpiration rate in ryegrass, thereby increasing the Flu translocation factor, a trend reversed by Flu+NPA treatment. This research highlights crucial factors influencing Flu accumulation in ryegrass, offering potential new avenues for controlling the gathering of contaminants within plant systems.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38625732

RESUMO

A novel Gram-stain-negative and facultatively anaerobic bacterium, designated A6E488T, was isolated from intertidal sediment collected from Xiaoshi Island, Weihai, PR China (122° 1' E 37° 31' N). Cells of strain A6E488T were rod-shaped with widths of 0.3-0.4 µm and lengths of 1.1-1.8 µm. The optimal growth conditions were determined to be in 1 % (w/v) NaCl, at 37 °C, and at pH 7.0. The predominant fatty acids (≥10 %) were C19 : 0 cyclo ω8c (59.7 %) and summed feature 8 (13.8 %, C18 : 1 ω7c and/or C18 : 1 ω6c). The sole isoprenoid quinone was Q-10. Oxidase activity was negative but catalase activity was positive. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid, one unidentified aminolipid, one unidentified glycolipid, and one unidentified lipid. Based on phylogenetic analysis of 16S rRNA gene sequences, strain A6E488T showed the highest sequence similarity to Microbaculum marinum MCCC 1K03192T (97.6 %). The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain A6E488T and M. marinum MCCC 1K03192T did not exceed 78 and 22 %, respectively. These values are below the recommended thresholds of 95 % (ANI) and 70 % (dDDH) for prokaryotic species delineation. On the basis of gene annotation, it was observed that strain A6E488T possesses the capability for thiosulphate oxidation, suggesting that this strain might be important in the sulphur cycle. Based on the results of phenotypic, genotypic, and chemical characterization, strain A6E488T is considered to represent a novel species of the genus Microbaculum, for which the name Microbaculum marinisediminis sp. nov. is proposed. The type strain is A6E488T (=KCTC 92197T=MCCC 1H00516T).


Assuntos
Ácidos Graxos , Sedimentos Geológicos , Composição de Bases , Ácidos Graxos/química , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , DNA Bacteriano/genética , Técnicas de Tipagem Bacteriana , Nucleotídeos
4.
Anal Chem ; 96(15): 5913-5921, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38563119

RESUMO

CRISPR/Cas technology has made great progress in the field of live-cell imaging beyond genome editing. However, effective and easy-to-use CRISPR systems for labeling multiple RNAs of interest are still needed. Here, we engineered a CRISPR/dCas12a system that enables the specific recognition of the target RNA under the guidance of a PAM-presenting oligonucleotide (PAMmer) to mimic the PAM recognition mechanism for DNA substrates. We demonstrated the feasibility and specificity of this system for specifically visualizing endogenous mRNA. By leveraging dCas12a-mediated precursor CRISPR RNA (pre-crRNA) processing and the orthogonality of dCas12a from different bacteria, we further demonstrated the proposed system as a simple and versatile molecular toolkit for multiplexed imaging of different types of RNA transcripts in live cells with high specificity. This programmable dCas12a system not only broadens the RNA imaging toolbox but also facilitates diverse applications for RNA manipulation.


Assuntos
Sistemas CRISPR-Cas , RNA , RNA/genética , Sistemas CRISPR-Cas/genética , RNA Guia de Sistemas CRISPR-Cas , Edição de Genes/métodos , Bactérias/genética , Precursores de RNA
5.
Mol Pharm ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38576375

RESUMO

In the present study, we investigated the role of lipid composition of camptothecin (CPT)-loaded liposomes (CPT-Lips) to adjust their residence time, drug distribution, and therefore the toxicities and antitumor activity. The CPT was loaded into liposomes using a click drug loading method, which utilized liposomes preloaded with GSH and then exposed to CPT-maleimide. The method produced CPT-Lips with a high encapsulation efficiency (>95%) and sustained drug release. It is shown that the residence times of CPT-Lips in the body were highly dependent on lipid compositions with an order of non-PEGylated liposomes of unsaturated lipids < non-PEGylated liposomes of saturated lipids < PEGylated liposomes of saturated lipids. Interestingly, the fast clearance of CPT-Lips resulted in significantly decreased toxicities but did not cause a significant decrease in their in vivo antitumor activity. These results suggested that the lipid composition could effectively adjust the residence time of CPT-Lips in the body and further optimize their therapeutic index, which would guide the development of a liposomal formulation of CPT.

6.
Front Neurosci ; 18: 1337739, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38586196

RESUMO

Background: Anxiety and depression are prevalent mental disorders. As modern society continues to face mounting pressures, the incidence of anxiety and depression is on the rise. In recent years, there has been an increasing breadth of research exploring the relationship between anxiety, depression, and physical activity (PA). However, the current research progress and future development trends are unclear. The purpose of this study is to explore the research hotspots and development trends in this field, and to provide guidance for future studies and to provide some reference for clinicians. Methods: We searched the relevant literature of Web of Science Core Collection from the establishment of the database to August 15, 2023. CiteSpace, VOSviewer and Bibliometrix Packages based on the R language were used to analyze the number of publications, countries, institutions, journals, authors, references, and keywords. Results: A total of 1,591 studies were included in the analysis, and the research in the field of PA on anxiety or depression has consistently expanded. The USA (304 publications), Harvard University (93 publications), and the journal of affective disorders (97 publications) were the countries, institutions, and journals that published the highest number of articles, respectively. According to the keywords, students and pregnant women, adult neurogenesis, and Tai Chi were the groups of concern, physiological and pathological mechanisms, and the type of PA of interest, respectively. Conclusion: The study of PA on anxiety or depression is experiencing ongoing expansion. Clinicians can consider advising patients to take mind-body exercise to improve mood. In addition, future researchers can explore the mind-body exercise and its impact on anxiety or depression, PA and anxiety or depression in specific populations, and adult neurogenesis of various exercise in anxiety or depression.

7.
BMJ Open ; 14(4): e077623, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38569691

RESUMO

INTRODUCTION: Considering the increasing incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) worldwide, there is an urgent need to identify efficacious, safe and convenient treatments. Numerous investigations have been conducted on the use of supplements in this domain, with oral supplementation emerging as a viable therapeutic approach for AD or MCI. Nevertheless, given the multitude of available supplements, it becomes imperative to identify the optimal treatment regimen. METHODS AND ANALYSIS: Eight academic databases and three clinical trial registries will be searched from their inception to 1 June 2023. To identify randomised controlled trials investigating the effects of supplements on patients with AD or MCI, two independent reviewers (X-YZ and Y-QL) will extract relevant information from eligible articles, while the risk of bias in the included studies will be assessed using the Rob 2.0 tool developed by the Cochrane Collaboration. The primary outcome of interest is the overall cognitive function. Pair-wise meta-analysis will be conducted using RevMan V.5.3, while network meta-analysis will be carried out using Stata 17.0 and ADDIS 1.16.8. Heterogeneity test, data synthesis and subgroup analysis will be performed if necessary. The GRADE system will be employed to assess the quality of evidence. This study is scheduled to commence on 1 June 2023 and conclude on 1 October 2023. ETHICS AND DISSEMINATION: Ethics approval is not required for systematic review and network meta-analysis. The results will be submitted to a peer-reviewed journal or at a conference. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42023414700).


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/tratamento farmacológico , Metanálise em Rede , Revisões Sistemáticas como Assunto , Disfunção Cognitiva/terapia , Cognição , Suplementos Nutricionais , Metanálise como Assunto
8.
Food Chem ; 450: 139287, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38640541

RESUMO

The effects of ultrasonic pretreatment on the drying characteristics and microstructure of strawberry slices were investigated. The rehydration characteristics of freeze-dried products, which were pre-frozen at -20 °C and - 80 °C were explored, with a focus on water mobility and distribution. The ultrasonic pretreatment significantly increased the water mobility of the strawberry slices, resulting in a reduction in their water content. However, the application of ultrasound significantly decreased the rehydration speed, indicating a lower moisture absorption capacity in the pretreated sample. The micrographs revealed that the structure of the tissue was more uniform after ultrasonic treatment, and water loss was accelerated. In addition, the contact angle measurements showed that the samples were more hydrophobic after ultrasonic treatment, and the eutectic temperature and fold point of the samples increased. Therefore, this study found that ultrasonic-assisted freeze vacuum drying technology effectively reduces hygroscopicity, improves product storage, and represents a potential method for dried production.

9.
Medicine (Baltimore) ; 103(16): e37895, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38640287

RESUMO

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphoma, also known as extranodal marginal zone lymphoma, is more commonly detected in the stomach and rarely in the breast. Our study presented a clinical and pathological examination of a patient diagnosed with breast MALT lymphoma, supplemented with pertinent research, to offer guidance for the diagnosis and treatment of this condition. PEOPLE CONCERNS: The occurrence of breast MALT lymphoma has risen in the past decade, but its etiology, progression and treatment response are less well-studied. DIAGNOSIS: Breast MALT lymphoma was diagnosed by excisional biopsy and histopathology. INTERVENTIONS: Following breast MALT lymphoma diagnosis, the patient was transferred to the hematology department for further treatment, and she made the decision to continue observing. OUTCOMES: After 3 months of observation, the patient remained asymptomatic. CONCLUSION: Breast MALT lymphoma is an indolent disease with an asymptomatic presentation, There are no standardized treatment guidelines for breast MALT lymphoma, treatment must be tailored to the patient willingness to treat and the severity of the disease. Hence, in order to give patients a better chance of cure, more research is needed to explore its pathogenesis and more clinical trials are needed investigate the treatment of this disease.


Assuntos
Neoplasias da Mama , Linfoma de Zona Marginal Tipo Células B , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Biópsia
10.
BMJ Open ; 14(4): e073639, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38631839

RESUMO

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Doença de Crohn/tratamento farmacológico , Colite Ulcerativa/terapia , Medicina de Precisão , Estudos Prospectivos , Qualidade de Vida , Doenças Inflamatórias Intestinais/tratamento farmacológico , Estudos Observacionais como Assunto , Estudos Multicêntricos como Assunto
11.
Angew Chem Int Ed Engl ; : e202405444, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637320

RESUMO

Unlocking the full potential of mRNA immunotherapy necessitates targeted delivery to specific cell subsets in the spleen. Four-component lipid nanoparticles (LNPs) utilized in numerous clinical trials are primarily limited in hepatocyte and muscular targeting, highlighting the imperative demand for targeted and simplified non-liver mRNA delivery systems. Herein, we report the rational design of one-component ionizable cationic lipids to selectively deliver mRNA to the spleen and T cells with high efficacy. Unlike the tertiary amine-based ionizable lipids involved in LNPs, the proposed cationic lipids rich in secondary amines can efficiently deliver mRNA both in vitro and in vivo as the standalone carriers. Furthermore, these vectors facilitate efficacious mRNA delivery to the T cell subsets following intravenous administration, demonstrating substantial potential for advancing immunotherapy applications. This straightforward strategy extends the utility of lipid family for extrahepatic mRNA delivery, offering new insights into vector development beyond LNPs to further the field of precise mRNA therapy.

12.
Front Psychol ; 15: 1340456, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38646122

RESUMO

Background: In Chinese medicine, the mental focus and emotional stability of acupuncturists are key to optimal clinical outcomes. Many renowned acupuncturists utilize Traditional Chinese Qigong practices to enhance their concentration and emotional regulation abilities. Nevertheless, the existing literature lacks comprehensive evidence addressing this matter. Methods: This study will enroll 99 acupuncturists and randomly allocate them to one of three groups: Baduanjin, aerobic exercise, or a waiting-list control. The Baduanjin group will undertake 24 weeks of training, with three one-hour sessions weekly. The aerobic group will engage in brisk walking for the same duration and frequency. The control group will not receive any specific training. Assessments of emotion regulation, attention, cognitive functions, finger sensation, and athletic ability will be conducted at baseline (-1 week), mid-intervention (12 weeks), and post-intervention (24 weeks). Additionally, 20 participants from each group will undergo fMRI scans before and after the intervention to explore brain functional and structural changes relating to emotion, attention, cognition, motor skills, and sensory perception. Discussion: This study aims to contribute valuable insights into the effectiveness of Qigong practice, specifically Baduanjin, in enhancing emotional regulation, attention, and cognitive functions in acupuncturists and to investigate the neuroimaging mechanisms behind these effects. Ethics and dissemination: Approved by the Sichuan Regional Ethics Review Committee on Traditional Chinese Medicine (No. 2023KL - 118) and adhering to the Declaration of Helsinki. Results will be shared through policy briefs, workshops, peer-reviewed journals, and conferences.Clinical trial registrationwww.chictr.org.cn, ChiCTR2300076447.

13.
Plant Biotechnol J ; 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38491985

RESUMO

Genetic transformation is a critical tool for gene editing and genetic improvement of plants. Although many model plants and crops can be genetically manipulated, genetic transformation systems for fruit trees are either lacking or perform poorly. We used Rhizobium rhizogenes to transfer the target gene into the hairy roots of Malus domestica and Actinidia chinensis. Transgenic roots were generated within 3 weeks, with a transgenic efficiency of 78.8%. Root to shoot conversion of transgenic hairy roots was achieved within 11 weeks, with a regeneration efficiency of 3.3%. Finally, the regulatory genes involved in stem cell activity were used to improve shoot regeneration efficiency. MdWOX5 exhibited the most significant effects, as it led to an improved regeneration efficiency of 20.6% and a reduced regeneration time of 9 weeks. Phenotypes of the overexpression of RUBY system mediated red roots and overexpression of MdRGF5 mediated longer root hairs were observed within 3 weeks, suggesting that the method can be used to quickly screen genes that influence root phenotype scores through root performance, such as root colour, root hair, and lateral root. Obtaining whole plants of the RUBY system and MdRGF5 overexpression lines highlights the convenience of this technology for studying gene functions in whole plants. Overall, we developed an optimized method to improve the transformation efficiency and stability of transformants in fruit trees.

14.
Molecules ; 29(6)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38542902

RESUMO

The extraction of rare earth elements (REEs) from phosphogypsum (PG) is of great significance for the effective utilization of rare earth resources and enhancing the resource value of PG waste residues. This study used Aspergillus niger (A. niger) fungal culture filtrate as a leaching agent to investigate the behavior of extracting REEs from PG through direct and indirect contact methods. According to the ICP-MS results, direct leaching at a temperature of 30 °C, shaking speed of 150 rpm, and a solid-liquid ratio of 2:1, achieved an extraction rate of 74% for REEs, with the main elements being yttrium (Y), lanthanum (La), cerium (Ce), and neodymium (Nd). Under the same conditions, the extraction rate of REEs from phosphogypsum using an A. niger culture filtrate was 63.3% higher than that using the simulated organic acid-mixed solution prepared with the main organic acid components in the A. niger leachate. Moreover, the morphological changes observed in A. niger before and after leaching further suggest the direct involvement of A. niger's metabolic process in the extraction of REEs. When compared to using organic acids, A. niger culture filtrate exhibits higher leaching efficiency for extracting REEs from PG. Additionally, using A. niger culture filtrate is a more environmentally friendly method with the potential for industrial-scale applications than using inorganic acids for the leaching of REEs from PG.


Assuntos
Aspergillus niger , Metais Terras Raras , Fósforo , Lantânio , Sulfato de Cálcio
15.
Zool Res ; 45(2): 381-397, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38485507

RESUMO

The autotetraploid Carassius auratus (4nRR, 4 n=200, RRRR) is derived from whole-genome duplication of Carassius auratus red var. (RCC, 2 n=100, RR). In the current study, we demonstrated that chromatophores and pigment changes directly caused the coloration and variation of 4nRR skin (red in RCC, brownish-yellow in 4nRR). To further explore the molecular mechanisms underlying coloration formation and variation in 4nRR, we performed transcriptome profiling and molecular functional verification in RCC and 4nRR. Results revealed that scarb1, associated with carotenoid metabolism, underwent significant down-regulation in 4nRR. Efficient editing of this candidate pigment gene provided clear evidence of its significant role in RCC coloration. Subsequently, we identified four divergent scarb1 homeologs in 4nRR: two original scarb1 homeologs from RCC and two duplicated ones. Notably, three of these homeologs possessed two highly conserved alleles, exhibiting biased and allele-specific expression in the skin. Remarkably, after precise editing of both the original and duplicated scarb1 homeologs and/or alleles, 4nRR individuals, whether singly or multiply mutated, displayed a transition from brownish-yellow skin to a cyan-gray phenotype. Concurrently, the proportional areas of the cyan-gray regions displayed a gene-dose correlation. These findings illustrate the subfunctionalization of duplicated scarb1, with all scarb1 genes synergistically and equally contributing to the pigmentation of 4nRR. This is the first report concerning the functional differentiation of duplicated homeologs in an autopolyploid fish, substantially enriching our understanding of coloration formation and change within this group of organisms.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Carpa Dourada/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/veterinária , Pigmentação/genética , Genoma , Neoplasias Renais/genética , Neoplasias Renais/veterinária
16.
J Med Chem ; 67(6): 4641-4654, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38478885

RESUMO

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest; however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report the structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site. We demonstrate that their incorporation in bifunctional degraders induces targeted protein degradation of BRD4 or the androgen receptor without further linker optimization. Our study discloses the first covalent VHL ligands which can be implemented directly in bifunctional degrader design, expanding the substrate scope of covalent E3 ligase PROTACs.


Assuntos
Proteínas Nucleares , Ácidos Sulfínicos , Fatores de Transcrição , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteólise , Ligantes
17.
ACS Nano ; 18(11): 7868-7876, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38440979

RESUMO

Diodes based on p-n junctions are fundamental building blocks for numerous circuits, including rectifiers, photovoltaic cells, light-emitting diodes (LEDs), and photodetectors. However, conventional doping techniques to form p- or n-type semiconductors introduce impurities that lead to Coulomb scattering. When it comes to low-dimensional materials, controllable and stable doping is challenging due to the feature of atomic thickness. Here, by selectively depositing dielectric layers of Y2O3 and AlN, direct formation of wafer-scale carbon-nanotube (CNT) diodes are demonstrated with high yield and spatial controllability. It is found that the oxygen interstitials in Y2O3, and the oxygen vacancy together with Al-Al bond in AlN/Y2O3 electrostatically modulate the intrinsic CNTs channel, which leads to p- and n-type conductance, respectively. These CNTs diodes exhibit a high rectification ratio (>104) and gate-tunable rectification behavior. Based on these results, we demonstrate the applicability of the diodes in electrostatic discharge (ESD) protection and photodetection.

18.
JBI Evid Implement ; 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38470610

RESUMO

INTRODUCTION: Diarrhea, the most common complication for patients during enteral nutrition, poses a range of risks and care burdens. Medical staff are aware of the importance of proactively preventing and managing enteral nutrition-related diarrhea. However, clinical prevention and management methods are not standardized, and the scientific basis and effectiveness of these methods need to be further verified. OBJECTIVES: This project aimed to promote evidence-based practices for the prevention and management of enteral nutrition-related diarrhea among adult inpatients in a public tertiary hospital in China. METHODS: This project was guided by the JBI Evidence Implementation Framework and used the JBI Practical Application of Clinical Evidence System (PACES) and the JBI Getting Research into Practice (GRiP) tools. Twelve audit criteria were developed to conduct a baseline audit to measure compliance with best practices. A barrier analysis was conducted, and strategies were implemented to overcome the barriers. The project was finalized with a follow-up audit to determine any changes in compliance with best practices. RESULTS: The overall compliance rate for the audit criteria increased from 27.37% at baseline to 89.62% in the follow-up audit, with six criteria achieving a compliance rate of 100%. CONCLUSIONS: The implementation of evidence-based practices can effectively narrow the gap between current practice and best practice. This project improved the ability of medical staff to prevent and manage enteral nutrition-related diarrhea, as well as promoting evidence-based practice in the hospital. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A168.

19.
Ying Yong Sheng Tai Xue Bao ; 35(1): 169-176, 2024 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-38511453

RESUMO

Microbial residues are an important component of soil organic carbon (SOC). It is unclear how long-term thinning affects the accumulation characteristics of microbial residue carbon (C). We analyzed the differences in soil physicochemical properties, microbial communities, extracellular enzyme activities, and microbial residue C in topsoil (0-10 cm) and subsoil (20-30 cm) in Picea asperata plantation of non-thinned (control, 4950 trees·hm-2) and thinned for 14 years (1160 trees·hm-2) stands, aiming to reveal the regulatory mechanism of thinning on microbial residue C accumulation. The results showed that thinning significantly increased SOC content, total nitrogen content, available phosphorus content, the proportion of particulate organic C, soil water content, C-cycle hydrolase, and acid phosphatase activities, but significantly reduced the proportion of mineral-associated organic C. Thinning significantly affected the content of fungal and microbial residue C, and the contribution of microbial residue C to SOC, and these effects were independent of soil layer. The content of fungal and microbial residue C was 25.0% and 24.5% higher under thinning treatments. However, thinning significantly decreased the contribution of microbial residue C to SOC by 12.3%, indicating an increase in the proportion of plant-derived C in SOC. Stepwise regression analysis showed that total nitrogen and soil water content were key factors influencing fungal and micro-bial residue C accumulation. In summary, thinning promoted microbial residue C sequestration by altering soil pro-perties and changed the composition of SOC sources.


Assuntos
Picea , Solo , Solo/química , Carbono/análise , Microbiologia do Solo , Região dos Alpes Europeus , Minerais , China , Nitrogênio/análise , Água/análise
20.
Front Neurosci ; 18: 1333782, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505770

RESUMO

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) and colocalization analysis to investigate this causal relationship. Methods: Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes. Results: In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits. Conclusion: Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets.

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