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1.
Heliyon ; 10(19): e38285, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39381093

RESUMO

Background: Pulmonary infections resulting from respiratory syncytial virus (RSV) continue to pose a significant threat to the well-being of infants and the elderly, but there is no safe, effective and specific treatment except symptomatic treatment. Forsythia Suspensa Leaf (FSL) is cold in nature and bitter in taste, and has the efficacy of clearing away heat and toxic materials. Previous research by our research group showed that the active components in FSL have the pharmacological effect of anti-RSV. Based on that, this study aims further to clarify the anti-RSV active components and mechanism of FSL. Methods: Firstly, we established the BALB/c mouse model of RSV infection, assessed the in vivo anti-RSV efficacy, and determined the optimal dosage of FSL and its active components. Evaluation parameters included body weight changes, organ indices, lung tissue pathological sections, lung tissue viral load, and inflammatory factors. Additionally, we used RT-PCR, Western Blot and other molecular biology techniques to determine the expression changes of key factors such as Nrf2 and NLRP3 in PI3K/Akt-NLRP3 pathway, and revealed the anti-RSV mechanism of FSL and its active components. Results: Pharmacodynamic experiments in animals showed that the FSL Low (0.4 g/kg·d), RosA Low (100 mg/kg·d) and Phillyrin Medium (100 mg/kg·d) groups could effectively improve the pathological conditions of mice with RSV pneumonia, such as weight loss, the level of pulmonary inflammatory factors and the increase of viral load. In addition, oral administration of Phillyrin at a dose of 100 mg/kg d to RSV-infected mice can effectively control the trend that the expression of Nrf2 protein decreases and the expression of NLRP3 protein increases in RSV pneumonia mice. Conclusion: Phillyrin, the active component in FSL, can not only directly inhibit the replication of RSV, but also effectively control the inflammatory reaction caused by RSV infection and improve lung injury, which is expected to become a potential drug against RSV pneumonia.

2.
Ann Hematol ; 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39407036

RESUMO

Central nervous system leukemia (CNSL) and central nervous system infection (CNSI) are the most important complications in patients with acute leukemia (AL). However, the differential diagnosis could represent a major challenge since the two disorders are all heterogeneous entities with overlapping clinical characteristics and radiological appearances. In this paper, we conduct a retrospective study to develop a model based on clinical data and magnetic resonance imaging (MRI) to distinguish CNSL from CNSI. A total of 108 patients with AL who underwent cranial MRI between January 2020 and December 2023 in our hospital were included. Univariate and multivariate logistic regression analyses were used to determine the independent predictors. A nomogram was developed based on the predictors, and the performance of the nomogram was evaluated by the area under the receiver operating characteristic (ROC) curve. The validation cohort was used to test the predictive model. Hyperleukocytosis at initial diagnosis, marrow state, fever, conscious disturbance, coinfection in other sites and MRI (parenchyma type) were identified as independent factors. A nomogram was constructed and the discrimination was presented as AUC = 0.947 (95% CI 0.9105-0.984). Calibration of the nomogram showed that the predicted probability matched the actual probability well.

3.
Cell Rep ; 43(11): 114883, 2024 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-39427316

RESUMO

Filamentous bacteriophages play a critical role in biofilm formation and virulence in the opportunistic pathogen Pseudomonas aeruginosa. Here, studies of the filamentous Pf4 prophage life cycle within P. aeruginosa biofilms revealed that the prophage-encoded reverse transcriptase (RT) regulates phage genome dynamics. The RT and the non-coding RNA PhrD collaborate to edit the Pf4 phage genome to generate superinfective Pf4 variants capable of rapid propagation within biofilms by preserving genes essential for virion assembly and reconstituting a promoter for the phage excisionase gene. Mutant cells emerge in biofilms where intact Pf4 prophages are replaced by these reduced-genome phage variants, further enhancing virion production. The discovery of RT's role in phage genome reduction expands understanding of RT functions and of the versatility of phage biology and its impact on microbial community dynamics within biofilms.

4.
Angew Chem Int Ed Engl ; : e202418174, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39460426

RESUMO

Piezocatalysis is considered to be a favorable catalytic technology by utilizing external mechanical stimulation to promote the specific redox reactions. The application of piezocatalysis in batteries is promising but faces formidable challenges. Herein, the operation principles of piezocatalysis were successfully demonstrated by constructing a solid-state Li-Se (S) battery model with interfacial stress accumulation. Lead zirconate titanate with an ultra-high piezoelectric coefficient was applied as the piezoelectric catalyst. The uniformity of the dipole orientation in materials was essential for achieving piezocatalysis in batteries. The accumulated high-stress converts to piezopotential for catalyzing most reaction processes in batteries, while the rapid stress change prevents the internal charge reorganization, ensuring continuous efficient catalysis. The internal stress change alters the internal polarisation strength, driving excess screening charge to participate in the electrochemical reaction. Under piezocatalysis, solid-state Li-Se batteries exhibited a initial discharge capacity of 670.9 mAh g-1 (99.4% of the theoretical value) at 0.1C, and Li-S batteries showed a capacity of 1463 mAh g-1 at 0.2C, which was still maintained up to 1084 mAh g-1 at an elevated rate of 0.5C. This piezocatalysis strategy provides a strong theoretical basis and design specification for enhancing Li-Se (S) cell reaction kinetics.

5.
World J Clin Oncol ; 15(10): 1324-1332, 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39473855

RESUMO

BACKGROUND: Cervical myeloid sarcoma (MS) is a rare hematological malignancy characterized by the formation of extramedullary soft tissue masses in the cervical region. Due to its uncommon presentation in the female reproductive system, cervical MS poses significant diagnostic and therapeutic challenges. Consequently, there is a pressing need for more research and clinical experience to better understand, diagnose, and manage this condition effectively. CASE SUMMARY: This report details four cases, the diagnostic process, treatment strategy, and outcomes, discussing cervical MS as an initial clinical manifestation. The disease exhibits varied clinical presentations, such as irregular vaginal bleeding and palpation of cervical masses. The treatment approaches discussed include neoadjuvant chemotherapy, surgery, and postoperative chemotherapy, though managing the disease remains challenging. The report also features a comprehensive literature review that underscores the importance of immunohistochemistry for accurate diagnosis, identifying key markers, including myeloperoxidase, cluster of differentiation (CD) 68, and CD43, stressing the need for further research to improve treatment strategies and prognosis. CONCLUSION: Immunohistochemical diagnosis and tailored therapeutic strategies are essential. Further research is crucial in improving outcomes and developing effective treatment protocols.

6.
J Environ Manage ; 370: 122460, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39288498

RESUMO

China has explicitly prioritized the enhancement of ecosystem quality and stability(EQS) as a governmental objective. However, our understanding of systematic and comprehensive assessment methods for EQS remains limited. The development and investigation of corresponding evaluation frameworks and their underlying mechanisms remain insufficiently explored. This study employs the concept of an "ideal reference system and key indicators," integrating diverse ecosystem and human activity characteristics from perspectives such as ecosystem structure, function, and landscape vulnerability, to determine indicator weights using the Analytic Hierarchy Process(AHP) and entropy weight method, thereby constructing an evaluation framework for assessing the quality and stability of the Qinghai-Tibet Plateau(QTP) ecosystem. The spatiotemporal variations in EQS from 2000 to 2018 were examined, and the key driving factors were identified using the optimal parameter-based geographical detector (OPGD). The results indicate that the EQS of the QTP exhibit a spatial distribution pattern characterized by higher values in the southeast and lower values in the northwest. From 2000 to 2018, there has been a consistent improvement in the overall ecosystem quality and stability across the QTP. The EQS exhibit a significant synergistic effect, with high-high(26.59 ± 1.26%) and low-low(32.61 ± 1.45%) matching combinations becoming the predominant regional patterns. However, in climatic transition zones and glacial areas, the relationship between these factors is particularly distinctive, indicating ecosystem response mechanisms specific to certain natural environmental conditions. Vegetation cover(>0.697), evapotranspiration(>0.620), and precipitation(>0.688) are the primary natural factors influencing EQS, while the impact of human activities has become increasingly significant. Furthermore, the research findings underscore the positive effects of the variable climatic conditions of the QTP on ecosystems within the context of global climate warming, while the stringent implementation of ecological protection measures has collectively contributed to the enhancement of EQS. The proposed evaluation framework not only facilitates a comprehensive and precise assessment of regional EQS, but also provides a scientific basis for understanding and managing the adaptive responses of plateau ecosystems under the complex interplay of natural and anthropogenic factors.

7.
Colloids Surf B Biointerfaces ; 245: 114261, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39317041

RESUMO

Conventional hypotensive eye drops remain suboptimal for glaucoma management, primarily due to their limited intraocular bioavailability and the growing concern regarding ocular surface side effects. Therefore, there is an urgent need to develop innovative intraocular pressure (IOP)-lowering formulations that not only possess enhanced corneal penetration ability but also provide ocular surface protection. Herein, anti-oxidative mesoporous polydopamine nanoparticles (MPDA NPs) were explored as a nano-carrier for Brimonidine to address the above issues. Nearly monodisperse MPDA NPs with obvious nanopores were successfully prepared by template-removal method and used for encapsulation of Brimonidine benefiting from their high specific surface area. Interestingly, the PEGylated and drug loaded MPDA-PEG@Brim NPs showed a near neutral surface charge, which is expected to enhance intraocular drug delivery. Consequently, much higher concentration of Brimonidine in the aqueous humor was found after topical administration of MPDA-PEG@Brim nano-dispersion as compared to free Brimonidine solution. Accordingly, superior IOP reduction effect was achieved for the nano-formulation in both hypertensive and normotensive rat eyes. Moreover, MPDA-PEG NPs showed good capability in scavenging diverse free radicals, alleviating intracellular oxidative stress, and mitigating ocular surface oxidative level in a mouse model of preservative-induced dry eye. In addition, the excellent biosafety of this novel Brimonidine nanodrug was confirmed both in vitro and in vivo. Therefore, the present work may shed light on the development of next generation hypotensive formulations for extended ocular surface protection and glaucoma management.

8.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 42(5): 581-592, 2024 Oct 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-39304502

RESUMO

OBJECTIVES: This study aimed to identifyPAX9variants in non-syndromic tooth agenesis families of China, as well as to analyze the genotype⁃phenotype of non-syndromic tooth agenesis caused by PAX9variants, which can provide a basis for the genetic diagnosis of tooth agenesis. METHODS: We collected the data of 44 patients with non-syndromic oligodontia who underwent treatment at Stomatological Hospital of Hebei Medical University between 2018 and 2023. Whole-exome sequencing was performed on the peripheral blood of the proband and its core family members, and the variants were verified by Sanger sequencing. Pathogenicity analysis and function prediction of the variants were performed using bioinformatics tools. The correlation between the genotype of PAX9 variant and its corresponding phenotype was examined by reviewing 55 publications retrieved from PubMed. The studies involved 232 tooth agenesis patients with PAX9 variants. RESULTS: A novel PAX9 c.447delG (p.Pro150Argfs*62) and a reported PAX9 c.406C>T (p.Gln136*) were identified in two Chinese families. Through bioinformatics analysis and three-dimensional structural modeling, we postulated that the frameshift variant was pathogenic. The outcome was the premature cessation of PAX9 protein, which caused severe structural and functional deficiencies. Summarizing the PAX9 genotype-phenotype relationship revealed that patients carrying the PAX9 variant commonly led to loss of the second molars. CONCLUSIONS: We identified the novel PAX9 c.447delG (p.Pro150Argfs*62) in a Chinese family of non-syndromic oligodontia, expanding the known variant spectrum of PAX9. The most susceptible tooth position for PAX9 variants of tooth agenesis was the second molars and the deciduous molars during the deciduous dentition.


Assuntos
Anodontia , Sequenciamento do Exoma , Genótipo , Fator de Transcrição PAX9 , Fenótipo , Humanos , Fator de Transcrição PAX9/genética , Anodontia/genética , China , Estudos de Associação Genética , Linhagem , População do Leste Asiático
9.
PLoS Biol ; 22(9): e3002788, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39231149

RESUMO

The bacterial pathogen Vibrio coralliilyticus induces severe coral diseases in warming oceans. A study in PLOS Biology reveals that high temperatures activate 2 type VI secretion systems in V. coralliilyticus, enhancing pathogenicity by deploying toxic effectors against competing bacteria and coral cells.


Assuntos
Antozoários , Temperatura Alta , Sistemas de Secreção Tipo VI , Vibrio , Vibrio/patogenicidade , Vibrio/fisiologia , Antozoários/microbiologia , Animais , Sistemas de Secreção Tipo VI/metabolismo , Sistemas de Secreção Tipo VI/genética , Virulência , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética
10.
BMC Public Health ; 24(1): 2568, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39300416

RESUMO

OBJECTIVES: Evidence suggests that environmental support, personality traits, and psychological factors can influence seasonal changes in human mood and behavior, particularly in rural middle-aged women and older people. This study aimed to quantify the associations between personality traits, seasonal affective disorder symptoms, and sun exposure in rural older people. METHODS: This study is a cross-sectional analytical study, the participants were 300 rural older persons from 12 natural villages and 5 geriatric service centers in 4 different cities in Jiangxi Province, China. The Eysenck Personality Questionnaire (EPQ), the Personal Inventory of Depression and Seasonal Affective Disorder (PIDS-SA-SimpChi), and the Sunlight Exposure Scale were used to conduct follow-up interviews throughout the year. Spatial analysis was performed using ArcGIS and Geodetic Probes. The data were analyzed using SPSS 21 and Amos 23.0 mediated models. RESULTS: Rural older people with low sun exposure exhibited higher personality trait scores (p < 0.001). Personality traits were directly associated with seasonal affective disorder symptoms(p < 0.01); Sun exposure mediated this effect in rural older people (p < 0.05). CONCLUSION: High-scoring personalities are more typical of rural older people with low sun exposure, and there is a greater risk of emotional and behavioral instability. Latitudinal differences are not a determinant of SAD. Increased sun exposure is associated with symptom relief. The promotion of light therapy devices in rural areas with low sunlight is warranted.


Assuntos
População Rural , Transtorno Afetivo Sazonal , Luz Solar , Humanos , Estudos Transversais , Feminino , Idoso , Masculino , População Rural/estatística & dados numéricos , China/epidemiologia , Transtorno Afetivo Sazonal/epidemiologia , Transtorno Afetivo Sazonal/psicologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Inquéritos e Questionários , Personalidade
11.
Brief Bioinform ; 25(5)2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39256199

RESUMO

Deoxyribonucleic acid (DNA) methylation plays a key role in gene regulation and is critical for development and human disease. Techniques such as whole-genome bisulfite sequencing (WGBS) and reduced representation bisulfite sequencing (RRBS) allow DNA methylation analysis at the genome scale, with Illumina NovaSeq 6000 and MGI Tech DNBSEQ-T7 being popular due to their efficiency and affordability. However, detailed comparative studies of their performance are not available. In this study, we constructed 60 WGBS and RRBS libraries for two platforms using different types of clinical samples and generated approximately 2.8 terabases of sequencing data. We systematically compared quality control metrics, genomic coverage, CpG methylation levels, intra- and interplatform correlations, and performance in detecting differentially methylated positions. Our results revealed that the DNBSEQ platform exhibited better raw read quality, although base quality recalibration indicated potential overestimation of base quality. The DNBSEQ platform also showed lower sequencing depth and less coverage uniformity in GC-rich regions than did the NovaSeq platform and tended to enrich methylated regions. Overall, both platforms demonstrated robust intra- and interplatform reproducibility for RRBS and WGBS, with NovaSeq performing better for WGBS, highlighting the importance of considering these factors when selecting a platform for bisulfite sequencing.


Assuntos
Ilhas de CpG , Metilação de DNA , Análise de Sequência de DNA , Humanos , Análise de Sequência de DNA/métodos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sulfitos/química , Pareamento de Bases , Sequenciamento Completo do Genoma/métodos , Reprodutibilidade dos Testes
12.
Neuropsychology ; 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39347770

RESUMO

OBJECTIVE: The present study endeavored to investigate the potential neural underpinnings of disparities in audiovisual integration (AVI) between valid and invalid targets, modulated by nonspatial inhibition of return (IOR). Concurrently, we sought to delineate the distinct roles subserved by Chinese character primes and color block primes throughout this process. METHOD: We employed a prime-neutral cue-target paradigm, wherein 25 college students participated in the experiment. Behavioral measures encompassed the reaction time, IOR effect, multisensory response enhancement, and race model analysis. Besides, we examined the N200, N400, and P300 components elicited by the target stimulus presentation in a time-locked fashion to investigate the neural underpinnings of AVI disparities in the context of valid and invalid targets. RESULTS: Behavioral analyses unveiled a significant attenuation of AVI for valid targets, with this effect being particularly pronounced in trials involving Chinese character primes. Intriguingly, event-related potential (ERP) data evinced AVI within the N400 and P300 components. Moreover, the novelty of this study resides in identifying the P300 component as the principal neural correlate underpinning the attenuation of AVI arising from nonspatial IOR-a finding that was not replicated when employing color block primes. CONCLUSIONS: This research furnishes novel ERP evidence that elucidates the mechanisms through which nonspatial IOR modulates AVI. This contributes significantly to a broader understanding of the cognitive processes underpinning multisensory perception and attentional dynamics. These insights not only corroborate the late attention theory and the coactivation model but also lend credence to the context-updating hypothesis. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

13.
Acta Pharm Sin B ; 14(8): 3493-3512, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39220878

RESUMO

Amino acid metabolic remodeling is a hallmark of cancer, driving an increased nutritional demand for amino acids. Amino acids are pivotal for energetic regulation, biosynthetic support, and homeostatic maintenance to stimulate cancer progression. However, the role of phenylalanine in multiple myeloma (MM) remains unknown. Here, we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow (BM) cells. After the treatment, phenylalanine levels increase in plasma and decrease in BM. This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression. The requirement for phenylalanine by MM cells exhibits a similar pattern. Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib (BTZ) treatment in vitro and murine models. Mechanistically, phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3-CHOP-DR5 pathway. Interference with ATF3 significantly affects phenylalanine deprivation therapy. In conclusion, we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling. Phenylalanine is necessary for MM proliferation, and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.

14.
ACS Sens ; 9(10): 5156-5166, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39316657

RESUMO

MXene-based conductive hydrogels hold significant promise as epidermal sensors, yet their susceptibility to oxidation represents a formidable limitation. This study addresses this challenge by incorporating MXene into a tannic acid (TA) cross-linked silk fibroin matrix. The resulting conductive hydrogel (denoted as e-dive) exhibits favorable characteristics such as adjustable mechanical properties, self-healing capabilities (both mechanically and electrically), and strong underwater adhesion. The existence of a percolation network of MXene within the nanocomposites guarantees good electrical conductivity. Importantly, the surface interaction of MXene nanosheets with the hydrophobic moiety from TA substantially reduced moisture and oxygen interactions with MXene, thereby effectively mitigating MXene oxidation within hydrogel matrices. This preservation of the electrical characteristics ensures prolonged functional stability. Furthermore, the e-dive demonstrates inherent antibacterial properties, making it suitable for use in underwater environments where bacterial contamination is a concern. The utilization of this advanced e-dive system extends to the correction of diving postures and the facilitation of underwater healthcare and security alerts. Our study presents a robust methodology for enhancing the stability of MXene-based conductive hydrogel electronics, thereby expanding their scope of potential applications.


Assuntos
Hidrogéis , Taninos , Taninos/química , Hidrogéis/química , Antioxidantes/química , Dispositivos Eletrônicos Vestíveis , Condutividade Elétrica , Antibacterianos/química , Antibacterianos/farmacologia , Humanos , Fibroínas/química , Nanocompostos/química , Polifenóis
15.
Eur Spine J ; 33(10): 3915-3932, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39122847

RESUMO

PURPOSE: Laminoplasty (LP) combined with C3 laminectomy (LN) can effectively achieve spinal cord decompression while maintaining the integrity of the posterior ligament-muscle complex, thereby minimizing cervical muscle damage. However, its necessity and safety remain controversial. This study aimed to compare the safety and efficacy of LP and LP combined with C3 LN in the treatment of patients with multilevel degenerative cervical spondylotic myelopathy (DCM). METHODS: A systematic review and meta-analysis of the literature was performed. A search of PubMed, Web of Science, Embase, and the Cochrane Library databases was conducted from inception through December 2023 and updated in February 2024. Search terms included laminoplasty, laminectomy, C3 and degenerative cervical spondylosis. The literature search yielded 14 studies that met our inclusion criteria. Outcomes included radiographic results, neck pain, neurologic function, surgical parameters, and postoperative complications. We also assessed methodologic quality, publication bias, and quality of evidence. RESULTS: Fourteen studies were identified, including 590 patients who underwent LP combined with C3 LN (modified group, MG) compared to 669 patients who underwent LP (traditional group, TG). The results of the study indicated a statistically significant improvement in cervical range of motion (WMD = 3.62, 95% CI: 0.39 to 6.85) and cervical sagittal angle (WMD = 2.07, 95% CI: 0.40 to 3.74) in the MG compared to the TG at the last follow-up (very low-level evidence). The TG had a higher number of patients with complications, especially C2-3 bone fusion. There was no significant difference found in improvement of neck pain, JOA, NDI, cSVA, T1 slope at latest follow-up. CONCLUSION: LP combined with C3 LN is an effective and necessary surgical method for multilevel DCM patients to maintain cervical sagittal balance. However, due to the low quality of evidence in existing studies, more and higher quality research on the technology is needed in the future.


Assuntos
Vértebras Cervicais , Laminectomia , Laminoplastia , Espondilose , Humanos , Laminoplastia/métodos , Laminectomia/métodos , Vértebras Cervicais/cirurgia , Espondilose/cirurgia , Espondilose/diagnóstico por imagem , Doenças da Medula Espinal/cirurgia , Resultado do Tratamento , Descompressão Cirúrgica/métodos
16.
J Int Med Res ; 52(8): 3000605241271756, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39197860

RESUMO

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), also known as type II enteropathy-associated T-cell lymphoma, is a rare malignant lymphoma of the extranodal lymphoid tissue derived from interepithelial T lymphocytes. MEITL is a primary intestinal T-cell lymphoma with a challenging diagnosis and aggressive progression, and it can invade other extraintestinal sites. In this study, we report four patients diagnosed with MEITL. All patients presented with abdominal pain, and one patient was admitted because of acute intestinal perforation. Two patients presented with unformed defecation and diarrhea. All patients carried the immunophenotypes CD3, CD7, CD8, CD20, and CD56, and the Ki-67 index ranged 60% to 90%. Three cases were analyzed using next-generation sequencing. One case displayed possibly relevant alterations of CREBBP, NOTCH2, SETD2, and STAT5B, and another case exhibited definite alteration of NOTCH1, possibly relevant alterations of CCND1 and DNMT3A, and potentially relevant alterations of HISTH3B, IGLL5, KMT2C, and KRAS. Different chemotherapy regimens were used, but the prognosis was poor. Hence, we illustrated that because of its low incidence, challenging diagnosis, and difficult treatment, further therapeutic improvements are urgently warranted.


Assuntos
Linfoma de Células T Associado a Enteropatia , Humanos , Linfoma de Células T Associado a Enteropatia/diagnóstico , Linfoma de Células T Associado a Enteropatia/tratamento farmacológico , Linfoma de Células T Associado a Enteropatia/genética , Linfoma de Células T Associado a Enteropatia/imunologia , Imunofenotipagem , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/genética , Neoplasias Intestinais/imunologia , Prognóstico
17.
Eur J Med Chem ; 277: 116711, 2024 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-39094277

RESUMO

To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Mutação , Inibidores de Proteínas Quinases , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Animais , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Camundongos Nus , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química
18.
Nat Commun ; 15(1): 7244, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39174532

RESUMO

The filamentous 'Pf' bacteriophages of Pseudomonas aeruginosa play roles in biofilm formation and virulence, but mechanisms governing Pf prophage activation in biofilms are unclear. Here, we identify a prophage regulatory module, KKP (kinase-kinase-phosphatase), that controls virion production of co-resident Pf prophages and mediates host defense against diverse lytic phages. KKP consists of Ser/Thr kinases PfkA and PfkB, and phosphatase PfpC. The kinases have multiple host targets, one of which is MvaU, a host nucleoid-binding protein and known prophage-silencing factor. Characterization of KKP deletion and overexpression strains with transcriptional, protein-level and prophage-based approaches indicates that shifts in the balance between kinase and phosphatase activities regulate phage production by controlling MvaU phosphorylation. In addition, KKP acts as a tripartite toxin-antitoxin system that provides defense against some lytic phages. A conserved lytic phage replication protein inhibits the KKP phosphatase PfpC, stimulating toxic kinase activity and blocking lytic phage production. Thus, KKP represents a phosphorylation-based mechanism for prophage regulation and antiphage defense. The conservation of KKP gene clusters in >1000 diverse temperate prophages suggests that integrated control of temperate and lytic phage infection by KKP-like regulatory modules may play a widespread role in shaping host cell physiology.


Assuntos
Lisogenia , Prófagos , Pseudomonas aeruginosa , Lisogenia/genética , Pseudomonas aeruginosa/virologia , Pseudomonas aeruginosa/genética , Prófagos/genética , Prófagos/fisiologia , Fosforilação , Monoéster Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/genética , Proteínas Virais/metabolismo , Proteínas Virais/genética , Fagos de Pseudomonas/genética , Fagos de Pseudomonas/metabolismo , Biofilmes/crescimento & desenvolvimento , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Regulação Viral da Expressão Gênica
19.
J Environ Manage ; 368: 122096, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39121629

RESUMO

Protected area are the cornerstone of biodiversity and ecosystem service conservation at the local, regional, and global levels. In 2019, China proposed the establishment of a nature reserve system (NRS)centered on national parks, integrating and improving various existing protected areas. This study focuses on the Qinling‒Daba Mountains, an area crucial for both biodiversity and ecosystem services. Through assessments of carbon storage (CS), water yield (WY), soil conservation (SC), and habitat quality (HQ), different conservation scenarios are considered in the context of Systematic conservation planning (SCP). An optimization scheme for the NRS in the Qinling-Daba Mountains is proposed, incorporating ecosystem services and comparing them with the existing system. Research indicates that the main protected areas are concentrated in the Min Mountain‒Motian Mountain‒Longmen Mountain region, the central Qinling region, and the Shennongjia‒Daba Mountain region. Compared with the original system, the area of protected regions in the NRS expanded by 52,000 km2 after the SCP scheme was incorporated. The number of patches decreased to 50, and the patch density reduced from 2.1 × 10-4(/100 ha) to 1.7 × 10-4(/100 ha), thereby reducing the fragmentation of the conservation system. Additionally, the optimized scheme achieved a conservation ratio of over 30% for CS, WY, SC, and HQ, with the conservation efficiency for WY and HQ increasing by 0.18 and 0.22, respectively. The study results provide support for optimizing the Qinling-Daba Mountains NRS and offer a reference for constructing NRSs in other regions. Considering ecosystem services in the optimization of the NRS helps enhance the supply capacity of ecological products, maintain national ecological security, and achieve harmonious coexistence and sustainable development between humans and nature.


Assuntos
Biodiversidade , Conservação dos Recursos Naturais , Ecossistema , Conservação dos Recursos Naturais/métodos , China , Solo
20.
Adv Mater ; 36(44): e2407718, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39194367

RESUMO

Photo-assisted Zn-air batteries can accelerate the kinetics of oxygen reduction and oxygen evolution reactions (ORR/OER); however, challenges such as rapid charge carrier recombination and continuous electrolyte evaporation remain. Herein, for the first time, piezoelectric catalysis is introduced in a photo-assisted Zn-air battery to improve carrier separation capability and accelerate the ORR/OER kinetics of the photoelectric cathode. The designed microhelical catalyst exploits simple harmonic vibrations to regenerate the built-in electric field continuously. Specifically, in the presence of the low-frequency kinetic energy that occurs during water flow, the piezoelectric-photocoupling catalyst of poly(vinylidene fluoride-co-trifluoroethylene)@ferric oxide(Fe@P(V-T)) is periodically deformed, generating a constant reconfiguration of the built-in electric field that separates photogenerated electrons and holes continuously. Further, on exposure to microvibrations, the gap between the charge and discharge potentials of the Fe@P(V-T)-based photo-assisted Zn-air battery is reduced by 1.7 times compared to that without piezoelectric assistance, indicating that piezoelectric catalysis is highly effective for enhancing photocatalytic efficiency. This study provides a thorough understanding of coupling piezoelectric polarization and photo-assisted strategy in the field of energy storage and opens a fresh perspective for the investigation of multi-field coupling-assisted Zn-air batteries.

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