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1.
Front Immunol ; 15: 1354613, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38617840

RESUMO

Metastatic colon cancer remains an incurable disease, and it is difficult for existing treatments to achieve the desired clinical outcome, especially for colon cancer patients who have received first-line treatment. Although immune checkpoint inhibitors (ICIs) have demonstrated durable clinical efficacy in a variety of solid tumors, their response requires an inflammatory tumor microenvironment. However, microsatellite-stable (MSS) colon cancer, which accounts for the majority of colorectal cancers, is a cold tumor that does not respond well to ICIs. Combination regimens open the door to the utility of ICIs in cold tumors. Although combination therapies have shown their advantage even for MSS colon cancer, it remains unclear whether combination therapies show their advantage in patients with pretreated metastatic colon cancer. We report a patient who has achieved complete remission and good tolerance with sintilimab plus bevacizumab and platinum-based chemotherapy after postoperative recurrence. The patient had KRAS mutation and MSS-type colon cancer, and his PD-1+CD8+ and CD3-CD19-CD14+CD16-HLA-DR were both positive. He has achieved a progression-free survival of 43 months and is still being followed up at our center. The above results suggest that this therapeutic regimen is a promising treatment modality for the management of pretreated, MSS-type and KRAS-mutated metastatic colorectal cancer although its application to the general public still needs to be validated in clinical trials.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias do Colo , Proteínas Proto-Oncogênicas p21(ras) , Masculino , Humanos , Bevacizumab/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , 60410 , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Platina , Repetições de Microssatélites , Microambiente Tumoral
2.
Food Sci Nutr ; 12(4): 2908-2916, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38628221

RESUMO

Asparagus, a vital economic contributor, is a well-liked vegetable grown around the globe, and some secondary metabolites in its spear are beneficial to human health. Asparagus spears possess a significant quantity of nutrients and phytochemicals; however, the difference in these chemical compositions among various varieties has not been sufficiently studied. This work aimed to detect the chemical compositions of 30 varieties of asparagus and to assess them by principal component analysis (PCA). The results showed that the contents of these chemical compositions varied in varieties. Selenium (Se, 1.12-2.9 µg/100 g dry-weight [DW]) was abundant in asparagus, with an average dry matter content of 8.25%. Free amino acids (5.60-9.98 g/100 g DW) and polyphenols (6.34-8.67 mg/g DW) were both present in high amounts, along with flavonoids (4.218-8.22 mg/g DW) and protodioscin (0.44-1.96 mg/g DW). Correlation analysis, PCA, and hierarchical cluster analysis were used to conduct a comprehensive evaluation of asparagus. Atlas, Appolo, Jinggang 111, Jingke 2, and WS-1 were the top five varieties with comprehensive scores. This study provided valuable data for the breeding, quality improvement, processing, and utilization of asparagus varieties in the future.

3.
J Colloid Interface Sci ; 666: 572-584, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38613979

RESUMO

Volatile organic compounds (VOCs) have always been a major concern as a global environmental problem. As a low-cost, high-efficiency and visual sensor, photonic crystals (PCs) have been actively studied in VOCs detection. Herein, a one-dimensional PC sensor for visual sensing of highly toxic benzene series VOC vapors is prepared for the first time by integrating a new photo-crosslinked polymer-poly(styrene-benzoylphenyl acrylate) P(St-BPA) and a high specific surface area metal-organic framework (MOF) MIL-101(Cr). The PC can detect VOCs quantitatively and visually, and clearly distinguish 7 benzene series vapors. The detection limit of the benzene series VOCs is as low as 0.06-3.45 g/m3. Meanwhile, owing to the ultra-thin layer and porous structure, the PC can reach a response equilibrium to the VOCs within 1-2.6 s. Moreover, the PC has a good organic vapor tolerance and can maintain stable optical performance after 1000 times of reuse in VOCs. Besides, 4 other PCs assembled with different aryl polymers and MOFs are first fabricated and their sensing performance to benzene series VOCs are studied and compared, which provides a valuable reference for the selection of materials for the preparation of such PC sensors.

4.
Ecotoxicol Environ Saf ; 276: 116317, 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38615641

RESUMO

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

5.
Artigo em Inglês | MEDLINE | ID: mdl-38619977

RESUMO

A Gram-stain-negative, non-motile, and slightly halophilic alphaproteobacterium, designated strain EGI FJ00035T, was isolated from enrichment sediment samples of a saline lake in Xinjiang Uygur Autonomous Region, PR China. The taxonomic position of the isolate was determined using the polyphasic taxonomic and phylogenomic analyses. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that strain EGI FJ00035T formed a distinct clade with 'Chelativorans alearense' UJN715 and 'Chelativorans xinjiangense' lm93 with sequence similarities of 98.44 and 98.22 %, respectively, while sharing less than 96.7 % with other valid type strains. The novel isolate could be distinguished from other species of the genus Chelativorans by its distinct phenotypic, physiological, and genotypic characteristics. Optimal growth of strain EGI FJ00035T occurred on marine agar 2216 at pH 7.0 and 30 °C. The major respiratory quinone was Q-10, while the major fatty acids (>5 %) were C19 : 0 cyclo ω8c, summed feature 8 (C17 : 1 ω6c and/or C17 : 1 ω7c), C16 : 0, C18 : 0, and iso-C17 : 0. The detected polar lipids included diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, unidentified aminophospholipids, unidentified glycolipids, and an unidentified lipid. Based on its genome sequence, the G+C content of strain EGI FJ00035T was 63.2 mol%. The average nucleotide identity, average amino acid identity, and digital DNA-DNA hybridization values of strain EGI FJ00035T against related members of the genus Chelativorans were below the thresholds for delineation of a novel species. According our polyphasic taxonomic data, strain EGI FJ00035T represents a new species of the genus Chelativorans, for which the name Chelativorans salis sp. nov. is proposed. The type strain of the proposed novel isolate is EGI FJ00035T (=KCTC 92251T=CGMCC 1.19480T).


Assuntos
Ácidos Graxos , Phyllobacteriaceae , Ácidos Graxos/química , Fosfolipídeos/química , Ubiquinona/química , Filogenia , RNA Ribossômico 16S/genética , Lagos/análise , Composição de Bases , Técnicas de Tipagem Bacteriana , DNA Bacteriano/genética , Análise de Sequência de DNA , China , Phyllobacteriaceae/genética
6.
J Chem Phys ; 160(13)2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38568943

RESUMO

Tert-butyl functional groups can modulate the self-assembly behavior of organic molecules on surfaces. However, the precise construction of supramolecular architectures through their controlled thermal removal remains a challenge. Herein, we precisely controlled the removal amount of tert-butyl groups in tetraazaperopyrene derivatives by stepwise annealing on Ag(111). The evolution of 4tBu-TAPP supramolecular self-assembly from the grid-like structure composed of 3tBu-TAPP through the honeycomb network formed by 2tBu-TAPP to the one-dimensional chain co-assembled by tBu-TAPP and TAPP was successfully realized. This series of supramolecular nanostructures were directly visualized by high resolution scanning tunneling microscopy. Tip manipulation and density functional theory calculations show that the formation of honeycomb network structure can be attributed to the van der Waals interactions, N-Ag-N coordination bonds, and weak C-H⋯N hydrogen bonds. Further addition of two tert-butyl groups (6tBu-TAPP) leads to a completely different assembly evolution, due to the fact that the additional tert-butyl groups affect the molecular adsorption behavior and ultimately induce desorption. This work can possibly be exploited in constructing stable and long-range ordered nanostructures in surface-assisted systems, which can also promote the development of nanostructures in functional molecular devices.

7.
Public Health Nurs ; 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38572771

RESUMO

OBJECTIVES: To analyze the mode of school physical activity, the relationship with obesity, and participation willingness and behavior in the relationship between modes of school physical activity and BMI in students with overweight or obesity. DESIGN: Cross-sectional study. SAMPLE: Data from the 2014 Physical Fitness and Health Surveillance of Chinese School Students was used, wherein physical measurements and questionnaires of 3476 middle school students were collected. MEASUREMENTS: Physical measurements and questionnaires were completed. Latent profile analysis and mediated effects analysis were conducted using Mplus 8.3 and IBM SPSS 26.0 for data description and statistical analysis. RESULT: After latent profile analysis divided into poor (9.35%), medium (65.16%), and good (25.49%) groups of school physical activity, among junior middle school students, medium (OR = 0.428, 95% CI = 0.259-0.707, p = .001) and good (OR = 0.448, 95% CI = 0.255-0.718, p = .002) groups were positive for controlling overweight. Among students with overweight or obesity, participation willingness mediated the relationship between the mode of school physical activity and BMI, with effect coefficients of -0.120 (95% CI = -0.264 to -0.016) and -0.240 (95% CI = -0.426 to -0.099). CONCLUSIONS: School physical activity modes have a positive effect only on preventing and controlling overweight in junior middle school students. For middle school students with obesity, weight-specific measures should be considered for their prevention and control.

8.
BMJ Open ; 14(4): e080796, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38643014

RESUMO

INTRODUCTION: Surgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. This protocol presents a single-site, prospective observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association could be moderated or mediated by Alzheimer's disease (AD) pathology and genetic risk for AD. METHODS AND ANALYSIS: Study staff members will screen for eligible patients (age ≥70) seeking joint replacement or spinal surgery at Massachusetts General Hospital (MGH). At the inclusion visit, patients will be asked a series of questionnaires related to sleep and cognition, conduct a four-lead ECG recording and be fitted for an actigraphy watch to wear for 7 days before surgery. Blood samples will be collected preoperatively and postoperatively and will be used to gather information about AD variant genes (APOE-ε4) and AD-related pathology (total and phosphorylated tau). Confusion Assessment Method-Scale and Montreal Cognitive Assessment will be completed twice daily for 3 days after surgery. Seven-day actigraphy assessments and Patient-Reported Outcomes Measurement Information System questionnaires will be performed 1, 3 and 12 months after surgery. Relevant patient clinical data will be monitored and recorded throughout the study. ETHICS AND DISSEMINATION: This study is approved by the IRB at MGH, Boston, and it is registered with the US National Institutes of Health on ClinicalTrials.gov (NCT06052397). Plans for dissemination include conference presentations at a variety of scientific institutions. Results from this study are intended to be published in peer-reviewed journals. Relevant updates will be made available on ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT06052397.


Assuntos
Delírio , Delírio do Despertar , Humanos , Estudos Prospectivos , Delírio/diagnóstico , Delírio/etiologia , Complicações Pós-Operatórias/diagnóstico , Estudos de Coortes , Sono , Biomarcadores , Estudos Observacionais como Assunto
9.
Oncol Rep ; 51(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38639185

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive, heterogeneous tumour usually caused by alcohol and tobacco consumption, making it one of the most common malignancies worldwide. Despite the fact that various therapeutic approaches such as surgery, radiation therapy (RT), chemotherapy (CT) and targeted therapy have been widely used for HNSCC in recent years, its recurrence rate and mortality rate remain high. RT is the standard treatment choice for HNSCC, which induces reactive oxygen species production and causes oxidative stress, ultimately leading to tumour cell death. CT is a widely recognized form of cancer treatment that treats a variety of cancers by eliminating cancer cells and preventing them from reproducing. Immune checkpoint inhibitor and epidermal growth factor receptor are important in the treatment of recurrent or metastatic HNSCC. Iron death, a type of cell death regulated by peroxidative damage to phospholipids containing polyunsaturated fatty acids in cell membranes, has been found to be a relevant death response triggered by tumour RT in recent years. In the present review, an overview of the current knowledge on RT and combination therapy and iron death in HNSCC was provided, the mechanisms by which RT induces iron death in tumour cells were summarized, and therapeutic strategies to target iron death in HNSCC were explored. The current review provided important information for future studies of iron death in the treatment of HNSCC.


Assuntos
Ferroptose , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Terapia Combinada , Ferro
10.
Sci Rep ; 14(1): 8921, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637615

RESUMO

Durability is one of the technical bottlenecks restricting fuel cell electric vehicle development. As a result, significant time and resources have been invested in research related to this area worldwide. Current durability research mainly focuses on the single cell and stack levels, which is quite different from the usage scenarios of actual vehicles. There is almost no research on developing durability test cycles on the fuel cell system level. This paper proposes a universal model for developing a durability test cycle for fuel cell system based on the China automotive test cycle. Large-scale comparison tests of the fuel cell systems are conducted. After 1000 h test, the output performance degradation of three mass-produced fuel cell system is 14.49%, 9.59%, and 4.21%, respectively. The test results show that the durability test cycle proposed in this paper can effectively accelerate the durability test of the fuel cell system and evaluate the durability performance of the fuel cell system. Moreover, the methodology proposed in this paper could be used in any other test cycles such as NEDC (New European Driving Cycle), WLTC (Worldwide Harmonized Light Vehicles Test Procedure), etc. And it has comprehensive application value and are significant for reducing the cost of durability testing of fuel cell systems and promoting the industrialization of fuel cell electric vehicles.

11.
EMBO Rep ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600346

RESUMO

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

12.
Public Health Nurs ; 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38602094

RESUMO

OBJECTIVE: To analyze the co-existing patterns of health-related behaviors among children and adolescents at different education stages and the association with obesity. DESIGN: Cross-sectional study. SAMPLE: A total of 5651 primary and secondary school students were drawn from the National Student Physical Health Survey in 2014 with an average age of 13.53 ± 2.87 years. MEASUREMENTS: Physical measurements and questionnaires were completed, which concluded height, weight, and health-related behaviors (sleep, physical activity, dietary, and screen behavior et al.). Latent profile analysis (LPA) was conducted using Mplus 8.3 and SPSS 26.0 was used for other statistical analysis. RESULTS: Three latent classes of health-related behaviors were fitted for each of the education stages. After adjustment for age, gender, and region, the high-screen behavior group were 2.217 (95%CI = 1.030-4.772, p = .042) times more likely to be obesity than the health-behavior group in primary school, and the poor-diet group and poor-diet and high-screen behavior group were 2.101 (95%CI = 1.396-3.396, p < .001) and 1.788 (95%CI = 1.003-3.190, p = .049) times more likely to be overweight than the health-behavior group in junior middle school respectively. CONCLUSION: Obesity is mainly influenced by screen behavior and dietary patterns among children and adolescents. Health-related behavior patterns should be accurately identified and comprehensive joint interventions should be carried out to prevent obesity.

14.
Front Neurol ; 15: 1376336, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38645742

RESUMO

Purpose: To investigate the effects of nonpharmacological interventions (NPIs) on poststroke depression (PSD) in stroke patients. Methods: Computer searches were conducted on the PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases from their establishment to December 2023. The selection was made using the inclusion and exclusion criteria, and 40 articles were included to compare the effects of the 17 NPIs on patients with PSD. Results: Forty studies involving seventeen interventions were included. The network findings indicated that compared with conventional therapy (COT), superior PSD improvement was observed for cognitive behavioral therapy (CBT) + acupoint acupuncture (CBTA) (mean difference [MD], -4.25; 95% CI, -5.85 to -2.65), team positive psychotherapy (MD, -4.05; 95% CI, -5.53 to -2.58), music therapy (MT) + positive psychological intervention (MD, -2.25; 95% CI, -3.65 to -0.85), CBT (MD, -1.52; 95% CI, -2.05 to -0.99), mindfulness-based stress reduction (MD, -1.14; 95% CI, -2.14 to -0.14), MT (MD, -0.95; 95% CI, -1.39 to -0.52), acupoint acupuncture + MT (AAMT) (MD, -0.69; 95% CI, -1.25 to -0.14). Furthermore, CBT (MD, -3.87; 95% CI, -4.57 to -3.17), AAMT (MD, -1.02; 95% CI, -1.41 to -0.62), acupressure + MT (MD, -0.91; 95% CI, -1.27 to -0.54), and narrative care + acupressure (MD, -0.74; 95% CI, -1.19 to -0.29) demonstrated superior Pittsburgh Sleep Quality Index (PSQI) improvement compared with COT. Conclusion: Evidence from systematic reviews and meta-analyses suggests that CBTA improves depression in patients with PSD. Moreover, CBT improves sleep in these patients. Additional randomized controlled trials are required to further investigate the efficacy and mechanisms of these interventions.

15.
Food Chem ; 449: 139215, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38581791

RESUMO

Misuse of amide herbicides in the fisheries environment can pose unpredictable harm to aquatic products and ultimately human health. Thus, the development of a real-time, rapid on-site detection method is crucial. This study proposes for the first time, a paper-based visual detection method for amide herbicides in fish serum, by coating the molecularly imprinted polymer layer onto quantum dots, prepared fluorescent sensing materials (QDs@MIPs) for the detection of amide herbicides in aquatic products. These materials specifically cause fluorescence quenching in the presence of amide herbicides resulting in a color change. For practical application, this research designed a rapid test strip based on QDs@MIPs, meanwhile, incorporate a smartphone or a fluorescence spectrophotometer for qualitative and quantitative measurements, the limit of detection ranges of 0.061-0.500 µM. The method can be used for on-site evaluation of aquatic products, providing new technology for monitoring the safety of aquatic products.

16.
Adv Sci (Weinh) ; : e2303471, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38481061

RESUMO

The generation of cultured red blood cells (cRBCs) ex vivo represents a potentially unlimited source for RBC transfusion and other cell therapies. Human cRBCs can be generated from the terminal differentiation of proliferating erythroblasts derived from hematopoietic stem/progenitor cells or erythroid precursors in peripheral blood mononuclear cells. Efficient differentiation and maturation into cRBCs highly depend on replenishing human plasma, which exhibits variable potency across donors or batches and complicates the consistent cRBC production required for clinical translation. Hence, the role of human plasma in erythroblast terminal maturation is investigated and uncovered that 1) a newly developed cell culture basal medium mimicking the metabolic profile of human plasma enhances cell growth and increases cRBC yield upon erythroblast terminal differentiation and 2) LDL-carried cholesterol, as a substitute for human plasma, is sufficient to support erythroid survival and terminal differentiation ex vivo. Consequently, a chemically-defined optimized medium (COM) is developed, enabling robust generation of cRBCs from erythroblasts of multiple origins, with improved enucleation efficiency and higher reticulocyte yield, without the need for supplementing human plasma or serum. In addition, the results reveal the crucial role of lipid metabolism during human terminal erythropoiesis.

17.
Protein Cell ; 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38518087

RESUMO

Developing an intracellular delivery system is of key importance in the expansion of protein-based therapeutics acting on cytosolic or nuclear targets. Recently, extracellular vesicles (EVs) have been exploited as next-generation delivery modalities due to their natural role in intercellular communication and biocompatibility. However, fusion of protein of interest to a scaffold represents a widely-used strategy for cargo enrichment in EVs, which could compromise t the stability and functionality of cargo. Herein, we report intracellular delivery via EV-based approach (IDEA) that efficiently packages and delivers native proteins both in vitro and in vivo without the use of a scaffold. As a proof-of-concept, we applied the IDEA to deliver cyclic GMP-AMP synthase (cGAS), an innate immune sensor. The results showed that cGAS-carrying EVs activated interferon signaling and elicited enhanced antitumor immunity in multiple syngeneic tumor models. Combining cGAS EVs with immune checkpoint inhibition further synergistically boosted antitumor efficacy in vivo. Mechanistically, scRNA-seq demonstrated that cGAS EVs mediated significant remodelling of intratumoral microenvironment, revealing a pivotal role of infiltrating neutrophils in the antitumor immune milieu. Collectively, IDEA, as a universal and facile strategy, can be applied to expand and advance the development of protein-based therapeutics.

18.
Blood ; 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38484137

RESUMO

Although CD20xCD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in CNS lymphoma is unknown. Here, we report the CD20xCD3 bispecific, glofitamab, penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces responses in CNS lymphoma.

19.
Nat Commun ; 15(1): 2492, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509059

RESUMO

Biosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these DAs have evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses the oxidative cyclisation reactions of isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, we identified several critical substitutions, including S348L, A357L, D389E and H418R that alter the substrate-binding mode and enable the OCs to gain intermolecular DA activity during evolution. This work provides mechanistic insights into the evolutionary rationale of DAs and paves the way for mining and engineering new DAs from other protein families.


Assuntos
Morus , Morus/genética , Morus/química , Terpenos , Catálise , Reação de Cicloadição
20.
Microbes Infect ; : 105331, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38537769

RESUMO

Bats are important mammal reservoirs of zoonotic pathogens. However, due to research limitations involving species, locations, pathogens, or sample types, the full diversity of viruses in bats remains to be discovered. We used next-generation sequencing technology to characterize the mammalian virome and analyze the phylogenetic evolution and diversity of mammalian viruses carried by bats from Haikou City and Tunchang County in Hainan Province, China. We collected 200 pharyngeal swab and anal swab samples from Rhinolophus affinis, combining them into nine pools based on the sample type and collection location. We subjected the samples to next-generation sequencing and conducted bioinformatics analysis. All samples were screened via specific PCR and phylogenetic analysis. The diverse viral reads, closely related to mammals, were assigned into 17 viral families. We discovered many novel bat viruses and identified some closely related to known human/animal pathogens. In the current study, 6 complete genomes and 2 partial genomic sequences of 6 viral families and 8 viral genera have been amplified, among which 5 strains are suggested to be new virus species. These included coronavirus, pestivirus, bastrovirus, bocavirus, papillomavirus, parvovirus, and paramyxovirus. The primary finding is that a SADS-related CoV and a HoBi-like pestivirus identified in R. affinis in Hainan Province could be pathogenic to livestock. This study expands our understanding of bats as a virus reservoir, providing a basis for further research on the transmission of viruses from bats to humans.

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