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Background: Physical activity (PA) exerts an important influence on glycemic control in type 2 diabetes (T2D) patients. Alterations in body composition in patients with T2D may be involved in the overall pathophysiologic process, but PAs and alterations in body composition have been poorly studied. Methods: A total of 615 patients with T2D were selected by convenient sampling. The patients were investigated with the International Physical Activity Questionnaire (IPAQ-S). Moreover, biochemical indices were collected, and the progression of the body composition of the subjects was determined via dual-energy X-ray absorptiometry (DXA). The variables included lumbar bone mineral density (LSBMD), femoral neck bone mineral density (FNBMD), hip bone mineral density (HBMD), whole-body bone mineral density (TBMD), limb skeletal muscle mass index (ASMI), whole-body fat percentage (B-FAT) and trunk fat percentage (T-FAT). Moreover, the levels of physical activity (high level of physical activity [H-PA], medium level of physical activity [M-PA] and low level of physical activity [L-PA]) were divided into three groups to analyze the changes in patient body composition with changes in physical activity level. Results: One-way analysis of variance showed that ß-CTX, TP1NP, HbA1c, B-FAT and T-FAT increased significantly (p<0.05), while 25(OH)D, LSBMD, FNBMD, HBMD, TBMD and ASMI decreased significantly (p<0.001) with the decrease of physical activity. However, there was no significant difference in serum lipids between lnHOMA-ir and lnHOMA-ß (p>0.05). Multiple linear regression model was established to gradually adjust for clinical confounding factors. It was found that physical activity level was independently positively correlated with LSBMD, FNBMD, HBMD, TBMD, and ASMI, and was independently negatively correlated with B-FAT and T-FAT in patients with type 2 diabetes. Conclusion: A lack of physical activity is an independent risk factor for decreased bone mineral density, decreased skeletal muscle content and increased fat content in patients with T2D.
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This article is committed to studying projective synchronization and complete synchronization (CS) issues for one kind of discrete-time variable-order fractional neural networks (DVFNNs) with time-varying delays. First, two new variable-order fractional (VF) inequalities are built by relying on nabla Laplace transform and some properties of Mittag-Leffler function, which are extensions of constant-order fractional (CF) inequalities. Moreover, the VF Halanay inequality in discrete-time sense is strictly proved. Subsequently, some sufficient projective synchronization and CS criteria are derived by virtue of VF inequalities and hybrid controllers. Finally, we exploit numerical simulation examples to verify the validity of the derived results, and a practical application of the obtained results in image encryption is also discussed.
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BACKGROUND: Functional redundancy (FR) is widely present, but there is no consensus on its formation process and influencing factors. Taxonomically distinct microorganisms possessing genes for the same function in a community lead to within-community FR, and distinct assemblies of microorganisms in different communities playing the same functional roles are termed between-community FR. We proposed two formulas to respectively quantify the degree of functional redundancy within and between communities and analyzed the FR degrees of carbohydrate degradation functions in global environment samples using the genetic information of glycoside hydrolases (GHs) encoded by prokaryotes. RESULTS: Our results revealed that GHs are each encoded by multiple taxonomically distinct prokaryotes within a community, and the enzyme-encoding prokaryotes are further distinct between almost any community pairs. The within- and between-FR degrees are primarily affected by the alpha and beta community diversities, respectively, and are also affected by environmental factors (e.g., pH, temperature, and salinity). The FR degree of the prokaryotic community is determined by deterministic factors. CONCLUSIONS: We conclude that the functional redundancy of GHs is a stabilized community characteristic. This study helps to determine the FR formation process and influencing factors and provides new insights into the relationships between prokaryotic community biodiversity and ecosystem functions. Video Abstract.
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Bactérias , Biodiversidade , Glicosídeo Hidrolases , Polissacarídeos , Glicosídeo Hidrolases/metabolismo , Glicosídeo Hidrolases/genética , Polissacarídeos/metabolismo , Bactérias/genética , Bactérias/classificação , Bactérias/metabolismo , Ecossistema , Microbiota , Células Procarióticas/metabolismo , Células Procarióticas/classificação , Filogenia , Concentração de Íons de HidrogênioRESUMO
The impact of climate warming on soil microbes has been well documented, with studies revealing its effects on diversity, community structure and network dynamics. However, the consistency of soil microbial community assembly, particularly in response to diverse plant root exudates under varying temperature conditions, remains an unresolved issue. To address this issue, we employed a growth chamber to integrate temperature and root exudates in a controlled experiment to examine the response of soil bacteria, fungi, and protists. Our findings revealed that temperature independently regulated microbial diversity, with distinct patterns observed among bacteria, fungi, and protists. Both root exudates and temperature significantly influenced microbial community composition, yet interpretations of these factors varied among prokaryotes and eukaryotes. In addition to phototrophic bacteria and protists, as well as protistan consumers, root exudates determined to varying degrees the enrichment of other microbial functional guilds at specific temperatures. The effects of temperature and root exudates on microbial co-occurrence patterns were interdependent; root exudates primarily simplified the network at low and high temperatures, while responses to temperature varied between single and mixed exudate treatments. Moreover, temperature altered the composition of keystone species within the microbial network, while root exudates led to a decrease in their number. These results emphasize the substantial impact of plant root exudates on soil microbial community responses to temperature, underscoring the necessity for future climate change research to incorporate additional environmental variables.
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Bactérias , Fungos , Raízes de Plantas , Microbiologia do Solo , Temperatura , Raízes de Plantas/microbiologia , Fungos/classificação , Fungos/metabolismo , Bactérias/classificação , Bactérias/metabolismo , Microbiota , Mudança Climática , Eucariotos/crescimento & desenvolvimento , Biodiversidade , Exsudatos de Plantas/metabolismo , Exsudatos de Plantas/química , Solo/químicaRESUMO
PURPOSE: The extent of tumor regression varies widely among locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME). The purpose of this retrospectively study is to assess prognostic factors in LARC patients with NCRT, and further to analyze survival outcomes in patients with different tumor regression grades (TRGs). METHODS: This study includes LARC patients who underwent NCRT and TME at our institution. We retrospectively analyzed the clinicopathological characteristics and survival of all patients, and performed subgroup analysis for patients with different TRGs. Survival differences were compared using the Kaplan-Meier method and the log rank test. Additionally, a multiple Cox proportional hazard model was used to identify independent prognostic factors. RESULTS: The study included 393 patients, with 21.1%, 26.5%, 45.5%, and 6.9% achieving TRG 0, TRG 1, TRG 2, and TRG 3, respectively. The overall survival (OS) rate and disease-free survival (DFS) rate for all patients were 89.4% and 70.7%, respectively. Patients who achieved TRG 0-3 had different 5-year OS rates (96.9%, 91.1%, 85.2%, and 68.8%, P = 0.001) and 5-year DFS rates (80.8%, 72.4%, 67.0%, 55.8%, P = 0.031), respectively. Multivariate analyses showed that the neoadjuvant rectal (NAR) score was an independent prognostic indicator for both overall survival (OS) (HR = 4.040, 95% CI = 1.792-9.111, P = 0.001) and disease-free survival (DFS) (HR = 1.971, 95% CI = 1.478-2.628, P Ë 0.001). In the subgroup analyses, the NAR score was found to be associated with DFS in patients with TRG 1 and TRG 2. After conducting multivariate analysis, it was found that ypT stage was a significant predictor of DFS for TRG 1 patients (HR = 4.384, 95% CI = 1.721-11.168, P = 0.002). On the other hand, ypN stage was identified as the dominant prognostic indicator of DFS for TRG 2 patients (HR = 2.795, 95% CI = 1.535-5.091, P = 0.001). However, none of these characteristics was found to be correlated with survival in patients with TRG 0 or TRG 3. CONCLUSION: NAR score, in particular, appears to be the most powerful prognostic factor. It is important to consider various prognostic predictors for patients with different TRGs.
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Terapia Neoadjuvante , Neoplasias Retais , Humanos , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Neoplasias Retais/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso , Intervalo Livre de Doença , Adulto , Quimiorradioterapia , Estimativa de Kaplan-Meier , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise MultivariadaRESUMO
BACKGROUND: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. METHODS: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. FINDINGS: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. INTERPRETATION: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Terapia Neoadjuvante , Piridinas , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Terapia Neoadjuvante/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto Jovem , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , AdolescenteRESUMO
Ischemic stroke ranks among the leading causes of death and disability in humans and is accompanied by motor and cognitive impairment. However, the precise mechanisms underlying injury after stroke and effective treatment strategies require further investigation. Peroxiredoxin-1 (PRDX1) triggers an extensive inflammatory cascade that plays a pivotal role in the pathology of ischemic stroke, resulting in severe brain damage from activated microglia. In the present study, we used molecular dynamics simulation and nuclear magnetic resonance to detect the interaction between PRDX1 and a specific interfering peptide. We used behavioral, morphological, and molecular experimental methods to demonstrate the effect of PRDX1-peptide on cerebral ischemia-reperfusion (I/R) in mice and to investigate the related mechanism. We found that PRDX1-peptide bound specifically to PRDX1 and improved motor and cognitive functions in I/R mice. In addition, pretreatment with PRDX1-peptide reduced the infarct area and decreased the number of apoptotic cells in the penumbra. Furthermore, PRDX1-peptide inhibited microglial activation and downregulated proinflammatory cytokines including IL-1ß, IL-6, and TNF-α through inhibition of the TLR4/NF-κB signaling pathway, thereby attenuating ischemic brain injury. Our findings clarify the precise mechanism underlying PRDX1-induced inflammation after ischemic stroke and suggest that the PRDX1-peptide can significantly alleviate the postischemic inflammatory response by interfering with PRDX1 amino acids 70-90 and thereby inhibiting the TLR4/NF-κB signaling pathway. Our study provides a theoretical basis for a new therapeutic strategy to treat ischemic stroke.
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This study aims to explore the mechanism of Shoutai Pills in treating threatened abortion. According to the random number table method, ICR female mice were randomized into a normal group, a model group, a dydrogesterone group, and a Shoutai Pills group, with 15 mice in each group. Mice were administrated with normal saline(normal and model groups) or the suspension of Shoutai Pills or dydrogesterone by gavage at 9:00 am every day. At 16:00 every day, mice in the normal group were administrated with an equal volume of distilled water, while those in the model, Shoutai Pills, and dydrogesterone groups were administrated with hydrocortisone solution by gavage for 4 consecutive days. ICR female and male mice were caged in a ratio of 2â¶1 during the pre-estrous or estrous period. From the first day of pregnancy, drug administration was continued for 5 consecutive days. On day 6, mice were administrated with mifepristone by gavage to establish the model of kidney deficiency-induced abortion. On day 6 of pregnancy, 10 female ICR mice were randomly selected from each group, and the uterus was collected for observation of the pathological changes of trophoblasts at the maternal-fetal interface by hematoxylin-eosin(HE) staining. The protein levels of key enzymes of glycolysis, hexokinase 2(HK2), enolase 1(ENO1), pyruvate kinase M2(PKM2), and lactate dehydrogenase A(LDHA), were determined by Western blot and immunofluorescence. The expression of apoptosis-related proteins including B cell lymphoma-2(Bcl-2), Bcl-2-associated protein X(Bax), and cysteinyl aspartate-specific proteinase-3(caspase-3) was determined by Western blot and real-time PCR. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling was employed to examine apoptosis. The embryo loss rate of the remaining five female mice was calculated by trypan blue staining method on day 14 of pregnancy. On day 14 of pregnancy, the embryo loss rate of the normal group was 5.00%, which was lower than that(27.78%) in the model group(P<0.05). Dydrogesterone and Shoutai Pills groups showed reduced embryo loss rates(10.26% and 7.50%, respectively) compared with the model group. On day 6 of pregnancy, compared with the normal group, the model group showed down-regulated expression of HK2, ENO1, PKM2, LDHA, and Bcl-2 and up-regulated expression of Bax and caspase-3(P<0.05). Compared with the model group, dydrogesterone and Shoutai Pills up-regulated the expression of HK2, ENO1, PKM2, LDHA, and Bcl-2 and down-regulated the expression of Bax and caspase-3(P<0.05). Compared with that in the normal group, the apoptosis rate in the model group increased(P<0.05). Compared with the model group, dydrogesterone and Shoutai Pills reduced the apoptosis rate(P<0.05). In conclusion, Shoutai Pills can reduce the embryo loss rate and protect embryos by promoting aerobic glycolysis at the maternal-fetal interface and inhibiting the apoptosis of trophoblasts in mice.
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Apoptose , Medicamentos de Ervas Chinesas , Camundongos Endogâmicos ICR , Animais , Feminino , Camundongos , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Gravidez , Ameaça de Aborto/tratamento farmacológico , Ameaça de Aborto/metabolismo , Glicólise/efeitos dos fármacos , Masculino , Modelos Animais de Doenças , HumanosRESUMO
More and more evidence shows that small noncoding RNAs (ncRNAs) play diverse roles in development, stress response and other cellular processes, but functional study of intermediate-size ncRNAs is still rare. Here, the expression profile of 16 intermediate-size ncRNAs in ovary and testis of silkworm Bombyx mori were analyzed. Twelve ncRNAs, including 5 small nucleolar RNAs (snoRNAs) and 7 unclassified ncRNAs, accumulated more in the testis than in the ovary of silkworm, especially Bm-163, Bm-51 and Bm-68. Four ncRNAs (including three orphan snoRNAs and one unclassified ncRNA) had higher expression level in the ovary than in the testis, especially Bm-86. Overexpression of the testis-enriched snoRNA Bm-68 in the female led to the accumulation of male-specific isoform of doublesex (BmdsxM) and increased the expression ratio of BmdsxM: BmdsxF. While overexpression of ovary-enriched snoRNA Bm-86 in the male decreased the expression ratio of BmdsxM: BmdsxF, indicating the roles of the two snoRNAs played in the alternative splicing of Bmdsx of silkworm, which will provide new clues for the functional study of snoRNAs in insects.
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Processamento Alternativo , Bombyx , Proteínas de Ligação a DNA , Proteínas de Insetos , RNA Nucleolar Pequeno , Animais , Feminino , Masculino , Bombyx/genética , Bombyx/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Ovário/metabolismo , RNA Nucleolar Pequeno/genética , RNA Nucleolar Pequeno/metabolismo , Testículo/metabolismoRESUMO
Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.
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Artrite , Doenças Inflamatórias Intestinais , Animais , Humanos , Complexo Antígeno-Anticorpo/uso terapêutico , Artrite/etiologia , Inflamação , Artralgia/etiologiaRESUMO
OBJECTIVE: To provide novel insights into the aetiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) by integrating multi-omics data and exploring susceptibility genes associated with NSCL/P. METHODS: A two-stage genome-wide association study (GWAS) of NSCL/P was performed, involving a total of 1,069 cases and 1,724 controls. Using promoter capture Hi-C (pCHi-C) datasets in human embryonic stem cells (hESC) and chromatin immunoprecipitation sequencing (ChIP-seq) in craniofacial tissues, we filtered out single nucleotide polymorphisms (SNPs) with active cis-regulation and their target genes. Additionally, we employed expression quantitative trait loci (eQTL) analysis to identify candidate genes. RESULTS: Thirteen SNPs were identified as cis-regulation units associated with the risk of NSCL/P. Five of these were proven to be active in chromatin states in early human craniofacial development (rs7218002: odds ratio [OR] 1.50, P = 8.14E-08; rs835367: OR 0.78, P = 3.48E- 05; rs77022994: OR 0.55, P = 1.05E-04; rs961470: OR 0.73, P = 1.38E-04; rs17314727: OR 0.73, P = 1.85E-04). Additionally, pCHi-C and eQTL analysis prioritised three candidate genes (rs7218002: NTN1, rs835367: FGGY, LINC01135). NTN1 and FGGY were expressed in mouse orofacial development. Deficiencies in NTN1, FGGY and LINC01135 were associated with cleft palate and cleft lip, abnormal facial shape and bifid uvula, and abnormality of the face, respectively. CONCLUSION: Our study identified five SNPs (rs7218002, rs835367, rs77022994, rs961470 and rs17314727) and three susceptibility genes (NTN1, FGGY and LINC01135) associated with NSCL/P. These findings contribute to a better understanding of the genetic factors involved.
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Fenda Labial , Fissura Palatina , Ictiose Lamelar , Humanos , Animais , Camundongos , Fissura Palatina/genética , Fenda Labial/genética , Estudo de Associação Genômica Ampla , Multiômica , CromatinaRESUMO
BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.
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Neoplasias Colorretais , Neoplasias Retais , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Imunoterapia , Instabilidade de Microssatélites , Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
2,5-Dimethylpyrazine (2,5-DMP) is important pharmaceutical raw material and food flavoring agent. Recently, engineering microbes to produce 2,5-DMP has become an attractive alternative to chemical synthesis approach. In this study, metabolic engineering strategies were used to optimize the modified Escherichia coli BL21 (DE3) strain for efficient synthesis of 2,5-DMP using L-threonine dehydrogenase (EcTDH) from Escherichia coli BL21, NADH oxidase (EhNOX) from Enterococcus hirae, aminoacetone oxidase (ScAAO) from Streptococcus cristatus and L-threonine transporter protein (EcSstT) from Escherichia coli BL21, respectively. We further optimized the reaction conditions for synthesizing 2,5-DMP. In optimized conditions, the modified strain can convert L-threonine to obtain 2,5-DMP with a yield of 2897.30 mg/L. Therefore, the strategies used in this study contribute to the development of high-level cell factories for 2,5-DMP.
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Microorganisms encode most of the functions of life on Earth. However, conventional research has primarily focused on specific environments such as humans, soil and oceans, leaving the distribution of functional families throughout the global biosphere poorly comprehended. Here, we present the database of the global distribution of prokaryotic protein families (GDPF, http://bioinfo.qd.sdu.edu.cn/GDPF/), a data resource on the distribution of functional families across the global biosphere. GDPF provides global distribution information for 36 334 protein families, 19 734 superfamilies and 12 089 KEGG (Kyoto Encyclopedia of Genes and Genomes) orthologs from multiple source databases, covering typical environments such as soil, oceans, animals, plants and sediments. Users can browse, search and download the distribution data of each entry in 10 000 global microbial communities, as well as conduct comparative analysis of distribution disparities among multiple entries across various environments. The GDPF data resource contributes to uncovering the geographical distribution patterns, key influencing factors and macroecological principles of microbial functions at a global level, thereby promoting research in Earth ecology and human health.
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Ecologia , Células Procarióticas , Proteínas , Animais , Humanos , Solo , Família Multigênica , Proteínas/genéticaRESUMO
A central question in microbial ecology is how immense microbes are assembled in changing natural environments while executing critical ecosystem functions. Over the past decade, effort has been made to unravel the contribution of stochasticity and determinism to the compositional of microbial communities. However, most studies focus on microbial taxa, ignoring the importance of functional traits. By employing shotgun metagenomic sequencing and state-of-the-art bioinformatics approaches, this study comprehensively investigated the microbially mediated nitrogen (N) cycling processes in two geographically distant coastal locations. Both shotgun and 16S rRNA gene amplicon sequencing demonstrated significantly differed taxonomic compositions between the two sites. The relative abundance of major microbial phyla, such as Pseudomonadota, Thaumarchaeota, and Bacteroidota, significantly differed. In contrast, high homogeneity was observed for N-cycling functional traits. Statistical analyses suggested that N-cycling taxonomic groups were more related to geographic distance, whereas microbial functional traits were more influenced by environmental factors. Multiple community assembly models demonstrated that determinism strongly governed the microbial N-cycling functional traits, whereas their carrying taxonomic groups were highly stochastic. Such discordant patterns between N-cycling functional traits and taxa demonstrated an important mechanism in microbial ecology in which essential ecosystem functions are stably maintained despite geographic distance and stochastic community assembly.
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The extensive use of carbamate pesticides has led to a range of environmental and health problems, such as surface and groundwater contamination, and endocrine disorders in organisms. In this study, we focused on examining the effects of toxic exposure to the carbamate pesticide methomyl on the hatching, morphology, immunity and developmental gene expression levels in zebrafish embryos. Four concentrations of methomyl (0, 2, 20, and 200 µg/L) were administered to zebrafish embryos for a period of 96 h. The study found that exposure to methomyl accelerated the hatching process of zebrafish embryos, with the strongest effect recorded at the concentration of 2 µg/L. Methomyl exposure also trigged significantly reductions in heart rate and caused abnormalities in larvae morphology, and it also stimulated the synthesis and release of several inflammatory factors such as IL-1ß, IL-6, TNF-α and INF-α, lowered the IgM contents, ultimately enhancing inflammatory response and interfering with immune function. All of these showed the significant effects on exposure time, concentration and their interaction (Time × Concentration). Furthermore, the body length of zebrafish exposed to methomyl for 96 h was significantly shorter, particularly at higher concentrations (200 µg/L). Methomyl also affected the expression levels of genes associated with development (down-regulated igf1, bmp2b, vasa, dazl and piwi genes), demonstrating strong developmental toxicity and disruption of the endocrine system, with the most observed at the concentration of 200 µg/L and 96 h exposure to methomyl. The results of this study provide valuable reference information on the potential damage of methomyl concentrations in the environment on fish embryo development, while also supplementing present research on the immunotoxicity of methomyl.
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Praguicidas , Poluentes Químicos da Água , Animais , Peixe-Zebra/metabolismo , Metomil/metabolismo , Metomil/farmacologia , Embrião não Mamífero , Sistema Endócrino , Praguicidas/metabolismo , Carbamatos/metabolismo , Larva , Poluentes Químicos da Água/metabolismoRESUMO
Both edible fungal polysaccharides (Auricularia and Tremellan) and Crataegus flavonoids promote the balance of dyslipidemia, which have a positive biological regulating effect on intestinal flora. In this study, the extraction of water-soluble polysaccharides from Auricularia and Tremellan was investigated and optimized firstly. Polysaccharides and flavonoids were then combined to study the effects on the mediating role of abnormal blood lipid concentration and intestinal flora in vivo. The rats were divided into 10 groups, the NC (normal control), HM (model), PCI (Simvastatin control), PCII (Fenofibrate control), AAP (Auricularia auricular Polysaccharide), TFP (Tremella fuciformis Polysaccharide), HF (Crataegus Flavonoid), LDC (Low-dose combination), MDC (Medium dose combination), and HDC (High-dose combination), used to explore the impact of polysaccharides and flavonoids complex on state of blood lipid, liver, and intestinal flora of dyslipidemia rats. The results showed that the combination of polysaccharides and flavonoids could significantly decrease the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), and increase the level of high-density lipoprotein cholesterol (HDL-C). It also significantly decreased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and improved liver morphology. What is more, the HDC favorably alters the intestinal microflora balance, promotes intestinal integrity and mobility, and inhibits the growth of harmful bacteria such as Escherichia coli/Shigella and Clostridium compared with HM group. In brief, the combination of polysaccharides and flavonoids had a synergistic effect on the remission of dyslipidemia, and promoted health by improving lipid metabolism, protecting liver tissue, and regulating the intestinal flora in hyperlipidemia rats.
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BACKGROUND: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. METHODS: LS patients with CRC who had evaluable tumours and received at least 2 cycles of PD-1 inhibitors were retrospectively included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies, including anticytotoxic T-lymphocyte-associated antigen-4 treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analysed. RESULTS: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3-71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses and 42.7% (n = 32) partial responses. Four of five cases of LS CRCs displaying proficient MMR (pMMR) or microsatellite stable (MSS) were not responsive. Mucinous/signet-ring cell differentiation was associated with a lower ORR (P = 0.013). The 3-year overall survival and progression-free survival were 91.2% and 82.2%, respectively. A polyp was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment, and they were all larger than 7 mm. CONCLUSION: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. Large LS adenomas may also be eliminated by anti-PD-1 treatment. DATA AVAILABILITY STATEMENT: Due to the privacy of patients, the related data cannot be available for public access but can be obtained from Pei-Rong Ding (dingpr@sysucc.org.cn) upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform (www.researchdata.org.cn).
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Humanos , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Inibidores de Checkpoint Imunológico , Estudos Retrospectivos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Instabilidade de MicrossatélitesRESUMO
In our search for peroxisome proliferator-activated receptor (PPAR) agonists, five undescribed compounds, namely two acyclic diterpenes (1 and 2; cladopsol A and cladopsol B), two sesquiterpenes (3 and 4; cladopsol C and cladopsol D), and one C21-ecdysteroid (5; cladopsol E), and 15 known compounds were isolated from the jellyfish-derived fungus - Cladosporium oxysporum. The structures of the undescribed compounds were defined using UV, NMR, HR-ESI-MS, and electronic circular dichroism (ECD) spectroscopy and a modified Mosher's method. Luciferase reporter assay and docking analysis suggested that cladopsol B may function as a PPAR-γ partial agonist with a potential antidiabetic lead which may evade the side effects of full agonists. Moreover, cladopsol B stimulated glucose uptake in HepG2 cells with an efficacy comparable to that of rosiglitazone, but with less side effect induced by lipid accumulation in 3T3-L1 cells. Therefore, cladopsol B could serve as a molecular skeleton in a study of advanced antidiabetic lead with less side effect.
Assuntos
Agonistas PPAR-gama , Receptores Ativados por Proliferador de Peroxissomo , Hipoglicemiantes/farmacologia , Cladosporium , PPAR gama/agonistasRESUMO
Two synthetic compounds, MHY1383, azo-resveratrol and MHY1387, 5-[4-hydroxy-3,5-methoxybenzy]-2-thioxodihydropyrimidine-4,6[1H,5H]-dione have been reported to have an anti-biofilm effect on Pseudomonas aeruginosa at very low concentrations (1-10 pM). Here, we investigated the anti-biofilm effects of these compounds in various bacteria. We found that MHY1383 significantly inhibited Escherichia coli, Bacillus subtilis, and Staphylococcus aureus biofilm formation at 1 pM, 1 nM, and 10 nM, respectively. MHY1387 also inhibited the biofilm formation of E. coli, B. subtilis, and S. aureus at 1 pM, 10 nM, and 100 pM, respectively. Both MHY1383 and MHY1387 showed medium-dependent anti-biofilm effects on Salmonella enterica at high concentrations (10 µM). We also tested the susceptibility to antibiotics by measuring the minimum inhibitory concentration (MIC) in various bacteria. When P. aeruginosa, E. coli, B. subtilis, S. enterica, and S. aureus were treated with MHY1383 or MHY1387 in combination with four different antibiotics, the MICs of carbenicillin against B. subtilis and S. aureus were lowered more than two-fold by the combination with MHY1387. However, in all other combinations, the MIC changed within two-fold. The results of this study suggest that MHY1383 and MHY1387 are effective anti-biofilm agents and can be used at very low concentrations against biofilms formed by various types of bacteria. We also suggest that even if a substance that inhibits biofilm is used together with antibiotics, it does not necessarily have the effect of lowering the MIC of the antibiotics.