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1.
bioRxiv ; 2024 May 21.
Article in English | MEDLINE | ID: mdl-38826355

ABSTRACT

An "induced PARP inhibitor (PARPi) sensitivity by epigenetic modulation" strategy is being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARPi treatments. To expand its clinical applications and identify more efficient combinations, we performed a drug screen by combining PARPi with 74 well-characterized epigenetic modulators that target five major classes of epigenetic enzymes. Both type I PRMT inhibitor and PRMT5 inhibitor exhibit high combination and clinical priority scores in our screen. PRMT inhibition significantly enhances PARPi treatment-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMTs maintain the expression of genes associated with DNA damage repair and BRCAness and regulate intrinsic innate immune pathways in cancer cells. Analyzing large-scale genomic and functional profiles from TCGA and DepMap further confirms that PRMT1, PRMT4, and PRMT5 are potential therapeutic targets in oncology. Finally, PRMT1 and PRMT5 inhibition act synergistically to enhance PARPi sensitivity. Our studies provide a strong rationale for the clinical application of a combination of PRMT and PARP inhibitors in patients with HR-proficient ovarian or breast cancer.

2.
Article in English | MEDLINE | ID: mdl-38822723

ABSTRACT

OBJECTIVE: Previous studies have indicated that there is an association between cervical cerclage and type of suture material. However, it is still unclear which suture material can provide the greatest benefit to patients who have undergone cerclage. This study investigated the effect of two different suture materials (Mersilene tape vs braided suture) used for transvaginal cervical cerclage placement on maternal outcomes of women with cervical insufficiency. METHODS: In this retrospective case-control study, 170 women who underwent history-, ultrasound-, or physical examination-indicated transvaginal cervical cerclage were categorized according to suture materials used for cerclage: a total of 96 received Mersilene tape and 74 received braided suture. Study participants received a transvaginal cervical cerclage before 28 weeks and were followed up until delivery to assess pregnancy and neonatal outcomes. The primary outcome was gestational age at delivery. Secondary outcomes included preterm premature rupture of membranes (PPROM), premature rupture of membranes (PROM), chorioamnionitis, neonatal survival rate, and neonatal morbidity. RESULTS: Out of 170 eligible women, 74 (43.5%) received braided suture while 96 (56.5%) received Mersilene tape. Baseline characteristics were similar between the two groups. The group that received braided suture had a lower incidence of gestational age at delivery <37 weeks (29.2% vs 54.2%, P = 0.046), PPROM (9.5% vs 21.9%, P = 0.029) and PROM (17.6% vs 32.3%, P = 0.028) compared to the group that received Mersilene tape. However, there were no significant differences between the two groups in average gestational age at delivery, the rate of gestational age at delivery <24, <28, <32, and < 34 weeks, chorioamnionitis, and neonatal survival rate, as well as neonatal morbidity. CONCLUSION: Compared to Mersilene tape, the utilization of braided suture has been significantly associated with a reduction in the incidence of gestational age at delivery <37 weeks, as well as a decreased risk of PPROM and PROM. However, the use of braided sutures did not result in discernible differences in the rates of chorioamnionitis or adverse neonatal outcomes.

3.
J Genet Genomics ; 2024 May 31.
Article in English | MEDLINE | ID: mdl-38825039

ABSTRACT

Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy. Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4 (COXPD4), a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain (MRC) complexes. The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management. In this study, we construct a zebrafish tufm-/- mutant that closely resembles the COXPD4 syndrome, exhibiting compromised mitochondrial protein translation, dysfunctional mitochondria with oxidative phosphorylation (OXPHOS) defects, and significant metabolic suppression of the tricarboxylic acid (TCA) cycle. Leveraging this COXPD4 zebrafish model, we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4. Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.

4.
J Musculoskelet Neuronal Interact ; 24(2): 185-191, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38826001

ABSTRACT

OBJECTIVES: Total hip arthroplasty (THA) is a highly successful and effective surgery for improving hip functions and relieving pain. However, the lower extremities are prone to deep vein thrombosis (DVT) and swelling after surgery, thereby delaying recovery. In this study, we investigated the preventive effects of fondaparinux sodium (FS) and low-molecular-weight heparin (LMWH) on DVT of the lower extremity after THA. METHODS: Firstly, 60 patients who underwent THA at the First Affiliated Hospital of Wannan Medical College from March 2020 to December 2020 were included. Next, the patients were randomly divided into an LMWH group (n = 30) and an FS group (n = 30). Then, the indexes related to DVT were compared between both groups. RESULTS: Specifically, the differences in baseline data, such as age, gender and body mass index (BMI), between the two groups were not statistically significant. The postoperative weight bearing time of patients in the FS group was much shorter than that in the LMWH group. CONCLUSION: Subcutaneous injection of FS not only exhibits superior effects to LMWH in preventing DVT after THA but also has a correlation with reducing the risk of thrombosis and improving patient symptoms.


Subject(s)
Anticoagulants , Arthroplasty, Replacement, Hip , Fondaparinux , Heparin, Low-Molecular-Weight , Venous Thrombosis , Humans , Arthroplasty, Replacement, Hip/adverse effects , Heparin, Low-Molecular-Weight/therapeutic use , Heparin, Low-Molecular-Weight/administration & dosage , Fondaparinux/therapeutic use , Male , Female , Venous Thrombosis/prevention & control , Middle Aged , Aged , Anticoagulants/therapeutic use , Anticoagulants/administration & dosage , Postoperative Complications/prevention & control
5.
Langmuir ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38836786

ABSTRACT

Silica particles modified with amino groups hold immense potential across diverse fields, owing to their distinctive properties. The widely adopted method of surface modification, utilizing (3-aminopropyl)triethoxysilane (APTES), facilitates the incorporation of amino-functional groups onto the silica surface, thereby creating sites for subsequent functionalization with other molecules. In this context, the ability to precisely tailor the surface properties of amino-functionalized silica particles is crucial for optimizing their performance in various applications. In this work, we systematically investigated the influence of the APTES concentration and water content on the density of amino groups grafted on the silica surface within an ethanol-water mixture. The rational control of hydrolysis and condensation of APTES enabled the precise regulation of the amino density on the silica surface, resulting in a notable shift in the isoelectric point from 2.9 to 9.2. Subsequently, we assembled amino-functionalized silica with different isoelectric points with gold nanoparticles to demonstrate their tunable ability as surface-enhanced Raman scattering (SERS) substrates. This controlled and tailored amino-functionalization process opens up new routes for fine-tuning the properties of silica particles, thereby expanding their utility across various applications in materials science, nanotechnology, and biomedicine.

6.
Chem Sci ; 15(22): 8355-8362, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38846401

ABSTRACT

Biomarkers are present in various metabolism processes, demanding precise and meticulous analysis at the single-molecule level for accurate clinical diagnosis. Given the need for high sensitivity, biological nanopore have been applied for single biomarker sensing. However, the detection of low-volume biomarkers poses challenges due to their low concentrations in dilute buffer solutions, as well as difficulty in parallel detection. Here, a droplet nanopore technique is developed for low-volume and high-throughput single biomarker detection at the sub-microliter scale, which shows a 2000-fold volume reduction compared to conventional setups. To prove the concept, this nanopore sensing platform not only enables multichannel recording but also significantly lowers the detection limit for various types of biomarkers such as angiotensin II, to 42 pg. This advancement enables direct biomarker detection at the picogram level. Such a leap forward in detection capability positions this nanopore sensing platform as a promising candidate for point-of-care testing of biomarker at single-molecule level, while substantially minimizing the need for sample dilution.

7.
JTO Clin Res Rep ; 5(6): 100678, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38846810

ABSTRACT

Introduction: The available approved anticancer drugs for Chinese patients are relatively limited because of China's low participation rate in international clinical trials. Therefore, a focus on approved anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) drugs in China is needed. This study aims to assess the heterogeneity of anti-PD-1/PD-L1 antibodies manufactured in China (domestic PD-1/PD-L1) and overseas (imported PD-1/PD-L1) when combined with chemotherapy as the first-line treatment of NSCLC. Methods: A systematic search was performed using PubMed, EMBASE, and Cochrane Library of publications up to July 13, 2023. Meta-analysis was applied to compare the efficacy and safety profile between anti-PD-1/PD-L1 antibodies plus chemotherapy (PD-1/PD-L1+Chemo) and chemotherapy alone using STATA software. Pooled hazard ratios for progression-free survival and overall survival, odds ratios for objective response rate, and incidence rate of grade greater than or equal to three treatment-related adverse events with 95% confidence intervals were calculated in the domestic group and imported group by a random-effects model, and the heterogeneity between the two estimates was assessed. Results: There were 14 eligible clinical studies with a total of 3951 patients involved in this analysis, including eight studies of domestic PD-1/PD-L1+Chemo and six studies of imported PD-1/PD-L1+Chemo. The study revealed that there was no significant difference between domestic and imported PD-1/PD-L1+Chemo in overall survival (p = 0.80), progression-free survival (p = 0.53), and incidence rate of grade greater than or equal to three treatment-related adverse events (p = 0.10). Nevertheless, the objective response rate of imported PD-1/PD-L1+Chemo was significantly higher than that of domestic PD-1/PD-L1+Chemo (p = 0.03). Conclusions: Domestic anti-PD-1/PD-L1 antibodies plus chemotherapy were found to have comparable efficacy and safety to those combined with imported anti-PD-1/PD-L1 antibodies based on current evidence.

8.
J Sci Food Agric ; 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38843543

ABSTRACT

BACKGROUND: The ridge-furrow rainwater harvesting system (RFRH) is an advanced farmland management technology that plays a vital role in making full use of rainwater resources. However, it is not clear that RFRH affects crop yield and water use efficiency (WUE) by regulating soil water storage (SWS). Therefore, the present study conducted a meta-analysis to make a large compilation of previous studies and indirectly quantify the impact of RFRH on crop yield and WUE by analysing the effect of RFRH on SWS. RESULTS: The results showed that RFRH improved crop yield and WUE by 26.71% and 25.86%, respectively, by increasing SWS by 3.93% compared to the traditional flat cultivation. RFRH had a significant effect on increasing crop yield and WUE and improving SWS. A low ridge-furrow ratio and ridge-furrow mulching were recommended to obtain positive effects on crop yield and WUE when potatoes are grown in areas with high precipitation (600-800 mm). Furthermore, when nitrogen fertilization is applied during the crop growth period, we also found that a medium nitrogen fertilizer rate is recommended to achieve a significant positive effect on crop yield and WUE. Importantly, a win-win analysis showed the proportions of various groups in the target zone (zone I) to determine the appropriate strategy for RFRH of crops. CONCLUSION: The present study provides a scientific reference for the future application of the RFRH. The study provides scientific recommendations on crop types, ridge-furrow configurations, plastic mulching patterns and nitrogen fertilizer rate for future RFRH applications. © 2024 Society of Chemical Industry.

9.
Analyst ; 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38845587

ABSTRACT

Abrin toxin, highly dangerous with an estimated human lethal dose of 0.1-1 µg per kg body weight, has attracted much attention regarding criminal and terroristic misuse over the past decade. Therefore, developing a rapid detection method for abrin toxin is of great significance in the field of biosecurity. In this study, based on the specific dissociation method of an immobilized enzyme reactor, the trypsin immobilized reactor Fe3O4@CTS-GA-Try was prepared to replace free trypsin, and the immobilized enzyme digestion process was systematically investigated and optimized by using bovine serum albumin as the simulant of abrin. After 5 min one-step denaturation and reduction, a satisfactory peptide number and coverage were yielded with only 15 s assisted by an ultrasound probe to identify model proteins. Subsequently, abrin was rapidly digested using the established method, resulting in a stable and highly reproducible characteristic peptide number of 39, which can be analyzed by nanoelectrospray ionization coupled with high-resolution mass spectrometry. With the acquisition mode of full MS scan coupled with PRM, not only MS spectroscopy of total abrin peptides but also the corresponding MS/MS spectroscopy of specific abrin peptides can achieve the characteristic detection of abrin toxin and its different isoforms in less than 10 minutes, with high repeatability. This assay provides a universal platform and has great potential for the development of on-site detection and rapid mass spectrometric analysis techniques for macromolecular protein toxins and can further be applied to the integrated detection of chemical and biological agents.

10.
Cancer Drug Resist ; 7: 14, 2024.
Article in English | MEDLINE | ID: mdl-38835349

ABSTRACT

Human epidermal growth factor receptor 3 (HER3), which is part of the HER family, is aberrantly expressed in various human cancers. Since HER3 only has weak tyrosine kinase activity, when HER3 ligand neuregulin 1 (NRG1) or neuregulin 2 (NRG2) appears, activated HER3 contributes to cancer development and drug resistance by forming heterodimers with other receptors, mainly including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Inhibition of HER3 and its downstream signaling, including PI3K/AKT, MEK/MAPK, JAK/STAT, and Src kinase, is believed to be necessary to conquer drug resistance and improve treatment efficiency. Until now, despite multiple anti-HER3 antibodies undergoing preclinical and clinical studies, none of the HER3-targeted therapies are licensed for utilization in clinical cancer treatment because of their safety and efficacy. Therefore, the development of HER3-targeted drugs possessing safety, tolerability, and sensitivity is crucial for clinical cancer treatment. This review summarizes the progress of the mechanism of HER3 in drug resistance, the HER3-targeted therapies that are conducted in preclinical and clinical trials, and some emerging molecules that could be used as future designed drugs for HER3, aiming to provide insights for future research and development of anticancer drugs targeting HER3.

11.
Sci Adv ; 10(23): eadm9441, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38838143

ABSTRACT

Unlike aquaporins or potassium channels, ammonium transporters (Amts) uniquely discriminate ammonium from potassium and water. This feature has certainly contributed to their repurposing as ammonium receptors during evolution. Here, we describe the ammonium receptor Sd-Amt1, where an Amt module connects to a cytoplasmic diguanylate cyclase transducer module via an HAMP domain. Structures of the protein with and without bound ammonium were determined to 1.7- and 1.9-Ångstrom resolution, depicting the ON and OFF states of the receptor and confirming the presence of a binding site for two ammonium cations that is pivotal for signal perception and receptor activation. The transducer domain was disordered in the crystals, and an AlphaFold2 prediction suggests that the helices linking both domains are flexible. While the sensor domain retains the trimeric fold formed by all Amt family members, the HAMP domains interact as pairs and serve to dimerize the transducer domain upon activation.


Subject(s)
Ammonium Compounds , Cation Transport Proteins , Ammonium Compounds/metabolism , Ammonium Compounds/chemistry , Cation Transport Proteins/metabolism , Cation Transport Proteins/chemistry , Cation Transport Proteins/genetics , Signal Transduction , Models, Molecular , Binding Sites , Crystallography, X-Ray , Protein Domains , Protein Binding , Amino Acid Sequence
12.
Nat Commun ; 15(1): 4777, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38839748

ABSTRACT

Drawing inspiration from cohesive integration of skeletal muscles and sensory skins in vertebrate animals, we present a design strategy of soft robots, primarily consisting of an electronic skin (e-skin) and an artificial muscle. These robots integrate multifunctional sensing and on-demand actuation into a biocompatible platform using an in-situ solution-based method. They feature biomimetic designs that enable adaptive motions and stress-free contact with tissues, supported by a battery-free wireless module for untethered operation. Demonstrations range from a robotic cuff for detecting blood pressure, to a robotic gripper for tracking bladder volume, an ingestible robot for pH sensing and on-site drug delivery, and a robotic patch for quantifying cardiac function and delivering electrotherapy, highlighting the application versatilities and potentials of the bio-inspired soft robots. Our designs establish a universal strategy with a broad range of sensing and responsive materials, to form integrated soft robots for medical technology and beyond.


Subject(s)
Robotics , Robotics/instrumentation , Robotics/methods , Animals , Biomimetics/methods , Biomimetics/instrumentation , Humans , Prostheses and Implants , Skin , Equipment Design , Muscle, Skeletal/physiology , Wearable Electronic Devices
13.
J Anim Sci Biotechnol ; 15(1): 77, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38840220

ABSTRACT

BACKGROUND: Wooden breast (WB) myopathy is a common myopathy found in commercial broiler chickens worldwide. Histological examination has revealed that WB myopathy is accompanied by damage to the pectoralis major (PM) muscle. However, the underlying mechanisms responsible for the formation of WB in broilers have not been fully elucidated. This study aimed to investigate the potential role of hypoxia-mediated programmed cell death (PCD) in the formation of WB myopathy. RESULTS: Histological examination and biochemical analysis were performed on the PM muscle of the control (CON) and WB groups. A significantly increased thickness of the breast muscle in the top, middle, and bottom portions (P<0.01) was found along with pathological structure damage of myofibers in the WB group. The number of capillaries per fiber in PM muscle, and the levels of pO2 and sO2 in the blood, were significantly decreased (P < 0.01), while the levels of pCO2 and TCO2 in the blood were significantly increased (P < 0.05), suggesting hypoxic conditions in the PM muscle of the WB group. We further evaluated the PCD-related pathways including autophagy, apoptosis, and necroptosis to understand the consequence response to enhanced hypoxic conditions in the PM muscle of birds with WB. The ratio of LC3 II to LC3 I, and the autophagy-related factors HIF-1α, BNIP3, Beclin1, AMPKα, and ULK1 at the mRNA and protein levels, were all significantly upregulated (P < 0.05), showing that autophagy occurred in the PM muscle of the WB group. The apoptotic index, as well as the expressions of Bax, Cytc, caspase 9, and caspase 3, were significantly increased (P < 0.05), whereas Bcl-2 was significantly decreased (P < 0.05) in the WB-affected PM muscle, indicating the occurrence of apoptosis mediated by the mitochondrial pathway. Additionally, the expressions of necroptosis-related factors RIP1, RIP3, and MLKL, as well as NF-κB and the pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6, were all significantly enhanced (P < 0.05) in the WB-affected PM muscle. CONCLUSIONS: The WB myopathy reduces blood supply and induces hypoxia in the PM muscle, which is closely related to the occurrence of PCD including apoptosis, autophagy, and necroptosis within myofibers, and finally leads to abnormal muscle damage and the development of WB in broilers.

14.
Front Psychiatry ; 15: 1346881, 2024.
Article in English | MEDLINE | ID: mdl-38840950

ABSTRACT

Objective: Patients with chronic diseases may have some psychological problems due to their own or surrounding environmental factors, which can adversely affect the patient's illness and life. Given that the number of chronically ill patients in China is currently increasing every year, more research is needed to determine the best ways to manage changes in psychological status and psychological stress responses in chronically ill patients. The researchers constructed a mediated moderation model to explore the impact of stigma on the quality of life of chronically ill patients, as well as the mediating role of depression and the moderating role of psychological resilience. Methods: A stratified sampling method was used to select 363 middle-aged and old-aged patients with chronic diseases aged 45 years and older from the Affiliated Hospital of Zhejiang University for the study. Data were collected from patients with chronic diseases such as cardiac, respiratory, renal, and other chronic diseases using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G), the Stigma Scale for Patients with Chronic Diseases (SSCI), the Patient Health Questionaire-9 (PHQ-9), the Quality of Life Inventory (SF-12), and the Conner-Davidson Resilience Scale (CD-RISC) were collected from patients with cardiac, respiratory, renal, and other chronic diseases. A descriptive analysis was used to describe the sample. Linear regression was used to evaluate the relationship between the variables. Mediation and moderation analyses were used to explore the mediating role of depression and the moderating role of psychological resilience. Results: There was a moderate negative correlation between stigma and quality of life (r = -0.378, P < 0.01). There was a moderate negative correlation between depression and quality of life (r = -0.497, P < 0.01). There was a moderately positive correlation between psychological resilience and quality of life (r = 0.382, P < 0.01). There was a moderate negative correlation between psychological resilience and depression (r = -0.348, P < 0.01). There was a weak negative correlation between psychological resilience and stigma (r = -0.166, P < 0.01). There was a strong positive correlation between stigma and depression (r = 0.607, P < 0.01) The mediation study showed that stigma was a significant predictor of quality of life and that stigma and quality of life were mediated to some extent by depression, with the mediating effect accounting for 67.55% of the total effect. The direct path from stigma to depression is moderated by psychological resilience (ß = -0.0018, P < 0.01). Conclusions: Depression mediates the relationship between stigma and quality of life, while psychological elasticity plays a moderating role between stigma and depression, and when the level of psychological elasticity increases, the more significant the role of stigma on depression. As a physiologically and psychologically vulnerable group, patients with chronic diseases' overall quality of life and mental health should be taken more seriously, and clinical workers should pay timely attention to the psychological and mental conditions of patients with chronic diseases and provide timely and appropriate interventions and therapeutic measures. The relevant results of this study also provide a new perspective for clinical work on psychological intervention for patients with chronic diseases.

15.
BMC Geriatr ; 24(1): 480, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824515

ABSTRACT

OBJECTIVE: Research the dose-response relationship between overall and certain types of exercise and cognitive function in older adults with Alzheimer's disease and dementia. DESIGN: Systemic and Bayesian Model-Based Network Meta-Analysis. METHODS: In our study, we analyzed data from randomized controlled trials investigating the effects of different exercises on cognitive outcomes in older adults with AD. We searched the Web of Science, PubMed, Cochrane Central Register of Controlled Trials, and Embase up to November 2023. Using the Cochrane Risk of Bias tool (Rob2) for quality assessment and R software with the MBNMA package for data analysis, we determined standard mean differences (SMDs) and 95% confidence intervals (95%CrI) to evaluate exercise's impact on cognitive function in AD. RESULTS: Twenty-seven studies with 2,242 AD patients revealed a nonlinear relationship between exercise and cognitive improvement in AD patients. We observed significant cognitive enhancements at an effective exercise dose of up to 1000 METs-min/week (SMDs: 0.535, SD: 0.269, 95% CrI: 0.023 to 1.092). The optimal dose was found to be 650 METs-min/week (SMDs: 0.691, SD: 0.169, 95% CrI: 0.373 to 1.039), with AE (Aerobic exercise) being particularly effective. For AE, the optimal cognitive enhancement dose was determined to be 660 METs-min/week (SMDs: 0.909, SD: 0.219, 95% CrI: 0.495 to 1.362). CONCLUSION: Nonlinear dose-response relationship between exercise and cognitive improvement in Alzheimer's disease, with the optimal AE dose identified at 660 METs-min/week for enhancing cognitive function in AD.


Subject(s)
Alzheimer Disease , Bayes Theorem , Cognition , Network Meta-Analysis , Randomized Controlled Trials as Topic , Humans , Alzheimer Disease/psychology , Alzheimer Disease/therapy , Randomized Controlled Trials as Topic/methods , Cognition/physiology , Exercise Therapy/methods , Dementia/psychology , Dementia/therapy , Aged
16.
J Med Chem ; 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38847803

ABSTRACT

The NAD+-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from Schistosoma mansoni (SmSirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and SmSirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.

17.
Microbiome ; 12(1): 83, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38725008

ABSTRACT

BACKGROUND: Fungi and bacteria coexist in a wide variety of environments, and their interactions are now recognized as the norm in most agroecosystems. These microbial communities harbor keystone taxa, which facilitate connectivity between fungal and bacterial communities, influencing their composition and functions. The roots of most plants are associated with arbuscular mycorrhizal (AM) fungi, which develop dense networks of hyphae in the soil. The surface of these hyphae (called the hyphosphere) is the region where multiple interactions with microbial communities can occur, e.g., exchanging or responding to each other's metabolites. However, the presence and importance of keystone taxa in the AM fungal hyphosphere remain largely unknown. RESULTS: Here, we used in vitro and pot cultivation systems of AM fungi to investigate whether certain keystone bacteria were able to shape the microbial communities growing in the hyphosphere and potentially improved the fitness of the AM fungal host. Based on various AM fungi, soil leachates, and synthetic microbial communities, we found that under organic phosphorus (P) conditions, AM fungi could selectively recruit bacteria that enhanced their P nutrition and competed with less P-mobilizing bacteria. Specifically, we observed a privileged interaction between the isolate Streptomyces sp. D1 and AM fungi of the genus Rhizophagus, where (1) the carbon compounds exuded by the fungus were acquired by the bacterium which could mineralize organic P and (2) the in vitro culturable bacterial community residing on the surface of hyphae was in part regulated by Streptomyces sp. D1, primarily by inhibiting the bacteria with weak P-mineralizing ability, thereby enhancing AM fungi to acquire P. CONCLUSIONS: This work highlights the multi-functionality of the keystone bacteria Streptomyces sp. D1 in fungal-bacteria and bacterial-bacterial interactions at the hyphal surface of AM fungi. Video Abstract.


Subject(s)
Hyphae , Microbiota , Mycorrhizae , Plant Roots , Soil Microbiology , Streptomyces , Mycorrhizae/physiology , Mycorrhizae/classification , Streptomyces/classification , Streptomyces/isolation & purification , Streptomyces/genetics , Streptomyces/physiology , Hyphae/growth & development , Plant Roots/microbiology , Phosphorus/metabolism , Microbial Interactions/physiology , Soil/chemistry , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , Bacteria/metabolism
18.
Heliyon ; 10(9): e30550, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38726169

ABSTRACT

Background: The slash disposal-burning forest-in high-intensity management Eucalyptus grandis × urophylla plantation has accelerated soil degradation. Statement of the problem: Slash disposals is a contributing factor, but its specific role in the correlation between rainfall-runoff and soil erosion remains elusive. Objectives: his study investigated the characteristics of rainfall-runoff and soil erosion resistance in different methods of slash disposals in plantation. Methods: Three methods of slash disposal, namely burning forest (BF), moving away (MA), and spreading evenly (SE), were established. A field simulation experiment of rainfall was conducted, and path analysis was used. Results: The findings revealed that the water holding, infiltrating properties and the time the rainfall-runoff generated of SE were increased by approximately 10∼20 %, 100 %, and 80 %, respectively, compared with BF and MA. Water loss, soil loss and nutrient loss were significantly reduced by 62.23 % and 61.56 %, 69.06 % and 49.55 %, and 58.8 % and 65.42 % in SE and BF compared to MA. Path analysis suggested that different from BF and MA, the correlation between soil water properties and rainfall-runoff factors in SE was weakened, simultaneously considering the result that SE had the lower proportions of silt for sediment component (75.31 %), it stabilized the soil structure. Conclusions and prospect: Consequently, SE mitigated the erosion force by reducing rainfall-runoff and enhancing the anti-erosion of soil through improved water properties, making it a viable slash disposal. This work provides a detailed description of the soil erosion characteristics of plantation, including water, soil, and nutrient losses caused by rainfall-runoff, as well as the soil anti-erosion due to different slash disposals. These findings offer valuable insights for the management of high-intensity Eucalyptus grandis × urophylla plantations.

20.
BMC Cancer ; 24(1): 575, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38724921

ABSTRACT

OBJECTIVE: To identify the risk factors of cervical high-grade squamous intraepithelial lesion(HSIL) complicated with occult cervical cancer and standardize the management of initial treatment for HSIL. METHOD: The clinical data of patients who underwent total hysterectomy directly due to HSIL in the obstetrics and gynecology department of two tertiary hospitals and three secondary hospitals from 2018 to 2023 were collected. Their general characteristics, pathological parameters and survival status were analyzed. Logistic regression model was used to analyze the correlation between clinical parameters and postoperative pathological upgrading. RESULT: 1. Among the 314 patients with HSIL who underwent total hysterectomy directly, 73.2% were from primary hospitals. 2. 25 patients (7.9%) were pathologically upgraded to cervical cancer, all of which were early invasive cancer. 3. Up to now, there was no recurrence or death in the 25 patients with early-stage invasive cancer, and the median follow-up period was 21 months(range 2-59 months). 4. Glandular involvement(OR 3.968; 95%CI 1.244-12.662) and lesion range ≥ 3 quadrants (OR 6.527; 95% CI 1.78-23.931), HPV 16/18 infection (OR 5.382; 95%CI 1.947-14.872), TCT ≥ ASC-H (OR 4.719; 95%CI 1.892-11.766) were independent risk factors that affected the upgrading of postoperative pathology. 5. The area under the curve (AUC) calculated by the Logistic regression model was 0.840, indicating that the predictive value was good. CONCLUSION: There is a risk of occult cervical cancer in patients with HSIL. Glandular involvement, Lesion range ≥ 3 quadrants, HPV 16/18 infection and TCT ≥ ASC-H are independent risk factors for HSIL combined with occult cervical cancer. The prognosis of biopsy-proved HSIL patients who underwent extrafascial hysterectomy and unexpected early invasive cancer was later identified on specimen may be good.


Subject(s)
Hysterectomy , Uterine Cervical Neoplasms , Humans , Female , Hysterectomy/methods , Retrospective Studies , Middle Aged , Uterine Cervical Neoplasms/surgery , Uterine Cervical Neoplasms/pathology , Adult , Risk Factors , Aged , Squamous Intraepithelial Lesions of the Cervix/pathology , Squamous Intraepithelial Lesions of the Cervix/surgery , Squamous Intraepithelial Lesions/pathology , Squamous Intraepithelial Lesions/surgery , Papillomavirus Infections/complications , Papillomavirus Infections/virology , Papillomavirus Infections/pathology , Uterine Cervical Dysplasia/surgery , Uterine Cervical Dysplasia/pathology , Neoplasm Grading
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