Comprehensive analysis of ceRNA network and immune cell infiltration pattern of autophagy related genes in IgA nephropathy.

INTRODUCTION: IgA nephropathy (IgAN) is a prevalent worldwide glomerular disease with a complex pathophysiology that has significant economic implications. Despite the lack of successful research, this study aims to discover the potential competing endogenous RNA (ceRNA) network of autophagy-associated genes in IgAN and examine their correlation with immune cell infiltration. METHODS: Autophagy-related hub genes were discovered by assessing the GSE116626 dataset and constructing a protein-protein interaction network. Nephroseq v5 analysis engine was used to analyze correlations between hub genes and proteinuria, glomerular filtration rate (GFR) and serum creatinine levels. Then, a ceRNA network construction and the CIBERSORT tool for immune cell infiltration analysis were also performed. Additionally, the differentially expressed autophagy-related genes (DEARGs) were used to predict potential targeted medications for IgAN. RESULTS: 1396 differentially expressed genes (DEGs) were identified in IgAN along with 25 autophagy-related differentially expressed messenger RNAs (DEmRNAs). Enrichment analysis revealed significant involvement of autophagy and apoptosis in biological processes. Next, we evaluated the top hub nodes based on their highest degrees. The ability of IgAN discrimination was confirmed in the GSE35487 and GSE37460 datasets by validating the five hub genes: SIRT1, FOS, CCL2, CDKN1A and MYC. In the Nephroseq v5 analysis engine, the clinical correlation of the five hub genes was confirmed. Furthermore, the ceRNA network identified 18 circular RNAs and 2 microRNAs associated with hub autophagy-related genes in IgAN. Our investigation identified hsa-miR-32-3p and hsa-let-7i-5p as having elevated expression levels and substantial diagnostic value. Finally, four distinctively infiltrated immune cells were found to be associated with the hub autophagy-related genes, and 67 drugs were identified as potential therapeutic options for IgAN. CONCLUSION: This study sheds light on a novel ceRNA regulatory network mechanism associated with autophagy in IgAN development.

DNA methylation modification in Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease with a prognosis worse than lung cancer. It is a fatal lung disease with largely unknown etiology and pathogenesis, and no effective therapeutic drugs render its treatment largely unsuccessful. With continuous in-depth research efforts, the epigenetic mechanisms in IPF pathogenesis have been further discovered and concerned. As a widely studied mechanism of epigenetic modification, DNA methylation is primarily facilitated by DNA methyltransferases (DNMTs), resulting in the addition of a methyl group to the fifth carbon position of the cytosine base, leading to the formation of 5-methylcytosine (5-mC). Dysregulation of DNA methylation is intricately associated with the advancement of respiratory disorders. Recently, the role of DNA methylation in IPF pathogenesis has also received considerable attention. DNA methylation patterns include methylation modification and demethylation modification and regulate a range of essential biological functions through gene expression regulation. The Ten-Eleven-Translocation (TET) family of DNA dioxygenases is crucial in facilitating active DNA demethylation through the enzymatic conversion of the modified genomic base 5-mC to 5-hydroxymethylcytosine (5-hmC). TET2, a member of TET proteins, is involved in lung inflammation, and its protein expression is downregulated in the lungs and alveolar epithelial type II cells of IPF patients. This review summarizes the current knowledge of pathologic features and DNA methylation mechanisms of pulmonary fibrosis, focusing on the critical roles of abnormal DNA methylation patterns, DNMTs, and TET proteins in impacting IPF pathogenesis. Researching DNA methylation will enchance comprehension of the fundamental mechanisms involved in IPF pathology and provide novel diagnostic biomarkers and therapeutic targets for pulmonary fibrosis based on the studies involving epigenetic mechanisms.

Urinary proteomics for noninvasive monitoring of biomarkers of chronic mountain sickness in a young adult population using data-independent acquisition (DIA)-based mass spectrometry.

Different populations exhibit varying pathophysiological responses to plateau environments. Therefore, it is crucial to identify molecular markers in body fluids with high specificity and sensitivity to aid in determination. Proteomics offers a fresh perspective for investigating protein changes linked to diseases. We utilize urine as a specific biomarker for early chronic mountain sickness (CMS) detection, as it is a simple-to-collect biological fluid. We collected urine samples from three groups: plains health, plateau health and CMS. Using DIA's proteomic approach, we found differentially expressed proteins between these groups, which will be used as a basis for future studies to identify protein markers. Compared with the healthy plain population, 660 altering proteins were identified in plateau health, which performed the resistance to altitude response function by boosting substance metabolism and reducing immune stress function. Compared to the healthy plateau population, the CMS group had 140 different proteins identified, out of which 8 were potential biomarkers for CMS. Our study has suggested that CMS may be closely related to increased thyroid hormone levels, oxidative damage to the mitochondria, impaired cell detoxification function and inhibited hydrolase activity. SIGNIFICANCE: Our team has compiled a comprehensive dataset of urine proteomics for AMS disease. We successfully identified differentially expressed proteins between healthy and AMS groups using the DIA proteomic approach. We discovered that 660 proteins were altered in plateau health compared to the healthy plain population, resulting in a heightened resistance to altitude response function by boosting substance metabolism and reducing immune stress function. Additionally, we pinpointed 140 different proteins in the AMS group compared to the healthy plateau population, with 8 showing potential as biomarkers for AMS. Our findings suggest that the onset of AMS may be closely linked to increased thyroid hormone levels, oxidative damage to the mitochondria, impaired cell detoxification function and inhibited hydrolase activity.

Synthesis, magnetic properties, biotoxicity and potential mechanism of modified nano zero-valent iron for decolorization of dye wastewater.

SiO2-coated nano zero-valent iron (nZVI) has emerged as a fine material for the treatment of dye wastewater due to its large specific surface area, high surface activity, and strong reducibility. However, the magnetic properties based on which SiO2-coated nZVI (SiO2-nZVI) could effectively separate and recover from treated wastewater, and the biotoxicity analysis of degradation products of the dye wastewater treated by SiO2-nZVI remain unclear. In this study, SiO2-nZVI was synthesized using a modified one-step synthesis method. The SiO2-nZVI nanoparticles were characterized using Transmission electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, Fully automatic specific surface and porosity analyzer, Vibrating sample magnetometer, and Zeta potential analyzer. The removal rate of methyl orange (MO) by SiO2-nZVI composite reached 98.35% when the degradation performance of SiO2-nZVI treating MO was optimized. Since SiO2-nZVI analysed by magnetic hysteresis loops had large saturation magnetization and strong magnetic properties, SiO2-nZVI exhibited excellent ferromagnetic behaviour. The analysis of the degradation products showed that the MO treated by SiO2-nZVI was converted into a series of intermediates, resulting in reducing the toxicity of MO. The potential mechanism of MO degradated by SiO2-nZVI was speculated through degradation process and degradation kinetics analysis. Overall, the SiO2-nZVI composite may be regarded as a promising catalyst for decolorization of dye wastewater.

PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α.

Pyruvate dehydrogenase kinase 1 (PDK1) phosphorylates the pyruvate dehydrogenase complex, which inhibits its activity. Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis, which plays an important role in tumor progression. This study aims to elucidate how PDK1 promotes breast cancer progression. We found that PDK1 was highly expressed in breast cancer tissues, and PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α (hypoxia-inducible factor 1α) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α. The HIF-1α protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1α transcriptional activity. In summary, PDK1 enhances HIF-1α protein stability by phosphorylating HIF-1α at Ser451 and promotes HIF-1α transcriptional activity by enhancing the binding of HIF-1α to P300. PDK1 and HIF-1α form a positive feedback loop to promote breast cancer progression.

PGRN inhibits CD8+T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM.

BACKGROUND: Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8+T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood. METHODS: We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn-/-) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays. RESULTS: We found PGRN was involved in exhaustion of cytotoxic CD8+T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8+T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden. CONCLUSION: These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8+T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy.

PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling.

Fine particulate matter (PM2.5) has been linked to increased severity and incidence of airway diseases, especially chronic obstructive pulmonary disease (COPD) and asthma. Airway remodeling is an important event in both COPD and asthma, and airway smooth muscle cells (ASMCs) are key cells which directly involved in airway remodeling. However, it was unclear how PM2.5 affected ASMCs. This study investigates the effects of PM2.5 on airway smooth muscle and its mechanism. We first showed that inhaled particulate matter was distributed in the airway smooth muscle bundle, combined with increased airway smooth muscle bundle and collagen deposition in vivo. Then, we demonstrated that PM2.5 induced up-regulation of collagen-I and alpha-smooth muscle actin (α-SMA) expression in rat and human ASMCs in vitro. Next, we found PM2.5 led to rat and human ASMCs senescence and exhibited senescence-associated secretory phenotype (SASP) by autophagy-induced GATA4/TRAF6/NF-κB signaling, which contributed to collagen-I and α-SMA synthesis as well as airway smooth muscle remodeling. Together, our results provided evidence that SASP induced by PM2.5 in airway smooth muscle cells prompted airway remodeling.

Smart exosomes enhance PDAC targeted therapy.

Exosomes continue to attract interest as a promising nanocarrier drug delivery technology. They are naturally derived nanoscale extracellular vesicles with innate properties well suited to shuttle proteins, lipids, and nucleic acids between cells. Nonetheless, their clinical utility is currently limited by several major challenges, such as their inability to target tumor cells and a high proportion of clearance by the mononuclear phagocyte system (MPS) of the liver and spleen. To overcome these limitations, we developed "Smart Exosomes" that co-display RGD and CD47p110-130 through CD9 engineering (ExoSmart). The resultant ExoSmart demonstrates enhanced binding capacity to αvß3 on pancreatic ductal adenocarcinoma (PDAC) cells, resulting in amplified cellular uptake in in vitro and in vivo models and increased chemotherapeutic efficacies. Simultaneously, ExoSmart significantly reduced liver and spleen clearance of exosomes by inhibiting macrophage phagocytosis via CD47p110-130 interaction with signal regulatory proteins (SIRPα) on macrophages. These studies demonstrate that an engineered exosome drug delivery system increases PDAC therapeutic efficacy by enhancing active PDAC targeting and prolonging circulation times, and their findings hold tremendous translational potential for cancer therapy while providing a concrete foundation for future work utilizing novel peptide-engineered exosome strategies.

A New Strain of Metarhizium robertsii Isolated from Loess Plateau and Its Virulence and Pathological Characteristics against Monochamus alternatus.

Monochamus alternatus is a serious trunk-boring pest. The isolation and utilization of entomopathogenic fungi to manage M. alternatus is important. Here, a new strain GQH6 of Metarhizium robertsii, isolated from the Loess Plateau, was identified morphologically and molecularly. The virulence of the strain GQH6 against the third-instar larvae of M. alternatus was studied. Then, the pathological process, including symptom observation and histopathological observation, was also researched. The corrected mortality was 100% at 109 and 108 conidia/mL, and 88.89 ± 5.88% at 107 conidia/mL. The LC50 was 1.93 × 106 conidia/mL and the LC90 was 1.35 × 107 conidia/mL. And the LT50 of the strain GQH6 was 3.96 days at 109 conidia/mL, and 4.99 days at 108 conidia/mL. These virulence indices showed high virulence against M. alternatus larvae. In addition, the symptoms of the infected M. alternatus larvae were obvious. After one day, dark spots appeared and increased in number. By four days, white mycelia appeared. Finally, the larvae body became green. Similarly, the histopathological changes after infection were obvious, mainly manifested in muscle tissue rupture, adipose tissue fracture and midgut disintegration. These results demonstrated that the M. robertsii strain GQH6 isolated from the Loess Plateau was highly virulent against M. alternatus larvae of the third instar.

Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

A 3D-printed phantom for stereotactic body radiation therapy simulation.

In modern radiation therapy for lung cancer, examining the uncertainty between tumor motion and beam delivery is vitally important. To lower the radiation dose delivery to the patient's normal tissue, narrowing the irradiation field margin to hit the tumor accurately is critical. Thus we proposed a phantom that simulates the thorax and lung tumor's motions by employing a 3D printing technique. The lung tumor is controlled by a linear miniature Delta robot arm, with a maximum displacement of 20 mm in each direction. When we simulated the thoracic breathing movements at 12 mm in A-P (Anterior-Posterior), the control errors were within 10%. The average tracking errors of the prosthetic tumor were within 1.1 mm. Therefore, the 3D-printed phantom with a robot arm can provide a reliable simulation for training and dosimetry measurement before lung radiotherapy, especially SBRT.

No evidence of coronary plaque stabilization by allopurinol in patients with acute coronary syndrome.

BACKGROUND: Allopurinol, a xanthine inhibitor that lowers uric acid concentration, has been proven to reduce inflammation and oxidative stress in patients with cardiovascular disease. However, it is unknown whether these beneficial effects translate into favorable plaque modification in acute coronary syndromes (ACS). This study aimed to investigate whether allopurinol could improve coronary plaque stabilization using coronary computed tomography angiography (CCTA). METHODS: This was a prospective, single-center, randomized, double-blind clinical trial began in March 2019. A total of 162 ACS patients aged 18-80 years with a blood level of high-sensitivity C-reactive protein (hsCRP) â€‹> â€‹2 â€‹mg/L were included. The subjects were randomly assigned in a 1:1 ratio to receive either allopurinol sustained-release capsules (at a dose of 0.25 â€‹g once daily) or placebo for 12 months. The plaque analysis was performed at CCTA. The primary efficacy endpoint was the change in low-attenuation plaque volume (LAPV) from baseline to the 12-month follow-up. RESULTS: Among 162 patients, 54 in allopurinol group and 51 in placebo group completed the study. The median follow-up duration was 14 months in both groups. Compared with placebo, allopurinol therapy did not significantly alter LAPV (-13.4 â€‹± â€‹3.7 â€‹% vs. -17.8 â€‹± â€‹3.6 â€‹%, p â€‹= â€‹0.390), intermediate attenuation plaque volume (-16.1 â€‹± â€‹3.0 â€‹% vs. -16.2 â€‹± â€‹2.9 â€‹%, p â€‹= â€‹0.992), dense calcified plaque volume (12.2 â€‹± â€‹13.7 â€‹% vs. 9.7 â€‹± â€‹13.0 â€‹%, p â€‹= â€‹0.894), total atheroma volume (-15.2 â€‹± â€‹3.2 â€‹% vs. -16.4 â€‹± â€‹3.1 â€‹%, p â€‹= â€‹0.785), remodeling index (2.0 â€‹± â€‹3.9 â€‹% vs. 5.4 â€‹± â€‹3.8 â€‹%, p â€‹= â€‹0.536) or hsCRP levels (-73.6 [-91.6-17.9] % vs. -81.2 [-95.4-47.7] %, p â€‹= â€‹0.286). CONCLUSIONS: Our findings suggest that allopurinol does not improve atherosclerotic plaque stability or inflammation in ACS.

Radioactive iodine therapy for follicular thyroid cancer: a 15 years follow-up study of Chinese patients.

PURPOSE: To identify long-term predictors of distant metastases (DM) and the overall survival (OS) of follicular thyroid cancer (FTC) patients who underwent radioactive iodine (RAI) therapy. And to expand the knowledge about the clinical course and experience of RAI treatment for FTC. MATERIALS: A total of 117 FTC patients who underwent RAI therapy at our institution from 2005 to 2020 were retrospectively studied. Patient characteristics, serum stimulating thyroglobulin (sTg) and thyroglobulin antibody levels, treatment process and follow-up data were collected until 26 April 2022. RESULTS: A total of 16 patients (13.7%) were lost to follow-up. A total of 23 (19.7%) patients with DM died and all FTC without DM were still alive. DM was seen in 58.4% (59/101) of patients. The most common location for metastatic lesions was the lung. Then was bone. The mean survival time of FTC with RAI was 156 months [95% confidence interval (CI): 142-171]. Five-year and 10-year cumulative survival rates of them were 88.8% and 67.4%, respectively. As for patients with DM were 80.4% and 41.3%, respectively. Age at diagnosis [odds ratio (OR) = 1.080, P  = 0.009], RAI therapy sessions (OR = 2.959, P  = 0.001) and sTg level (OR = 1.006, P  = 0.002) were predictive of DM occurrence in FTC with RAI. In the group of FTC with DM, survival analysis showed that males were more likely to have a lower OS than females ( P  = 0.039). CONCLUSION: Age, number of RAI therapy sessions, and sTg level were predictive of the occurrence of DM in FTC patients with RAI. Sex would influence the OS of FTC patients with DM.

Experimental investigation on the aero-optical effects of supersonic gas films with various cooling fluids.

Despite the fact that a supersonic cooling gas film can efficiently insulate aerodynamic heating, its interaction with the mainstream generates a sophisticated flow structure which may cause significant aero-optical ramifications. This study aims to analyze the fluid structure and wavefront distortion of supersonic gas film when subjected to varying nozzle pressure ratios (NPR) by employing two distinct cooling refrigerants, namely C O 2 and air. Within the NPR range of 0 to 2, a linear relationship exists between the wavefront distortion of both C O 2 and air films, while the C O 2 film exhibits higher wavefront distortion than the air. Additionally, the influence of condensation on the discrepancies in aero-optical effects of the two refrigerants is discussed.

Research Progress on Microbial Community Succession in the Postmortem Interval Estimation.

The postmortem interval (PMI) estimation is a key and difficult point in the practice of forensic medicine, and forensic scientists at home and abroad have been searching for objective, quantifiable and accurate methods of PMI estimation. With the development and combination of high-throughput sequencing technology and artificial intelligence technology, the establishment of PMI model based on the succession of the microbial community on corpses has become a research focus in the field of forensic medicine. This paper reviews the technical methods, research applications and influencing factors of microbial community in PMI estimation explored by using high-throughput sequencing technology, to provide a reference for the related research on the use of microbial community to estimate PMI.

A new classification of periampullary diverticulum: cannulation of papilla on the inner margins of the diverticulum (Type IIa) is more challenging.

BACKGROUND: Periampullary diverticulum (PAD) may make the performance of endoscopic retrograde cholangiopancreatography (ERCP) in patients with choledocholithiasis more difficult and may increase complication rates. The present study evaluated the effects of PAD on first-time ERCP in patients with choledocholithiasis. METHODS: Outcomes were compared in patients with and without PAD and in those with four types of PAD: papilla located completely inside the diverticulum (type I), papilla located in the inner (type II a) and outer (type II b) margins of the diverticulum; and papilla located outside the diverticulum (type III). Parameters compared included cannulation time and rates of difficult cannulation, post-ERCP pancreatitis (PEP) and perforation. RESULTS: The median cannulation times in patients with types I, II a, II b, III PAD and in those without PAD were 2.0 min, 5.0 min, 0.67 min, 3.5 min, and 3.5 min, respectively, with difficult cannulation rates in these groups of 7.4%, 31.4%, 8.3%, 18.9%, and 23.2%, respectively. The rates of PEP in patients with and without PAD were 5.3% and 5.1%, respectively. Four patients with and one without PAD experienced perforation. CONCLUSIONS: The division of PAD into four types may be more appropriate than the traditional division into three types. Cannulation of type I and II b PAD was easier than cannulation of patients without PAD, whereas cannulation of type II a PAD was more challenging. PAD may not increase the rates of PEP.

Diatoms pass through the gastrointestinal barrier and lead to false-positive: an animal experiment.

The diatom test has been used by forensic pathologist as standard for drowning, but the occurrence of false-positive results (presence of diatoms found in the tissues of subjects who died from causes other than drowning) draws criticism regarding the specificity of the test. Diatoms within food or water can be ingested through the gastrointestinal tract. However, the mechanisms of how the diatoms reach distant organs such as the lung, liver, and kidney have not been studied. In this article, we simulated the process of diatoms entering the gastrointestinal tract using gastric lavage on experimental rabbits. Diatoms are detected in lymph from a lymphatic vessel at the root of the mesentery, portal vein blood, aortic blood, lung, liver, and kidney samples in the gavage group. Of diatoms, 76.24% were the centric diatom, 99.86% of diatoms have a maximum size of less than 50 µm, and most of diatoms concentrate in the lung. Our study provided the evidence supporting the theory that the diatoms could pass through the gastrointestinal barrier and reach the rabbits' other internal organs. The diatoms could reach internal organs through the portal vein and lymphatic vessel at the root of the mesentery. This provides us new insight into our understanding of false-positive diatom test in forensic pathology.

Discovery of selective HDAC6 inhibitors based on a multi-layer virtual screening strategy.

The abnormal enhancement of histone deacetylase 6 (HDAC6) has been demonstrated to be closely related to the occurrence and development of various malignant tumors, attracting extensive attention as a promising target for cancer therapy. Currently, only limited selective HDAC6 inhibitors have entered clinical trials, making the rapid discovery of selective HDAC6 inhibitors with safety profiles particularly urgent. In this study, a multi-layer virtual screening workflow was established, and the representative compounds screened were biologically evaluated in combination with enzyme inhibitory and anti-tumor cell proliferation experiments. The experimental results showed that the screened compounds L-25, L-32, L-45 and L-81 exhibited nanomolar inhibitory activity against HDAC6, and exerted a certain degree of anti-proliferative activities against tumor cells, especially the cytotoxicity of L-45 to A375 (IC50 = 11.23 ± 1.27 µM) and the cytotoxicity of L-81 against HCT-116 (IC50 = 12.25 ± 1.13 µM). Additionally, the molecular mechanisms underlying the subtype selective inhibitory activities of the selected compounds were further elucidated using computational approaches, and the hotspot residues on HDAC6 contributing to the ligands' binding were identified. In summary, this study established a multi-layer screening scheme to quickly and effectively screen out hit compounds with enzyme inhibitory activity and anti-tumor cell proliferation, providing novel scaffolds for the subsequent anti-tumor drug design based on HDAC6 target.

[Response of Soil Organic Carbon Accumulation in Paddy Fields in Fujian Province to Future Temperature Increases].

Understanding the effect of the soil carbon "source-sink" in cropland in China under future warming scenarios is the basis for making reasonable carbon neutralization policies. This study focused on the paddy soil in Fujian Province, a typical subtropical region in China including 84 counties (cities and districts). We employed the 1:50000 soil database and biogeochemical process model (DNDC) to simulate the dynamic changes in paddy soil organic carbon under different warming scenarios for the period of 2017-2053. The results indicated that in the context of normal temperature (control run) and 2, 4, and 6℃ of warming, the total amounts of carbon sequestration of paddy soil in Fujian Province were 11.56,9.44, 7.08, and 4.91 Tg, respectively; accordingly, the average annual carbon sequestration rates (expressed by C) were 173, 141, 106, and 74 kg·(hm2·a)-1, indicating that the rate of carbon sequestration was decreasing with the increase in future temperature. However, overall, the paddy field soil in the province was still a "carbon sink" under the warming of 6 (C. We also found that the gleyed paddy soil was mostly affected by the increase in temperature, and the decrease in carbon sequestration rate ranged from 20% to 69% using different treatments. In contrast, the salinized paddy soil was slightly affected, with a 14%-43% decrease in carbon sequestration rates. As for the different administrative regions, Sanming City was the most affected by temperature increase, with the rate of carbon sequestration decreasing by 27%-83% using different treatments. However, it was reduced by only 10%-41% and 14%-42% in Quanzhou and Putian (coastal areas), respectively. Overall, due to different soil properties, fertilization management, and climatic environment, there was a strong variability in the carbon sequestration rates of paddy soil for different soil subtypes and administrative regions in Fujian in response to future climatic warming.

Opioids increase the risk of delirium in critically ill patients: A propensity score analysis.

BACKGROUND: Medications are biologically plausible and potentially modifiable risk factors for delirium. Therapies for delirium might involve more specific strategies such as avoiding the use of delirium-inducing drugs to reduce the incidence of delirium. The association between opioid exposure within 24 hours prior to delirium assessment and the risk of delirium was studied. MATERIALS AND METHODS: Using three large databases, the MIMIC III v1.4, MIMIC-IV v0.4 and eICU Collaborative Research, we performed a multicenter, observational cohort study with two cohorts to estimate the relative risks of outcomes among patients administered opioids within 24 hours prior to delirium assessment. Propensity score matching was performed to generate a balanced 1 : 1 matched cohort and to identify potential prognostic factors. The outcomes included mortality, length of intensive care unit (ICU) stay, length of hospitalization, and odds of being discharged home. RESULTS: Propensity matching successfully balanced the covariates for the 9,529 patients in each group. Opioid use was associated with a significantly higher risk for delirium than not using opioids (p < 0.001). Additionally, treatment with opioids was associated with higher mortality and a longer ICU stay (p < 0.001) than treatment without opioids. However, patients treated with opioids were more likely to be discharged home (p < 0.001). CONCLUSION: Opioids may be an independent risk factor for delirium in critically ill patients.