Microglial exosome miR-124-3p in hippocampus alleviates cognitive impairment induced by postoperative pain in elderly mice.

Cognitive impairment induced by postoperative pain severely deteriorates the rehabilitation outcomes in elderly patients. The present study focused on the relationship between microglial exosome miR-124-3p in hippocampus and cognitive impairment induced by postoperative pain. Cognitive impairment model induced by postoperative pain was constructed by intramedullary nail fixation after tibial fracture. Morphine intraperitoneally was carried out for postoperative analgesia. Morris water maze tests were carried out to evaluate the cognitive impairment, while mRNA levels of neurotrophic factors (BDNF, NG) and neurodegenerative biomarker (VILIP-1) in hippocampus were tested by q-PCR. Transmission electron microscope was used to observe the axon degeneration in hippocampus. The levels of pro-inflammatory factors (TNF-α, IL-1ß, IL-6), the levels of anti-inflammatory factors (Ym, Arg-1, IL-10) and microglia proliferation marker cyclin D1 in hippocampus were measured to evaluate microglia polarization. Bioinformatics analysis was conducted to identify key exosomes while BV-2 microglia overexpressing exosome miR-124-3p was constructed to observe microglia polarization in vitro experiments. Exogenous miR-124-3p-loaded exosomes were injected into hippocampus in vivo. Postoperative pain induced by intramedullary fixation after tibial fracture was confirmed by decreased mechanical and thermal pain thresholds. Postoperative pain induced cognitive impairment, promoted axon demyelination, decreased BDNF, NG and increased VILIP-1 expressions in hippocampus. Postoperative pain also increased pro-inflammatory factors, cyclin D1 and decreased anti-inflammatory factors in hippocampus. However, these changes were all reversed by morphine analgesia. Bioinformatics analysis identified the critical role of exosome miR-124-3p in cognitive impairment, which was confirmed to be down-regulated in hippocampus of postoperative pain mice. BV-2 microglia overexpressing exosome miR-124-3p showed decreased pro-inflammatory factors, cyclin D1 and increased anti-inflammatory factors. In vivo, stereotactic injection of exogenous miR-124-3p into hippocampus decreased pro-inflammatory factors, cyclin D1 and increased anti-inflammatory factors. The cognitive impairment, axon demyelination, decreased BDNF, NG and increased VILIP-1 expressions in hippocampus were all alleviated by exogenous exosome miR-124-3p. Microglial exosome miR-124-3p in hippocampus alleviates cognitive impairment induced by postoperative pain through microglia polarization in elderly mice.

Penalized deep partially linear cox models with application to CT scans of lung cancer patients.

Lung cancer is a leading cause of cancer mortality globally, highlighting the importance of understanding its mortality risks to design effective patient-centered therapies. The National Lung Screening Trial (NLST) employed computed tomography texture analysis, which provides objective measurements of texture patterns on CT scans, to quantify the mortality risks of lung cancer patients. Partially linear Cox models have gained popularity for survival analysis by dissecting the hazard function into parametric and nonparametric components, allowing for the effective incorporation of both well-established risk factors (such as age and clinical variables) and emerging risk factors (eg, image features) within a unified framework. However, when the dimension of parametric components exceeds the sample size, the task of model fitting becomes formidable, while nonparametric modeling grapples with the curse of dimensionality. We propose a novel Penalized Deep Partially Linear Cox Model (Penalized DPLC), which incorporates the smoothly clipped absolute deviation (SCAD) penalty to select important texture features and employs a deep neural network to estimate the nonparametric component of the model. We prove the convergence and asymptotic properties of the estimator and compare it to other methods through extensive simulation studies, evaluating its performance in risk prediction and feature selection. The proposed method is applied to the NLST study dataset to uncover the effects of key clinical and imaging risk factors on patients' survival. Our findings provide valuable insights into the relationship between these factors and survival outcomes.

Influence of nanoscale sulfur on mercury accumulation and plant growth in oilseed rape seedlings (Brassica napus L.) grown on mercury-contaminated soil.

Mercury (Hg) pollution has seriously threatened the crop productivity and food security. In the present research, experiments were conducted to assess the influence of nanoscale sulfur/sulfur nanoparticles and the corresponding bulk and ionic sulfur forms on the growth and Hg accumulation of oilseed rape seedlings grown on Hg-contaminated soil, as well as the transformation of soil Hg fractions. The results showed a significant reduction in fresh biomass for seedlings grown on 80-200 mg/kg Hg-polluted soil after 30 days. At 120 mg/kg Hg treatment, 100-300 mg/kg sulfur nanoparticles (SNPs) application counteracted Hg toxicity more effectively compared to the corresponding bulk sulfur particles (BSPs) and ionic sulfur (sulfate) treatments. The seedlings treated with 120 mg/kg Hg + 300 mg/kg SNPs gained 54.2 and 56.9% more shoot and root biomass, respectively, compared to those treated with Hg alone. Meanwhile, 300 mg/kg SNPs application decreased Hg accumulation by 18.9 and 76.5% in shoots and roots, respectively, relative to Hg alone treatment.SNPs treatment caused more Hg to be blocked in the soil and accumulating significantly less Hg in plants as compared to other S forms. The chemical fractions of Hg in the soil were subsequently investigated, and the solubility of Hg was significantly decreased by applying SNPs to the soil. Especially 200-300 mg/kg SNPs treatments caused the ratio of the soluble/exchangeable and the specifically absorbed fraction to be the lowest, accounting for 1.95-4.13% of the total Hg of soil. These findings suggest that adding SNPs to Hg-contaminated soils could be an effective measure for immobilizing soluble Hg and decreasing the Hg concentration in the edible parts of crops. The results of the current study hold promise for the practical application of SNPs to Hg-contaminated farmland for better yields and simultaneously increasing the food safety.

The novelty of this study is the selection of oilseed rape and nanoscale sulfur (NS) or sulfur nanoparticles (SNPs) as nontoxic nanomaterial to counteract the Hg toxicity and accumulation. Oilseed rape was selected due to its wide adaptability to various environmental conditions and the high-value oil for human consumption and biofuels production. These advantages make oilseed rape a highly valuable crop for various applications. NS was selected due to its reported ability to limit the uptake of heavy metals in oilseed rape, rice, and wheat along with other crops and subsequently restrict the toxicity of heavy metals in these plants and improve food safety. In this study, we evaluated the growth, Hg accumulation, and the resulting toxicity in oilseed rape grown on Hg-contaminated soil, with or without amendments with NS. The outcomes from this study provided evidence of the significant potential of NS in preventing Hg bioaccumulation and improving crop yields in oilseed rape. This provides opportunity to use NS as an ideal non-GMO approach to limit toxic metals in crops.

Effects of sulfur nanoparticles on rhizosphere microbial community changes in oilseed rape plantation soil under mercury stress.

In the present study, experiments were conducted to assess the influence of nanoscale sulfur in the microbial community structure of metallophytes in Hg-contaminated rhizosphere soil for planting rapeseed. The results showed that the richness and diversity of the rhizobacteria community decreased significantly under Hg stress, but increased slightly after SNPs addition, with a reduction in the loss of Hg-sensitive microorganisms. Moreover, all changes in the relative abundances of the top ten phyla influenced by Hg treatment were reverted when subjected to Hg + SNPs treatment, except for Myxococcota and Bacteroidota. Similarly, the top five genera, whose relative abundance decreased the most under Hg alone compared to CK, increased by 19.05%-54.66% under Hg + SNPs treatment compared with Hg alone. Furthermore, the relative abundance of Sphingomonas, as one of the dominant genera for both CK and Hg + SNPs treatment, was actively correlated with plant growth. Rhizobacteria, like Pedobacter and Massilia, were significantly decreased under Hg + SNPs and were positively linked to Hg accumulation in plants. This study suggested that SNPs could create a healthier soil microecological environment by reversing the effect of Hg on the relative abundance of microorganisms, thereby assisting microorganisms to remediate heavy metal-contaminated soil and reduce the stress of heavy metals on plants.

In this manuscript, we first comprehensively investigated the changes in the rhizosphere microbial community structure of metallophytes in Hg-contaminated soil with SNPs addition, as well as the relationship between soil microbiology and plant resistance to Hg stress. Our results demonstrated that SNPs exhibit a significant advantage in improving rhizosphere microecology by increasing the abundance of beneficial rhizobacteria, thereby alleviating heavy metal toxicity, and promoting plant growth. This study is the first study describing the response of soil microorganisms coexposed to heavy metals and SNPs, providing valuable information for the potential use of SNPs to assist phytoremediation of toxic metal pollution and its impact on soil microbial communities.

Nitrogen starvation modulates the sensitivity of rhizobacterial community to drought stress in Stevia rebaudiana.

Alterations in water regimes or nitrogen (N) availability lead to shifts in the assemblage of rhizosphere microbial community; however, how the rhizosphere microbiome response to concurrent changes in water and N availability remains largely unclear. Herein, we investigated the taxonomic and functional characteristics of rhizobacteria associated with stevia (Stevia rebaudiana Bertoni) under varying combinations of water and N levels. Community diversity and predicted functions of rhizobacteria were predominantly altered by drought stress, with N-starvation modulating these effects. Moreover, N fertilization simplified the ecological interactions within rhizobacterial communities and heightened the relative role of stochastic processes on community assembly. In terms of rhizobacterial composition, we observed both common and distinctive changes in drought-responsive bacterial taxa under different N conditions. Generally, the relative abundance of Proteobacteria and Bacteroidetes phyla were depleted by drought stress but the Actinobacteria phylum showed increases. The rhizobacterial responses to drought stress were influenced by N availability, where the positive response of δ-proteobacteria and the negative response of α- and γ-proteobacteria, along with Bacteroidetes, were further heightened under N starvation. By contrast, under N fertilization conditions, an amplified negative or positive response to drought were demonstrated in Firmicutes and Actinobacteria phyla, respectively. Further, the drought-responsive rhizobacteria were mostly phylogenetically similar, but this pattern was modulated under N-rich conditions. Overall, our findings indicate an N-dependent specific restructuring of rhizosphere bacteria under drought stress. These changes in the rhizosphere microbiome could contribute to enhancing plant stress tolerance.

Real-world effectiveness of Azvudine versus nirmatrelvir-ritonavir in hospitalized patients with COVID-19: A retrospective cohort study.

Chinese guidelines prioritize the use of Azvudine and nirmatrelvir-ritonavir in COVID-19 patients. Nevertheless, the real-world effectiveness of Azvudine versus nirmatrelvir-ritonavir is still lacking, despite clinical trials showing their effectiveness compared with matched controls. To compare the effectiveness of Azvudine versus nirmatrelvir-ritonavir treatments in real-world clinical practice, we identified 2118 hospitalized COVID-19 patients, with a follow-up of up to 38 days. After exclusions and propensity score matching, we included 281 Azvudine recipients and 281 nirmatrelvir-ritonavir recipients who did not receive oxygen therapy at admission. The lower crude incidence rate of composite disease progression outcome (7.83 vs. 14.83 per 1000 person-days, p = 0.026) and all-cause death (2.05 vs. 5.78 per 1000 person-days, p = 0.052) were observed among Azvudine recipients. Azvudine was associated with lower risks of composite disease progression outcome (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.32-0.94) and all-cause death (HR: 0.40; 95% CI: 0.16-1.04). In subgroup analyses, the results of composite outcome retained significance among patients aged <65 years, those having a history of disease, those with severe COVID-19 at admission, and those receiving antibiotics. These findings suggest that Azvudine treatment showed effectiveness in hospitalized COVID-19 patients compared with nirmatrelvir-ritonavir in terms of composite disease progression outcome.

Plant secondary metabolic responses to global climate change: A meta-analysis in medicinal and aromatic plants.

Plant secondary metabolites (SMs) play crucial roles in plant-environment interactions and contribute greatly to human health. Global climate changes are expected to dramatically affect plant secondary metabolism, yet a systematic understanding of such influences is still lacking. Here, we employed medicinal and aromatic plants (MAAPs) as model plant taxa and performed a meta-analysis from 360 publications using 1828 paired observations to assess the responses of different SMs levels and the accompanying plant traits to elevated carbon dioxide (eCO2 ), elevated temperature (eT), elevated nitrogen deposition (eN) and decreased precipitation (dP). The overall results showed that phenolic and terpenoid levels generally respond positively to eCO2 but negatively to eN, while the total alkaloid concentration was increased remarkably by eN. By contrast, dP promotes the levels of all SMs, while eT exclusively exerts a positive influence on the levels of phenolic compounds. Further analysis highlighted the dependence of SM responses on different moderators such as plant functional types, climate change levels or exposure durations, mean annual temperature and mean annual precipitation. Moreover, plant phenolic and terpenoid responses to climate changes could be attributed to the variations of C/N ratio and total soluble sugar levels, while the trade-off supposition contributed to SM responses to climate changes other than eCO2 . Taken together, our results predicted the distinctive SM responses to diverse climate changes in MAAPs and allowed us to define potential moderators responsible for these variations. Further, linking SM responses to C-N metabolism and growth-defence balance provided biological understandings in terms of plant secondary metabolic regulation.

Large-scale exploration of nitrogen utilization efficiency in Asia region for rice crop: Variation patterns and determinants.

Improving rice nitrogen utilization efficiency (NUtE) is imperative to maximizing future food productivity while minimizing environmental threats, yet knowledge of its variation and the underlying regulatory factors is still lacking. Here, we integrated a dataset with 21,571 data compiled by available data from peer-reviewed literature and a large-scale field survey to address this knowledge gap. The overall results revealed great variations in rice NUtE, which were mainly associated with human activities, climate conditions, and rice variety. Specifically, N supply rate, temperature, and precipitation were the foremost determinants of rice NUtE, and NUtE responses to climatic change differed among rice varieties. Further prediction highlighted the improved rice NUtE with the increasing latitude or longitude. The indica and hybrid rice exhibited higher NUtE in low latitude regions compared to japonica and inbred rice, respectively. Collectively, our results evaluated the primary drivers of rice NUtE variations and predicted the geographic responses of NUtE in different varieties. Linking the global variations in rice NUtE with environmental factors and geographic adaptability provides valuable agronomic and ecological insights into the regulation of rice NUtE.

Efficacy and Safety of Photodynamic Therapy for the Treatment of Actinic Keratoses: A Meta-Analysis Update of Randomized Controlled Trials.

BACKGROUND: Actinic keratoses (AKs) are common and some may evolve into squamous cell carcinoma. Photodynamic therapy (PDT), imiquimod, cryotherapy, and other methods have been reported to have good effects. However, which treatment is the most effective with the best cosmetic results and fewest complications is uncertain. OBJECTIVE: To evaluate which method has the best efficacy and cosmetic results with less adverse events and recurrence rate. MATERIALS AND METHODS: All relevant articles up to July 31, 2022 were searched from Cochrane, Embase, and PubMed databases. Extract and analyze the data of efficacy, cosmetic results, local reactions, and adverse effects. RESULTS: Twenty-nine articles with 3,,850 participants and 24,747 lesions were included. Quality of evidence was generally high. The efficacy of PDT was better in complete response (CR) (lesions CR; risk ratio (RR) 1.87; 95% confidence interval (CI) 1.55-1.87/patient CR; RR 3.07; 95% CI 2.07-4.56), overall preference, and cosmetic results. The time cumulative meta-analysis showed that the curative effect was gradually increasing before 2004, and then gradually stabilizing. Two groups showed no statistically significant differences in recurrence. CONCLUSION: Compared with other methods, PDT is significantly more effective for AK with excellent cosmetic results and reversible adverse effects.

Effects of Dietary Protein and Lipid Levels in Practical Formulation on Growth, Feed Utilization, Body Composition, and Serum Biochemical Parameters of Growing Rockfish Sebastes schlegeli.

A 3 × 2 factorial experiment (protein levels, 42%, 46%, 50%; lipid levels, 9%, 12%) with three replicates was conducted in a circulating water system to investigate the effects of dietary protein and lipid levels on growth, feed utilization, body composition, and serum biochemical parameters of growing rockfish Sebastes schlegeli (initial weight, 29.98 ± 0.10 g). After an 8 weeks feeding trial, growth performance in terms of final body weight, percent weight gain, and specific growth rate increased with the increase of dietary protein level when fish fed diets containing a consistent level of dietary lipid. The feed conversion rate and daily feed intake were significantly affected by dietary protein and lipid levels, and decreased as dietary protein level increased from 42% to 46% or dietary lipid level increased from 9% to 12% (P < 0.05). Survival rate, viscerosomatic index, and hepatosomatic index were unaffected by dietary protein level (P > 0.05), but significantly increased with the increase of dietary lipid level (P < 0.05). On the contrary, condition factor was unaffected by dietary lipid level (P > 0.05), but significantly increased with dietary protein level increasing up to 46% (P < 0.05). The moisture contents of muscle and liver significantly decreased, but the whole-body crude lipid content, the crude protein and lipid contents of muscle increased as dietary protein or lipid level increased (P < 0.05). The contents of isoleucine, leucine, histidine, glycine, alanine of muscle, as well as the proportions of C14 : 0, C20 : 1, and C22 : 1n-9 in total fatty acids were higher in fish fed diets containing 12% lipid than those fed 9% lipid (P < 0.05), while C18 : 1n-9 and C18 : 2n-6 followed an opposite trend. The contents of phenylalanine, lysine, and tyrosine as well as the proportions of C18 : 0, C18 : 2n-6, C22 : 1n-9, and C22 : 6n-3 in total fatty acids decreased with the increase of dietary protein level (P < 0.05). Serum cholesterol and low-density lipoproteins increased significantly with dietary protein or lipid levels increasing, but TG concentration was elevated significantly in fish fed diets containing 12% lipid. Considering the present results in terms of growth and feed utilization, the suitable protein and lipid levels in diet for growing rockfish were 46% and 12%, respectively.