Brain endothelial cells promote breast cancer cell extravasation to the brain via EGFR-DOCK4-RAC1 signalling.

The role of endothelial cells in promoting cancer cell extravasation to the brain during the interaction of cancer cells with the vasculature is not well characterised. We show that brain endothelial cells activate EGFR signalling in triple-negative breast cancer cells with propensity to metastasise to the brain. This activation is dependent on soluble factors secreted by brain endothelial cells, and occurs via the RAC1 GEF DOCK4, which is required for breast cancer cell extravasation to the brain in vivo. Knockdown of DOCK4 inhibits breast cancer cell entrance to the brain without affecting cancer cell survival or growth. Defective extravasation is associated with loss of elongated morphology preceding intercalation into brain endothelium. We also show that brain endothelial cells promote paracrine stimulation of mesenchymal-like morphology of breast cancer cells via DOCK4, DOCK9, RAC1 and CDC42. This stimulation is accompanied by EGFR activation necessary for brain metastatic breast cancer cell elongation which can be reversed by the EGFR inhibitor Afatinib. Our findings suggest that brain endothelial cells promote metastasis through activation of cell signalling that renders breast cancer cells competent for extravasation. This represents a paradigm of brain endothelial cells influencing the signalling and metastatic competency of breast cancer cells.

Inhibition of miR-9 Combined With Cisplatin Targeting APE1 Against Angiogenesis in Osteosarcoma.

Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance suggests poor prognosis in OS patients. In this study, the authors discovered that miR-9 has a pro-angiogenic role in OS. The anti-angiogenic effects of cisplatin were greatly increased when miR-9 was suppressed in OS. In addition, the authors demonstrated that miR-9 plays a pro-angiogenic role by targeting apoptosis-inducing factor 1 (APE1) in OS. Importantly, our in vivo experiments showed that inhibition of miR-9 combined with cisplatin could suppress xenograft tumor growth by targeting APE1 and decreasing angiogenesis in OS. In summary, our results suggest that miR-9 plays a role as a tumor promoter, and inhibiting miR-9 and APE1 is a new strategy for inhibiting OS angiogenesis and chemotherapy resistance.

Prognostic value of measurement of myocardial extracellular volume using dual-energy CT in heart failure with preserved ejection fraction.

Diffuse myocardial fibrosis is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). Dual-energy CT (DECT) can noninvasively assess myocardial fibrosis by quantification of extracellular volume (ECV) fraction. This study evaluated the association between ECV measured by DECT and clinical outcomes in patients with HFpEF. 125 hospitalized HFpEF patients were enrolled in this retrospective cohort study. ECV was measured using DECT with late iodine enhancement. The composite endpoint was defined as HFpEF hospitalization and all-cause mortality during the follow-up. During the median follow-up of 10.4 months, 34 patients (27.20%) experienced the composite outcomes, including 5 deaths; and 29 HFpEF hospitalizations. The higher DECT-ECV group had higher rates of composite outcomes than the low ECV group (log-rank X2 = 6.818, P = 0.033). In multivariate Cox regression analysis, the ECV (HR 1.17, 95% CI 1.06-1.30, P = 0.001) and NT-pro BNP (HR 2.83, 95% CI 1.16-6.88, P = 0.022) were independent risk factors for the adverse outcomes. Myocardial ECV measured using DECT was an independent risk factor for adverse outcomes in patients with HFpEF.

The design, synthesis and bioactivity evaluation of novel androgen receptor degraders based on hydrophobic tagging.

Prostate Cancer (PCa) easily progress to metastatic Castration-Resistant Prostate Cancer (mCRPC) that remains a significant cause of cancer-related death. Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Proteolysis-targeting chimaera (PROTAC) technology based on Hydrophobic Tagging (HyT) represents an intriguing strategy to regulate the function of therapeutically androgen receptor proteins. In the present study, we have designed, synthesized, and evaluated a series of PROTAC-HyT AR degraders using AR antagonists, RU59063, which were connected with adamantane-based hydrophobic moieties by different alkyl chains. Compound D-4-6 exhibited significant AR protein degradation activity, with a degradation rate of 57 % at 5 µM and nearly 90 % at 20 µM in 24 h, and inhibited the proliferation of LNCaP cells significantly with an IC50 value of 4.77 ± 0.26 µM in a time-concentration-dependent manner. In conclusion, the present study lays the foundation for the development of a completely new class of therapeutic agents for the treatment of mCRPC, and further design and synthesis of AR-targeting degraders are currently in progress for better degradation rate.

High throughput amplicon analysis reveals potential novel ammonia oxidizing prokaryotes in the eutrophic Jiaozhou Bay.

Ammonia-oxidizing prokaryotes (AOPs) are the major contributors of ammonia oxidization with widely distribution. Here we investigated the phylogenetic diversity, community composition, and regulating factors of AOPs in Jiaozhou Bay (JZB) with high-throughput sequencing of amoA gene. Phylogenetic analysis showed most of the OTUs could not be clustered with any known AOPs, indicating there might exist putative novel AOPs. With new developed protocols for AOP community analysis, we confirmed that only 3 OTUs of ammonia-oxidizing archaea (AOA) could be affiliated to known Nitrosopumilaceae and Nitrososphaera, and the other OTUs were identified as novel AOA based on the threshold. All abstained OTUs of ammonia-oxidizing bacteria (AOB) were identified as novel clusters based on the threshold. Further analysis showed the novel AOPs had different distribution characteristics related to environmental factors. The high abundance and widespread distribution of these novel AOPs indicated that they played an important role in ammonia conversion in eutrophic JZB.

Novel database for accA gene revealed a vertical variability pattern of autotrophic carbon fixation potential of ammonia oxidizing archaea in a permeable subterranean estuary.

The autotrophic carbon fixation pathway of ammonia-oxidizing archaea (AOA) was the 3-hydroxypropionate/4-hydroxybutyrate (3-HP/4-HB) cycle, of which the acetyl-CoA carboxylase α-submit (accA) gene is widely recognized as the indicator. To date, there is no reference database or suitable cut-off value for operational taxonomic unit (OTU) clustering to analyze the diversity of AOA based on the accA gene. In this study, a reference database with 489 sequences was constructed, all the accA gene sequences was obtained from the AOA enrichment culture, pure culture and environmental samples. Additionally, the 79% was determined as the cut-off value for OTU clustering by comparing the similarity between the accA gene and the 16S rRNA gene. The developed method was verified by analyzing samples from the subterranean estuary and a vertical variation pattern of autotrophic carbon fixation potential of AOA was revealed. This study provided an effective method to analyze the diversity and autotrophic carbon fixation potential of AOA based on accA gene.

Biosynthesized tumor acidity and MMP dual-responsive plant toxin gelonin for robust cancer therapy.

Among all kinds of anticancer agents, small molecule drugs produce an unsatisfactory therapeutic effect due to the lack of selectivity, notorious drug resistance and side effects. Therefore, researchers have begun to pay extensive attention to macromolecular drugs with high efficacy and specificity. As a plant toxin, gelonin exerts potent antitumor activity via inhibiting intracellular protein synthesis. However, gelonin lacks a translocation domain, and thus its poor cellular uptake leads to low outcomes of antitumor response. Here, tumor acidity and matrix metalloproteinase (MMP) dual-responsive functional gelonin (Trx-PVGLIG-pHLIP-gelonin, TPpG), composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), an MMP-responsive motif PVGLIG hexapeptide and gelonin, was innovatively proposed and biologically synthesized by a gene recombination technique. TPpG exhibited good thermal and serum stability, showed MMP responsiveness and could enter tumor cells under weakly acidic conditions, especially for MMP2-overexpressing HT1080 cells. Compared to low MMP2-expressing MCF-7 cells, TPpG displayed enhanced in vitro antitumor efficacy to HT1080 cells at pH 6.5 as determined by different methods. Likewise, TPpG was much more effective in triggering cell apoptosis and inhibiting protein synthesis in HT1080 cells than in MCF-7 cells. Intriguingly, with enhanced stability and pH/MMP dual responsiveness, TPpG notably inhibited subcutaneous HT1080 xenograft growth in mice and no noticeable off-target side effect was observed. This ingeniously designed strategy aims at providing new perspectives for the development of a smart platform that can intelligently respond to a tumor microenvironment for efficient protein delivery.

Molecular targets and mechanisms of Guanxinning tablet in treating atherosclerosis: Network pharmacology and molecular docking analysis.

BACKGROUND: Guanxinning tablet (GXNT), a Chinese patent medicine, is composed of salvia miltiorrhiza bunge and ligusticum striatum DC, which may play the role of endothelial protection through many pathways. We aimed to explore the molecular mechanisms of GXNT against atherosclerosis (AS) through network pharmacology and molecular docking verification. METHODS: The active ingredients and their potential targets of GXNT were obtained in traditional Chinese medicine systems pharmacology database and analysis platform and bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine databases. DrugBank, TTD, DisGeNET, OMIM, and GeneCards databases were used to screen the targets of AS. The intersection targets gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were performed in DAVID database. GXNT-AS protein-protein interaction network, ingredient-target network and herb-target-pathway network were constructed by Cytoscape. Finally, we used AutoDock for molecular docking. RESULTS: We screened 65 active ingredients of GXNT and 70 GXNT-AS intersection targets. The key targets of protein-protein interaction network were AKT1, JUN, STAT3, TNF, TP53, IL6, EGFR, MAPK14, RELA, and CASP3. The Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling pathway were the main pathways. The ingredient-target network showed that the key ingredients were luteolin, tanshinone IIA, myricanone, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone. The results of molecular docking showed that tanshinone IIA, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone all had good binding interactions with AKT1, EGFR and MAPK14. CONCLUSION: The results of network pharmacology and molecular docking showed that the multiple ingredients within GXNT may confer protective effects on the vascular endothelium against AS through multitarget and multichannel mechanisms. AKT1, EGFR and MAPK14 were the core potential targets of GXNT against AS.

The imbalance between N2O production and reduction by multi-microbial communities determines sedimentary N2O emission potential in the Pearl River Estuary.

Denitrification is the dominant process of nitrogen removal and nitrous oxide (N2O) emissions in estuarine ecosystems. However, little is known regarding the microbial mechanism of the production and reduction of N2O in estuaries. We investigated in situ dissolved N2O as well as potential N2O production rate (NPR), reduction rate (NRR), and emission rate (NER), and key functional genes related to N2O transformation of denitrification in the Pearl River Estuary. Higher N2O emission potential was found in the upstream and midstream regions with higher NPR and lower NRR values. In contrast, higher NRR values were detected in downstream. Notably, nirS and nirK type N2O producers dominated the upstream zone, whereas abundant N2O reducers, especially nosZ II type N2O reducers, were observed in downstream. Most importantly, the gene abundance ratio (Rnir/nosZ) was significantly correlated with the N2O emission potential (Re). Niche differentiation between N2O producers and N2O reducers from upstream to downstream affected N2O emission potential. This study highlights the N2O emission potential in estuarine sediments is determined by an imbalance between N2O production and the reduction of multi-bacterial communities.

Humanistic care relieves mental distress of inpatients in the shelter hospital during COVID-19 pandemic in Shanghai: a cross-sectional observational study.

Objective: The prevalence of mental distress has been noted in shelter hospitals set up for COVID-19. Potential risk demographic and hospitalization factors were screened. We also aimed to determine whether humanistic care established in the shelter hospital was effective in ameliorating mental distress. Methods: A cross-sectional observational survey-based single-centered study was conducted from 28th April to 5th May 2022 during the COVID-19 pandemic in Shanghai. Asymptomatic adult inpatients and those with mild symptoms were recruited for this study, and humanistic care measures were carried out by the administrative office according to the Work Program on Psychological Assistance and Social Work Services at the Shelter Hospital launched on 5th March 2020. Symptoms of mental distress, such as reported stress, anxiety, depression, and insomnia were measured using the Chinese Stress Response Questionnaire-28, the Chinese version of Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, and Insomnia Severity Index-7, respectively. Results: In total, 1,246 out of 9,519 inpatients, including 565 (45.35%) women and 681 (54.65%) men, with a median age of 36 years responded to the survey. The overall prevalence of stress, anxiety, depression, and insomnia in inpatients was 94 (7.54%), 109 (8.75%), 141 (11.32%), and 144 (11.56%), respectively. Mental distress was aggravated by COVID-19-related symptoms, comorbidities, and prolonged hospital stays. A stable internet connection was the most effective measure to reduce stress and depression. Offering inpatient with study or work facilitations, and mental health education help to ameliorate anxiety and depression. Organizing volunteering was a potential protective factor against stress. Conclusion: Humanistic care is crucial and effective for protecting against mental distress, which should be emphasized in shelter hospitals.

Denitrification contributes to N2O emission in paddy soils.

Denitrification is vital to nitrogen removal and N2O release in ecosystems; in this regard, paddy soils exhibit strong denitrifying ability. However, the underlying mechanism of N2O emission from denitrification in paddy soils is yet to be elucidated. In this study, the potential N2O emission rate, enzymatic activity for N2O production and reduction, gene abundance, and community composition during denitrification were investigated using the 15N isotope tracer technique combined with slurry incubation, enzymatic activity detection, quantitative polymerase chain reaction (qPCR), and metagenomic sequencing. Results of incubation experiments showed that the average potential N2O emission rates were 0.51 ± 0.20 µmol⋅N⋅kg-1⋅h-1, which constituted 2.16 ± 0.85% of the denitrification end-products. The enzymatic activity for N2O production was 2.77-8.94 times than that for N2O reduction, indicating an imbalance between N2O production and reduction. The gene abundance ratio of nir to nosZ from qPCR results further supported the imbalance. Results of metagenomic analysis showed that, although Proteobacteria was the common phylum for denitrification genes, other dominant community compositions varied for different denitrification genes. Gammaproteobacteria and other phyla containing the norB gene without nosZ genes, including Actinobacteria, Planctomycetes, Desulfobacterota, Cyanobacteria, Acidobacteria, Bacteroidetes, and Myxococcus, may contribute to N2O emission from paddy soils. Our results suggest that denitrification is highly modular, with different microbial communities collaborating to complete the denitrification process, thus resulting in an emission estimation of 13.67 ± 5.44 g N2O⋅m-2⋅yr-1 in surface paddy soils.

Correlation between serum laminin level and prognosis of acute heart failure.

OBJECTIVE: To investigate the correlation between serum laminin (LN) level and the prognosis of acute heart failure (AHF). METHODS: A total of 199 patients with AHF treated in Nantong First People's Hospital from March 2019 to November 2021 were included in this study. The patients were divided into the event group and the non-event group according to whether major adverse cardiovascular events (MACEs) occurred during hospitalization. We collected the baseline data of all patients and their LN levels were measured. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of LN for the occurrence of MACE in AHF patients during hospitalization. Multivariate Logistic regression analysis was used to screen the independent factors associated with the occurrence of MACE in patients with AHF. RESULTS: Among 199 patients with AHF, 43 were in the event group and 156 were in the non-event group. The area under ROC curve of LN to predict MACE in AHF patients during hospitalization was 0.8144, 95% confidence interval (CI): 0.7433-0.8855, p < .0001, cutoff point = 77.9, specificity 58.33%, and sensitivity 88.37%. Multivariate logistic regression analysis showed that the independent factors associated with the occurrence of MACE in AHF patients were the increase of LN level (odds ratio [OR]: 1.020, 95% CI: 1.012-1.028), the decrease of ejection fraction (OR: 0.007, 95% CI: 0.000-0.362) and diastolic blood pressure (OR: 0.946, 95% CI: 0.913-0.981; p < .05). CONCLUSION: The increase of LN level is independently correlated with the occurrence of MACE in AHF patients during hospitalization, which has the potential to be a serological indicator for poor prognosis in patients with AHF.

Correlation of Serum Laminin Levels with Cardiac Function and In-Hospital Prognosis in Patients with Atrial Fibrillation.

We aimed to investigate the correlation between serum laminin (LN) levels and cardiac function in patients with atrial fibrillation (AF) and its predictive value for in-hospital prognosis. This study included 295 patients with AF who were admitted to the Second Affiliated Hospital of Nantong University from January 2019 to January 2021. The patients were divided into three groups according to the New York Heart Association (NYHA) functional classification (I-II, III, and IV); the LN levels increased with increasing NYHA class (P < 0.05). Spearman's correlation analysis revealed a positive correlation between LN and NT-proBNP (r = 0.527, P < 0.001). Of the patients, 36 had in-hospital major adverse cardiac events (MACEs), of whom 30 had acute heart failure, 5 had malignant arrhythmias, and one had stroke. The area under the ROC curve for predicting the in-hospital MACEs by LN was 0.815 (95% CI: 0.740-0.890, P < 0.001). Multivariate logistic regression analysis revealed that LN could be an independent predictor of in-hospital MACEs (odds ratio: 1.009, 95% confidence interval: 1.004-1.015, P = 0.001). In conclusion, LN may serve as a potential biomarker to evaluate the severity of cardiac function and predict in-hospital prognosis in AF patients.

Correlations between serum laminin level and severity of heart failure in patients with chronic heart failure.

Objective: This study aimed to investigate the correlation between serum laminin (LN) levels and clinical stages of heart failure in patients with chronic heart failure. Methods: A total of 277 patients with chronic heart failure were selected from September 2019 to June 2020 in the Department of Cardiology, Second Affiliated Hospital of Nantong University. Based on stages of heart failure, the patients were divided into four groups: stage A, stage B, stage C, and stage D, with 55, 54, 77, and 91 cases, respectively. At the same time, 70 healthy people in this period were selected as the control group. Baseline data were recorded and serum Laminin (LN) levels were measured. The research compared, the differences in baseline data among the four groups of HF and normal controls, and analyzed the correlation between N-terminal pro-brain natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of LN in the C-D stage of heart failure. Logistic multivariate ordered analysis was applied to screen the independent related factors of clinical stages of heart failure. Results: Serum LN levels in patients with chronic heart failure were significantly higher than those in healthy people, which were 33.2 (21.38, 101.9) ng/ml and 20.45 (15.53, 23.04) ng/ml, respectively. With the progression of clinical stages of HF, serum LN and NT-proBNP levels increased, while LVEF gradually decreased (P < 0.05). Correlation analysis showed that LN was positively correlated with NT-proBNP (r = 0.744, P = 0.000) and negatively correlated with LVEF (r = -0.568, P = 0.000). The area under the ROC curve of LN for predicting C and D stages of heart failure was 0.913, 95% confidence interval was 0.882-0.945, P = 0.000, specificity 94.97%, and sensitivity 77.38%. Multivariate Logistic analysis showed that LN, Total bilirubin, NT-proBNP and HA were all independent correlates of heart failure staging. Conclusion: Serum LN levels in patients with chronic heart failure are significantly increased and are independently correlated with the clinical stages of heart failure. It could potentially be an early warning index of the progression and severity of heart failure.

A nitric oxide responsive AIE probe for detecting the progression of osteoarthritis.

Nitric oxide (NO) is reported to be elevated in osteoarthritis (OA) both in vitro and in vivo and may be adopted to develop fluorescent probes for detecting the progression of OA. Here we report a nitric oxide responsive aggregation induced emission (AIE) probe TPE-2NHCOCH2CH2-(PEG)24-NH-Diacerein, which is derived from tetraphenylethene (TPE) modified with the hydrophilic group long poly(ethylene glycol) chain and an anti-inflammatory drug diacerein. o-Phenylenediamine within its structure can react with NO to form benzotriazole and emit fluorescence. The results show that the NO-responsive AIE probe can smartly monitor the progression of OA with the change of fluorescence intensity in vitro and in vivo. This study may provide a new development direction for early OA monitoring in clinics.

Novel database and cut-off value for bacterial amoA gene revealed a spatial variability pattern of the ammonia-oxidizing bacteria community from river to sea.

Ammonia-oxidizing bacteria (AOB) catalyze the first step of nitrification, oxidizing ammonia to nitrite, and are characterized by amoA gene encoding ammonia monooxygenase. To analyze the AOB community effectively, an integral taxonomy database containing 14,058 amoA sequences and the optimal cut-off value at 95 % for OTU clustering were determined. This method was evaluated to be efficient by the analysis of environmental samples from the river, estuary, and sea. Using this method, a significant spatial variance of the AOB community was found. The diversity of AOB was highest in the estuary and lowest in the ocean. Nitrosomonas were the predominant AOB in the sediments of the freshwater river and estuary. Nearly all the AOB-amoA sequences belonged to uncultured bacterium in the sediments of deep sea. In general, an integral AOB taxonomic database and a suitable cut-off value were constructed for the comprehensive exploration of the diversity of AOB from river to sea.

Existence and distribution of novel phylotypes of Nitrospira in water columnsof the South China Sea.

In the biological nitrogen cycle, nitrite oxidation is performed by nitrite oxidation bacteria, of which Nitrospira is widespread and diverse. Communities of Nitrospira were collected at 25-1500 m depths in the South China Sea. Phylogenetic diversity, community composition, and environmental factors were investigated using high-throughput sequencing targeting the nxrB gene and statistical analyses. The community composition of Nitrospira varied spatially and by depth. Among the 24 OTUs with relatively high abundance, 70% were unclassified and not affiliated with the known Nitrospira genus, suggesting a previously unrecognized high diversity of marine Nitrospira. Five known Nitrospira genera were detected, of which the common marine Nitrospira marina was not the dominant species, whereas Candidatus Nitrospira lenta and Candidatus Nitrospira defluvii dominated in shallow habitats. Comammox Candidatus Nitrospira nitrosa was discovered in the marine ecosystem. The niche differentiation of versatile Nitrospira species was mainly shaped by nitrate, temperature, and DO.

Diverse nirS-type Denitrifying Bacteria Contribute to Vital Nitrogen Loss in Natural Acidic Red Soils.

Denitrifying bacteria, playing a key role in nitrogen removal in ecosystem, are highly diverse and complex in their community composition. However, there were few reports on the abundance, community composition, and the contribution to nitrogen loss of denitrifiers in natural acidic red soils. In this study, we investigated the structure and function of nirS-type denitrifying bacteria in ten natural red soil samples collected from nine provinces in southern China, based on quantitative polymerase chain reaction (qPCR) and high-throughput sequencing techniques. Nitrogen loss from microbial denitrification in red soils of southern China was estimated up to 9.86 Tg N per year based on 15N isotope tracing method. The abundance of nirS-type denitrifiers varied from 8.41 × 105 to 2.55 × 109 copies per gram of dry weight. The community of nirS-type denitrifying bacterial was revealed, which contained 50 dominant OTUs assigned to 9 clusters phylogenetically related to Marinobacter, Rhodobacter, and other uncultured species. pH was the key factor affecting both denitrification rates and community composition. Our results demonstrate that nirS-type denitrifying bacteria have higher abundance, diversity, and contribution to the nitrogen loss in natural acidic red soils of southern China.

Synergistic Antinociceptive Effects of Indomethacin-Pregabalin and Meloxicam-Pregabalin in Paclitaxel-Induced Neuropathic Pain.

Neuropathic pain is often closely associated with nerve injury or inflammation, and the role of traditional nonsteroidal anti-inflammatory drugs as adjuvants for treating chemotherapy-induced peripheral neuropathic pain remains unclear. In this study, the potential synergistic antinociceptive effects of indomethacin-pregabalin and meloxicam-pregabalin were evaluated in paclitaxel-induced neuropathic pain and carrageenan-induced inflammatory pain in rodents. Although indomethacin and meloxicam alone only slightly relieved mechanical allodynia in the above two models, isobolographic analysis showed that the combination of indomethacin or meloxicam with pregabalin produced significant synergistic antinociceptive effects for paclitaxel-induced neuropathic pain (IN-PGB, experimental ED25 = [4.41 (3.13-5.82)] mg/kg, theoretical ED25 = [8.50 (6.62-10.32)] mg/kg; MEL-PGB, experimental ED25 = [3.96 (2.62-5.46)] mg/kg, theoretical ED25 = [7.52 (5.73-9.39)] mg/kg). In addition, MEL-PGB dosed via intraplantar injection into the left paw, intragastric injection, or intraperitoneal injection reversed paclitaxel-induced allodynia, indicating that they may act at multiple sites in the neuroaxis and periphery. However, indomethacin-pregabalin and meloxicam-pregabalin exerted antagonistic antiallodynic interactions in carrageenan-induced inflammatory pain in rats. Taken together, coadministration of indomethacin or meloxicam with pregabalin may possess potential therapeutic advantages for treating chemotherapy-induced neuropathic pain.

Niche differentiation of ammonia-oxidizing archaea and related autotrophic carbon fixation potential in the water column of the South China Sea.

The significant primary production by ammonia-oxidizing archaea (AOA) in the ocean was reported, but the carbon fixation process of AOA and its community composition along the water depth remain unclear. Here, we investigated the abundance, community composition, and potential carbon fixation of AOA in water columns of the South China Sea. Higher abundances of the amoA and accA genes of AOA were found below the euphotic zone. Similarly, higher carbon fixation potential of AOA, evaluated by the ratios of amoA to accA gene, was also observed below euphotic zone and the ratios increased with increasing water depth. The vertical niche differentiation of AOA was further evidenced, with the dominant genus shifting from Nitrosopelagicus in the epipelagic zone to uncultured genus in the meso- and bathypelagic zones. Our findings highlight the higher carbon fixation potential of AOA in deep water and the significance of AOA to the ocean carbon budget.