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.

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.

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.

Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing.

Aged skin wounds heal poorly, resulting in medical, economic, and social burdens posed by nonhealing wounds. Age-related defects in repair are associated with reduced myofibroblasts and dysfunctional extracellular matrix (ECM) deposition. Bidirectional cell-cell communication involving exosome-borne cargo such as micro RNAs (miRs) has emerged as a critical mechanism for wound healing and aged tissue regeneration. Here we report that at the wound edge, aged fibroblasts display reduced migration and differentiation into myofibroblasts, with impaired ECM deposition, when compared with young tissue. Proper activation of fibroblasts to myofibroblasts may alleviate age-related defects in wound healing. Herein, an exosome-guided cell technique was performed to induce effective wound healing. Supplementing wounds with exosomes isolated from young mouse wound-edge fibroblasts (exosomesYoung) significantly improved the abundance of myofibroblasts and wound healing in aged mice and caused fibroblasts to migrate and transition to myofibroblasts in vitro. To determine the underlying mechanism, we found that exosomal transfer of miR-125b to fibroblasts inhibited sirtuin 7 (Sirt7), thus accelerating myofibroblast differentiation and wound healing in aged mice. Notably, after epidermal inhibition of miR-125b or overexpression of Sirt7 in fibroblasts, migration and myofibroblast transition were perturbed. Our findings thus reveal that miR-125b is transferred through exosomes from young fibroblasts to old fibroblasts contributes to promoting fibroblast migration and transition to counteract aging, suggesting a potential avenue for anti-aging interventions in wound healing.

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.

Phylogeny of Leptographium qinlingensis cytochrome P450 genes and transcription levels of six CYPs in response to different nutrition media or terpenoids.

The ascomycete Leptographium qinlingensis is one of the major externally living fungal associates of Dendroctonus armandi, which can kill host trees when it invades Chinese white pine (Pinus armandii). We identified and phylogenetically analysed the cytochrome P450 (CYP) genes in the transcriptome of L. qinlingensis. Furthermore, the expression profiles of six CYPs in the mycelium of L. qinlingensis grown on different media or treated with terpenoids were detected, as well as their growth rates on different nutritional media and inhibition by terpenoids. The CYP evolution predicted that most of the CYPs occurred in a putative common ancestor shared between L. qinlingensis and Grosmannia clavigera. The growth rates and inhibition test result shows that L. qinlingensis has more similarity with G. clavigera, which can retrieve nutrition from pine wood and utilize monoterpenes as the sole carbon source. CYP582C and CYP52Z4 of L. qinlingensis might be involved in the metabolism of fatty acids and detoxification of terpenes and phenolics after the analysis of their transcription levels with different treatments.

Shift of DNRA bacterial community composition in sediment cores of the Pearl River Estuary and the impact of environmental factors.

Dissimilatory nitrate reduction to ammonia (DNRA) process, competing with denitrification and anaerobic ammonia oxidation (anammox) for nitrate, is an important nitrogen retention pathway in the environment. Previous studies on DNRA bacterial diversity and composition focused on the surface sediments in estuaries, but studies on the deep sediments are limited, and the linkage between DNRA community structure and complex estuarine environment remains unclear. In this study, through high-throughput sequencing of nrfA gene followed by high-resolution sample inference, we examined spatially and temporally the composition and diversity of DNRA bacteria along a salinity gradient in five sediment cores of the Pearl River Estuary (PRE). We found a higher diversity and richness of DNRA bacteria in sediments with lower organic carbon, where sea water intersects fresh water. Moreover, the DNRA bacterial communities had the specific spatially distribution coupling with their metabolic difference along the salinity gradient of the Pearl River Estuary, but no obvious difference along the sediment depth. The distribution of DNRA bacteria in the PRE was largely driven by various environmental factors, including salinity, Oxidation-Reduction Potential (ORP), ammonium, nitrate and Corg/NO3-. Furthermore, dominant DNRA bacteria were found to be the key populations of DNRA communities in the PRE sediments by network analysis. Collectively, our results showed that niche difference of DNRA bacteria indeed occurs in the Pearl River Estuary.

Estimating Residual Life Distributions of Complex Operational Systems Using a Remaining Maintenance Free Operating Period (RMFOP)-Based Methodology.

Recent developments in the area of condition monitoring research have been targeted towards predicting machinery health condition for the purpose of preventative maintenance. Typically, published research uses data collected from rotating components (bearings, cutting tools, etc.) working in an idealized lab environment as the case study for prognosis algorithm validations. However, the operational implementation in industry is still very sporadic, mainly owing to the lack of proper data allowing sufficiently mature development of comprehensive methodologies. The prognosis methodology presented herein bridges the gap between academic research and industrial implementations by employing a novel time period for prognosis and implementing random coefficients regression models. The definition of the remaining maintenance-free operating period (RMFOP) is proposed first, which helps to transform the usefulness of the degradation data that is readily available from data short of failure. Degradation patterns are subsequently extracted from the original degradation data, before fitting into either of two regression models (linear or exponential). The system residual life distributions are then computed and updated by estimating the parameter statistics within the model. This RMFOP-based methodology is validated using real-world degradation data collected from multiple operational railway switch systems across Great Britain. The results indicate that both the linear model and the exponential model can produce residual life distributions with a sufficient prediction accuracy for this specific application. The exponential model gives better predictions, the accuracy of which also improves as more of system life percentage has elapsed. By using the RMFOP methodology, switch system health condition affected by an incipient overdriving fault is recognized and predicted.

A Developmental Study of the Narrative Components and Patterns of Chinese Children Aged 3-6 Years.

To investigate the narrative development of Chinese-speaking children aged 3-6 years, 80 children were prompted to tell personal stories. High point analysis was used and both narrative components and overall narrative patterns were analyzed. In terms of narrative components, Chinese children were more skillful in using complicating action, orientation and evaluation than they were in resolution, direct and reported speech. With age, their narratives were longer and richer in content. No gender differences were found in any of the seven narrative components. For narrative patterns, the most frequent was the two-event pattern at age 3 and the chronological pattern from age 4 to age 6. However, the chronological pattern at age 5 and 6 differed from the chronological pattern at age 4. The proportion of leap-frog, two-event and one-event patterns decreased with age, but most Chinese children at age 6 have yet to develop the ability to tell a classic narrative that includes resolution. These findings provided evidence for a developmental pattern of the narrative development in preschool Chinese children and suggested more attention should be paid to improve children's ability to resolve a story, telling listeners how everything worked out in the end.

Attention-Based Recurrent Temporal Restricted Boltzmann Machine for Radar High Resolution Range Profile Sequence Recognition.

The High Resolution Range Profile (HRRP) recognition has attracted great concern in the field of Radar Automatic Target Recognition (RATR). However, traditional HRRP recognition methods failed to model high dimensional sequential data efficiently and have a poor anti-noise ability. To deal with these problems, a novel stochastic neural network model named Attention-based Recurrent Temporal Restricted Boltzmann Machine (ARTRBM) is proposed in this paper. RTRBM is utilized to extract discriminative features and the attention mechanism is adopted to select major features. RTRBM is efficient to model high dimensional HRRP sequences because it can extract the information of temporal and spatial correlation between adjacent HRRPs. The attention mechanism is used in sequential data recognition tasks including machine translation and relation classification, which makes the model pay more attention to the major features of recognition. Therefore, the combination of RTRBM and the attention mechanism makes our model effective for extracting more internal related features and choose the important parts of the extracted features. Additionally, the model performs well with the noise corrupted HRRP data. Experimental results on the Moving and Stationary Target Acquisition and Recognition (MSTAR) dataset show that our proposed model outperforms other traditional methods, which indicates that ARTRBM extracts, selects, and utilizes the correlation information between adjacent HRRPs effectively and is suitable for high dimensional data or noise corrupted data.

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.

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.

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.

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.

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.

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.

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.

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.

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.