Engineering interfacial molecular interactions on Ag Hollow fibre gas diffusion electrodes for high efficiency in CO2 conversion to CO.

The electrochemical CO2 reduction reaction (CO2RR) occurs at the nanoscale interface of the electrode-electrolyte. Therefore, tailoring the interfacial properties in the interface microenvironment provides a powerful strategy to optimise the activity and selectivity of electrocatalysts towards the desired products. Here, the microenvironment at the electrode-electrolyte interface of the flow-through Ag-based hollow fibre gas diffusion electrode (Ag HFGDE) is modulated by introducing surfactant cetyltrimethylammonium bromide (CTAB) as the electrolyte additive. The porous hollow fibre configuration and gas penetration mode facilitate the CO2 mass transfer and the formation of the triple-phase interface. Through the ordered arrangement of hydrophobic long-alkyl chains, CTAB molecules at the electrode/electrolyte interface promoted CO2 penetration to active sites and repelled water to reduce the activity of competitive hydrogen evolution reaction (HER). By applying CTAB-containing catholyte, Ag HFGDE achieved a high CO Faradaic efficiency (FE) of over 95 % in a wide potential range and double the partial current density of CO. The enhancement of CO selectivity and suppression of hydrogen was attributed to the improvement of charge transfer and the CO2/H2O ratio enhancement. These findings highlight the importance of adjusting the local microenvironment to enhance the reaction kinetics and product selectivity in the electrochemical CO2 reduction reaction CO2RR.

Regulatory network of flavonoids, phenolic acids and terpenoids biosynthesis in Zizyphus jujuba Mill. cv. Goutou jujube fruits.

Flavonoids, phenolic acids and terpenoids are important active ingredients that are biomarkers for evaluating the quality of Zizyphus jujuba Mill. Cv. Goutou jujube fruit. Nevertheless, regulatory network of these active ingredients biosynthesis in jujube fruit is still unclear. Here, integrated metabolomics and transcriptomics analyses were conducted at four different stages during the ripening of jujube fruits. Cytochrome P450 enzymes (CYP450s) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) are pivotal enzymes for flavonoids, phenolic acids and terpenoids biosynthesis in plants. Benzoylmalic acid, a phenolic acid, 4', 5, 7-trihydroxyflavanon and quercetin-3-O-(6″-p-coumaroyl), two flavonoid metabolites, and jujuboside B1, a triterpenoid metabolite were targeted as they were correlated with both CYP450s and UGTs. Furthermore, networks of TFs, CYP450s and UGTs involved in the target metabolites biosynthesis were elucidated. NAC_1 and bZIP2 up-regulated CYP71A7 expression, while G2-like2 and bHLH_1 positively regulated the CSE expression contributing to promoted benzoylmalic acid biosynthesis. G2-like2, bHLH_1 and bHLH_2 indicated a positive relationship with CYP93D1, CYP86C2/3 or UGT71A16 which were positively correlated with 4', 5, 7-trihydroxyflavanon biosynthesis. MYB1/2/3, C2H2_2 and WRKY positively regulated expression of CYP82A4 or UGT_1 resulted in increased quercetin-3-O-(6″-p-coumaroyl) galactoside biosynthesis. G2-like2 and bHLH_1 up-regulated 4 C L, CYP93D1 or UGT71A16 was the reason for an increase of jujuboside B1 biosynthesis. The findings provide new insight into molecular breeding of high-quality jujube fruits.

The synthesis and bioactivities of ROCK2 inhibitors with 1,2-dithiolan-3-yl motif.

Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound DC24 was identified as the optimal hit in enzymatic screening with an IC50 value of 0.124 µM against ROCK2 and 50-fold selectivity over ROCK1. DC24 has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and DC24 is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 via the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of DC24 with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, DC24 at a dose of 5 mg kg-1 exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, DC24 exhibits good safety in vivo.

Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines.

The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFRdel19/T790M/C797S). Compound b demonstrated slightly improved inhibition activity against PC-9del19/T790M/C797S (IC50 = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.

Bayesian phylogeographic inference of wheat yellow mosaic virus in China and Japan suggests that the virus migration history coincided with historical events.

Wheat yellow mosaic virus (WYMV) is one of the most serious viral pathogens causing reductions in wheat yield in East Asia. We investigated the phylodynamics of WYMV by analysing the CP, VPg and P1 genes to understand the origin and dispersal of the virus. A Bayesian phylogenetic analysis revealed that the most recent common WYMV ancestor occurred in approximately 1742 (95% credibility interval, 1439-1916) CE (Common Era), and the evolutionary rates of the VPg, CP and P1 genes were 6.669 × 10-4 (95% credibility interval: 4.575 × 10-4-8.927 × 10-4), 2.468 × 10-4 (95% credibility interval: 1.667 × 10-4-3.338 × 10-4) and 5.765 × 10-5 (95% credibility interval: 3.285 × 10-6-1.252 × 10-4), respectively. Our phylogeographic analysis indicated that the WYMV population may have originated in Henan Province, China, first spreading to Japan in the mid-19th century and stopping after the Japanese surrender in World War II. The second wave spread to Japan from Shandong Province, China, in approximately 1977, a few years after the establishment of diplomatic relations between China and Japan. Before the founding of the People's Republic of China, Henan Province was the emigration centre of WYMV in East Asia, and after the late 20th century, Jiangsu and Shandong Provinces were also the virus emigration centres in East Asia. In addition, there were two migration pathways from Japan to Jiangsu and Shandong Provinces, China, in approximately 1918 and approximately 1999 respectively. Our results suggest that the wide spread of WYMV in East Asia is strongly related to human factors.

Integration of Spinal Musculoskeletal System Parameters for Predicting OVCF in the Elderly: A Comprehensive Predictive Model.

STUDY DESIGN: Systematic literature review. OBJECTIVES: To develop a predictive model for osteoporotic vertebral compression fractures (OVCF) in the elderly, utilizing current tools that are sensitive to bone and paraspinal muscle changes. METHODS: A retrospective analysis of data from 260 patients from October 2020 to December 2022, to form the Model population. This group was split into Training and Testing sets. The Training set aided in creating a nomogram through binary logistic regression. From January 2023 to January 2024, we prospectively collected data from 106 patients to constitute the Validation population. The model's performance was evaluated using concordance index (C-index), calibration curves, and decision curve analysis (DCA) for both internal and external validation. RESULTS: The study included 366 patients. The Training and Testing sets were used for nomogram construction and internal validation, while the prospectively collected data was for external validation. Binary logistic regression identified nine independent OVCF risk factors: age, bone mineral density (BMD), quantitative computed tomography (QCT), vertebral bone quality (VBQ), relative functional cross-sectional area of psoas muscles (rFCSAPS), gross and functional muscle fat infiltration of multifidus and psoas muscles (GMFIES+MF and FMFIES+MF), FMFIPS, and mean muscle ratio. The nomogram showed an area under the curve (AUC) of 0.91 for the C-index, with internal and external validation AUCs of 0.90 and 0.92. Calibration curves and DCA indicated a good model fit. CONCLUSIONS: This study identified nine factors as independent predictors of OVCF in the elderly. A nomogram including these factors was developed, proving effective for OVCF prediction.

[Ilizarov technique combined with center of rotation dome-shaped osteotomy for the treatment of juvenile distal femoral valgus deformity].

OBJECTIVE: To investigate the effect of Ilizarov technique combined with rotational center dome-shaped osteotomy in the treatment of juvenile distal femoral valgus deformity. METHODS: A retrospective study was conducted to analyze the clinical data of 11 patients with valgus deformity of the distal femur who had been admitted and followed up completely from January 2016 to October 2020. There were 7 males and 4 females. The 6 patients were on the right side and 5 patients were on the left side. The age ranged from 10 to 14 years old. The center of roration of angulation(CORA) was identified at the distal femur deformity, and dome-shaped osteotomy was performed with the CORA as the midpoint. The annular external fixator was installed according to the needle threading principle of Ilizarov external fixation, and the distal femur was cut off. The valgus deformity under visual inspection of the distal femur was corrected immediately, and the external fixator was fixed and maintained. The residual deformity and shortening were corrected according to the force line and length of the lower limbs suggested by the weight-bearing full-length anteroposterior and lateral X-rays of both lower limbs. RESULTS: All 11 patients were followed up for 13 to 25 months. The time of wearing external fixator was 12 to 17 weeks. In the last follow-up, both lower limbs were measured by the weight-bearing full-length anteroposterior and lateral X-rays, and the length of both lower limbs of 11 patients were equal, and the deformities were corrected. The score of hospital for special surgery (HSS) was used to evaluate the knee function, all of which were excellent. CONCLUSION: The Ilizarov technique was applied in the treatment of distal femoral valgus deformity in adolescents using a rotating central dome-shaped osteotomy. Visual femoral valgus deformity was corrected immediately during the operation. After the operation, residual deformities and shortening were dynamically adjusted and corrected according to the force line and shortening degree of lower extremities indicated by the weight-bearing anteroposterior and lateral radiographs of both lower limbs, with minimal damage and fast recovery.

The dynamic response mechanism of crops to manganese uptake and transfer mediated by different intercropping crop attributes.

BACKGROUND: An issue of pressing concern is the manganese contamination in farmland soils adjacent to industrial areas. To address this, intercropping hyperaccumulator plants with crops emerges as a sustainable approach to ensuring food security. This study aims to investigate the influence of intercropping Sedum alfredii with maize or soybean on their growth and the dynamics of manganese accumulation through field experiments. RESULTS: The results showed that compared with monoculture, the Sedum alfredii-maize intercropping system exhibited a land equivalent ratio (LER) of 1.89, signifying a 71.13% augmentation in bioaccumulation amount (BCA). Additionally, it led to a significant reduction in manganese content in various organs, ranging from 17.05% to 25.50%. However, the Sedum alfredii-soybean intercropping system demonstrated a LER of 1.94, accompanied by a 66.11% increase in BCA, but did not significantly reduce the manganese content in the roots, stems, and pods of soybeans. Furthermore, manganese accumulation in maize and soybean grains was primarily attributed to the aboveground translocation of manganese. The intercropping effect on blocking manganese absorption of maize during growth and maturity is primarily attributed to the earlier manganese accumulation in intercropped maize by 2.63 to 4.35 days, and a reduction of 21.95% in the maximum manganese accumulation rate. CONCLUSIONS: The study found that manganese accumulation dynamics vary significantly depending on the crop family. Intercropping Sedum alfredii with maize enhances land-use efficiency and reduces manganese uptake by crops, making it a promising strategy for remediating manganese-contaminated farmland near industrial areas. © 2024 Society of Chemical Industry.

Exosomes originating from neural stem cells undergoing necroptosis participate in cellular communication by inducing TSC2 upregulation of recipient cells following spinal cord injury.

ABSTRACT: We previously demonstrated that inhibiting neural stem cells necroptosis enhances functional recovery after spinal cord injury. While exosomes are recognized as playing a pivotal role in neural stem cells exocrine function, their precise function in spinal cord injury remains unclear. To investigate the role of exosomes generated following neural stem cells necroptosis after spinal cord injury, we conducted single-cell RNA sequencing and validated that neural stem cells originate from ependymal cells and undergo necroptosis in response to spinal cord injury. Subsequently, we established an in vitro necroptosis model using neural stem cells isolated from embryonic mice aged 16-17 days and extracted exosomes. The results showed that necroptosis did not significantly impact the fundamental characteristics or number of exosomes. Transcriptome sequencing of exosomes in necroptosis group identified 108 differentially expressed messenger RNAs, 104 long non-coding RNAs, 720 circular RNAs, and 14 microRNAs compared with the control group. Construction of a competing endogenous RNA network identified the following hub genes: tuberous sclerosis 2 (Tsc2), solute carrier family 16 member 3 (Slc16a3), and forkhead box protein P1 (Foxpl). Notably, a significant elevation in TSC2 expression was observed in spinal cord tissues following spinal cord injury. TSC2-positive cells were localized around SRY-box transcription factor 2-positive cells within the injury zone. Furthermore, in vitro analysis revealed increased TSC2 expression in exosomal receptor cells compared with other cells. Further assessment of cellular communication following spinal cord injury showed that Tsc2 was involved in ependymal cellular communication at 1 and 3 days post-injury through the epidermal growth factor and midkine signaling pathways. In addition, Slc16a3 participated in cellular communication in ependymal cells at 7 days post-injury via the vascular endothelial growth factor and macrophage migration inhibitory factor signaling pathways. Collectively, these findings confirm that exosomes derived from neural stem cells undergoing necroptosis play an important role in cellular communication after spinal cord injury and induce TSC2 upregulation in recipient cells.

ISIS 449884 Injection Add-On to Metformin in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase II Clinical Study.

INTRODUCTION: ISIS 449884, a 2'-O-methoxyethyl antisense oligonucleotide that targets the glucagon receptor (GCGR), has demonstrated an ability to reduce hepatic glucose output and lower the blood glucose level. The primary objective of this study was to investigate the safety and efficacy of ISIS 449884 as an add-on to metformin in a population of Chinese patients with type 2 diabetes mellitus (T2DM). METHOD: This was a multicenter, placebo-controlled (2:1), randomized, double-blind, parallel-enrollment, multiple-dose phase II study in Chinese patients with T2DM. A total of 90 patients who were uncontrolled by stable metformin monotherapy were randomized into three cohorts. Thirty subjects were enrolled in each cohort and received injections of ISIS 449884 (50 mg or 60 mg weekly or 100 mg every other week) or a corresponding volume of placebo (0.25 mL and 0.3 mL weekly or 0.5 mL every other week) subcutaneously in a 2:1 ratio for 16 weeks. RESULTS: The primary efficacy endpoint was analyzed in 88 subjects (ISIS 449884, n = 59; placebo, n = 29). The corrected LS mean change from baseline in glycated hemoglobin (HbA1c) at week 17 in the pooled ISIS 449884 treatment group was - 1.31% (95% CI - 1.66%, - 0.96%), and that in the pooled placebo group was 0.15% (95% CI - 0.37%, 0.66%). The LS mean difference between the two groups was - 1.46% (95% CI - 1.92%, - 1.00%, P < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 53/60 subjects (88.3%) and 25/30 subjects (83.3%) in the pooled ISIS 449884 treatment group and the pooled placebo group, respectively, with similar incidences. Drug-related TEAEs occurred in 41/60 subjects (68.3%) and 9/30 subjects (30.0%), respectively. TEAEs of grade 3 or higher occurred in 5/60 (8.3%) subjects and 2/30 (6.7%) subjects, respectively, and none of them were drug related. CONCLUSIONS: The ISIS 449884 injection add-on to metformin significantly reduced HbA1c in patients with T2DM uncontrolled by stable metformin monotherapy and showed an acceptable benefit/risk profile. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn , CTR20191096.

Design and Synthesis of sEH/HDAC6 Dual-Targeting Inhibitors for the Treatment of Inflammatory Pain.

Soluble epoxide hydrolase (sEH) and HDAC6 mediate the NF-κB pathway in inflammatory responses, and their inhibitors exhibit powerful anti-inflammatory and analgesic activities in treating both inflammation and pain. Therefore, a series of dual-targeting inhibitors containing urea or squaramide and hydroxamic acid moieties were designed and synthesized, and their role as a new sEH/HDAC6 dual-targeting inhibitor in inflammatory pain was evaluated in a formalin-induced mice model and a xylene-induced mouse ear swelling model. Among them, compounds 28g and 28j showed the best inhibitory and selectivity of sEH and HDAC6. Compound 28g had satisfactory pharmacokinetic characteristics in rats. Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either an sEH inhibitor (GL-B437) or an HDAC6 inhibitor (Rocilinostat) alone and coadministration of both inhibitors. Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful analgesic activity in nociceptive behavior and are worthy of further development.

Quantization-Based Adaptive Fuzzy Consensus for Multiagent Systems Under Sensor Deception Attacks: A Novel Compensation Mechanism.

This study mainly investigates the adaptive leader-following consensus tracking control problem for a class of nonlinear multiagent systems (MASs) subjected to unknown control directions, external disturbances, and sensor deception attacks. To start with, an equivalent MAS with known control directions is obtained by introducing a linear state transformation. For the purpose of estimating the unavailable system states caused by malicious attacks, a quantization-based fuzzy state observer is designed, and the fuzzy-logic system (FLS) is utilized to approximate nonlinear functions. Moreover, a dynamic uniform quantizer with scaling function is established to reduce information transmission. With the help of coordinate transformation and available compromised states, a novel compensation mechanism is designed to offset the influence of filter errors while avoiding the problem of "explosion of complexity" in the backstepping design process. In addition, the Nussbaum-type function is considered to eliminate the design obstacle of unknown control gains resulting from the attacks. Under the constructed consensus protocol, it is proved theoretically that the consensus tracking error converges to an adjustable small neighborhood of the origin, and all signals in the closed-loop system are bounded. Finally, the feasibility of the provided secure control scheme is verified through two simulation examples.

A quinolinyl resveratrol derivative alleviates acute ischemic stroke injury by promoting mitophagy for neuroprotection via targeting CK2α'.

Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS.

Lower psoas mass indicates worse prognosis in percutaneous vertebroplasty-treated osteoporotic vertebral compression fracture.

The correlation between lower psoas mass and the prognosis of osteoporotic vertebral compression fractures (OVCF) is still unclear. This study aims to investigate the impact of lower psoas mass on the prognosis of patients undergoing percutaneous vertebroplasty (PVP). One hundred and sixty-three elderly patients who underwent single-segment PVP from January 2018 to December 2021 were included. The psoas to L4 vertebral index (PLVI) via MRI were measured to assess psoas mass. Patients were divided into high PLVI (> 0.79) and low PLVI (≤ 0.79) groups based on the median PLVI in the cohort. The basic information (age, gender, body mass index (BMI) and bone mineral density (BMD)), surgical intervention-related elements (duration of operation, latency to ambulation, period of hospital stay, and surgical site), postoperative clinical outcomes (Visual Analog Scale (VAS) scores, Oswestry Disability Index (ODI) scores, Japanese Orthopaedic Association (JOA) scores), and incidence of secondary fractures) were compared. Patients showed no statistically significant differences in terms of age, gender, surgical sute, BMI, BMD and preoperative VAS, ODI, JOA scores (P > 0.05) between the two groups. However, there were significant differences in terms of latency to ambulation, period of hospital stay (P < 0.05). VAS, ODI, and JOA scores at 1, 6, and 12 months after surgery showed that the high PLVI group had significantly better outcomes than the low PLVI group (P < 0.05). Additionally, the low PLVI group had a significantly higher incidence of recurrent fracture (P < 0.05). Lower psoas mass can reduce the clinical effect of PVP in patients with osteoporotic vertebral compression fractures, and is a risk factor for recurrent vertebral fracture.

Genome-editing of a circadian clock gene TaPRR95 facilitates wheat peduncle growth and heading date.

Plant height and heading date are important agronomic traits in wheat (Triticum aestivum L.) that affect final grain yield. In wheat, knowledge of pseudo-response regulator (PRR) genes on agronomic traits is limited. Here, we identify a wheat TaPRR95 gene by genome-wide association studies to be associated with plant height. Triple allele mutant plants produced by CRISPR/Cas9 show increased plant height, particularly the peduncle, with an earlier heading date. The longer peduncle is mainly caused by the increased cell elongation at its upper section, whilst the early heading date is accompanied by elevated expression of flowering genes, such as TaFT and TaCO1. A peduncle-specific transcriptome analysis reveals up-regulated photosynthesis genes and down-regulated IAA/Aux genes for auxin signaling in prr95aabbdd plants that may act as a regulatory mechanism to promote robust plant growth. A haplotype analysis identifies a TaPRR95-B haplotype (Hap2) to be closely associated with reduced plant height and increased thousand-grain weight. Moreover, the Hap2 frequency is higher in cultivars than that in landraces, suggesting the artificial selection on the allele during wheat breeding. These findings suggest that TaPRR95 is a regulator for plant height and heading date, thereby providing an important target for wheat yield improvement.

Parasite-derived microRNA let-7-5p detection for metacestodiasis based on rolling circular amplification-assisted CRISPR/Cas9.

Metacestodiasis is an infectious disease caused by the larval stage of cestode parasites. This disease poses a serious health hazard to wildlife, livestock, and humans, and it incurs substantial economic losses by impacting the safety of the livestock industry, the quality of meat production, and public health security. Unfortunately, there is currently no available molecular diagnostic method capable of distinguishing cysticercus- and Echinococcus-derived microRNAs (miRNAs) from other helminthes and hosts in the plasma of metacestode-infected animals. This study aims to develop a specific, sensitive, and cost-efficient molecular diagnostic method for cysticercosis and echinococcosis, particularly for early detection. The study developed a rolling circular amplification (RCA)-assisted CRISPR/Cas9 detection method based on parasite-derived miRNA let-7-5p. Using a series of dilutions of the let-7 standard, the limit of detection (LOD) of the qPCR, RCA, and RCA-assisted CRISPR/Cas9 methods was compared. The specificity of qPCR and CRISPR/Cas9 was evaluated using four artificially synthesized let-7 standards from different species. A total of 151 plasma samples were used to evaluate the diagnostic performance. Additionally, the study also assessed the correlation between plasma levels of let-7-5p, the number of Taenia pisiformis cysticerci, and the weight of Echinococcus multilocularis cysts. The results demonstrated that the RCA-assisted CRISPR/Cas9 assay could significantly distinguish let-7 from cestodes and other species, achieving a LOD of 10 aM; the diagnostic sensitivity and specificity for rabbit cysticercosis and mouse E. multilocularis were 100% and 97.67%, and 100% and 100%, respectively. Notably, let-7-5p gradually increased in the plasma of T. pisiformis-infected rabbits from 15 days post infection (dpi), peaked at 60 dpi, and persisted until 120 dpi. In E. multilocularis-infected mice, let-7-5p gradually increased from 15 dpi and persisted until 90 dpi. Furthermore, the expression of let-7-5p positively correlated with the number of cysticerci and cyst weight. These results indicated that the let-7-5p-based RCA-assisted CRISPR/Cas9 assay is a sensitive and specific detection method that can be used as a universal diagnostic method for metacestodiasis, particularly for early diagnosis (15 dpi).

2,2- dimethylbenzopyran derivatives containing pyridone structural fragments as selective dual-targeting inhibitors of HIF-1α and EZH2 for the treatment of lung cancer.

We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds.

Murine skeletal muscle satellite cells isolation and preliminary study on regulation in immune microenvironment during nurse cells formation of Trichinella spiralis infection.

As an intracellular parasitic nematode, Trichinella spiralis (T. spiralis) can induce the formation of nurse cells (NC) in host muscles and keep it to survive within the NC for an extended period. The formation of NC is similar to muscle cell injury and repair which lead to the arrest of satellite cells in the G2/M phase and build a suitable parasitic environment for the muscle larvae of T. spiralis. However, the molecular mechanisms involved in skeletal muscle repair through skeletal muscle satellite cells (SMSC) and the host immune response during T. spiralis infection have not been fully elucidated. In this study, histopathological examination revealed that the severity of damage increased as the infection progressed in the soleus muscle. SMSCs were isolated from BALB/c mice infected with T. spiralis at 4, 21 and 35 days post-infection (dpi). The immunological characteristics of these cells were analyzed by real-time PCR and flow cytometry (FCM). FCM analysis revealed a notable increase in the expression of B7 homolog 1 (B7-H1) in SMSCs following T. spiralis infection, while conversely, the expression of inducible costimulatory ligand (ICOSL) significantly decreased. Furthermore, real-time PCR results showed that toll like receptor 3 (TLR3) expression in SMSCs of the infected mice was upregulated at 21 dpi. The expression levels of three subtypes (PPARα, PPARß and PPARγ) of peroxisome proliferator-activated receptors (PPARs) also increased in the cells. This study highlights the immunological regulation significance of SMSCs host during T. spiralis infection and suggests that SMSCs actively participant in the local immune response to T. spiralis by regulating the interaction between the parasite and the host.