Transcriptional Self-Regulation of the Master Nitrogen Regulator GlnR in Mycobacteria.

As a master nitrogen regulator in most actinomycetes, GlnR both governs central nitrogen metabolism and regulates many carbon, phosphate, and secondary metabolic pathways. To date, most studies have been focused on the GlnR regulon, while little is known about the transcriptional regulator for glnR itself. It has been observed that glnR transcription can be upregulated in Mycobacterium smegmatis under nitrogen-limited growth conditions; however, the detailed regulatory mechanism is still unclear. Here, we demonstrate that the glnR gene in M. smegmatis is transcriptionally activated by its product GlnR in response to nitrogen limitation. The precise GlnR binding site was successfully characterized in its promoter region using the electrophoretic mobility shift assay and the DNase I footprinting assay. Site mutagenesis and genetic analyses confirmed that the binding site was essential for in vivo self-activation of glnR transcription. Moreover, based on bioinformatic analyses, we discovered that most of the mycobacterial glnR promoter regions (144 out of 147) contain potential GlnR binding sites, and we subsequently proved that the purified M. smegmatis GlnR protein could specifically bind 16 promoter regions that represent 119 mycobacterial species, including Mycobacterium tuberculosis. Together, our findings not only elucidate the transcriptional self-regulation mechanism of glnR transcription in M. smegmatis but also indicate the ubiquity of the mechanism in other mycobacterial species. IMPORTANCE In actinomycetes, the nitrogen metabolism not only is essential for the construction of life macromolecules but also affects the biosynthesis of secondary metabolites and even virulence (e.g., Mycobacterium tuberculosis). The transcriptional regulation of genes involved in nitrogen metabolism has been thoroughly studied and involves the master nitrogen regulator GlnR. However, the transcriptional regulation of glnR itself remains elusive. Here, we demonstrated that GlnR functions as a transcriptional self-activator in response to nitrogen starvation in the fast-growing model Mycobacterium species Mycobacterium smegmatis. We further showed that this self-regulation mechanism could be widespread in other mycobacteria, which might be beneficial for those slow-growing mycobacteria to adapt to the nitrogen-starvation environments such as within human macrophages for M. tuberculosis.

Injectable and Self-Adaptive Gel Scaffold Based on Heparin Microspheres for Adipogenesis of Human Adipose-Derived Stem Cells.

An injectable and self-adaptive heparin microsphere-based cell scaffold was developed to achieve adipose regeneration. Simultaneously, the cell scaffold exhibited a dynamic architecture, self-regulated glucose levels, sustained insulin delivery, and steady viscoelastic properties for adipogenesis. The dynamic cell scaffold is cross-linked by the boronate-diol interaction among heparin-based microspheres, which have boronate and maltose groups. Because of the boronate-maltose ester bonds, the gelatinous complex would be partially dismantled and readily display glucose-sensitive performance by free glucose via competitive displacement. The dynamic cross-linking heparin microsphere scaffold can deliver the lipogenic drug insulin to enhance lipid filling, which has an impact on fat tissue enhancement. A 4-week in vitro cell culture demonstrated that the dynamic heparin microsphere-based cell scaffold, through loading with insulin, showed significantly higher efficiency in promoting ASC differentiation compared with traditional 3D culture methods. In vivo histological results further demonstrated that there was a significant increase in adipose in the proposed cell scaffold, which proved to be statistically significant compared with traditional biomaterials. Notable stain expression of the FABP4 and PPAR-γ genes was also observed in the dynamic cell scaffold containing insulin, which was more similar to natural fat.

Parameter Estimation of Poisson-Gaussian Signal-Dependent Noise from Single Image of CMOS/CCD Image Sensor Using Local Binary Cyclic Jumping.

Since signal-dependent noise in a local weak texture region of a noisy image is approximated as additive noise, the corresponding noise parameters can be estimated from a given set of weakly textured image blocks. As a result, the meticulous selection of weakly textured image blocks plays a decisive role to estimate the noise parameters accurately. The existing methods consider the finite directions of the texture of image blocks or directly use the average value of an image block to select the weakly textured image block, which can result in errors. To overcome the drawbacks of the existing methods, this paper proposes a novel noise parameter estimation method using local binary cyclic jumping to aid in the selection of these weakly textured image blocks. The texture intensity of the image block is first defined by the cumulative average of the LBCJ information in the eight neighborhoods around the pixel, and, subsequently, the threshold is set for selecting weakly textured image blocks through texture intensity distribution of the image blocks and inverse binomial cumulative function. The experimental results reveal that the proposed method outperforms the existing alternative algorithms by 23% and 22% for the evaluative measures of MSE (a) and MSE (b), respectively.

Genome-wide patterns of copy number variations in Spodoptera litura.

Spodoptera litura is a polyphagous pest and can feed on more than 100 species of plants, causing great damage to agricultural production. The SNP results showed that there were gene exchanges between different regions. To explore the variations of larger segments in S. litura genome, we used genome resequencing samples from 14 regions of China, India, and Japan to study the copy number variations (CNVs). We identified 3976 CNV events and 1581 unique copy number variation regions (CNVRs) occupying the 108.5 Mb genome of S. litura. A total of 5527 genes that overlapped with CNVRs were detected. Selection signal analysis identified 19 shared CNVRs and 105 group-specific CNVRs, whose related genes were involved in various biological processes in S. litura. We constructed the first CNVs map in S. litura genome, and our findings will be valuable for understanding the genomic variations and population differences of S. litura.

Average intensity and directionality of partially coherent model beams propagating in turbulent ocean.

We studied Gaussian beams with three different partially coherent models, including the Gaussian-Schell model (GSM), Laguerre-Gaussian Schell model (LGSM), and Bessel-Gaussian Schell model (BGSM), propagating through oceanic turbulence. The expressions of average intensity, beam spreading, and beam wander for GSM, LGSM, and BGSM beams in the paraxial channel are derived. We make a contrast for the three models in numerical simulations and find that the GSM beam has smaller spreading than the others, and the LGSM beam needs longer propagation distance to transform into a well-like profile of average intensity than the BGSM beam in the same conditions. The salinity fluctuation has a greater contribution to the wander of LGSM and BGSM beams than that of the temperature fluctuation. Our results can be helpful in the design of an optical wireless communication link operating in oceanic environment.

Genome-Wide Analysis of Host Responses to Four Different Types of Microorganisms in Bombyx Mori (Lepidoptera: Bombycidae).

Several pathogenic microorganisms have been used to investigate the genome-wide transcriptional responses of Bombyx mori to infection. However, studies have so far each focused on one microorganism, and systematic genome-wide comparison of transcriptional responses to different pathogenic microorganisms has not been undertaken. Here, we surveyed transcriptional responses of B. mori to its natural bacterial, viral, and fungal pathogens, Bacillus bombyseptieus, B. mori nucleopolyhedrovirus (BmNPV), and Beauveria bassiana, respectively, and to nonpathogenic Escherichia coli, by microarray analysis. In total, the expression of 2,436, 1,804, 1,743, and 912 B. mori genes was modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, and E. coli, respectively. Notably, the expression of 620, 400, 177, or 165 of these genes was only modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, or E. coli, respectively. In contrast to the expression of genes related to juvenile hormone synthesis and metabolism, that of genes encoding juvenile hormone binding proteins was microorganism-specific. Three basal metabolic pathways were modulated by infection with any of the four microorganisms, and 3, 14, 5, and 2 metabolic pathways were specifically modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, and E. coli, respectively. Interestingly, BmNPV infection modulated the JAK/STAT signaling pathway, whereas both the Imd and Toll signaling pathways were modulated by infection with B. bombyseptieus, B. bassiana, or E. coli These results elucidate potential molecular mechanisms of the host response to different microorganisms, and provide a foundation for further work on host-pathogen interaction.

CRISPR/Cas9-mediated targeted mutagenesis in Nicotiana tabacum.

Genome editing is one of the most powerful tools for revealing gene function and improving crop plants. Recently, RNA-guided genome editing using the type II clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (Cas) system has been used as a powerful and efficient tool for genome editing in various organisms. Here, we report genome editing in tobacco (Nicotiana tabacum) mediated by the CRISPR/Cas9 system. Two genes, NtPDS and NtPDR6, were used for targeted mutagenesis. First, we examined the transient genome editing activity of this system in tobacco protoplasts, insertion and deletion (indel) mutations were observed with frequencies of 16.2-20.3% after transfecting guide RNA (gRNA) and the nuclease Cas9 in tobacco protoplasts. The two genes were also mutated using multiplexing gRNA at a time. Additionally, targeted deletions and inversions of a 1.8-kb fragment between two target sites in the NtPDS locus were demonstrated, while indel mutations were also detected at both the sites. Second, we obtained transgenic tobacco plants with NtPDS and NtPDR6 mutations induced by Cas9/gRNA. The mutation percentage was 81.8% for NtPDS gRNA4 and 87.5% for NtPDR6 gRNA2. Obvious phenotypes were observed, etiolated leaves for the psd mutant and more branches for the pdr6 mutant, indicating that highly efficient biallelic mutations occurred in both transgenic lines. No significant off-target mutations were obtained. Our results show that the CRISPR/Cas9 system is a useful tool for targeted mutagenesis of the tobacco genome.

Genome-wide patterns of genetic variation among silkworms.

Although the draft genome sequence of silkworm is available for a decade, its genetic variations, especially structural variations, are far from well explored. In this study, we identified 1,298,659 SNPs and 9,731 indels, of which 32 % of SNPs and 92.2 % of indels were novel compared to previous silkworm re-sequencing analysis. In addition, we applied a read depth-based approach to investigate copy number variations among 21 silkworm strains at genome-wide level. This effort resulted in 562 duplicated and 41 deleted CNV regions, and among them 442 CNV were newly identified. Functional annotation of genes affected by these genetic variations reveal that these genes include a wide spectrum of molecular functions, such as immunity and drug detoxification, which are important for the adaptive evolution of silkworms. We further validated the predicted CNV regions using q-PCR. 94.7 % (36/38) of the selected regions show divergent copy numbers compared to a single-copy gene OR2. In addition, potential presence/absence variations are also observed in our study: 11 genes are present in the reference genome, but absent in other strains. Overall, we draw an integrative map of silkworm genetic variation at genome-wide level. The identification of genetic variations in this study improves our understanding that these variants play important roles in shaping phenotypic variations between wild and domesticated silkworms.

Cloning and characterization of a novel Nicotiana tabacum ABC transporter involved in shoot branching.

The ATP-binding cassette (ABC) superfamily is a large protein family with diverse physiological functions in all kingdoms of life. One distinguished subfamily, the pleiotropic drug resistance (PDR) transporters, has only been identified in plants and fungi. Here, we identified a Nicotiana tabacum PDR gene, NtPDR6, which is a homolog of Petunia hybrida PDR1. The full-length cDNA of NtPDR6 had a 4482-bp open reading frame encoding a full-size ABC transporter with 1493 amino acids. Sequence comparison showed that NtPDR6 had high homology with plant PDR proteins. NtPDR6 was strongly induced by phosphate starvation as well as by 1-naphthalene acetic acid. Tissue expression pattern analysis showed that NtPDR6 was detected in all surveyed tissues but preferentially in roots. We cloned the 1.3-kb NtPDR6 promoter and found that there was one phosphate starvation response-related element Pho-like and several root-specific expression-related elements rootmotiftapox1 in the NtPDR6 promoter. A tissue-specific pattern of NtPDR6 promoter-ß-glucuronidase expression was dominantly observed in subepidermal cells and the elongation zone of lateral roots. RNA interference technology was used to knock down NtPDR6 expression, and there was a significantly increased branching phenotype in the NtPDR6 knockdown plants. These data suggest that NtPDR6 plays a key role in regulation of shoot branching processes.

Evaluating the impact of school-based influenza vaccination programme on absenteeism and outbreaks at schools in Hong Kong: a retrospective cohort study protocol.

INTRODUCTION: Seasonal influenza causes annual school breaks and student absenteeism in Hong Kong schools and kindergartens. This proposal aims to conduct a retrospective cohort study to evaluate the impact of a school-based influenza vaccination (SIV) programme on absenteeism and outbreaks at schools in Hong Kong. METHODS: The study will compare schools that implemented the SIV programme with schools that did not. The data will be sourced from school records, encompassing absenteeism records, outbreak reports, and vaccination rates. We will recruit 1000 students from 381 schools and kindergartens in 18 districts of Hong Kong starting June 2024. The primary outcome measures will include absenteeism rates due to influenza and school influenza outbreaks. Secondary outcomes will consist of vaccination coverage rates and the impact of the SIV programme on hospitalisations due to influenza-like illness. A t-test will be conducted to compare the outcomes between schools with and without the SIV programme. ETHICS AND DISSEMINATION: The school completed signing the participants' informed consent form before reporting the data to us. Our study has been approved by the Hospital Authority Hong Kong West Cluster IRB Committee (IRB No: UW 17-111) and was a subtopic of the research "The estimated age-group specific influenza vaccine coverage rates in Hong Kong and the impact of the school outreach vaccination program". TRIAL REGISTRATION: This study will be retrospectively registered.

Efficacy and safety of dorzagliatin, a novel glucokinase activators, in the treatment of T2DM: A meta-analysis of randomized controlled trials.

OBJECT: To evaluate the efficacy and safety of dorzagliatin for the treatment of type 2 diabetes (T2DM). METHODS: Seven databases were systematically searched, spanning the interval from 2016 to August 2023. Randomized controlled trials (RCTS) comparing dorzagliatin with placebo for the treatment of T2DM were applicable for containing this study. The relevant data were extracted, and a meta-analysis was implemented using RevMan 5.4 software. RESULTS: A total of 3 studies involving 1332 patients were included. We use glycated hemoglobin (HbA1c) levels as the major indicator of efficacy, FBG, 2h postprandial blood glucose, Homa-ß and Homa-IR to be Secondary outcome measures. Compared with placebo group, dorzagliatin significantly reduced blood glucose levels as well as enhanced insulin resistance. In terms of safety, no serious adverse events occurred. However, lipid-related indicators, especially triglycerides levels, and the incidence of hypoglycemia were higher in patients in the dorzagliatin group compared with those in the control group, but the increase from baseline was mild. CONCLUSIONS: Dorzagliatin exerted favorable effects in hypoglycemic control, effectively reduced the HbA1c, FBG, and 2h postprandial blood glucose levels in T2DM patients, stimulated the secretion of insulin during the initial phase, and exerted a consistent hypoglycemic effect. However, the incidence of adverse events such as elevated blood lipids and cardiovascular risk warrants further investigations through long-term clinical trials.

Comparative efficacy and safety of cabozantinib for malignant tumors: a systematic review and meta-analysis.

OBJECTIVES: To provide a more comprehensive understanding of the efficacy and safety profile of cabozantinib versus placebo in malignant tumors, we conducted a systematic review and meta-analysis. This involved analyzing a collection of published randomized controlled trials to assess the outcomes. METHODS: We used RevMan5.3 software to evaluate the outcomes of the collected studies. The primary outcome we focused on was progression-free survival (PFS), and the secondary outcomes included overall survival (OS) and disease control rate (DCR). RESULTS: Our findings revealed that compared to placebo, cabozantinib significantly extended the PFS of patients [hazard ratios (HR) 0.37, 95% confidence intervals (CI): 0.32, 0.43, p < 0.00001]. Additionally, cabozantinib improved the OS of patients [HR 0.78, 95%CI: 0.68, 0.91, p = 0.002]. While it is important to note that cabozantinib was associated with a higher likelihood of causing digestive, cutaneous, and cardiovascular related adverse events [relative risk (RR) 4.40, 95% CI: 3.10, 6.25, p < 0.00001]. CONCLUSION: Based on our analysis, cabozantinib significantly prolonged the PFS and OS of patients with malignant tumors (p < 0.01). We recommend the use of cabozantinib in treating advanced malignant tumors. However, it is important to continuously monitor and manage the drug-related adverse events. REGISTRATION: PROSPERO (No. CRD42023449261).

Cabozantinib in combination with immune checkpoint inhibitors for renal cell carcinoma: a systematic review and meta-analysis.

Context: Cabozantinib combined with immune checkpoint inhibitors (ICIs) has brought a new therapeutic effect for the medical treatment of renal cell carcinoma (RCC). Objectives: We performed a meta-analysis of randomized controlled trials and single-arm trials to evaluate the efficacy and safety of cabozantinib plus ICIs in RCC. Methods: We extracted data from PubMed, Cochrane, Medline and Embase databases, and rated literature quality through Cochrane risk of bias tool and MINORS. RevMan5.3 software was used to analyze the results of randomized controlled trials and single-arm trials. Results: A total of 7 studies were included. Treatment with cabozantinib plus ICIs improved PFS [HR 0.75, (95%CI: 0.52, 1.08), p = 0.12] and the OS [HR 0.80, (95%CI: 0.60, 1.07), p = 0.13] in randomized controlled trials. Meanwhile, the result of the ORR in randomized controlled trials was [risk ratio (RR) 1.37, (95%CI: 1.21, 1.54), p < 0.00001] and in single-arm trials was [risk difference (RD) 0.49, (95%CI: 0.26, 0.71), p < 0.0001]. Conclusion: Cabozantinib plus ICIs prolonged the PFS and OS, and improved ORR in patients with RCC. Our recommendation is to use cabozantinib plus ICIs to treat advanced RCC, and to continuous monitor and manage the drug-related adverse events. Systematic Review Registration: identifier CRD42023455878.

3α-Hydroxylup-20(29)-ene-23,28-dioic Acid as a Phytogenic Chemical Marker for Authenticating Schefflera octophylla (Lour.) Harms Monofloral Honey.

The monofloral honey from Schefflera octophylla (Lour.) Harms (MH-Sco) are of high economic value due to their rarity and potential medicinal benefits. However, the limited investigations on the relationship of phytogenic components between the plant S. octophylla (P-Sco) and MH-Sco have an impact on MH-Sco authentication. Herein, the tentative phytogenic markers of MH-Sco were screened by comparing the metabolites of MH-Sco obtained by ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS)-based untargeted metabolomics with the identified phytogenic chemicals from P-Sco. Combined with the mass and NMR spectral information, 3α-hydroxylup-20(29)-ene-23,28-dioic acid (HLEDA) was finally identified as the phytogenic marker of MH-Sco. A targeted ultrahigh-performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS)-based method was established and validated based on the purified monomer standard to measure HLEDA levels in honey samples. HLEDA determined in MH-Sco was with the content from 0.303 to 0.440 mg/kg, while HLEDA was absent in honey samples from other botanical origins, indicating the reliability of HLEDA as a chemical marker in MH-Sco authentication. This study provides the theoretical basis and industry guidance for honey quality control for commercial consumption.

Rehabilitation with brain-computer interface and upper limb motor function in ischemic stroke: A randomized controlled trial.

BACKGROUND: Upper limb motor dysfunction is a major problem in the rehabilitation of patients with stroke. Brain-computer interface (BCI) is a kind of communication system that converts the "ideas" in the brain into instructions and has been used in stroke rehabilitation. This study aimed to investigate the efficacy and safety of BCI in rehabilitation training on upper limb motor function among patients with ischemic stroke. METHODS: This was an investigator-initiated, multicenter, randomized, open-label, blank-controlled clinical trial with blinded outcome assessment conducted at 17 centers in China. Patients were assigned in a 1:1 ratio to the BCI group or the control group based on traditional rehabilitation training. The primary efficacy outcome is the difference in improvement of the Fugl-Meyer Assessment upper extremity (FMA-UE) score between two groups at month 1 after randomization. The safety outcomes were any adverse events within 3 months. FINDINGS: A total of 296 patients with ischemic stroke were enrolled and randomly allocated to the BCI group (n = 150) and the control group (n = 146). The primary efficacy outcomes of FMA-UE score change from baseline to 1 month were 13.17 (95% confidence interval [CI], 11.56-14.79) in the BCI group and 9.83 (95% CI, 8.19-11.47) in the control group (mean difference between groups was 3.35; 95% CI, 1.05-5.65; p = 0.0045). Adverse events occurred in 33 patients (22.00%) in the BCI group and in 31 patients (21.23%) in the control group. CONCLUSIONS: BCI rehabilitation training can further improve upper limb motor function based on traditional rehabilitation training in patients with ischemic stroke. This study was registered at ClinicalTrials.gov: NCT04387474. FUNDING: This work was supported by the National Key R&D Program of China (2018YFC1312903), the National Key Research and Development Program of China (2022YFC3600600), the Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University (CCMU2022ZKYXZ009), the Beijing Natural Science Foundation Haidian original innovation joint fund (L222123), the Fund for Young Talents of Beijing Medical Management Center (QML20230505), and the high-level public health talents (xuekegugan-02-47).

Ecoclimate drivers shape virome diversity in a globally invasive tick species.

Spillovers of viruses from animals to humans occur more frequently under warmer conditions, particularly arboviruses. The invasive tick species Haemaphysalis longicornis, the Asian longhorned tick, poses a significant public health threat due to its global expansion and its potential to carry a wide range of pathogens. We analyzed meta-transcriptomic data from 3595 adult H. longicornis ticks collected between 2016 and 2019 in 22 provinces across China encompassing diverse ecological conditions. Generalized additive modeling revealed that climate factors exerted a stronger influence on the virome of H. longicornis than other ecological factors, such as ecotypes, distance to coastline, animal host, tick gender, and antiviral immunity. To understand how climate changes drive the tick virome, we performed a mechanistic investigation using causality inference with emphasis on the significance of this process for public health. Our findings demonstrated that higher temperatures and lower relative humidity/precipitation contribute to variations in animal host diversity, leading to increased diversity of the tick virome, particularly the evenness of vertebrate-associated viruses. These findings may explain the evolution of tick-borne viruses into generalists across multiple hosts, thereby increasing the probability of spillover events involving tick-borne pathogens. Deep learning projections have indicated that the diversity of the H. longicornis virome is expected to increase in 81.9% of regions under the SSP8.5 scenario from 2019 to 2030. Extension of surveillance should be implemented to avert the spread of tick-borne diseases.

Gelatin-based Targeted Delivery Systems for Tissue Engineering.

Gelatin is an attractive material for drug delivery and tissue engineering applications due to its excellent biocompatibility and biodegradability, which has been utilized as cell, drug, and gene carriers. Gelatin is less immunogenic compared to collagen and its precursor and retains informational signals, such as RGD (Arg-Gly-Asp) sequence, thus promoting cell adhesion and proliferation. To tune the mechanical strength and bioactivity, gelatin can be easily modified via chemical reactions and physical methods to obtain various derivatives. Furthermore, gelatin-based biomaterials can be achieved through chemical immobilization of specific molecules and physical combination with other biopolymers. This review focuses on the recent advances of gelatin and its derivatives as biomaterials in the field of drug delivery, including cell scaffolds for tissue engineering applications.

Stathmin1 promotes lymph node metastasis in hypopharyngeal squamous cell carcinoma via regulation of HIF­1α/VEGF­A axis and MTA1 expression.

Extensive neck lymph node metastasis (LNM) is an important clinical feature of hypopharyngeal squamous cell carcinoma (HSCC). Stathmin1 (STMN1) is closely associated with LNM in numerous human cancers. In the present study, the association between STMN1 and neck LNM in HSCC and the underlying molecular mechanisms were explored. First, postoperative samples of HSCC were screened and the association between STMN1 and neck LNM in HSCC was analyzed. Then, cell functional experiments were performed to assess the potential of STMN1 to promote invasion and migration. Subsequently, the potential target genes and pathways of STMN1 were predicted using bioinformatics analysis. Finally, the obtained target genes and pathways of STMN1 were validated by reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses to confirm the potential mechanisms by which STMN1 promotes LNM in HSCC. As a result, a total of 117 postoperative samples of HSCC were screened, and STMN1 was proven to be associated with neck LNM in HSCC. Further, cell functional experiments established that high expression of STMN1 could actually promote FaDu cell invasion and metastasis. Bioinformatics analysis revealed that high expression of STMN1 was associated with the activation of hypoxia inducible factor-1alpha (HIF-1α) pathway and increased expression of metastasis-associated protein 1 (MTA1). Finally, RT-qPCR and western blot analyses confirmed that STMN1 promotes the expression levels of HIF-1α/vascular endothelial growth factor (VEGF)-A and MTA1 in FaDu cell lines. In conclusion, it was found that high expression of STMN1 promoted neck LNM in HSCC and the potential mechanisms may be via regulation of the HIF-1α/VEGF-A axis and MTA1 expression.

Radiation-induced NF-κB activation is involved in cochlear damage in mice via promotion of a local inflammatory response.

The radiation-induced inflammatory response is involved in radiation damage to the cochlea and causes sensorineural hearing loss (SNHL). NF-κB, as the master switch of the inflammatory response, regulates the expression of many inflammation-related genes and thus the inflammatory response. Therefore, in this study we used a mouse model to determine whether radiation-induced NF-κB activation is involved in damage to the cochlea and to investigate the underlying mechanism. Eventually, we found that NF-κB was activated after radiation of the cochleae and the activation reached a maximum at 2-6 h after radiation. And morphological analysis showed severe damage to the cochleae after radiation, but this damage was significantly ameliorated by JSH-23 (an inhibitor of NF-κB) pretreatment. Along with these morphological changes, the expression levels of proinflammatory molecules (including proinflammatory cytokines IL-6, TNF-α, COX-2 and inflammation-related proteins VCAM-1, MIP-1ß) in the cochlear tissues were significantly increased after radiation, but were significantly decreased by JSH-23 pretreatment compared to radiation alone. Therefore, these results indicated that radiation-induced NF-κB activation was involved in damage to the cochleae and resultant SNHL via its promotion of the inflammatory response mediated by overexpression of some proinflammatory molecules in cochlear tissues, and inhibition of radiation-induced NF-κB was conducive to preventing such damage.

FKA-A NPs enhances PTX-A NPs efficacy to suppress ovarian cancer via regulating Skp2/YAP pathway.

Recurrence and distant metastasis after paclitaxel (PTX)-based chemotherapy in ovarian cancer (OC) patients remains a clinical obstacle. Flavokawain A (FKA) is a novel chalcone from kava plant that can induce G2/M arrest and inhibit invasion and metastasis in different tumor cells. In this study, we examined the effects and the molecular mechanism of sodium aescinate (Aes)-stabilized nanoparticles FKA-A NPs in enhancing the efficacy of PTX-A NPs in vitro and in vivo. We showed that FKA-A NPs combined with PTX-A NPs notably inhibited the proliferation and migration and reduced the expression of EMT-related markers in OCs. YAP nuclear translocation and its downstream signaling pathway were remarkably activated after PTX-A NPs treatment in OCs. FKA-A NPs obviously inhibited YAP nuclear translocation and reduced the transcriptional activity of YAP target genes. Simultaneously, FKA-A NPs dose and time dependently inhibited Skp2 expression in A2780 and Skov3 cells. In contrast, overexpression of Skp2 significantly attenuated the inhibition of FKA-A NPs on YAP nuclear translocation. In OC homograft mice, treatment with FKA-A NPs and PTX-A NPs significantly suppressed the growth of homograft tumor compared with PTX-A NPs but did not decrease mice's body weight. In summary, we demonstrate that FKA-A NPs enhance the efficacy of PTX-A NPs against OCs in vitro and in vivo via reducing Skp2 expression, thus suppressing YAP nuclear translocation and activity of its target genes.