TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Diagnosis of membranous nephropathy with Anti-GBM glomerulonephritis: a case series report.

BACKGROUND: The concomitant occurrence of membranous nephropathy and anti-glomerular basement (anti-GBM) disease has been previously described but is extremely rare. However, delayed recognition or misdiagnosis leads to delayed treatment, resulting in worse renal and patient outcomes. CASE PRESENTATION: We present 3 patients with rapidly progressive glomerulonephritis (RPGN), anti-GBM and serum-positive M-type phospholipase A2 receptor (anti-PLA2R) antibody. Renal biopsies revealed PLA2R-associated membranous nephropathy with anti-GBM glomerulonephritis. We analyzed the clinical and pathological characteristics and discussed that the correct diagnosis of membranous nephropathy with anti-GBM should rely on a combination of renal biopsy findings and serological testing. Despite aggressive treatment, one patient received maintenance hemodialysis, one patient progressed to CKD 3 stage, and the other patient died of cerebral infarction. CONCLUSION: The simultaneous occurrence of membranous nephropathy and anti-GBM disease is extremely rare. The correct diagnosis of membranous nephropathy with anti-GBM relies on a combination of renal biopsy findings and serological testing. Early diagnosis is needed to improve the renal dysfunction.

Volatile Organic Compounds Produced by a Deep-Sea Bacterium Efficiently Inhibit the Growth of Pseudomonas aeruginosa PAO1.

The deep-sea bacterium Spongiibacter nanhainus CSC3.9 has significant inhibitory effects on agricultural pathogenic fungi and human pathogenic bacteria, especially Pseudomonas aeruginosa, the notorious multidrug-resistant pathogen affecting human public health. We demonstrate that the corresponding antibacterial agents against P. aeruginosa PAO1 are volatile organic compounds (VOCs, namely VOC-3.9). Our findings show that VOC-3.9 leads to the abnormal cell division of P. aeruginosa PAO1 by disordering the expression of several essential division proteins associated with septal peptidoglycan synthesis. VOC-3.9 hinders the biofilm formation process and promotes the biofilm dispersion process of P. aeruginosa PAO1 by affecting its quorum sensing systems. VOC-3.9 also weakens the iron uptake capability of P. aeruginosa PAO1, leading to reduced enzymatic activity associated with key metabolic processes, such as reactive oxygen species (ROS) scavenging. Overall, our study paves the way to developing antimicrobial compounds against drug-resistant bacteria by using volatile organic compounds.

SETD2-mediated H3K14 trimethylation promotes ATR activation and stalled replication fork restart in response to DNA replication stress.

Ataxia telangiectasia and Rad3 related (ATR) activation after replication stress involves a cascade of reactions, including replication protein A (RPA) complex loading onto single-stranded DNA and ATR activator loading onto chromatin. The contribution of histone modifications to ATR activation, however, is unclear. Here, we report that H3K14 trimethylation responds to replication stress by enhancing ATR activation. First, we confirmed that H3K14 monomethylation, dimethylation, and trimethylation all exist in mammalian cells, and that both SUV39H1 and SETD2 methyltransferases can catalyze H3K14 trimethylation in vivo and in vitro. Interestingly, SETD2-mediated H3K14 trimethylation markedly increases in response to replication stress induced with hydroxyurea, a replication stress inducer. Under these conditions, SETD2-mediated H3K14me3 recruited the RPA complex to chromatin via a direct interaction with RPA70. The increase in H3K14me3 levels was abolished, and RPA loading was attenuated when SETD2 was depleted or H3K14 was mutated. Rather, the cells were sensitive to replication stress such that the replication forks failed to restart, and cell-cycle progression was delayed. These findings help us understand how H3K14 trimethylation links replication stress with ATR activation.

Whole-Transcriptome Profiling and Functional Prediction of Long Non-Coding RNAs Associated with Cold Tolerance in Japonica Rice Varieties.

Low-temperature chilling is a major abiotic stress leading to reduced rice yield and is a significant environmental threat to food security. Low-temperature chilling studies have focused on physiological changes or coding genes. However, the competitive endogenous RNA mechanism in rice at low temperatures has not been reported. Therefore, in this study, antioxidant physiological indices were combined with whole-transcriptome data through weighted correlation network analysis, which found that the gene modules had the highest correlation with the key antioxidant enzymes superoxide dismutase and peroxidase. The hub genes of the superoxide dismutase-related module included the UDP-glucosyltransferase family protein, sesquiterpene synthase and indole-3-glycerophosphatase gene. The hub genes of the peroxidase-related module included the WRKY transcription factor, abscisic acid signal transduction pathway-related gene plasma membrane hydrogen-ATPase and receptor-like kinase. Therefore, we selected the modular hub genes and significantly enriched the metabolic pathway genes to construct the key competitive endogenous RNA networks, resulting in three competitive endogenous RNA networks of seven long non-coding RNAs regulating three co-expressed messenger RNAs via four microRNAs. Finally, the negative regulatory function of the WRKY transcription factor OsWRKY61 was determined via subcellular localization and validation of the physiological indices in the mutant.

The novel amylase function of the carboxyl terminal domain of Amy63.

α-amylase plays a crucial role in regulating metabolism and health by hydrolyzing of starch and glycogen. Despite comprehensive studies of this classic enzyme spanning over a century, the function of its carboxyl terminal domain (CTD) with a conserved eight ß-strands is still not fully understood. Amy63, identified from a marine bacterium, was reported as a novel multifunctional enzyme with amylase, agarase and carrageenase activities. In this study, the crystal structure of Amy63 was determined at 1.8 Å resolution, revealing high conservation with some other amylases. Interestingly, the independent amylase activity of the carboxyl terminal domain of Amy63 (Amy63_CTD) was newly discovered by the plate-based assay and mass spectrometry. To date, the Amy63_CTD alone could be regarded as the smallest amylase subunit. Moreover, the significant amylase activity of Amy63_CTD was measured over a wide range of temperature and pH, with optimal activity at 60 °C and pH 7.5. The Small-angle X-ray scattering (SAXS) data showed that the high-order oligomeric assembly gradually formed with increasing concentration of Amy63_CTD, implying the novel catalytic mechanism as revealed by the assembly structure. Therefore, the discovery of the novel independent amylase activity of Amy63_CTD suggests a possible missing step or a new perspective in the complex catalytic process of Amy63 and other related α-amylases. This work may shed light on the design of nanozymes to process marine polysaccharides efficiently.

Large dynamic strain measurement via slope-assisted Brillouin optical time domain reflectometry using a frequency equalizer.

In this Letter, a method for measuring large dynamic strain via slope-assisted Brillouin optical time domain reflectometry (SA-BOTDR) is proposed. A linear artificial slope created by a frequency equalizer is used instead of the traditional slope of the Brillouin gain spectrum (BGS) as the linear response region between the Brillouin frequency shift (BFS) and signal intensity. This method makes the strain measurement range independent of the bandwidth of the BGS. The large dynamic strain with a maximum value of 3108 µÎµ and the spatial resolution of 5 m along the ∼1.94-km single-mode fiber (SMF) are obtained by means of the proposed technique. Meanwhile, a strong linear relationship is also established between the signal strength and strain at the vibration frequencies of 10.3 and 13.1 Hz. The maximum measured errors of vibration frequency are 0.5 Hz@10.3 Hz and 0.8 Hz@13.1 Hz.

Systematic review and meta-analysis of neonatal outcomes of COVID-19 vaccination in pregnancy.

BACKGROUND: The safety of coronavirus disease 2019 (COVID-19) vaccines during pregnancy is a particular concern. Here, we addressed the neonatal outcomes after maternal vaccination of COVID-19 during pregnancy. METHODS: We systematically searched PubMed, EMBASE, and the WHO COVID-19 Database for studies on neonatal outcomes after maternal COVID-19 vaccination from inception to 3 July 2022. Main neonatal outcomes were related to preterm, small for gestation (SGA), NICU admission, low Apgar score at 5 min (<7), and additional neonatal outcomes such as gestation <34 weeks, low birth weight and some neonatal morbidity were all also analyzed. RESULTS: A total of 15 studies were included. We found that maternal vaccination during pregnancy was related to the reduction rates of Preterm, SGA, Low Apgar score at 5 min (<7). In addition, there was no evidence of a higher risk of adverse neonatal outcomes after maternal vaccination of COVID-19 during pregnancy, including NICU admission, preterm birth with gestation <34 weeks, low birth weight, very low birth weight, congenital anomalies, and so on. CONCLUSIONS: COVID-19 vaccination in pregnant women does not raise significant adverse effects on neonatal outcomes and is related to a protective effect on some neonatal outcomes. IMPACT: Present study has addressed the neonatal outcomes after maternal vaccination of COVID-19 during pregnancy. COVID-19 vaccination in pregnant women does not raise significant adverse effects on neonatal outcomes and is related to a protective effect on some neonatal outcomes. The present study could encourage pregnant women to be vaccinated against COVID-19.

APOL1 and the risk of adverse renal outcomes in patients of African ancestry with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) disproportionately affects individuals of African ancestry (AA) compared to European ancestry (EA). In the general population, high risk (HR) variants in the apolipoprotein L1 (APOL1) gene increase the risk of renal and hypertensive disorders in individuals of AA. Since SLE is characterized by an interferon signature and APOL1 expression is driven by interferon, we examined the hypothesis that APOL1 HR genotypes predominantly drive higher rates of renal and hypertensive-related comorbidities observed in SLE patients of AA versus those of EA. METHODS: We performed a retrospective cohort study in patients with SLE of EA and AA using a genetic biobank linked to de-identified electronic health records. APOL1 HR genotypes were defined as G1/G1, G2/G2, or G1/G2 and low risk (LR) genotypes as 1 or 0 copies of the G1 and G2 alleles. To identify renal and hypertensive-related disorders that differed in prevalence by ancestry, we used a phenome-wide association approach. We then used logistic regression to compare the prevalence of renal and hypertensive-related disorders in EA and AA patients, both including and excluding patients with the APOL1 HR genotype. In a sensitivity analysis, we examined the association of end stage renal disease secondary to lupus nephritis (LN-related ESRD) with ancestry and the APOL1 genotype. RESULTS: We studied 784 patients with SLE; 195 (24.9%) were of AA, of whom 27 (13.8%) had APOL1 HR genotypes. Eighteen renal and hypertensive-related phenotypes were more common in AA than EA patients (p-value ≤ 1.4E-4). All phenotypes remained significantly different after exclusion of patients with APOL1 HR genotypes, and most point odds ratios (ORs) decreased only slightly. Even among ORs with the greatest decrease, risk for AA patients without the APOL1 HR genotype remained significantly elevated compared to EA patients. In the sensitivity analysis, LN-related ESRD was more prevalent in SLE patients of AA versus EA and AA patients with the APOL1 HR genotype versus LR (p-value < .05 for both). CONCLUSION: The higher prevalence of renal and hypertensive disorders in SLE patients of AA compared to those of EA is not fully explained by the presence of APOL1 high risk variants.

Photocatalytic Decarboxylative Coupling of Arylacetic Acids with Aromatic Aldehydes.

An efficient protocol was proposed for the preparation of secondary alcohols in good to excellent yields via photoredox-catalyzed decarboxylative couplings between readily available arylacetic acids and a variety of less reactive (hetero)aromatic aldehydes. The formation of carbanion is the key intermediate in this reaction. Various substituted arylacetic acids and aldehydes were all compatible with this transformation under mild reaction conditions. Furthermore, the current protocol was successfully applied to the direct alcoholization of several drug acids.

Platelet-activating factor (PAF) enhances guinea pig detrusor smooth muscle contractile activities by stimulating voltage-dependent Ca2+ channels and store-operated Ca2+ channels.

We investigated the extracellular Ca2+ influx pathways involved in platelet-activating factor (PAF)-enhanced guinea pig detrusor smooth muscle (DSM) contractile activities. One micromolar PAF-enhanced DSM contractile activities were completely inhibited by extracellular Ca2+ removal and strongly suppressed by voltage-dependent Ca2+ channel (VDCC) inhibitors. PAF-enhanced DSM contractile activities remaining in the presence of verapamil (10 µM) were not inhibited by LOE-908 (30 µM, an inhibitor of receptor-operated Ca2+ channels (ROCCs)), but were almost completely inhibited by SKF-96365 (30 µM, an inhibitor of store-operated Ca2+ channels (SOCCs) and ROCCs). These results suggest that VDCCs and SOCCs are responsible for PAF-enhanced DSM contractile activities.

Regional disparities and influencing factors of high quality medical resources distribution in China.

BACKGROUND: With the gradual increase of residents' income and the continuous improvement of medical security system, people's demand for pursuing higher quality and better medical and health services has been released. However, so far little research has been published on China's high quality medical resources (HQMR). This study aims to understand the spatiotemporal variation trend of HQMR from 2006 to 2020, analyze regional disparity of HQMR in 2020, and further explore the main factors influencing the distribution of HQMR in China. METHODS: The study selected Class III level A hospitals (the highest level medical institutions in China) to represent HQMR. Descriptive statistical methods were used to address the changes in the distribution of HQMR from 2006 to 2020. Lorentz curve, Gini coefficient (G), Theil index (T) and High-quality health resource density index (HHRDI) were used to calculate the degree of inequity. The geographical detector method was used to reveal the key factors influencing the distribution of HQMR. RESULTS: The total amount of HQMR in China had increased year by year, from 647 Class III level A hospitals in 2006 to 1580 in 2020. In 2020, G for HQMR by population was 0.166, while by geographic area was 0.614. T was consistent with the results for G, and intra-regional contribution rates were higher than inter-regional contribution rates. HHRDI showed that Beijing, Shanghai, and Tianjin had the highest allocated amounts of HQMR. The results of the geographical detector showed that total health costs, government health expenditure, size of resident populations, GDP, number of medical colleges had a significant impact on the spatial distribution of HQMR and the q values were 0.813, 0.781, 0.719, 0.661, 0.492 respectively. There was an interaction between the influencing factors. CONCLUSIONS: China's total HQMR is growing rapidly but is relatively inadequate. The distribution of HQMR by population is better than by geography, and the distribution by geography is less equitable. Population size and geographical area both need to be taken into account when formulating policies, rather than simply increasing the number of HQMR.

Pharmacological Studies on the Ca2+ Influx Pathways in Platelet-Activating Factor (PAF)-Induced Mouse Urinary Bladder Smooth Muscle Contraction.

Platelet-activating factor (PAF) not only acts as a mediator of platelet aggregation, inflammation, and allergy responses but also as a constrictor of various smooth muscle (SM) tissues, including gastrointestinal, tracheal/bronchial, and pregnancy uterine SMs. Previously, we reported that PAF induces basal tension increase (BTI) and oscillatory contraction (OC) in mouse urinary bladder SM (UBSM). In this study, we examined the Ca2+ influx pathways involved in PAF-induced BTI and OC in the mouse UBSM. PAF (10-6 M) induced BTI and OC in mouse UBSM. However, the PAF-induced BTI and OC were completely suppressed by extracellular Ca2+ removal. PAF-induced BTI and OC frequencies were markedly suppressed by voltage-dependent Ca2+ channel (VDCC) inhibitors (verapamil (10-5 M), diltiazem (10-5 M), and nifedipine (10-7 M)). However, these VDCC inhibitors had a minor effect on the PAF-induced OC amplitude. The PAF-induced OC amplitude in the presence of verapamil (10-5 M) was strongly suppressed by SKF-96365 (3 × 10-5 M), an inhibitor of receptor-operated Ca2+ channel (ROCC) and store-operated Ca2+ channel (SOCC), but not by LOE-908 (3 × 10-5 M) (an inhibitor of ROCC). Overall, PAF-induced BTI and OC in mouse UBSM depend on Ca2+ influx and the main Ca2+ influx pathways in PAF-induced BTI and OC may be VDCC and SOCC. Of note, VDCC may be involved in PAF-induced BTI and OC frequency, and SOCC might be involved in PAF-induced OC amplitude.

Development and internal validation of a non-invasive clinical tool to predict sufficient omega-3 levels in early pregnancy.

BACKGROUND: Complications from preterm birth (PTB) are the leading cause of death and disability in those under five years. Whilst the role of omega-3 (n-3) supplementation in reducing PTB is well-established, growing evidence suggests supplementation use in those replete may increase the risk of early PTB. AIM: To develop a non-invasive tool to identify individuals with total n-3 serum levels above 4.3% of total fatty acids in early pregnancy. METHODS: We conducted a prospective observational study recruiting 331 participants from three clinical sites in Newcastle, Australia. Eligible participants (n = 307) had a singleton pregnancy between 8 and 20 weeks' gestation at recruitment. Data on factors associated with n-3 serum levels were collected using an electronic questionnaire; these included estimated intake of n-3 (including food type, portion size, frequency of consumption), n-3 supplementation, and sociodemographic factors. The optimal cut-point of estimated n-3 intake that predicted mothers with total serum n-3 levels likely above 4.3% was developed using multivariate logistic regression, adjusting for maternal age, body mass index, socioeconomic status, and n-3 supplementation use. Total serum n-3 levels above 4.3% was selected as previous research has demonstrated that mothers with these levels are at increased risk of early PTB if they take additional n-3 supplementation during pregnancy. Models were evaluated using various performance metrics including sensitivity, specificity, area under receiver operator characteristic (AUROC) curve, true positive rate (TPR) at 10% false positive rate (FPR), Youden Index, Closest to (0,1) Criteria, Concordance Probability, and Index of Union. Internal validation was performed using 1000-bootstraps to generate 95% confidence intervals for performance metrics generated. RESULTS: Of 307 eligible participants included for analysis, 58.6% had total n-3 serum levels above 4.3%. The optimal model had a moderate discriminative ability (AUROC 0.744, 95% CI 0.742-0.746) with 84.7% sensitivity, 54.7% specificity and 37.6% TPR at 10% FPR. CONCLUSIONS: Our non-invasive tool was a moderate predictor of pregnant women with total serum n-3 levels above 4.3%; however, its performance is not yet adequate for clinical use. TRIAL REGISTRATION: This trial was approved by the Hunter New England Human Research Ethics Committee of the Hunter New England Local Health District (Reference 2020/ETH00498 on 07/05/2020 and 2020/ETH02881 on 08/12/2020).

Circular RNAs: Promising Treatment Targets and Biomarkers of Ischemic Stroke.

Ischemic stroke is one of the most significant causes of morbidity and mortality worldwide. However, there is a dearth of effective drugs and treatment methods for ischemic stroke. Significant numbers of circular RNAs (circRNAs) exhibit abnormal expression following ischemic stroke and are considered potential therapeutic targets. CircRNAs have emerged as promising biomarkers due to their stable expression in peripheral blood and their potential significance in ischemic stroke diagnosis and prognosis. This review provides a summary of 31 circRNAs involved in the pathophysiological processes of apoptosis, autophagy, inflammation, oxidative stress, and angiogenesis following ischemic stroke. Furthermore, we discuss the mechanisms of action of said circRNAs and their potential clinical applications. Ultimately, circRNAs exhibit promise as both therapeutic targets and biomarkers for ischemic stroke.

Marine bacterial exopolysaccharide EPS11 inhibits migration and invasion of liver cancer cells by directly targeting collagen I.

Many natural polysaccharides have significant anticancer activity with low toxicity, but the complex chemical structures make in-depth studies of the involved mechanisms extremely difficult. The purpose of this study was to investigate the effect of the marine bacterial exopolysaccharide (exopolysaccharide 11 [EPS11]) on liver cancer metastasis to explore the underlying target protein and molecular mechanism. We found that EPS11 significantly suppressed cell adhesion, migration, and invasion in liver cancer cells. Proteomic analysis showed that EPS11 induced downregulation of proteins related to the extracellular matrix-receptor interaction signaling pathway. In addition, the direct pharmacological target of EPS11 was identified as collagen I using cellular thermal shift assays. Surface plasmon resonance and pull-down assays further confirmed the specific binding of EPS11 to collagen I. Moreover, EPS11 was shown to inhibit tumor metastasis by directly modulating collagen I activity via the ß1-integrin-mediated signaling pathway. Collectively, our study demonstrated for the first time that collagen I could be a direct pharmacological target of polysaccharide drugs. Moreover, directly targeting collagen I may be a promising strategy for finding novel carbohydrate-based drugs.

CUX1 promotes epithelial-mesenchymal transition (EMT) in renal fibrosis of UUO model by targeting MMP7.

Epithelial-to-mesenchymal transition (EMT) displays a critical role in the development of renal fibrosis, an important pathological process of chronic kidney disease (CKD). Transcription factor Cut-like homeobox 1 (CUX1) has shown profound effects on several kidney diseases. However, its role in CKD has not been understood yet. In this study, unilateral ureteric obstruction (UUO) surgery was performed on male C57BL/6 mice to simulate CKD in vivo. Renal fibrosis was further induced in human proximal tubular epithelial cell (HK-2) by TGF-ß1 stimulation. CUX1 and MMP7 were found to be over-expressed in renal tissue of UUO mice. Renal functional analyses and histological assessment indicated that CUX1 knockdown alleviated renal injury in UUO mice. Mitochondrial dysfunction was determined in UUO group and improved after CUX1 silencing. Besides, CUX1 knockdown suppressed EMT in UUO mice and TGF-ß1 treated HK-2 cells, as evidenced by reduced expressions of α-SMA, vimentin, fibronectin and augmented abundance of E-cadherin. Furthermore, CUX1 knockdown decreased MMP7 expression by targeting at its promoter region. MMP7 was responsible for the inhibitory effect of CUX1 knockdown on EMT in HK-2 cells. In summary, our findings suggest that CUX1 promotes EMT in CKD by targeting MMP7, and highlight the crucial role of CUX1 in CKD pathogenesis.

Large dynamic strain range slope-assisted Brillouin optical time domain reflectometry based on a graded-index multi-mode fiber.

A slope-assisted Brillouin optical time domain reflectometry system with large dynamic strain range was proposed and demonstrated using graded-index multi-mode fiber (GI-MMF) as sensing fiber. Analysis of the simulated and experimental results indicated that the Brillouin gain spectrum in GI-MMF could be broadened by controlling the coupling efficiency of optical and acoustic modes. The coupling efficiency could be controlled by adjusting lateral offset between single mode fiber (SMF) and GI-MMF. The system realized the maximum strain dynamic measurement of 3000 µÉ› with the spatial resolution of 5 m along ∼1 km GI-MMF, and exhibited significant linear relationship between signal intensity and strain at vibrational frequency of 7.83 and 15.47 Hz. The measured error of vibration frequency was less than 0.2 and 1.5 Hz, respectively. The measured strain range of this system was more than three times that of traditional systems based on SMF and could be achieved at relatively low cost.