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Retinoblastoma, the most common pediatric intraocular malignancy, can develop during embryogenesis, with most children being diagnosed at 3-4 years of age. Multimodal therapies are typically associated with high levels of cytotoxicity and side effects. Therefore, the development of novel treatments with minimal side effects is crucial. Magnolol has a significant anti-tumor effect on various cancers. However, its antitumor effect on retinoblastoma remains unclear.The study aimed to determine the effects of magnolol on the regulation of EMT, migration, invasion, and cancer progression in retinoblastoma and the modulation of miR-200c-3p expression and the Wnt/ zinc finger E-box binding homeobox 1 (ZEB1)/E-cadherin axis in vivo and in vitro.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay was used to evaluate magnolol-induced cell toxicity in the Y79 retinoblastoma cell line. Flow cytometry and immunostaining assays were performed to investigate the magnolol-regulated mitochondrial membrane potential and the intracellular and mitochondrial reactive oxygen species levels in Y79 retinoblastoma cells. Orthotopic and subcutaneous xenograft experiments were performed in eight-week-old male null mice to study retinoblastoma progression and metastasis. In situ hybridization and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays were performed to evaluate the level of the anti-cancer miRNA miR-200c-3p. The mRNA and protein levels of E-cadherin, β-catenin, α-smooth muscle actin (α-SMA), fibronectin-1, and ZEB1 were analyzed using RT-qPCR, immunoblot, immunocytochemistry, and immunohistochemistry assays in vitro and in vivo.Magnolol increased E-cadherin levels and reduced the activation of the EMT signaling pathway, EMT, tumor growth, metastasis, and cancer progression in the Y79 retinoblastoma cell line as well as in the orthotopic and subcutaneous xenograft animal models. Furthermore, magnolol increased the expression of miR-200c-3p. Our results demonstrate that miRNA-200c-3p inhibits EMT progression through the Wnt16/β-catenin/ZEB1/E-cadherin axis, and the ZEB1 silencing response shows that miR-200c-3p regulates ZEB1-mediated EMT in retinoblastoma.Magnolol has an antitumor effect by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma. The anti-tumor effect of magnolol by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma has been elucidated for the first time.

The accumulation of unknown polymorphic composites in the endocardium damages the endocardial endothelium (EE). However, the composition and role of unknown polymorphic composites in heart failure (HF) progression remain unclear. Here, we aimed to explore composite deposition during endocardium damage and HF progression. Adult male Sprague–Dawley rats were divided into two HF groups—angiotensin II-induced HF and left anterior descending artery ligation-induced HF. Heart tissues from patients who had undergone coronary artery bypass graft surgery (non-HF) and those with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) were collected. EE damage, polymorphic unknown composite accumulation, and elements in deposits were examined. HF progression reduced the expression of CD31 in the endocardium, impaired endocardial integrity, and exposed the myofibrils and mitochondria. The damaged endocardial surface showed the accumulation of unknown polymorphic composites. In the animal HF model, especially HF caused by myocardial infarction, the weight and atomic percentages of O, Na, and N in the deposited composites were significantly higher than those of the other groups. The deposited composites in the human HF heart section (DCM) had a significantly higher percentage of Na and S than the other groups, whereas the percentage of C and Na in the DCM and ICM groups was significantly higher than those of the control group. HF causes widespread EE dysfunction, and EndMT was accompanied by polymorphic composites of different shapes and elemental compositions, which further damage and deteriorate heart function.

The aim of this study was to gain insight into the knowledge of, attitude toward, and practical experience with listeriosis among medical staff. In two hospitals in Fangshan, Beijing, 410 medical staff members were randomly selected using a random sampling method. Each selected staff member was invited to participate in a standardized questionnaire interview. In total, 397 valid questionnaires were collected. With regard to the staff members' general knowledge of listeriosis, they answered 65.96% of the items correctly. The knowledge scores among obstetricians and gynecologists were higher than those of other clinical doctors (

Motivated by the asymptotic estimates and Hasse principle for multidimensional Waring's problem via the circle method, we prove for the first time that the corresponding singular series is bounded below by an absolute positive constant without any nonsingular local solubility assumption. The number of variables we need is near-optimal. By proving a more general uniform density result over certain complete discrete valuation rings with finite residue fields, we also establish uniform lower bounds for both singular series and singular integral in F q [ t ] . We thus obtain asymptotic formulas and the Hasse principle for multidimensional Waring's problem in F q [ t ] via a variant of the circle method.

Background and purpose Mitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins), which inhibit ROS synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear. Experimental approach Rats were treated with angiotensin II (1.5 mg·kg-1 ·day-1 ) or co-administered simvastatin (oral, 10 mg·kg-1 ) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated, and intracellular ROS and mitochondrial membrane potential (ΔΨm ) changes were measured by flow cytometry and JC-1 staining, respectively. Autophagy and mitophagy-related and mitochondria-regulated apoptotic proteins were identified by immunohistochemistry and western blotting. Key results Simvastatin significantly reduced ROS production and attenuated the disruption of ΔΨm . Simvastatin induced the accumulation of lipid droplets to provide energy for maintaining mitochondrial function, promoted autophagy and mitophagy, and inhibited mitochondria-mediated apoptosis. These findings suggest that mitochondrial protection mediated by simvastatin plays a therapeutic role in heart failure prevention by modulating antioxidant status and promoting energy supplies for autophagy and mitophagy to inhibit mitochondrial damage and cardiomyocyte apoptosis. Conclusion and implications Mitochondria play a key role in mediating heart failure progression. Simvastatin attenuated heart failure, induced by angiotensin II, via mitochondrial protection and might provide a new therapy to prevent heart failure.

IGZO-based Schottky diodes have applications in high-speed electronics. However, these devices generally require noble metals to form a Schottky contact, which was one of the problems for their early commercialization. This study demonstrates the successful use of a semi-transparent carbon paste (CP) that is low-cost and which has a high work function as the Schottky contact for a Schottky junction for a-IGZO. After sintering, the crystalline quality of CP is improved so the series resistance of IGZO-based Schottky diodes decreases. Increasing the sintering temperature of the CP produces an increase in the work function of 0.24 eV, which gives a higher Schottky barrier height and better rectified performance. Using CP as the Schottky contact allows the manufacture of low-cost high performance IGZO-based Schottky diodes.

Recent data suggest that patients with a basal/stem-like bladder cancer (BC) subtype tend to have metastatic disease, but this is unconfirmed. Here we report the identification of murine MB49 cell line sub-clones with stem-like characteristics in culture. Subcutaneous implantation of S2 and S4 MB49 sub-clones into immunocompetent mice resulted in lung metastases in 50% and 80% of mice respectively, whereas none of the mice implanted with the parental cells developed metastasis. Gene profiling of cells cultured from S2 and S4 primary and metastatic tumors revealed that a panel of genes with basal/stem-like/EMT properties is amplified during metastatic progression. Among them, ITGB1, TWIST1 and KRT6B are consistently up-regulated in metastatic tumors of both MB49 sub-clones. To evaluate clinical relevance, we examined these genes in a human public dataset and found that ITGB1 and KRT6B expression in BC patient tumor samples are positively correlated with tumor grade. Likewise, the expression levels of these three genes are correlated with worse clinical outcomes. This MB49 BC metastatic pre-clinical model provides a unique opportunity to validate and recapitulate results discovered in patient studies and to pursue future mechanistic therapeutic interventions for BC metastasis.

We construct a shifted version of the Turán sieve method developed by R. Murty and the second author and apply it to counting problems on tournaments. More precisely, we obtain upper bounds for the number of tournaments which contain a fixed number of restricted $r$-cycles. These are the first concrete results which count the number of cycles over “all tournaments”.

Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression, however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects.

Strand displacement DNA synthesis (SDDS) is an essential step in DNA replication. With magnetic tweezers, we investigated SDDS kinetics of wild-type gp90 and its exonuclease-deficient polymerase gp90 exo- at single-molecule level. A novel binding state of gp90 to the fork flap was confirmed prior to SDDS, suggesting an intermediate in the initiation of SDDS. The rate and processivity of SDDS by gp90 exo- or wt-gp90 are increased with force and dNTP concentration. The rate and processivity of exonuclease by wt-gp90 are decreased with force. High GC content decreases SDDS and exonuclease processivity but increases exonuclease rate for wt-gp90. The high force and dNTP concentration and low GC content facilitate the successive SDDS but retard the successive exonuclease for wt-gp90. Furthermore, increasing GC content accelerates the transition from SDDS or exonuclease to exonuclease. This work reveals the kinetics of SDDS in detail and offers a broader cognition on the regulation of various factors on SDDS at single-polymerase level.

Detection and characterization of an individual cisplatin adduct on a single DNA molecule is a demanding task. We explore the characteristic features of cisplatin adducts in the nanopore sequencing signal in aspects of dwell time, genome anchored current trace, and basecalling accuracy. The offset between the motor protein and the nanopore constriction region is revealed by dwell time analysis to be about 14 bases in the nanopore device as we examined. Characteristic distortions due to cisplatin adducts are illustrated in genome anchored current trace analysis, constituting the fingerprint for identification of cisplatin adduct. The sharp increase in odds ratio at the location of adducting sites provides additional feature in the detection of the adduct. By these combined methods, single cisplatin adducts can be detected with high fidelity on a single read of the DNA sequence. The study demonstrates an effective method in the detection and characterization of single cisplatin adducts on DNA at the single-molecule level and with single nucleotide spatial resolution.

High mobility group box 1 (HMGB1) has been demonstrated to promote the migration and invasion of non-small cell lung cancer (NSCLC). However, the mechanism of action of HMGB1 in regulating tumor mobility remains unclear. Therefore, we aimed to investigate whether HMGB1 affects mitochondria distribution and regulates dynamin-related protein 1 (DRP1)-mediated lamellipodia/filopodia formation to promote NSCLC migration. The regulation of mitochondrial membrane tension, dynamics, polarization, fission process, and cytoskeletal rearrangements in lung cancer cells by HMGB1 was analyzed using confocal microscopy. The HMGB1-mediated regulation of DRP1 phosphorylation and colocalization was determined using immunostaining and co-immunoprecipitation assays. The tumorigenic potential of HMGB1 was assessed in vivo and further confirmed using NSCLC patient samples. Our results showed that HMGB1 increased the polarity and mobility of cells (mainly by regulating the cytoskeletal system actin and microtubule dynamics and distribution), promoted the formation of lamellipodia/filopodia, and enhanced the expression and phosphorylation of DRP1 in both the nucleus and cytoplasm. In addition, HMGB1 and DRP1 expressions were positively correlated and exhibited poor prognosis and survival in patients with lung cancer. Collectively, HMGB1 plays a key role in the formation of lamellipodia and filopodia by regulating cytoskeleton dynamics and DRP1 expression to promote lung cancer migration.

Thrombospondin-1 (TSP1) is involved in corneal wound healing caused by chemical injury. Herein, we examined the effects of TSP1 on hypoxia-induced damages and wound-healing activity in human corneal epithelial (HCE) cells. Exosomal protein expression was determined using liquid chromatography-tandem mass spectrometry, and HCE cell migration and motility were examined through wound-healing assay and time-lapse microscopy. Reestablishment of cell junctions by TSP1 was assessed through confocal microscopy and 3D image reconstruction. Our results show that CoCl2 -induced hypoxia promoted HCE cell death by paraptosis. TSP1 protected these cells against paraptosis by attenuating mitochondrial membrane potential depletion, swelling and dilation of endoplasmic reticulum and mitochondria, and mitochondrial fission. Exosomes isolated from HCE cells treated with TSP1 contained wound healing-associated proteins that were taken up by HCE cells to promote tissue remodeling and repair. TSP1 protected HCE cells against hypoxia-induced damages and inhibited paraptosis progression by promoting cell migration, cell-cell adhesion, and extracellular matrix remodeling. These findings indicate that TSP1 ameliorates hypoxia-induced paraptosis in HCE cells and promotes wound healing and remodeling by regulating exosomal protein expression. TSP1 may, therefore, play important roles in the treatment of hypoxia-associated corneal diseases.

Kinesin is a molecular motor that can step processively on microtubules via the hydrolysis of ATP molecules. An important factor characterizing the processivity of the kinesin motor is its dissociation from the microtubule. Here, using all-atom molecular dynamics simulations, we studied the dissociation process of the kinesin head in weak-microtubule-binding or ADP state from tubulin on the basis of the available high-resolution structural data for the head and tubulin. By analyzing the simulated snapshots of the structure of the head-tubulin complex we provided detailed structural and dynamic information for the dissociation process. We found that the dissociation of the head along different directions relative to the tubulin exhibits very different dynamic behaviors. Moreover, the potential forms or energy landscapes of the interaction between the head and tubulin along different directions were determined. The studies have important implications for the detailed molecular mechanism of the dissociation of the kinesin motor and thus are critical to the mechanism of its processivity.

Intracellular transport of cellular proteins and organelles is critical for establishing and maintaining intracellular organization and cell physiology. Apoptosis is a process of programmed cell death with dramatic changes in cell morphology and organization, during which signaling molecules are transported between different organelles within the cells. However, how the intracellular transport changes in cells undergoing apoptosis remains unknown. Here, we study the dynamics of intracellular transport by using the single-particle tracking method and find that both directed and diffusive motions of endocytic vesicles are accelerated in early apoptotic cells. With careful elimination of other factors involved in the intracellular transport, the reason for the acceleration is attributed to the elevation of adenosine triphosphate (ATP) concentration. More importantly, we show that the accelerated intracellular transport is critical for apoptosis, and apoptosis is delayed when the dynamics of intracellular transport is regulated back to the normal level. Our results demonstrate the important role of transport dynamics in apoptosis and shed light on the apoptosis mechanism from a physical perspective.

DNA polymerases are an essential class of enzymes or molecular motors that catalyze processive DNA syntheses during DNA replications. A critical issue for DNA polymerases is their molecular mechanism of processive DNA replication. We have proposed a model for chemomechanical coupling of DNA polymerases before, based on which the predicted results have been provided about the dependence of DNA replication velocity upon the external force on Klenow fragment of DNA polymerase I. Here, we performed single molecule measurements of the replication velocity of Klenow fragment under the external force by using magnetic tweezers. The single molecule data verified quantitatively the previous theoretical predictions, which is critical to the chemomechanical coupling mechanism of DNA polymerases. A prominent characteristic for the Klenow fragment is that the replication velocity is independent of the assisting force whereas the velocity increases largely with the increase of the resisting force, attains the maximum velocity at about 3.8 pN and then decreases with the further increase of the resisting force.

The elasticity of polypeptide chains is usually characterized by the worm-like chain model that was proposed first to describe the elasticity of double-stranded DNA. However, the molecular dynamics simulation data on the elasticity of the polypeptide chains are deviated significantly away from the theoretical data obtained based on the worm-like chain model. Here, we provide a revised worm-like chain model by considering entropic, enthalpic, and hydrophobic effects and the effect of the compressing force applied to the polypeptide chains. The theoretical data obtained based on the revised model are in good agreement with the molecular dynamics simulation data. Additionally, we reveal that, besides the positive-force regime in the elasticity of polypeptide chains, the negative-force regime also plays important roles in the biological functions of proteins. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2017

Damage to the blood-brain barrier (BBB) resulting from systemic inflammation caused by surgical trauma is associated with cognitive dysfunction, and individuals with hyperlipidemia are more sensitive to such impairment. The present study was designed to ascertain whether dexmedetomidine (Dex) treatment could reduce the incidence of cognitive dysfunction following surgery in a hyperlipidemia model. Hyperlipidemia was induced in Sprague-Dawley rats (male, 6–7 months old) by consuming a high-fat diet, and rats were divided into three groups (n=10 each) and underwent: exploratory laparotomy to introduce surgical trauma (surgery group), laparotomy and Dex treatment (surgery+Dex group), or sham surgery (sham group). Learning, memory and exploration behavior were assessed using the Morris water maze. Concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, were determined by enzyme-linked immunosorbent assay. BBB permeability was assessed by Evans blue staining. Relative major facilitator superfamily domain-containing protein 2 (Mfsd2a) mRNA expression was determined by quantitative PCR. In the Morris water maze test, the time and distance ratio for the surgery group was significantly lower than those of the sham and surgery+Dex groups (P

Exosomes are implicated in cancer cell development, migration and invasion. Pigment epithelium-derived factor (PEDF) is a secreted anticancer protein that can regulate lung cancer progression; however, the role of PEDF in non-small cell lung cancer (NSCLC), including metastasis and cancer cell-derived exosome secretion, is unclear. In this study, we analyzed the effects of PEDF on exosome-mediated migration, invasion, and tumorigenicity of cultured NSCLC cells. The results showed that PEDF overexpression significantly reduced NSCLC invasion and migration, while inducing cell aggregation, whereas PEDF knockdown had the opposite effects. Exosomes from NSCLC cells treated with recombinant PEDF had a significantly reduced ability to promote cancer cell motility, migration, and invasion compared to exosomes from untreated cells. Exosomes from PEDF-treated cells contained thrombospondin 1 (THBS1), which inhibited cytoskeletal remodeling and exosome-induced lung cancer cell motility, migration, and invasion. Furthermore, PEDF-overexpressing NSCLC cells formed smaller xenograft tumors with higher THBS1 expression compared to control tumors. Our findings indicate that PEDF decreases the metastatic potential of NSCLC cells through regulation of THBS1 release in cancer cell-derived exosomes, thus uncovering a new mechanism of lung cancer progression.

In this paper, we apply the Turan sieve and the simple sieve developed by R. Murty and the first author to study problems in random graph theory. In particular, we obtain upper and lower bounds on the probability of a graph on n vertices having diameter 2 (or diameter 3 in the case of bipartite graphs) with edge probability p(n) where the edges are chosen independently . An interesting feature revealed in these results is that the Turan sieve and the simple sieve `almost completely' complement each other. As a corollary to our result, we note that the probability of a random graph having diameter 2 approaches 1 as n approaches infinity for constant edge probability p(n)=1/2. This is an appendix of a shorter version of this paper.

// Christopher R. Silvers 1 , Yu-Ru Liu 1 , Chia-Hao Wu 1 , Hiroshi Miyamoto 2 , Edward M. Messing 1 , Yi-Fen Lee 1 1 Department of Urology, University of Rochester Medical Center, Rochester, NY, USA 2 Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence to: Yi-Fen Lee, e-mail: yifen_lee@urmc.rochester.edu Keywords: periostin, extracellular vesicle, exosome, muscle-invasive bladder cancer and biomarker Received: August 24, 2015 Accepted: February 25, 2016 Published: March 10, 2016 ABSTRACT Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high mortality, and heterogeneity in MIBC results in variable clinical outcomes, posing challenges for clinical management. Extracellular vesicles (EVs) derived from MIBC have been shown to promote cancer progression. EVs derived from bladder cell lines were subjected to proteomic analysis, and periostin was chosen for further characterization due to its stage-specific gene expression profile. Knockdown of periostin by RNA interference reduces invasiveness in vitro and produces a rounder morphology. Importantly, treating low grade BC cells with periostin-rich EVs promotes cell aggressiveness and activates ERK oncogenic signals, and periostin suppression reverses these effects. These data suggest that MIBC might transfer periostin in an EV-mediated paracrine manner to promote the disease. To determine the potential of periostin as a bladder cancer indicator, patient urinary EVs were examined and found to have markedly higher levels of periostin than controls. In addition, immunohistochemical staining of a bladder cancer tissue microarray revealed that the presence of periostin in MIBC cells is correlated with worse prognosis. In conclusion, periostin is a component of bladder cancer cells associated with poor clinical outcome, and EVs can transfer oncogenic molecules such as periostin to affect the tumor environment and promote cancer progression.

Heart failure due to myocardial infarction (MI) is a major cause of morbidity and mortality in the world. We found previously that A83-01, a TGFβRI inhibitor, could facilitate cardiac repair in post-MI mice and induce the expansion of a Nkx2.5 + cardiomyoblast population. This study aimed to investigate the key autocrine/paracrine factors regulated by A83-01 in the injured heart and the mechanism of cardioprotection by this molecule. Using a previously described transgenic Nkx2.5 enhancer-green fluorescent protein (GFP) reporter mice, we isolated cardiac progenitor cells (CPC) including Nkx2.5-GFP + (Nkx2.5+), sca1+, and Nkx2.5+/sca1 + cells. A83-01 was found to induce proliferation of these three subpopulations mainly through increasing Birc5 expression in the MEK/ERK-dependent pathway. Survivin, encoded by Birc5, could also directly proliferate Nkx2.5 + cells and enhance cultured cardiomyocytes viability. A83-01 could also reverse the downregulation of Birc5 in postinjured mice hearts (n = 6) to expand CPCs. Moreover, the increased Wnt3a in postinjured hearts could decrease CPCs, which could be reversed by A83-01 via inhibiting Fzd6 and Wnt1-induced signaling protein 1 expressions in CPCs. Next, we used inducible αMHC-cre/mTmG mice to label cardiomyocytes with GFP and nonmyocytes with RFP. We found A83-01 preserved more GFP + myocytes (68.6% ± 3.1% vs. 80.9% ± 3.0%; p

Let 𝔽q[t] denote the polynomial ring over the finite field 𝔽q. We employ Wooley's new efficient congruencing method to prove certain multidimensional Vinogradov-type estimates in 𝔽q[t]. These results allow us to apply a variant of the circle method to obtain asymptotic formulas for a system connected to the problem about linear spaces lying on hypersurfaces defined over 𝔽q[t].

Exosome-mediated communication within the cardiac microenvironment is associated with cardiac fibrosis. Simvastatin (SIM), a potent statin, protects against cardiac fibrosis, but its mechanism of action is unclear. We investigated the inhibitory effects and underlying mechanism of simvastatin in cardiac fibrosis, by regulating exosome-mediated communication. Male Sprague-Dawley rats were treated with angiotensin (Ang) II alone, or with SIM for 28 d. Cardiac fibrosis, expressions of fibrosis-associated proteins and mRNAs, and collagen fiber arrangement and deposition were examined. Protein expressions in exosomes isolated from Ang II-treated cardiomyocytes (CMs) were evaluated using nano-ultra-performance liquid chromatographic system, combined with tandem mass spectrometry. Transformation of fibroblasts to myofibroblasts was evaluated using scanning electron and confocal microscopy, and migration assays. Our results showed that SIM attenuated in vivo expression of collagen and collagen-associated protein, as well as collagen deposition, and cardiac fibrosis. The statin also upregulated decorin and downregulated periostin in CM-derived exosomes. Furthermore, it suppressed Ang II-induced transformation of fibroblast to myofibroblast, as well as fibroblast migration. Exosome-mediated cell-cell communication within the cardiac tissue critically regulated cardiac fibrosis. Specifically, SIM regulated the release of CM exosomes, and attenuated Ang II-induced cardiac fibrosis, highlighting its potential as a novel therapy for cardiac fibrosis.

An aluminum foil with a rough surface was first prepared by anodic treatment in a neutral aqueous solution with the help of pitting corrosion of chlorides. First, the hydrophobic Al surface (contact angle around 79°) became superhydrophilic (contact angle smaller than 5°) after the anodizing process. Secondly, the superhydrophilic Al surface became superhydrophobic (contact angle larger than 150°) after being modified by oleic acid. Finally, the icing property of superhydrophilic, untreated, and superhydrophobic Al foils were investigated in a refrigerated cabinet at −12 °C. The mean total times to freeze a water droplet (6 μL) on the three foils were 17 s, 158 s and 1604 s, respectively. Thus, the superhydrophilic surface accelerates the icing process, while the superhydrophobic surface delays the process. The main reason for this transition might mainly result from the difference of the contact area of the water droplet with Al substrate: the increase in contact area with Al substrate will accelerate the heat conduct process, as well as the icing process; the decrease in contact area with Al substrate will delay the heat conduct process, as well as the icing process. Compared to the untreated Al foil, the contact area of the water droplet with the Al substrate was higher on superhydrophilic surface and smaller on the superhydrophobic surface, which led to the difference of the heat transfer time as well as the icing time.

Tumor-derived extracellular vesicles (TEVs) are membrane-bound, nanosized vesicles released by cancer cells and taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. In this report, we summarize the pivotal roles of TEVs involved in bladder cancer (BC) development, progression and treatment resistance through transferring their bioactive cargos, including proteins and nucleic acids. We also report on the molecular profiling of TEV cargos derived from urine and blood of BC patients as non-invasive disease biomarkers. The current hurdles in EV research and plausible solutions are discussed.

Formation of the organizer is one of the most central patterning events in vertebrate development. Organizer-derived signals are responsible for establishing the CNS and patterning the dorsal ventral axis. The mechanisms promoting organizer formation are known to involve cooperation between Nodal and Wnt signalling. However, the organizer forms in a very restricted region, suggesting the presence of mechanisms that repress its formation. Here, we show in zebrafish that the transcription factor Sox3 represses multiple steps in the signalling events that lead to organizer formation. Although β-catenin, Bozozok and Squint are known to play major roles in establishing the dorsal organizer in vertebrate embryos, overexpression of any of these is insufficient to induce robust expression of markers of the organizer in ectopic positions in the animal pole, where Sox3 is strongly expressed. We show that a dominant-negative nuclear localisation mutant of Sox3 can cause ectopic expression of organizer genes via a mechanism that activates all of these earlier factors, resulting in later axis duplication including major bifurcations of the CNS. We also find that the related SoxB1 factor, Sox19b, can act redundantly with Sox3 in these effects. It therefore seems that the broad expression of these SoxB1 genes throughout the early epiblast and their subsequent restriction to the ectoderm is a primary regulator of when and where the organizer forms.

Let Fq(t) denote the ring of polynomials over the nite eld Fq of characteristic p, and write J k (t) for the additive closure of the set of kth powers of polynomials in Fq(t). Dene Gq(k) to be the least integer s satisfying the property that every polynomial in J k (t) of suciently large degree admits a strict representation as a sum of s kth powers. We employ a version of the Hardy-Littlewood method involving the use of smooth polynomials in order to establish a bound of the shape Gq(k) Ck logk + O(k log logk). Here, the coecient C is equal to 1 when k p, but in any case satises C 4=3. There are associated conclusions for the solubility of diagonal equations over Fq(t), and for exceptional set estimates in Waring's problem. Z to Fq(t), therefore, is the derivation of results uniform in the characteristic. In this paper we investigate the analogue of Waring's problem over Fq(t), our aim being to establish conclusions that are relatively robust to changes in the characteristic of Fq. We concentrate, in particular, on methods having the potential to impact questions that concern the density of rational points on algebraic varieties in function elds, a topic to which we intend to return on a future occasion. Some preparation is required before we can announce our principal conclusions. Let k be an integer with k 2, let s2 N, and consider a polynomial m in Fq(t). We seek to

Let Fq[t] denote the polynomial ring over the finite field Fq, and let SN denote the subset of Fq[t] containing all polynomials of degree strictly less than N . For a matrix Y = ` ai,j ∈ FR×S q satisfying ai,1 + · · ·+ai,S = 0 (1 ≤ i ≤ R), let DY (SN ) denote the maximal cardinality of a set A ⊆ SN for which the equations ai,1x1 + · · ·+ai,SxS = 0 (1 ≤ i ≤ R) are never satisfied simultaneously by distinct elements x1, . . . , xS ∈ A. Under certain assumptions on Y , we prove an upper bound of the form DY (SN ) ≤ q (C/N) for positive constants C and γ.

Let 𝔽q[t] denote the polynomial ring over the finite field 𝔽q, and let [Formula: see text] denote the subset of 𝔽q[t] containing all polynomials of degree strictly less than N. For non-zero elements r1, …, rs of 𝔽q satisfying r1 + ⋯ + rs = 0, let [Formula: see text] denote the maximal cardinality of a set [Formula: see text] which contains no non-trivial solution of r1x1 + ⋯ + rsxs = 0 with xi ∈ A (1 ≤ i ≤ s). We prove that [Formula: see text].

Let A = 𝔽q[T] be the polynomial ring over the finite field 𝔽q, k = 𝔽q(T) the rational function field, and K a finite extension of k. Let ϕ be a Drinfeld A-module over K of rank r. For a place 𝔓 of K of good reduction, write [Formula: see text], where [Formula: see text] is the valuation ring of 𝔓 and [Formula: see text] its maximal ideal. Let P𝔓, ϕ(X) be the characteristic polynomial of the Frobenius automorphism of 𝔽𝔓acting on a Tate module of ϕ. Let χϕ(𝔓) = P𝔓, ϕ(1), and let ν(χϕ(𝔓)) be the number of distinct primes dividing χϕ(𝔓). If ϕ is of rank 2 with [Formula: see text], we prove that there exists a normal distribution for the quantity [Formula: see text] For r ≥ 3, we show that the same result holds under the open image conjecture for Drinfeld modules. We also study the number of distinct prime divisors of the trace of the Frobenius automorphism of 𝔽𝔓acting on a Tate module of ϕ and obtain similar results.

Let A = Fq[T] be the polynomial ring over the finite field Fq, let k = Fq(T) be the rational function field, and let K be a finite extension of k. For a prime P of K, we denote by OP the valuation ring of P, byMP the maximal ideal of OP, and by FP the residue field OP/MP. Let �O be a Drinfeld A-module over K of rank r. If �O has good reduction at P, let �O . FP denote the reduction of �O at P and let �O(FP) denote the A-module (�O . FP)(FP). If �O is of rank 2 with End �PK (�O) = A, then we obtain an asymptotic formula for the number of primes P of K of degree x for which �O(FP) is cyclic. This result can be viewed as a Drinfeld module analogue of Serre�fs cyclicity result on elliptic curves. We also show that when �O is of rank r 3 a similar result follows.

Let A = F q [ T ] A=\mathbb {F}_q[T] be the ring of polynomials over the finite field F q \mathbb {F}_q and 0 ≠ a ∈ A 0 \neq a \in A . Let C C be the A A -Carlitz module. For a monic polynomial m ∈ A m\in A , let C ( A / m A ) C(A/mA) and a ¯ \bar {a} be the reductions of C C and a a modulo m A mA respectively. Let f a ( m ) f_a(m) be the monic generator of the ideal { f ∈ A , C f ( a ¯ ) = 0 ¯ } \{f\in A, C_f(\bar {a}) =\bar {0}\} on C ( A / m A ) C(A/mA) . We denote by ω ( f a ( m ) ) \omega (f_a(m)) the number of distinct monic irreducible factors of f a ( m ) f_a(m) . If q ≠ 2 q\neq 2 or q = 2 q=2 and a ≠ 1 , T a\neq 1, T , or ( 1 + T ) (1+T) , we prove that there exists a normal distribution for the quantity \[ ω ( f a ( m ) ) − 1 2 ( log ⁡ deg ⁡ m ) 2 1 3 ( log ⁡ deg ⁡ m ) 3 / 2 . \frac {\omega (f_a(m))-\frac {1}{2}(\log \deg m)^2}{\frac {1}{\sqrt {3}}{(\log \deg m)^{3/2}}}. \] This result is analogous to an open conjecture of Erdős and Pomerance concerning the distribution of the number of distinct prime divisors of the multiplicative order of b b modulo n n , where b b is an integer with | b | > 1 |b|>1 , and n n a positive integer.