Design principles for metamorphic block copolymer assemblies

Certain block copolymer assemblies in selective solvents undergo dynamic morphology transitions (metamorphism) on varying the solution temperature. Despite the great application potential, there is a lack of fundamental understanding of the relationship between copolymer composition and the thermally-induced metamorphic behavior. Herein this relationship is studied by applying Scheutjens-Fleer Self-Consistent Field (SF-SCF) theory to develop fundamental design principles for thermoresponsive diblock copolymers exhibiting metamorphic behavior. It is found that metamorphism is caused by variation in the degree of stretching of the lyophobic blocks in response to changes in solvency. An optimal lyophobic/lyophilic block length ratio interval 3.5 ≲ fB ≲ 5.5 is identified. Such a fB window allows switching between spheres, cylinders and vesicles as preferred morphologies, with relatively small changes in the lyophobic block solvency. The transition from spheres to cylinders and from cylinders to bilayers can be controlled by varying fB, the overall degree of polymerization of the diblock copolymer, and by choosing an appropriate lyophilic block. Empirical relationships are provided to establish a connection between the SCF–SCF predictions and experimental observations

Lactoferrin's anti-cancer properties. Safety, selectivity, and wide range of action

Despite recent advances in cancer therapy, current treatments, including radiotherapy, chemotherapy, and immunotherapy, although beneficial, present attendant side effects and long-term sequelae, usually more or less affecting quality of life of the patients. Indeed, except for most of the immunotherapeutic agents, the complete lack of selectivity between normal and cancer cells for radio- and chemotherapy can make them potential antagonists of the host anti-cancer self-defense over time. Recently, the use of nutraceuticals as natural compounds corroborating anti-cancer standard therapy is emerging as a promising tool for their relative abundance, bioavailability, safety, low-cost effectiveness, and immuno-compatibility with the host. In this review, we outlined the anti-cancer properties of Lactoferrin (Lf), an iron-binding glycoprotein of the innate immune defense. Lf shows high bioavailability after oral administration, high selectivity toward cancer cells, and a wide range of molecular targets controlling tumor proliferation, survival, migration, invasion, and metastasization. Of note, Lf is able to promote or inhibit cell proliferation and migration depending on whether it acts upon normal or cancerous cells, respectively. Importantly, Lf administration is highly tolerated and does not present significant adverse effects. Moreover, Lf can prevent development or inhibit cancer growth by boosting adaptive immune response. Finally, Lf was recently found to be an ideal carrier for chemotherapeutics, even for the treatment of brain tumors due to its ability to cross the blood-brain barrier, thus globally appearing as a promising tool for cancer prevention and treatment, especially in combination therapies

IR wall heat transfer in swirling impinging jets

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Sensing the turbulent large-scale motions with their wall signature

This study assesses the capability of extended proper orthogonal decomposition (EPOD) and convolutional neural networks (CNNs) to reconstruct large-scale and very-large-scale motions (LSMs and VLSMs respectively) employing wall-shear-stress measurements in wall-bounded turbulent flows. Both techniques are used to reconstruct the instantaneous LSM evolution in the flow field as a combination of proper orthogonal decomposition (POD) modes, employing a limited set of instantaneous wall-shear-stress measurements. Due to the dominance of nonlinear effects, only CNNs provide satisfying results. Being able to account for nonlinearities in the flow, CNNs are shown to perform significantly better than EPOD in terms of both instantaneous flow-field estimation and turbulent-statistics reconstruction. CNNs are able to provide a more effective reconstruction performance employing more POD modes at larger distances from the wall and employing lower wall-measurement resolutions. Furthermore, the capability of tackling nonlinear features of CNNs results in estimation capabilities that are weakly dependent on the distance from the wall.This work has been partially supported by Grant No. DPI2016-79401-R funded by the Spanish State Research Agency (SRA) and the European Regional Development Fund (ERDF). A.G. acknowledges Dr. A. Sánchez for insightful discussions about CNN architecture. The authors acknowledge Dr. R. Vinuesa for insightful comments and discussions

Epid-based in\ua0vivo dose verification for lung stereotactic treatments delivered with multiple breath-hold segmented volumetric modulated arc therapy

We evaluated an EPID-based in-vivo dosimetry (IVD) method for the dose verification and the treatment reproducibility of lung SBRT-VMAT treatments in clinical routine. Ten patients with lung metastases treated with Elekta VMAT technique were enrolled. All patients were irradiated in five consecutive fractions, with total doses of 50 Gy. Set-up was carried out with the Elekta stereotactic body frame. Eight patients were simulated and treated using the Active Breath Control (ABC) system, a spirometer enabling patients to maintain a breath-hold at a predetermined lung volume. Two patients were simulated and treated in free-breathing using an abdominal compressor. IVD was performed using the SOFTDISO software. IVD tests were evaluated by means of (a) ratio R between daily in-vivo isocenter dose and planned dose and (b) gamma-analysis between EPID integral portal images in terms of percentage of points with gamma-value smaller than one (gamma(%)) and mean gamma-values (gamma(mean)) using a 3%(global)/3 mm criteria. Alert criteria of +/- 5% for R ratio, gamma(%) < 90%, and gamma(mean) > 0.67 were chosen. 50 transit EPID images were acquired. For the patients treated with ABC spirometer, the results reported a high level of accuracy in dose delivery with 100% of tests within +/- 5%. The gamma-analysis showed a mean value of gamma(mean) equal to 0.21 (range: 0.04-0.56) and a mean gamma(%) equal to 96.9 (range: 78-100). Relevant discrepancies were observed only for the two patients treated without ABC, mainly due to a blurring dose effect due to residual respiratory motion. Our method provided a fast and accurate procedure in clinical routine for verifying delivered dose as well as for detecting errors

Lactoferrin in the prevention and treatment of intestinal inflammatory pathologies associated with colorectal cancer development

The connection between inflammation and cancer is well-established and supported by genetic, pharmacological and epidemiological data. The inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, have been described as important promoters for colorectal cancer development. Risk factors include environmental and food-borne mutagens, dysbalance of intestinal microbiome composition and chronic intestinal inflammation, with loss of intestinal epithelial barrier and enhanced cell proliferation rate. Therapies aimed at shutting down mucosal inflammatory response represent the foundation for IBDs treatment. However, when applied for long periods, they can alter the immune system and promote microbiome dysbiosis and carcinogenesis. Therefore, it is imperative to find new safe substances acting as both potent anti-inflammatory and anti-pathogen agents. Lactoferrin (Lf), an iron-binding glycoprotein essential in innate immunity, is generally recognized as safe and used as food supplement due to its multifunctionality. Lf possesses a wide range of immunomodulatory and anti-inflammatory properties against different aseptic and septic inflammatory pathologies, including IBDs. Moreover, Lf exerts anti-adhesive, anti-invasive and anti-survival activities against several microbial pathogens that colonize intestinal mucosa of IBDs patients. This review focuses on those activities of Lf potentially useful for the prevention/treatment of intestinal inflammatory pathologies associated with colorectal cancer development

In-situ liquid phase imaging of block copolymer vesicle assembly

Amphiphilic block copolymers in aqueous solution can assemble into various ordered molecular architectures, which have a wide range of applications in, for example, drug delivery and catalytic nanoreactors.1 While sustained efforts, both experimentally and theoretically, have been made to better understand the mechanism of self- assembly in order to gain more control over this process,2, 3 there has never been a real-time, real space investigation of the assembly process on the nanoscale. Here we show the first observation of block copolymer vesicle assembly via the solvent switch protocol4 using liquid phase transmission electron microscopy (LP-TEM). We also discuss the different mechanisms of self-assembly with the ex-situ cryo-TEM observation and compare them with self-consistent field (SCF) lattice calculations. Our findings illustrate the ability of LP-TEM to implement quantitative visualization of local formation process of the block copolymer vesicles to reveal the formation mechanism on an individual particle level Please click Additional Files below to see the full abstract

Lactoferrin Binding to SARS-CoV-2 Spike Glycoprotein Blocks Pseudoviral Entry and Relieves Iron Protein Dysregulation in Several In Vitro Models

SARS-CoV-2 causes COVID-19, a predominantly pulmonary disease characterized by a burst of pro-inflammatory cytokines and an increase in free iron. The viral glycoprotein Spike mediates fusion to the host cell membrane, but its role as a virulence factor is largely unknown. Recently, the antiviral activity of lactoferrin against SARS-CoV-2 was demonstrated in vitro and shown to occur via binding to cell surface receptors, and its putative interaction with Spike was suggested by in silico analyses. We investigated the anti-SARS-CoV-2 activity of bovine and human lactoferrins in epithelial and macrophagic cells using a Spike-decorated pseudovirus. Lactoferrin inhibited pseudoviral fusion and counteracted the deleterious effects of Spike on iron and inflammatory homeostasis by restoring basal levels of iron-handling proteins and of proinflammatory cytokines IL-1β and IL-6. Using pull-down assays, we experimentally proved for the first time that lactoferrin binds to Spike, immediately suggesting a mechanism for the observed effects. The contribution of transferrin receptor 1 to Spike-mediated cell fusion was also experimentally demonstrated. In silico analyses showed that lactoferrin interacts with transferrin receptor 1, suggesting a multifaceted mechanism of action for lactoferrin. Our results give hope for the use of bovine lactoferrin, already available as a nutraceutical, as an adjuvant to standard therapies in COVID-19