TGF-ß Tumor Suppression through a Lethal EMT.

TGF-ß signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-ß mediator Smad4. We show that TGF-ß induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-ß-sensitive PDA cells, EMT becomes lethal by converting TGF-ß-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-ß. TGF-ß-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-ß tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

Publisher Correction: TGF-ß orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

TGF-ß orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1.

Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer1-4. EMTs are driven by SNAIL, ZEB and TWIST transcription factors5,6 together with microRNAs that balance this regulatory network7,8. Transforming growth factor ß (TGF-ß) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-ß signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer4,11. TGF-ß depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12-19. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector20,21, as a key partner of TGF-ß-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-ß-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-ß-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal-SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-ß pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.

Design methodology for catadioptric zoom panoramic optical systems based on image plane bending matched correction.

Zoom panoramic optical systems incorporate a panoramic peripheral vision zoom imaging function, enabling swift wide-area coarse and localized precise detection. These systems find applicability in examining pipes and other internal structures. This study centers on the catadioptric zoom panoramic optical system and its associated optical design method. A mathematical model of the front mirror was formulated based on the imaging relationship. Subsequently, the bending of the image plane of the front mirror was computed and simplified through curve fitting. The object surface bending of the zoom subsystem was established correspondingly, leveraging the solution for the mirror bending curve matched correction, culminating in deriving the initial structure of the zoom. Integrating the front mirror and zoom subsystems facilitated the comprehensive design realization of the catadioptric zoom panoramic optical system. A catadioptric zoom panoramic optical system was designed to validate the proposed design method. This study introduces a novel, to the best of our knowledge, conceptual approach to crafting catadioptric zoom panoramic optical systems.

Crosstalk in monocentric multiscale systems based on an internal stray light stop suppression method.

Monocentric multi-scale (MMS) systems offer the advantages of a high resolution and wide field of view (FOV). These systems can improve the image resolution with a broad FOV by utilizing the stitching of the detectors. In addition to traditional stray light in optical systems, such as ghost reflection, scattering, and diffraction, the crosstalk between relay lenses cannot be ignored as a type of special stray light. Because of the intersection rays between the multiscale relay lenses in MMS systems, the rays enter the adjacent relay lens, which generates rays that do not belong to the corresponding relay lens in the corresponding image plane. Consequently, this crosstalk stray light affects the imaging contrast of the systems. This study aimed to investigate the crosstalk stray light in MMS systems. A simulation model of the MMS system was established. In the object-imaging process, the characteristic rays of a multiscale relay lens are traced using geometrical optics. Factors affecting the crosstalk stray light were studied in detail. The relationships between different parameters and crosstalk stray light were analyzed. A stray light suppression method is proposed based on incorporating a stray light stop in a monocentric (MC) objective to cut the crosstalk stray rays. The simulation results show that the crosstalk stray light can be effectively eliminated with this method, and the image contrast of the MMS systems is greatly improved.

Panoramic annular image restoration algorithm by prediction based on the lens design characteristics.

A panoramic annular lens optical system is important in circumferential detection. However, a panoramic annular image (PAI) has severe tangential and radial distortion. This study proposes a 3σ guideline-based method, which determines the unwrapping center point of the PAI, and a prediction method based on the lens design characteristics according to the intrinsic distortion of the PAL to correct, respectively, the tangential distortion and the radial distortion. The proposed methods can ensure the restoration ability and simplify the dependence on experimental conditions. The experimental results confirm the effectiveness of the proposed method, thus enabling future panoramic optical image detection.

Analysis and design of a microlens array scanning system based on spherical aberration.

The microlens array (MLA) scanning system is a relatively new solution for beam scanning. The excrescent light generated by overlapping divergent beams from adjacent microlenses increases with the scanning angle, and as a result, the rays do not fill the clear aperture of the MLA. The effect on the detection distance and imaging resolution of the MLA system are analyzed. Based on the principle of minimum spherical aberration, a design method for initial configuration of the MLA system is proposed. The findings of this paper can be beneficial for the design and evaluation of MLA systems.

Analysis and calculation of the fill factor for microlens array scanning systems.

Microlens array (MLA) scanning systems are used in numerous applications, such as laser radar and optical communications. Excrescent light generated by overlapping divergent beams from adjacent microlenses increases with scanning angle, thereby reducing the relative aperture and affecting the MLA system resolution. The fill factor is hence proposed to characterize the relative aperture, and its effects on the modulation transfer function are analyzed. The fill factor is calculated from matrix optics paraxial ray tracing using the system parameters. The simulated results of the MLA system and theoretical calculations are in good agreement. This work can benefit the design and evaluation of MLA systems.

Astigmatism analysis and correction method introduced by an inclined plate in a convergent optical path.

A plate beam splitter can simultaneously increase the transmittances and reflectances of different split spectrum segments. The splitter has been widely used in optical systems. However, when a beam passes through a beam splitter in a convergent optical path, the image quality may be degraded severely because the tilted plate may introduce aberrations such as astigmatism at the on-axis point. The formula for calculating this astigmatism is established. The calculated results are consistent with the simulated results, and the validity of the formula is verified through experiments. A cylindrical lens curvature calculation formula is derived to correct the on-axis astigmatism, which reduces the aberrations introduced by the tilted plate and improves the imaging performance. The imaging characteristics of the off-axis field of view and the reasons for the changes in image quality are analyzed. The F-number range of the converging light path is calculated, which provides a reference for tilted applications of flat-panel optical elements in converging light paths.

Modeling and analysis of a monocentric multi-scale optical system.

A monocentric lens combined with a multi-scale form can achieve a large field of view while maintaining the resolution. This report describes an analytical model that is suitable for both Galilean- and Keplerian-type monocentric multi-scale (MMS) systems; this model also analyzes the correlation between the two types of systems. Moreover, the off-axis aberration associated with the analytical model was derived, on this basis, the Galilean- and Keplerian-type MMS systems were compared. It was concluded that the Galilean-type MMS system performs better with respect to aberration performance. This report provides a useful reference for further applications and developments of MC systems.

Design and analysis of inner focus for a large spectral bandwidth optical system.

In this paper, we present a method of solving the chromatic aberration problem of large spectral bandwidth optical systems encountered during the internal focusing process. Rational selection of the focal length of each lens group and the distance between them retained the achromatic characteristic of the optical system when the inner focus lens group was mobilized. The proposed design was experimentally validated. This paper can be useful to research on internal focusing in wide-band systems.

Design and analysis of a triple reflection grazing incidence x-ray telescope.

A triple reflection grazing incidence x-ray telescope is proposed and evaluated. This form of an optical system can detect x-ray energy that is close to the optical axis, which solves the problems encountered by traditional Wolter-type systems. In this paper, we also propose a new design method to ensure that the entire telescope structure is compact and integrated. Finally, a proof-of-concept design with an acceptable image quality is proposed.

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist.

The trillions of bacteria that make up the human microbiome are believed to encode functions that are important to human health; however, little is known about the specific effectors that commensal bacteria use to interact with the human host. Functional metagenomics provides a systematic means of surveying commensal DNA for genes that encode effector functions. Here, we examine 3,000 Mb of metagenomic DNA cloned from three phenotypically distinct patients for effectors that activate NF-κB, a transcription factor known to play a central role in mediating responses to environmental stimuli. This screen led to the identification of 26 unique commensal bacteria effector genes (Cbegs) that are predicted to encode proteins with diverse catabolic, anabolic, and ligand-binding functions and most frequently interact with either glycans or lipids. Detailed analysis of one effector gene family (Cbeg12) recovered from all three patient libraries found that it encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide). This metabolite was also found in culture broth from the commensal bacterium Bacteroides vulgatus, which harbors a gene highly similar to Cbeg12. Commendamide resembles long-chain N-acyl-amides that function as mammalian signaling molecules through activation of G-protein-coupled receptors (GPCRs), which led us to the observation that commendamide activates the GPCR G2A/GPR132. G2A has been implicated in disease models of autoimmunity and atherosclerosis. This study shows the utility of functional metagenomics for identifying potential mechanisms used by commensal bacteria for host interactions and outlines a functional metagenomics-based pipeline for the systematic identification of diverse commensal bacteria effectors that impact host cellular functions.

Design of a compact two-channel panoramic optical system.

We propose a new panossramic optical system that provides an additional field of view (FOV) channel without expanding the physical size of a conventional panoramic annular lens (PAL). The two channels are contained within one PAL, their optical paths do not interfere with each other, and the two images are realized on a single image plane. A prototype panoramic lens was developed that provides a 360° × (38-80°) front FOV channel and a 360° × (102-140°) back FOV channel.

Renal myopericytoma: A case report with a literature review.

Myopericytoma is a rare soft tissue tumor characterized by differentiation into perivascular muscle-like cells or perimuscular cells. This tumor primarily affects adults and is uncommon in children. It is predominantly found in the subcutaneous soft tissues of the distal limbs, and cases originating in the kidney are exceedingly rare. In this report, we present a case of a patient with renal myopericytoma admitted to our hospital. We also summarize the diagnostic and therapeutic features by reviewing relevant domestic and international literature.

Assessment of Protein-Protein Docking Models Using Deep Learning.

Protein-protein interactions are involved in almost all processes in a living cell and determine the biological functions of proteins. To obtain mechanistic understandings of protein-protein interactions, the tertiary structures of protein complexes have been determined by biophysical experimental methods, such as X-ray crystallography and cryogenic electron microscopy. However, as experimental methods are costly in resources, many computational methods have been developed that model protein complex structures. One of the difficulties in computational protein complex modeling (protein docking) is to select the most accurate models among many models that are usually generated by a docking method. This article reviews advances in protein docking model assessment methods, focusing on recent developments that apply deep learning to several network architectures.

The mechanical effects of chemical stimuli on neurospheres.

The formulation of more accurate models to describe tissue mechanics necessitates the availability of tools and instruments that can precisely measure the mechanical response of tissues to physical loads and other stimuli. In this regard, neuroscience has trailed other life sciences owing to the unavailability of representative live tissue models and deficiency of experimentation tools. We previously addressed both challenges by employing a novel instrument called the cantilevered-capillary force apparatus (CCFA) to elucidate the mechanical properties of mouse neurospheres under compressive forces. The neurospheres were derived from murine stem cells, and our study was the first of its kind to investigate the viscoelasticity of living neural tissues in vitro. In the current study, we demonstrate the utility of the CCFA as a broadly applicable tool to evaluate tissue mechanics by quantifying the effect that oxidative stress has on the mechanical properties of neurospheres. We treated mouse neurospheres with non-cytotoxic levels of hydrogen peroxide and subsequently evaluated the storage and loss moduli of the tissues under compression and tension. We observed that the neurospheres exhibit viscoelasticity consistent with neural tissue and show that elastic modulus decreases with increasing size of the neurosphere. Our study yields insights for establishing rheological measurements as biomarkers by laying the groundwork for measurement techniques and showing that the influence of a particular treatment may be misinterpreted if the size dependence is ignored.

An Enzyme-responsive Porphyrin Metal-organic Framework Nanosystem for Targeted and Enhanced Synergistic Cancer Photo-chemo Therapy.

BACKGROUND: The clinical efficiency of photodynamic therapy (PDT) in combination with chemotherapy has proven to be a promising strategy for tumor treatment, yet is restricted by the high glutathione (GSH) concentration at the tumor site and nonspecific drug targeting. OBJECTIVE: The goal of the current research was to create a biocompatible GSH-depleting and tumor- targeting nanoparticle (denoted as DOX/CA@PCN-224@HA) for the combined photodynamic and chemo photo-chemo) therapy. METHODS: The nanoparticles were characterized by transmission electron microscopy (TEM). A UV-vis spectrophotometer was used to measure the drug loading efficiency (DE) and encapsulation efficiency (EE). The GSH-depleting ability was measured using Ellman's test. Confocal laser scan microscopy (CLSM) was used to assess the cellular uptake. MTT was adopted to evaluate the cytotoxicity of DOX/CA@PCN-224@HA against 4T1 cells. RESULTS: The altered PCN-224 showed excellent monodispersing with a dimension of approximately 193 nm ± 2 nm in length and 79 nm ± 3 nm in width. The larger and spindle grid-like structure of PCN-224 obtains better dual-drug loading ability (DOX: 20.58% ± 2.60%, CA: 21.81% ± 1.98%) compared with other spherical PCN-224 nanoparticles. The ultimate cumulative drug release rates with hyaluronidase (HAase) were 74% ± 1% (DOX) and 45% ± 2% (CA) after 72 h. DOX/CA@PCN-224@HA showed GSH-consuming capability, which could improve the PDT effect. The drug-loaded nanoparticles could accurately target 4T1 cells through biological evaluations. Moreover, the released DOX and CA display cooperative effects on 4T1 cells in vitro. DOX/CA@PCN-224@HA nanoparticles showed inhibition against 4T1 cells with an IC50 value of 2.71 µg mL-1. CONCLUSION: This nanosystem displays great potential for tumor-targeted enhanced (photo-chemo) therapy.

Gene patents: a broken incentives system.

The proliferation of patents on human genes has raised important ethical questions centered on the conflict of patient rights and intellectual property rights. With the Supreme Court's June 2013 decision that altered the patent eligibility of genetic material, it is important to reexamine the ethical implications of gene patents as a concept. Such patents suggest an ownership of genetic material that may hinder access to healthcare and inhibit medical progress. The application of the current patent system to genetic material thus violates patients' rights without fulfilling the system's goal of promoting innovation, suggesting a need for a revised incentives infrastructure.

A new instrument for interfacial dilational rheology.

We present a new design for an interfacial dilational rheometer that can generate oscillatory dilational strain on a planar air-liquid interface. The strain is generated by a pneumatic mechanism involving a deformable film, which forms a circular barrier that can contract or expand under different pressures. The interfacial stress is measured using a Wilhelmy rod. We carefully examine and demonstrate the effects of potential sources of measurement error, including inertia, drag, buoyancy, flow from the bulk phase, and surface waves. The design avoids mixed deformations present in other instruments and is currently capable of accurate measurements at frequencies up to ∼0.1 Hz and dilational strains below 0.001, with potential for higher frequencies after further theoretical development. We demonstrate the integration of the interfacial dilational rheometer with a Langmuir trough by measuring the compression isotherm of an insoluble surfactant, stearic acid. Furthermore, we verify the capability of the interfacial dilational rheometer to perform frequency and amplitude sweeps and present the storage and loss moduli for a water-soluble surfactant, sodium dodecylbenzenesulfonate, at different concentrations.