Integrins mediate cell adhesion and transmit mechanical and chemical signals to the cell interior. Various mechanisms deregulate integrin signaling in cancer, empowering tumor cells with the ability ...to proliferate without restraint, to invade through tissue boundaries, and to survive in foreign microenvironments. Recent studies have revealed that integrin signaling drives multiple stem cell functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to oncogene- and immune-targeted therapies. Here, we discuss the mechanisms leading to the deregulation of integrin signaling in cancer and its various consequences. We place emphasis on novel functions, determinants of context dependency, and mechanism-based therapeutic opportunities.
Integrins mediate cell adhesion and transmit mechanical and chemical signals to the cell interior. Various mechanisms deregulate integrin signaling in cancer, empowering tumor cells with the ability to proliferate without restraint, to invade through tissue boundaries, and to survive in foreign microenvironments. Recent studies have revealed that integrin signaling drives multiple stem cell functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to oncogene- and immune-targeted therapies. Here, we discuss the mechanisms leading to the deregulation of integrin signaling in cancer and its various consequences. We place emphasis on novel functions, determinants of context dependency, and mechanism-based therapeutic opportunities.
Many neurons resemble other cells in developing embryos in migrating long distances before they differentiate. However, despite shared basic machinery, neurons differ from other migrating cells. Most ...dramatically, migrating neurons have a long and dynamic leading process, and may extend an axon from the rear while they migrate. Neurons must coordinate the extension and branching of their leading processes, cell movement with axon specification and extension, switching between actin and microtubule motors, and attachment and recycling of diverse adhesion proteins. New research is needed to fully understand how migration of such morphologically complicated cells is coordinated over space and time.
Projection neurons migrate from the ventricular zone to the neocortical plate during the development of the mouse brain. Their overall movement is radial, but they become multipolar and move ...nonradially in the intermediate zone. Here we show that Reelin, the Rap1 GTPase and N-cadherin (NCad) are important for multipolar neurons to polarize their migration toward the cortical plate. Inhibition and rescue experiments indicated that Reelin regulates migration through Rap1 and Akt, and that the Rap1-regulated GTPases RalA, RalB, Rac1 and Cdc42 are also involved. We found that Rap1 regulated the plasma membrane localization of NCad and NCad rescued radial polarization when Rap1 was inhibited. However, inhibition of Rap1 or NCad had little effect on glia-dependent locomotion. We propose a multistep mechanism in which Reelin activates Rap1, Rap1 upregulates NCad, and NCad is needed to orient cell migration.
Color filters based upon nanostructured metals have garnered significant interest in recent years, having been positioned as alternatives to the organic dye-based filters which provide color ...selectivity in image sensors, as nonfading “printing” technologies for producing images with nanometer pixel resolution, and as ultra-high-resolution, small foot-print optical storage and encoding solutions. Here, we demonstrate a plasmonic filter set with polarization-switchable color properties, based upon arrays of asymmetric cross-shaped nanoapertures in an aluminum thin-film. Acting as individual color-emitting nanopixels, the plasmonic cavity-apertures have dual-color selectivity, transmitting one of two visible colors, controlled by the polarization of the white light incident on the rear of the pixel and tuned by varying the critical dimensions of the geometry and periodicity of the array. This structural approach to switchable optical filtering enables a single nanoaperture to encode two information states within the same physical nanoaperture, an attribute we use here to create micro image displays containing duality in their optical information states.
Despite the reality of intersex individuals whose biological markers do not necessarily all point towards a traditional binary understanding of either male or female, the vast majority of sports ...divide competition into categories based on a binary notion of biological sex and develop policies and regulations to police the divide. In so doing, sports governing bodies (SGBs) adopt an imperfect model of biological sex in order to serve their particular purposes, which, typically, will include protecting the fundamental sporting value of fair competition. Yet, one potential consequence of enforcing such an approach would seem to be the exclusion or marginalization of individuals whose biological development does not fit within the binary model, whether due to genetics or through a choice to undergo medical intervention to better represent a chosen gender identity. Any such exclusion or marginalization will inevitably tend to undermine another fundamental value of sport, that of inclusivity. In the context of those with differences of sex development, SGBs appear to be faced with a difficult problem: dealing with a conflict between two fundamental values of sport. Different approaches to this problem have been suggested, with some academics proposing that sports organisations, in general, ought to prioritise fairness above, while others suggest the need to ‘balance’ competing values or even to prioritise inclusion over fairness. However, it is argued that any of these approaches are, in principle, justifiable as any sport should be free to prioritise or balance its own values. What seems more important for any SGB is the need for a rational and transparent justification of regulations that pursue fair competition at the expense of inclusivity. Furthermore, where fair competition and inclusivity are fundamental values, any such justification would seem to demand adherence to some basic norms. First, the regulations should be built on (and articulate) a consistent and principled basis of what ‘fair competition’ means in a particular sport. Second, any regulations should only exclude or restrict participation to the minimum degree necessary to achieve the sense of fair competition so articulated. Third, SGBs should be transparent about what their values are and where their priorities lie so that participants and other stakeholders are able to make an informed choice as to whether they wish to participate in, support, or be associated with a particular sport. With reference to the adoption of the Eligibility Regulations for Athletes with Differences of Sex Development (the ‘DSD Regulations’) by the International Association of Athletic Federations (IAAF), this article seeks to evaluate whether the approach of the IAAF satisfied these basic requirements.
Rapid, low-cost, species-specific diagnosis, based upon DNA testing, is becoming important in the treatment of patients with infectious diseases. Here, we demonstrate an innovation that uses origami ...to enable multiplexed, sensitive assays that rival polymerase chain reactions (PCR) laboratory assays and provide high-quality, fast precision diagnostics for malaria. The paper-based microfluidic technology proposed here combines vertical flow sample-processing steps, including paper folding for whole-blood sample preparation, with an isothermal amplification and a lateral flow detection, incorporating a simple visualization system. Studies were performed in village schools in Uganda with individual diagnoses being completed in <50 min (faster than the standard laboratory-based PCR). The tests, which enabled the diagnosis of malaria species in patients from a finger prick of whole blood, were both highly sensitive and specific, detecting malaria in 98% of infected individuals in a double-blind first-in-human study. Our method was more sensitive than other field-based, benchmark techniques, including optical microscopy and industry standard rapid immunodiagnostic tests, both performed by experienced local healthcare teams (which detected malaria in 86% and 83% of cases, respectively). All assays were independently validated using a real-time double-blinded reference PCR assay. We not only demonstrate that advanced, low-cost DNA-based sensors can be implemented in underserved communities at the point of need but also highlight the challenges associated with developing and implementing new diagnostic technologies in the field, without access to laboratories or infrastructure.
Most neurons migrate with an elongated, "bipolar" morphology, extending a long leading process that explores the environment. However, when immature projection neurons enter the intermediate zone ...(IZ) of the neocortex they become "multipolar". Multipolar cells extend and retract cytoplasmic processes in different directions and move erratically-sideways, up and down. Multipolar cells extend axons while they are in the lower half of the IZ. Remarkably, the cells then resume radial migration: they reorient their centrosome and Golgi apparatus towards the pia, transform back to bipolar morphology, and commence locomotion along radial glia (RG) fibers. This reorientation implies the existence of directional signals in the IZ that are ignored during the multipolar stage but sensed after axonogenesis. In vivo genetic manipulation has implicated a variety of candidate directional signals, cell surface receptors, and signaling pathways, that may be involved in polarizing multipolar cells and stabilizing a pia-directed leading process for radial migration. Other signals are implicated in starting multipolar migration and triggering axon outgrowth. Here we review the molecules and mechanisms that regulate multipolar migration, and also discuss how multipolar migration affects the orderly arrangement of neurons in layers and columns in the developing neocortex.
Cell response to matrix rigidity has been explained by the mechanical properties of the actin-talin-integrin-fibronectin clutch. Here the molecular clutch model is extended to account for cell ...interactions with purely viscous surfaces (i.e., without an elastic component). Supported lipid bilayers present an idealized and controllable system through which to study this concept. Using lipids of different diffusion coefficients, the mobility (i.e., surface viscosity) of the presented ligands (in this case RGD) was altered by an order of magnitude. Cell size and cytoskeletal organization were proportional to viscosity. Furthermore, there was a higher number of focal adhesions and a higher phosphorylation of FAK on less-mobile (more-viscous) surfaces. Actin retrograde flow, an indicator of the force exerted on surfaces, was also seen to be faster on more mobile surfaces. This has consequential effects on downstream molecules; the mechanosensitive YAP protein localized to the nucleus more on less-mobile (more-viscous) surfaces and differentiation of myoblast cells was enhanced on higher viscosity. This behavior was explained within the framework of the molecular clutch model, with lower viscosity leading to a low force loading rate, preventing the exposure of mechanosensitive proteins, and with a higher viscosity causing a higher force loading rate exposing these sites, activating downstream pathways. Consequently, the understanding of how viscosity (regardless of matrix stiffness) influences cell response adds a further tool to engineer materials that control cell behavior.
•Au@Ag core-shell nanoparticles for highly sensitivite SERS assay.•Fabrication of Au@Ag-pLL on glass nanofibrous paper as SERS substrate.•A paper-based SERS nanosensor for the sensitive detection of ...methamphetamine in sewage.•Evaluation of community-wide illicit drugs consumption ifor wastewater-based epidemiology.
Wastewater-based epidemiology (WBE) is a powerful technique for monitoring illicit drugs of abuse in the community. Here, we report upon a surface-enhanced Raman spectroscopy (SERS) sensor for the sensitive and selective detection of methamphetamine based upon the assembly of noble metal core-shell nanoparticles on a bespoke glassy nanofibrous electrospun paper matrix. The hierarchical structure of the fibrous paper, modified with the synthesized Au@Ag core-shells (Au@Ag) gave strong SERS signalling, enabling us to evaluate the community-wide prevalence of methamphetamine in wastewater treatment plants within Beijing. We show that, when normalized for the daily flow of the wastewater treatment plants and for population density, higher mass loads of drugs are generally found in sewage influent from urban areas, implying greater local methamphetamine usage than that in less populated areas. The user-friendly and disposable paper sensors demonstrate the applicability of rapid on-site illicit drug detection, illustrating the application to wastewater-based epidemiology, which has the potential to inform government agencies regarding societal interventions.
Despite over 2 million papers published on cancer so far, malignancy still remains a puzzlingly complex disease with overall low survival rates. Expanding our knowledge of the molecular mechanisms of ...malignancy and of resistance to therapy is crucial in guiding the successful design of anti-cancer drugs and new point-of-care diagnostics. The up-and-coming microfluidic Lab-on-a-Chip (LOC) technology and micro-total analysis systems (μTAS) are arguably the most promising platforms to address the inherent complexity of cellular systems with massive experimental parallelization and 4D analysis on a single cell level. This review discusses the emerging applications of microfluidic technologies and their advantages for cancer biology and experimental oncology. We also summarize the recent advances in miniaturized systems to study cancer cell microenvironment, cancer cytomics, and real-time (4D) pharmacological screening. Microfabricated systems, such as cell microarrays, together with on-chip label-less cytometry, and micro-sorting technologies, are all highlighted with the view of describing their potential applications in pharmacological screening, drug discovery, and clinical oncology. It is envisaged that microfluidic solutions may well represent the platform of choice for next generation
in vitro cancer models.
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