Easter Song

G majorMaestosoA man is dead, yet is He living (Un homme est mort, Il va renaître)4-79-63394-1

Autonomous push button-controlled rapid insulin release from a piezoelectrically activated subcutaneous cell implant

Traceless physical cues are desirable for remote control of the in situ production and real-time dosing of biopharmaceuticals in cell-based therapies. However, current optogenetic, magnetogenetic, or electrogenetic devices require sophisticated electronics, complex artificial intelligence-assisted software, and external energy supplies for power and control. Here, we describe a self-sufficient subcutaneous push button-controlled cellular implant powered simply by repeated gentle finger pressure exerted on the overlying skin. Pushing the button causes transient percutaneous deformation of the implant's embedded piezoelectric membrane, which produces sufficient low-voltage energy inside a semi-permeable platinum-coated cell chamber to mediate rapid release of a biopharmaceutical from engineered electro-sensitive human cells. Release is fine-tuned by varying the frequency and duration of finger-pressing stimulation. As proof of concept, we show that finger-pressure activation of the subcutaneous implant can restore normoglycemia in a mouse model of type 1 diabetes. Self-sufficient push-button devices may provide a new level of convenience for patients to control their cell-based therapies.ISSN:2375-254

Smartphone-Flashlight-Mediated Remote Control of Rapid Insulin Secretion Restores Glucose Homeostasis in Experimental Type-1 Diabetes

Emerging digital assessment of biomarkers by linking health-related data obtained from wearable electronic devices and embedded health and fitness sensors in smartphones is opening up the possibility of creating a continuous remote-monitoring platform for disease management. It is considered that the built-in flashlight of smartphones may be utilized to remotely program genetically engineered designer cells for on-demand delivery of protein-based therapeutics. Here, the authors present smartphone-induced insulin release in β-cell line (iβ-cell) technology for traceless light-triggered rapid insulin secretion, employing the light-activatable receptor melanopsin to induce calcium influx and membrane depolarization upon illumination. This iβ-cell-based system enables repeated, reversible secretion of insulin within 15 min in response to light stimulation, with a high induction fold both in vitro and in vivo. It is shown that programmable percutaneous remote control of implanted microencapsulated iβ-cells with a smartphone's flashlight rapidly reverses hyperglycemia in a mouse model of type-1 diabetes.ISSN:1613-6810ISSN:1613-682

Smart-watch-programmed green-light-operated percutaneous control of therapeutic transgenes

Wearable smart electronic devices, such as smart watches, are generally equipped with green-light-emitting diodes, which are used for photoplethysmography to monitor a panoply of physical health parameters. Here, we present a traceless, green-light-operated, smart-watch-controlled mammalian gene switch (Glow Control), composed of an engineered membrane-tethered green-light-sensitive cobalamin-binding domain of Thermus thermophilus (TtCBD) CarH protein in combination with a synthetic cytosolic TtCBD-transactivator fusion protein, which manage translocation of TtCBD-transactivator into the nucleus to trigger expression of transgenes upon illumination. We show that Apple-Watch-programmed percutaneous remote control of implanted Glow-controlled engineered human cells can effectively treat experimental type-2 diabetes by producing and releasing human glucagon-like peptide-1 on demand. Directly interfacing wearable smart electronic devices with therapeutic gene expression will advance next-generation personalized therapies by linking biopharmaceutical interventions to the internet of things.ISSN:2041-172

Electrogenetic cellular insulin release for real-time glycemic control in type 1 diabetic mice

ISSN:0036-8075ISSN:1095-920

In vivo screening of tumor-hepatocyte interactions identifies Plexin B2 as a gatekeeper of liver metastasis

It is estimated that only 0.02% of disseminated tumor cells are able to seed overt metastases1. While this indicates the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unknown. Combining transposon technology2 and fluorescent niche labeling3, we developed an in vivo CRISPR activation screen to systematically investigate the influence of hepatocytes on metastatic seeding in the liver. Our approach enabled the identification of Plexin B2 as a critical host-derived regulator of metastasis. Plexin B2 upregulation in hepatocytes dramatically enhances grafting in colorectal and pancreatic cancer syngeneic models, and promotes seeding and survival of patient-derived organoids. Notably, ablation of Plexin B2 in hepatocytes prevents mesenchymal-to-epithelial transition of extravasated tumor cells and thereby almost entirely suppresses liver metastasis. We dissect a mechanism by which Plexin B2 interacts with class 4 semaphorins on tumor cells, activating Rac1 signaling and actin cytoskeleton remodeling, thereby promoting the acquisition of epithelial traits. Our findings highlight the essential role of signals from the liver parenchyma for the survival of disseminated tumor cells, prior to the establishment of a growth promoting niche. They further suggest that acquisition of epithelial traits is required for the adaptation of extravasated cells to their new tissue environment. Targeting of Plexin B2 on hepatocytes shields the liver from colonizing cells and thus presents an innovative therapeutic strategy for preventing metastasis. Finally, our screening technology, which evaluates host-derived extrinsic signals rather than tumor-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints on metastasis in other organs and cancer types

Morphometry and mechanical instability at the onset of epithelial bladder cancer

Malignancies of epithelial tissues, called carcinomas, account for the majority of cancer cases. Much cancer research has focused on genetic alterations and their relation to different carcinoma phenotypes. Besides a rewiring in the signalling networks, carcinoma progression is accompanied by mechanical changes in the epithelial cells and the extracellular matrix. Here, we reveal intricate morphologies in the basement membrane at the onset of bladder cancer, and propose that they emerge from a mechanical buckling instability upon epithelial overgrowth. Using a combination of microscopy imaging of the mouse and human bladder tissue, elasticity theory, and numerical simulations of differential growth in the bladder mucosa, we find that aberrant tissue morphologies can emerge through stiffness changes in the different mucosa layers. The resulting thickening, wrinkles and folds exhibit qualitative and quantitative similarity with imaged early papillary tumors and carcinomas in situ. Atomic force microscopy indeed reveals local stiffness changes in the pathological basement membrane. Our findings suggest a mechanical origin of the different carcinoma subtypes in the bladder, which have vastly different clinical prognosis. They might provide the basis for a new line of attack in medical carcinoma treatment and prophylaxis