Perspectives of RAS and RHEB GTPase Signaling Pathways in Regenerating Brain Neurons. Schöneborn Hendrik,Raudzus Fabian,Coppey Mathieu,Neumann Sebastian,Heumann Rolf International journal of molecular sciences Cellular activation of RAS GTPases into the GTP-binding "ON" state is a key switch for regulating brain functions. Molecular protein structural elements of rat sarcoma (RAS) and RAS homolog protein enriched in brain (RHEB) GTPases involved in this switch are discussed including their subcellular membrane localization for triggering specific signaling pathways resulting in regulation of synaptic connectivity, axonal growth, differentiation, migration, cytoskeletal dynamics, neural protection, and apoptosis. A beneficial role of neuronal H-RAS activity is suggested from cellular and animal models of neurodegenerative diseases. Recent experiments on optogenetic regulation offer insights into the spatiotemporal aspects controlling RAS/mitogen activated protein kinase (MAPK) or phosphoinositide-3 kinase (PI3K) pathways. As optogenetic manipulation of cellular signaling in deep brain regions critically requires penetration of light through large distances of absorbing tissue, we discuss magnetic guidance of re-growing axons as a complementary approach. In Parkinson's disease, dopaminergic neuronal cell bodies degenerate in the substantia nigra. Current human trials of stem cell-derived dopaminergic neurons must take into account the inability of neuronal axons navigating over a large distance from the grafted site into striatal target regions. Grafting dopaminergic precursor neurons directly into the degenerating substantia nigra is discussed as a novel concept aiming to guide axonal growth by activating GTPase signaling through protein-functionalized intracellular magnetic nanoparticles responding to external magnets. 10.3390/ijms19124052
    Cryptochrome mediates light-dependent magnetosensitivity in Drosophila. Gegear Robert J,Casselman Amy,Waddell Scott,Reppert Steven M Nature Although many animals use the Earth's magnetic field for orientation and navigation, the precise biophysical mechanisms underlying magnetic sensing have been elusive. One theoretical model proposes that geomagnetic fields are perceived by chemical reactions involving specialized photoreceptors. However, the specific photoreceptor involved in such magnetoreception has not been demonstrated conclusively in any animal. Here we show that the ultraviolet-A/blue-light photoreceptor cryptochrome (Cry) is necessary for light-dependent magnetosensitive responses in Drosophila melanogaster. In a binary-choice behavioural assay for magnetosensitivity, wild-type flies show significant naive and trained responses to a magnetic field under full-spectrum light ( approximately 300-700 nm) but do not respond to the field when wavelengths in the Cry-sensitive, ultraviolet-A/blue-light part of the spectrum (<420 nm) are blocked. Notably, Cry-deficient cry(0) and cry(b) flies do not show either naive or trained responses to a magnetic field under full-spectrum light. Moreover, Cry-dependent magnetosensitivity does not require a functioning circadian clock. Our work provides, to our knowledge, the first genetic evidence for a Cry-based magnetosensitive system in any animal. 10.1038/nature07183
    Animal cryptochromes mediate magnetoreception by an unconventional photochemical mechanism. Gegear Robert J,Foley Lauren E,Casselman Amy,Reppert Steven M Nature Understanding the biophysical basis of animal magnetoreception has been one of the greatest challenges in sensory biology. Recently it was discovered that the light-dependent magnetic sense of Drosophila melanogaster is mediated by the ultraviolet (UV)-A/blue light photoreceptor cryptochrome (Cry). Here we show, using a transgenic approach, that the photoreceptive, Drosophila-like type 1 Cry and the transcriptionally repressive, vertebrate-like type 2 Cry of the monarch butterfly (Danaus plexippus) can both function in the magnetoreception system of Drosophila and require UV-A/blue light (wavelength below 420 nm) to do so. The lack of magnetic responses for both Cry types at wavelengths above 420 nm does not fit the widely held view that tryptophan triad-generated radical pairs mediate the ability of Cry to sense a magnetic field. We bolster this assessment by using a mutant form of Drosophila and monarch type 1 Cry and confirm that the tryptophan triad pathway is not crucial in magnetic transduction. Together, these results suggest that animal Crys mediate light-dependent magnetoreception through an unconventional photochemical mechanism. This work emphasizes the utility of Drosophila transgenesis for elucidating the precise mechanisms of Cry-mediated magnetosensitivity in insects and also in vertebrates such as migrating birds. 10.1038/nature08719
    Magnetic nanoparticles for the manipulation of proteins and cells. Pan Yue,Du Xuewen,Zhao Fan,Xu Bing Chemical Society reviews In the rapidly developing areas of nanobiotechnology, magnetic nanoparticles (MNPs) are one type of the most well-established nanomaterials because of their biocompatibility and the potential applications as alternative contrast enhancing agents for magnetic resonance imaging (MRI). While the development of MNPs as alternative contrast agents for MRI application has moved quickly to testing in animal models and clinical trials, other applications of biofunctional MNPs have been explored extensively at the stage of qualitative or conceptual demonstration. In this critical review, we summarize the development of two straightforward applications of biofunctional MNPs--manipulating proteins and manipulating cells--in the last five years or so and hope to provide a relatively comprehensive assessment that may help the future developments. Specifically, we start with the examination of the strategy for the surface functionalization of MNPs because the applications of MNPs essentially depend on the molecular interactions between the functional molecules on the MNPs and the intended biological targets. Then, we discuss the use of MNPs for manipulating proteins since protein interactions are critical for biological functions. Afterwards, we evaluate the development of the use of MNPs to manipulate cells because the response of MNPs to a magnetic field offers a unique way to modulate cellular behavior in a non-contact or "remote" mode (i.e. the magnet exerts force on the cells without direct contact). Finally, we provide a perspective on the future directions and challenges in the development of MNPs for these two applications. By reviewing the examples of the design and applications of biofunctional MNPs, we hope that this article will provide a reference point for the future development of MNPs that address the present challenges and lead to new opportunities in nanomedicine and nanobiotechnology (137 references). 10.1039/c2cs15315g
    Cre-Lox Neurogenetics: 20 Years of Versatile Applications in Brain Research and Counting…. Tsien Joe Z Frontiers in genetics Defining and manipulating specific neurons in the brain has garnered enormous interest in recent years, because such an approach is now widely recognized as crucial for deepening our understanding of how the brain works. When I started exploring the Cre-loxP recombination for brain research in the early 1990s, it was written off as a dead-end project by a young fool. Yet over the past 20 years, Cre-lox recombination-mediated neurogenetics has emerged as one of the most powerful and versatile technology platforms for cell-specific gene knockouts, transgenic overexpression, Brainbow imaging, neural pathway tracing with retrovirus and CLARITY, chemical genetics, and optogenetics. Its popularity and greater utility in neuroscience research is also largely thanks to the NIH's bold Blueprint for Neuroscience Research Initiative to launch several Cre-driver resource projects, as well as individual laboratories and private research organizations. With newly-discovered, genetically-encoded molecules that are capable of responding to sonar and magnetic stimulation, for sonogenetics or magnetogenetics, respectively, or detecting rapid voltage changes in neurons, Cre-lox neurogenetics will continue to aid brain research for years to come. 10.3389/fgene.2016.00019
    Magnetic control of cellular processes using biofunctional nanoparticles. Monzel Cornelia,Vicario Chiara,Piehler Jacob,Coppey Mathieu,Dahan Maxime Chemical science Remote control of cellular functions is a key challenge in biomedical research. Only a few tools are currently capable of manipulating cellular events at distance, at spatial and temporal scales matching their naturally active range. A promising approach, often referred to as 'magnetogenetics', is based on the use of magnetic fields, in conjunction with targeted biofunctional magnetic nanoparticles. By triggering molecular stimuli mechanical, thermal or biochemical perturbations, magnetic actuation constitutes a highly versatile tool with numerous applications in fundamental research as well as exciting prospects in nano- and regenerative medicine. Here, we highlight recent studies, comment on the advancement of magnetic manipulation, and discuss remaining challenges. 10.1039/c7sc01462g
    High-Throughput Microfluidic Sorting of Live Magnetotactic Bacteria. Tay Andy,Pfeiffer Daniel,Rowe Kathryn,Tannenbaum Aaron,Popp Felix,Strangeway Robert,Schüler Dirk,Di Carlo Dino Applied and environmental microbiology Magnetic nanoparticles (MNPs) are useful for many biomedical applications, but it is challenging to synthetically produce them in large numbers with uniform properties and surface functionalization. Magnetotactic bacteria (MTB) produce magnetosomes with homogenous sizes, shapes, and magnetic properties. Consequently, there is interest in using MTB as biological factories for MNP production. Nonetheless, MTB can only be grown to low yields, and wild-type strains produce low numbers of MNPs/bacterium. There are also limited technologies to facilitate the selection of MTB with different magnetic contents, such as MTB with compromised and enhanced biomineralization ability. Here, we describe a magnetic microfluidic platform combined with transient cold/alkaline treatment to temporarily reduce the rapid flagellar motion of MTB without compromising their long-term proliferation and biomineralization ability for separating MTB on the basis of their magnetic contents. This strategy enables live MTB to be enriched, which, to the best of our knowledge, has not been achieved with another previously described magnetic microfluidic device that makes use of ferrofluid and heat. Our device also facilitates the high-throughput (25,000 cells/min) separation of wild-type (MSR-1) from nonmagnetic Δ MSR-1 mutants with a sensitivity of up to 80% and isolation purity of up to 95%, as confirmed with a gold-standard fluorescent-activated cell sorter (FACS) technique. This offers a 25-fold higher throughput than other previously described magnetic microfluidic platforms (1,000 cells/min). The device can also be used to isolate (AMB-1) mutants with different ranges of magnetosome numbers with efficiencies close to theoretical estimates. We believe this technology will facilitate the magnetic characterization of genetically engineered MTB for a variety of applications, including using MTB for large-scale, controlled MNP production. Our magnetic microfluidic technology can greatly facilitate biological applications with magnetotactic bacteria, from selection and screening to analysis. This technology will be of interest to microbiologists, chemists, and bioengineers who are interested in the biomineralization and selection of magnetotactic bacteria (MTB) for applications such as directed evolution and magnetogenetics. 10.1128/AEM.01308-18
    The Future of Surgical Treatments for Parkinson's Disease. Lee Darrin J,Lozano Andres M Journal of Parkinson's disease The surgical treatment of Parkinson's disease has made significant progress over the past 70 years; however, its scope of effectiveness remains limited to motor symptoms like bradykinesia, rigidity, tremor and medication-induced dyskinesias. The field of surgery initially developed from lesioning procedures and then transitioned largely to deep brain stimulation due to its properties of adaptability and reversibility. Interestingly, there has been a renewed interest in lesioning procedures secondary to the introduction of focused ultrasound, a non-invasive technology. Despite the various current therapies' effectiveness, there is a significant need for developing treatments to modify the disease process itself. To date, gene therapy, immunotherapy, and cell transplantation trials have had both promising and disappointing results. Newer techniques being developed (optogenetics, magnetogenetics, and sonogenetics) are exciting possibilities for the future. Here, we examine and speculate on novel potential surgical treatments for Parkinson's disease. 10.3233/JPD-181467
    Magnetogenetic control of protein gradients inside living cells with high spatial and temporal resolution. Etoc Fred,Vicario Chiara,Lisse Domenik,Siaugue Jean-Michel,Piehler Jacob,Coppey Mathieu,Dahan Maxime Nano letters Tools for controlling the spatial organization of proteins are a major prerequisite for deciphering mechanisms governing the dynamic architecture of living cells. Here, we have developed a generic approach for inducing and maintaining protein gradients inside living cells by means of biofunctionalized magnetic nanoparticles (MNPs). For this purpose, we tailored the size and surface properties of MNPs in order to ensure unhindered mobility in the cytosol. These MNPs with a core diameter below 50 nm could be rapidly relocalized in living cells by exploiting biased diffusion at weak magnetic forces in the femto-Newton range. In combination with MNP surface functionalization for specific in situ capturing of target proteins as well as efficient delivery into the cytosplasm, we here present a comprehensive technology for controlling intracellular protein gradients with a temporal resolution of a few tens of seconds. 10.1021/acs.nanolett.5b00851
    Remote Neural Stimulation Using Magnetic Nanoparticles. Tay Andy,Di Carlo Dino Current medicinal chemistry Neural stimulation provides a means for scientists to investigate brain functions and neurological diseases. There is also mounting interest in using remote stimulation of neuronal circuits for brain-machine interfaces. In this review, we highlight recently developed technologies utilizing magnetic nanoparticles to generate heat or exert mechanical forces for remote control of brain circuits and compare these with conventional (electrical stimulation and drugs) and second-generation (ultrasound and light) techniques. We also present some of the challenges and progress in areas like genetics, nanoparticle synthesis and energy delivery devices to translate the use of these innovative nanoparticle-based platforms in research and clinical settings. 10.2174/0929867323666160814000442
    Problems on the back of an envelope. Anikeeva Polina,Jasanoff Alan eLife Claims that magnetic fields can be used to manipulate biological systems contradict some basic laws of physics. 10.7554/eLife.19569
    Investigating metabolic regulation using targeted neuromodulation. Devarakonda Kavya,Stanley Sarah Annals of the New York Academy of Sciences The central nervous system (CNS) plays a vital role in regulating energy balance and metabolism. Over the last 50 years, studies in animal models have allowed us to identify critical CNS regions involved in these processes and even crucial cell populations. Now, techniques for genetically and anatomically targeted manipulation of specific neural populations using light (optogenetic), ligands (chemogenetic), or magnetic fields (radiogenetic/magnetogenetic) allow detailed investigation of circuits involved in metabolic regulation. In this review, we provide a brief overview of recent studies using light- and magnetic field-regulated neural activity to investigate the neural circuits contributing to metabolic control. 10.1111/nyas.13468
    Development of Magnetic Torque Stimulation (MTS) Utilizing Rotating Uniform Magnetic Field for Mechanical Activation of Cardiac Cells. Song Myeongjin,Kim Jongseong,Shin Hyundo,Kim Yekwang,Jang Hwanseok,Park Yongdoo,Kim Seung-Jong Nanomaterials (Basel, Switzerland) Regulation of cell signaling through physical stimulation is an emerging topic in biomedicine. BACKGROUND:While recent advances in biophysical technologies show capabilities for spatiotemporal stimulation, interfacing those tools with biological systems for intact signal transfer and noncontact stimulation remains challenging. Here, we describe the use of a magnetic torque stimulation (MTS) system combined with engineered magnetic particles to apply forces on the surface of individual cells. MTS utilizes an externally rotating magnetic field to induce a spin on magnetic particles and generate torsional force to stimulate mechanotransduction pathways in two types of human heart cells-cardiomyocytes and cardiac fibroblasts. METHODS:The MTS system operates in a noncontact mode with two magnets separated (60 mm) from each other and generates a torque of up to 15 pN µm across the entire area of a 35-mm cell culture dish. The MTS system can mechanically stimulate both types of human heart cells, inducing maturation and hypertrophy. RESULTS:Our findings show that application of the MTS system under hypoxic conditions induces not only nuclear localization of mechanoresponsive YAP proteins in human heart cells but also overexpression of hypertrophy markers, including β-myosin heavy chain (βMHC), cardiotrophin-1 (CT-1), microRNA-21 (miR-21), and transforming growth factor beta-1 (TGFβ-1). CONCLUSIONS:These results have important implications for the applicability of the MTS system to diverse in vitro studies that require remote and noninvasive mechanical regulation. 10.3390/nano10091684
    Engineered Ferritin for Magnetogenetic Manipulation of Proteins and Organelles Inside Living Cells. Liße Domenik,Monzel Cornelia,Vicario Chiara,Manzi John,Maurin Isabelle,Coppey Mathieu,Piehler Jacob,Dahan Maxime Advanced materials (Deerfield Beach, Fla.) Magnetogenetics is emerging as a novel approach for remote-controlled manipulation of cellular functions in tissues and organisms with high spatial and temporal resolution. A critical, still challenging issue for these techniques is to conjugate target proteins with magnetic probes that can satisfy multiple colloidal and biofunctional constraints. Here, semisynthetic magnetic nanoparticles are tailored based on human ferritin coupled to monomeric enhanced green fluorescent protein (mEGFP) for magnetic manipulation of proteins inside living cells. This study demonstrates efficient delivery, intracellular stealth properties, and rapid subcellular targeting of those magnetic nanoparticles via GFP-nanobody interactions. By means of magnetic field gradients, rapid spatial reorganization in the cytosol of proteins captured to the nanoparticle surface is achieved. Moreover, exploiting efficient nanoparticle targeting to intracellular membranes, remote-controlled arrest of mitochondrial dynamics using magnetic fields is demonstrated. The studies establish subcellular control of proteins and organelles with unprecedented spatial and temporal resolution, thus opening new prospects for magnetogenetic applications in fundamental cell biology and nanomedicine. 10.1002/adma.201700189
    Remote control of glucose-sensing neurons to analyze glucose metabolism. Alvarsson Alexandra,Stanley Sarah A American journal of physiology. Endocrinology and metabolism The central nervous system relies on a continual supply of glucose, and must be able to detect glucose levels and regulate peripheral organ functions to ensure that its energy requirements are met. Specialized glucose-sensing neurons, first described half a century ago, use glucose as a signal and modulate their firing rates as glucose levels change. Glucose-excited neurons are activated by increasing glucose concentrations, while glucose-inhibited neurons increase their firing rate as glucose concentrations fall and decrease their firing rate as glucose concentrations rise. Glucose-sensing neurons are present in multiple brain regions and are highly expressed in hypothalamic regions, where they are involved in functions related to glucose homeostasis. However, the roles of glucose-sensing neurons in healthy and disease states remain poorly understood. Technologies that can rapidly and reversibly activate or inhibit defined neural populations provide invaluable tools to investigate how specific neural populations regulate metabolism and other physiological roles. Optogenetics has high temporal and spatial resolutions, requires implants for neural stimulation, and is suitable for modulating local neural populations. Chemogenetics, which requires injection of a synthetic ligand, can target both local and widespread populations. Radio- and magnetogenetics offer rapid neural activation in localized or widespread neural populations without the need for implants or injections. These tools will allow us to better understand glucose-sensing neurons and their metabolism-regulating circuits. 10.1152/ajpendo.00469.2017
    Optical Magnetometry of Single Biocompatible Micromagnets for Quantitative Magnetogenetic and Magnetomechanical Assays. Toraille Loïc,Aïzel Koceila,Balloul Élie,Vicario Chiara,Monzel Cornelia,Coppey Mathieu,Secret Emilie,Siaugue Jean-Michel,Sampaio João,Rohart Stanislas,Vernier Nicolas,Bonnemay Louise,Debuisschert Thierry,Rondin Loïc,Roch Jean-François,Dahan Maxime Nano letters The mechanical manipulation of magnetic nanoparticles is a powerful approach to probing and actuating biological processes in living systems. Implementing this technique in high-throughput assays can be achieved using biocompatible micromagnet arrays. However, the magnetic properties of these arrays are usually indirectly inferred from simulations or Stokes drag measurements, leaving unresolved questions about the actual profile of the magnetic fields at the micrometer scale and the exact magnetic forces that are applied. Here, we exploit the magnetic field sensitivity of nitrogen-vacancy color centers in diamond to map the 3D stray magnetic field produced by a single soft ferromagnetic microstructure. By combining this wide-field optical magnetometry technique with magneto-optic Kerr effect microscopy, we fully analyze the properties of the micromagnets, including their magnetization saturation and their size-dependent magnetic susceptibility. We further show that the high magnetic field gradients produced by the micromagnets, greater than 10 T·m under an applied magnetic field of about 100 mT, enables the manipulation of magnetic nanoparticles smaller than 10 nm inside living cells. This work paves the way for quantitative and parallelized experiments in magnetogenetics and magnetomechanics in cell biology. 10.1021/acs.nanolett.8b03222
    Lipid Oxidation Induced by RF Waves and Mediated by Ferritin Iron Causes Activation of Ferritin-Tagged Ion Channels. Hernández-Morales Miriam,Shang Trisha,Chen Jingjia,Han Victor,Liu Chunlei Cell reports One approach to magnetogenetics uses radiofrequency (RF) waves to activate transient receptor potential channels (TRPV1 and TRPV4) that are coupled to cellular ferritins. The mechanisms underlying this effect are unclear and controversial. Theoretical calculations suggest that the heat produced by RF fields is likely orders of magnitude weaker than needed for channel activation. Using the FeRIC (Ferritin iron Redistribution to Ion Channels) system, we have uncovered a mechanism of activation of ferritin-tagged channels via a biochemical pathway initiated by RF disturbance of ferritin and mediated by ferritin-associated iron. We show that, in cells expressing TRPV channels, RF increases the levels of the labile iron pool in a ferritin-dependent manner. Free iron participates in chemical reactions, producing reactive oxygen species and oxidized lipids that ultimately activate the TRPV channels. This biochemical pathway predicts a similar RF-induced activation of other lipid-sensitive TRP channels and may guide future magnetogenetic designs. 10.1016/j.celrep.2020.02.070
    Engineering a Genetically Encoded Magnetic Protein Crystal. Li Thomas L,Wang Zegao,You He,Ong Qunxiang,Varanasi Vamsi J,Dong Mingdong,Lu Bai,Paşca Sergiu P,Cui Bianxiao Nano letters Magnetogenetics is a new field that leverages genetically encoded proteins and protein assemblies that are sensitive to magnetic fields to study and manipulate cell behavior. Theoretical studies show that many proposed magnetogenetic proteins do not contain enough iron to generate substantial magnetic forces. Here, we have engineered a genetically encoded ferritin-containing protein crystal that grows inside mammalian cells. Each of these crystals contains more than 10 million ferritin subunits and is capable of mineralizing substantial amounts of iron. When isolated from cells and loaded with iron , these crystals generate magnetic forces that are 9 orders of magnitude larger than the forces from the single ferritin cages used in previous studies. These protein crystals are attracted to an applied magnetic field and move toward magnets even when internalized into cells. While additional studies are needed to realize the full potential of magnetogenetics, these results demonstrate the feasibility of engineering protein assemblies for magnetic sensing. 10.1021/acs.nanolett.9b02266
    Regulation of glucose homeostasis using radiogenetics and magnetogenetics in mice. Leibiger Ingo B,Berggren Per-Olof Nature medicine 10.1038/nm.3782
    Physical limits to magnetogenetics. Meister Markus eLife This is an analysis of how magnetic fields affect biological molecules and cells. It was prompted by a series of prominent reports regarding magnetism in biological systems. The first claims to have identified a protein complex that acts like a compass needle to guide magnetic orientation in animals (Qin et al., 2016). Two other articles report magnetic control of membrane conductance by attaching ferritin to an ion channel protein and then tugging the ferritin or heating it with a magnetic field (Stanley et al., 2015; Wheeler et al., 2016). Here I argue that these claims conflict with basic laws of physics. The discrepancies are large: from 5 to 10 log units. If the reported phenomena do in fact occur, they must have causes entirely different from the ones proposed by the authors. The paramagnetic nature of protein complexes is found to seriously limit their utility for engineering magnetically sensitive cells. 10.7554/eLife.17210
    Is magnetogenetics the new optogenetics? Nimpf Simon,Keays David A The EMBO journal 10.15252/embj.201797177
    Uncovering a possible role of reactive oxygen species in magnetogenetics. Brier Matthew I,Mundell Jordan W,Yu Xiaofei,Su Lichao,Holmann Alexander,Squeri Jessica,Zhang Baolin,Stanley Sarah A,Friedman Jeffrey M,Dordick Jonathan S Scientific reports Recent reports have shown that intracellular, (super)paramagnetic ferritin nanoparticles can gate TRPV1, a non-selective cation channel, in a magnetic field. Here, we report the effects of differing field strength and frequency as well as chemical inhibitors on channel gating using a Ca-sensitive promoter to express a secreted embryonic alkaline phosphatase (SEAP) reporter. Exposure of TRPV1-ferritin-expressing HEK-293T cells at 30 °C to an alternating magnetic field of 501 kHz and 27.1 mT significantly increased SEAP secretion by ~ 82% relative to control cells, with lesser effects at other field strengths and frequencies. Between 30-32 °C, SEAP production was strongly potentiated 3.3-fold by the addition of the TRPV1 agonist capsaicin. This potentiation was eliminated by the competitive antagonist AMG-21629, the NADPH oxidase assembly inhibitor apocynin, and the reactive oxygen species (ROS) scavenger N-acetylcysteine, suggesting that ROS contributes to magnetogenetic TRPV1 activation. These results provide a rational basis to address the heretofore unknown mechanism of magnetogenetics. 10.1038/s41598-020-70067-1
    Possible magneto-mechanical and magneto-thermal mechanisms of ion channel activation in magnetogenetics. Barbic Mladen eLife The palette of tools for perturbation of neural activity is continually expanding. On the forefront of this expansion is magnetogenetics, where ion channels are genetically engineered to be closely coupled to the iron-storage protein ferritin. Initial reports on magnetogenetics have sparked a vigorous debate on the plausibility of physical mechanisms of ion channel activation by means of external magnetic fields. The criticism leveled against magnetogenetics as being physically implausible is based on the specific assumptions about the magnetic spin configurations of iron in ferritin. I consider here a wider range of possible spin configurations of iron in ferritin and the consequences these might have in magnetogenetics. I propose several new magneto-mechanical and magneto-thermal mechanisms of ion channel activation that may clarify some of the mysteries that presently challenge our understanding of the reported biological experiments. Finally, I present some additional puzzles that will require further theoretical and experimental investigation. 10.7554/eLife.45807
    Magnetogenetics: remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor. Long Xiaoyang,Ye Jing,Zhao Di,Zhang Sheng-Jia Science bulletin Current neuromodulation techniques such as optogenetics and deep-brain stimulation are transforming basic and translational neuroscience. These two neuromodulation approaches are, however, invasive since surgical implantation of an optical fiber or wire electrode is required. Here, we have invented a non-invasive magnetogenetics that combines the genetic targeting of a magnetoreceptor with remote magnetic stimulation. The non-invasive activation of neurons was achieved by neuronal expression of an exogenous magnetoreceptor, an iron-sulfur cluster assembly protein 1 (Isca1). In HEK-293 cells and cultured hippocampal neurons expressing this magnetoreceptor, application of an external magnetic field resulted in membrane depolarization and calcium influx in a reproducible and reversible manner, as indicated by the ultrasensitive fluorescent calcium indicator GCaMP6s. Moreover, the magnetogenetic control of neuronal activity might be dependent on the direction of the magnetic field and exhibits on-response and off-response patterns for the external magnetic field applied. The activation of this magnetoreceptor can depolarize neurons and elicit trains of action potentials, which can be triggered repetitively with a remote magnetic field in whole-cell patch-clamp recording. In transgenic expressing this magnetoreceptor in --specific muscle cells or --specific neurons, application of the external magnetic field triggered muscle contraction and withdrawal behavior of the worms, indicative of magnet-dependent activation of muscle cells and touch receptor neurons, respectively. The advantages of magnetogenetics over optogenetics are its exclusive non-invasive, deep penetration, long-term continuous dosing, unlimited accessibility, spatial uniformity and relative safety. Like optogenetics that has gone through decade-long improvements, magnetogenetics, with continuous modification and maturation, will reshape the current landscape of neuromodulation toolboxes and will have a broad range of applications to basic and translational neuroscience as well as other biological sciences. We envision a new age of magnetogenetics is coming. 10.1007/s11434-015-0902-0
    A magnetic protein biocompass. Qin Siying,Yin Hang,Yang Celi,Dou Yunfeng,Liu Zhongmin,Zhang Peng,Yu He,Huang Yulong,Feng Jing,Hao Junfeng,Hao Jia,Deng Lizong,Yan Xiyun,Dong Xiaoli,Zhao Zhongxian,Jiang Taijiao,Wang Hong-Wei,Luo Shu-Jin,Xie Can Nature materials The notion that animals can detect the Earth's magnetic field was once ridiculed, but is now well established. Yet the biological nature of such magnetosensing phenomenon remains unknown. Here, we report a putative magnetic receptor (Drosophila CG8198, here named MagR) and a multimeric magnetosensing rod-like protein complex, identified by theoretical postulation and genome-wide screening, and validated with cellular, biochemical, structural and biophysical methods. The magnetosensing complex consists of the identified putative magnetoreceptor and known magnetoreception-related photoreceptor cryptochromes (Cry), has the attributes of both Cry- and iron-based systems, and exhibits spontaneous alignment in magnetic fields, including that of the Earth. Such a protein complex may form the basis of magnetoreception in animals, and may lead to applications across multiple fields. 10.1038/nmat4484
    Magnetic immobilization of a quorum sensing signal hydrolase, AiiA. Wang Lin,Xu Haixing,Liu Zewen,Sun Taolei,Yuan Chengqing,Yang Ying,Guo Junhui,Xie Hao MicrobiologyOpen Magnetic immobilization of quorum sensing (QS) signal hydrolases provides a convenient solution for quenching QS process that is essential for bacterial biofilm formation and antimicrobial resistance. In the present study, a QS signal hydrolase, AiiA, was fused with a magnetic protein, MagR, and expressed in Escherichia coli. Magnetic immobilization of AiiA was achieved on Fe O -SiO iron beads and was confirmed via SDS-PAGE, zeta potential measurement, FTIR spectrometry, and SEM analysis. The magnetic immobilized AiiA exhibited activity in degrading the quorum sensing signal, C6-HSL. This study opens a new avenue to actively immobilize enzymes via magnetic interaction and quench quorum sensing. 10.1002/mbo3.797
    The Magnetic Receptor of M7: Gene Clone and Its Heterologous Expression in . Zhou Hongyi,Yang Shuyan,Chen Fusheng Frontiers in microbiology It is well known that many organisms can perceive the magnetic field (MF), including the geomagnetic field, but how to feel MF is unclear. Recently, a study has claimed that a biological compass, namely a complex of the magnetic receptor (MagR) and blue light (BL) receptor (cryptochrome), has been found in , , and , which may bring some new ideas to explore the mechanism of biomagnetism. spp. are edible filamentous fungi that can produce abundant beneficial secondary metabolites and have been used to produce food colorants for nearly 2000 years in the world, especially in China, Japan, and Korea. In this work, we firstly treated M7 by BL (500 lux,465-467 nm), MF (5, 10, 30 mT), and the combination of MF and BL (MF-BL), respectively. The results revealed that, compared with the control (CK, neither BL nor MF), the MF alone had no effect on the growth and morphological characteristics of M7, but BL made the colonial diameters only 66.7% of CK's and inhibited the formation of cleistothecia. Under MF-BL, the colony diameters were still 66.7% of CK's, but the colonial growth and cleistothecia production inhibited by BL were partially restored. Then, we have found that the gene widely exists in the genomes of animals, plants, and microorganisms, and we have also discovered a gene in the M7 genome, hereinafter referred to . Finally, the full-length cDNA of was successfully cloned and expressed in BL21 (DE3), and the Mr-MagR protein was purified by a Ni-NTA column and identified by Western blot. These results have laid a foundation for further investigation on the relationship between Mr-MagR and BL receptor(s) that might exist in M7. According to a literature search, it is the first time to report in filamentous fungi. 10.3389/fmicb.2020.01112
    MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation. Pang Keliang,You He,Chen Yanbo,Chu Pengcheng,Hu Meiqin,Shen Jianying,Guo Wei,Xie Can,Lu Bai Frontiers in neural circuits Magnetic manipulation of cell activity offers advantages over optical manipulation but an ideal tool remains elusive. The MagR protein was found through its interaction with cryptochrome (Cry) and the protein in solution appeared to respond to magnetic stimulation (MS). After we initiated an investigation on the specific role of MagR in cellular response to MS, a subsequent study claimed that MagR expression alone could achieve cellular activation by MS. Here we report that despite systematically testing different ways of measuring intracellular calcium and different MS protocols, it was not possible to detect any cellular or neuronal responses to MS in MagR-expressing HEK cells or primary neurons from the dorsal root ganglion and the hippocampus. By contrast, in neurons co-expressing MagR and channelrhodopin, optical but not MS increased calcium influx in hippocampal neurons. Our results indicate that MagR alone is not sufficient to confer cellular magnetic responses. 10.3389/fncir.2017.00011
    Commentary: MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation. Long Xiaoyang,Zhang Sheng-Jia Frontiers in neural circuits 10.3389/fncir.2018.00097
    Identification of medaka magnetoreceptor and cryptochromes. Wang Yunzhi,Chen Jianbin,Zhu Feng,Hong Yunhan Science China. Life sciences Magnetoreception is a hallmark ability of animals for orientation and migration via sensing and utilizing geomagnetic fields. Magnetoreceptor (MagR) and cryptochromes (Cry) have recently been identified as the basis for magnetoreception in Drosophila. However, it has remained unknown whether MagR and Cry have conserved roles in diverse animals. Here we report the identification and expression of magr and cry genes in the fish medaka (Oryzias latipes). Cloning and sequencing identified a single magr gene, four cry genes and one cry-like gene in medaka. By sequence alignment, chromosomal synteny and gene structure analysis, medaka cry2 and magr were found to be the orthologs of human Cry2 and Magr, with cry1aa and cry1ab being coorthologs of human Cry1. Therefore, magr and cry2 have remained as single copy genes, whereas cry1 has undergone two rounds of gene duplication in medaka. Interestingly, magr and cry genes were detected in various stages throughout embryogenesis and displayed ubiquitous expression in adult organs rather than specific or preferential expression in neural organs such as brain and eye. Importantly, magr knockdown by morpholino did not produce visible abnormality in developing embryos, pointing to the possibility of producing viable magr knockouts in medaka as a vertebrate model for magnet biology. 10.1007/s11427-016-0266-5
    Identification of zebrafish magnetoreceptor and cryptochrome homologs. Zhou Zuoqiong,Peng Xiyang,Chen Jianbin,Wu Xiushan,Wang Yuequn,Hong Yunhan Science China. Life sciences Magnetoreception is essential for magnetic orientation in animal migration. The molecular basis for magnetoreception has recently been elucidated in fruitfly as complexes between the magnetic receptor magnetoreceptor (MagR) and its ligand cryptochrome (Cry). MagR and Cry are present in the animal kingdom. However, it is unknown whether they perform a conserved role in diverse animals. Here we report the identification and expression of zebrafish MagR and Cry homologs towards understanding their roles in lower vertebrates. A single magr gene and 7 cry genes are present in the zebrafish genome. Zebrafish has four cry1 genes (cry1aa, cry1ab, cry1ba and cry1bb) homologous to human CRY1 and a single ortholog of human CRY2 as well as 2 cry-like genes (cry4 and cry5). By RT-PCR, magr exhibited a high level of ubiquitous RNA expression in embryos and adult organs, whereas cry genes displayed differential embryonic and adult expression. Importantly, magr depletion did not produce apparent abnormalities in organogenesis. Taken together, magr and cry2 exist as a single copy gene, whereas cry1 exists as multiple gene duplicates in zebrafish. Our result suggests that magr may play a dispensable role in organogenesis and predicts a possibility to generate magr mutants for analyzing its role in zebrafish. 10.1007/s11427-016-0195-x