An editorial that stands by itself and speaks volumes for many of the incredible facts I’ve revealed in my own editorials. I don’t endorse all this, I just chew the meat on the bones. Published in a journal called Expert Opinion on Drug Delivery
Manipulative magnetic nanomedicine: the future of COVID-19 pandemic/endemic therapy
By Ajeet Kaushik, Pages 531-534 | Received 06 Nov 2020, Accepted 03 Dec 2020, Published online: 14 Dec 2020
1. Introduction: COVID-19 pandemic or endemic as health emergency
Since the Spanish flu outbreak (1918), many pandemics and/or endemics related to a viral infection such as H1N1, H5N1, human immunodeficiency virus (HIV), Ebola, Zika, and coronavirus have surprised mankind time-to-time due to their sudden appearance, severe adverse health effect, loss of lives, socio-economic burden, and a damaged economy. Such deadly infectious viruses originated from natural reservoirs and then infect humans via spillover mechanism. During infection progression, viruses affect the human biological system and become a part of the host genome and then make structural changes in its structure to survive or infect longer. These infections can cause permanent disorders, may be death, if a patient is immunocompromised and could not fight against virus life-cycle associated pathways and viral infection progression.
One such pandemic and/or endemic is the recent COVID-19 infection associated with new server acute respiratory syndrome coronavirus (SARS-CoV-2), investigated by Chinese clinicians in Dec 2019. Chinese health agencies noticed a rapid increment in seasonal flu cases, and this emerged as a very serious health issue due to the ineffectiveness of prescribed therapies [1,2]. Systematic investigations conducted on this infectious disease by experts confirmed and claimed that SARS-CoV-2 virus infection is dramatically affecting the respiratory system of every age patient via affecting their lung function. Although SARS-CoV-2 virus protein exhibited 70% to 80% genomic profile like SARS-CoV-1 (2002 outbreak) and middle east respiratory syndrome (2012 outbreak), but its viral infection mechanism, pathogenesis, mortality per cent, and other risks are different, unknown, and serious than SARS and MERS . Considering the severity of COVID-19 infection and variation in SARS-CoV-2 virus strains, this outbreak was first declared as an international health emergency; then, a pandemic due to global spread , and now experts are projecting this as an endemic due to post-infection effects and possibilities of reoccurrence like HIV . This infection is emerging very challenging due to 1) human-to-human transmission via aerosolization, 2) ability to affect lung rapidly because of easy binding between Spike (S1) protein of SARS-COV-2 virus and host cell membrane receptors like angiotensin-converting enzyme 2 (ACE-2) and TMPRSS-2 protein, this makes virus replication easy .
A successful COVID-19 infection management is not the only issue to deal with the respiratory system as it affects lung function. But the SARS-CoV-2 virus infection also severely affects other important body organs including the heart, liver, eye, gut, and brain as well. This is the reason that recovery of a COVID-19 infected patient is slow and sometimes the patient exhibits permanent disorder in biological function due to weak organs and organ function . Such scenarios have been investigated in asymptomatic patients as well. Keeping complete COVID-19 outbreak into consideration, health agencies were focused on 1) preparation and execution of safety guidelines, 2) exploring virus structure, genomic profiles, variability, and generate bioinformatics to understand pathogenesis, 3) developing rapid diagnostic kits, 4) optimizing available therapies, alone or in combination, 5) exploring methodologies to prevent SARS-CoV-2 transmission, 6) exploring novel therapeutics, 7) exploring aspects of therapeutic delivery at disease location, and 8) exploring combinational aspects of nanobiotechnology to support rapid testing, trapping of SARS-CoV-2, and delivery of therapeutics for not only to eradicate SARS-CoV-2 but provide long-term immunity for COVID-19 infected patient [4–6].
Based on the outcomes of big data analytics based on artificial intelligence (AI), it is suggested that recognition and eradication of the SARS-CoV-2 virus may be a time-taking procedure. Thus, all the focus is toward rapid infection diagnostics and viral infection management using state-of-the-art technologies, for example, 1) promoting physical distance and using of a mask to avoid virus transmission, 2) developing AI and internet-of-medical-things (IoMT) based strategies for rapid testing, tracking of patients, big data analytics, bioinformatics generation, developing a novel sensor for early-stage SARS-CoV-2 detection [2,5,7], and novel therapeutics and successful delivery using nanobiotechnology approach , the main focus of this editorial.
2. Manipulative magnetic nanomedicine: the future of COVID-19 therapy
Nanobiotechnology is emerging very promising to investigate novel methodologies for managing COVID-19 pandemic/endemic successfully [2,5]. In this direction, experts have explored the opto-electro-magnetic nanosystem to detect the SARS-CoV-2 virus using a biosensing approach. Such optical, electrical, or magnetic biosensors function based on geno-sensing and immune-sensing has detected the SARS-CoV-2 virus selectively at a very low level [7,8]. These efficient-miniaturized biosensors can be operated using a smartphone and promoted for clinical application for early-stage diagnostics of COVID-19 infection. The successful integration of these SARS-CoV-2 virus sensors with AI and IoMT enables virus detection at point-of-location and sharing of bioinformatics with the medical center at the same time for timely therapeutics decision. This approach is also useful for tracking tasks and managing COVID-19 infection according to patient infection profiling. To avoid human-to-human SARS-CoV-2 virus transmission, experts have developed stimuli-responsive nanotechnology enable which can not only trap aerosol of virus size but can eradicate viruses on applying external stimulation for example nanoenable photo-sensitive virus degradation. Various types of clothes containing nanoparticles have demonstrated SARS-CoV-2 virus trapping and eradication successfully [2,9]. However, significant attention is required to increase the production and distribution of these masks for public use.
Besides, the contribution of biotech-pharma companies is also of high significance in terms of investigating novel therapeutic agents of higher efficacy with least/acceptable adverse effects. Though the SARS-CoV-2 virus is new and has exhibited strain variation which is making treatment optimization challenging. But biotechnology experts are analyzing every aspect of bioinformatics to design and develop an effective therapy based on novel anti-viral agents, CRISPR-Cas, antibodies, and vaccines5. Another approach to manage COVID-19 infection is to introduce or boost immunity through nutrition, for example, nutraceuticals have acted as inhibitors to prevent binding between SARS-CoV-2 virus and ACE-2 enzyme [2,8].
Investigating a therapeutic agent against the SARS-CoV-2 virus infection seems possible now but the delivery of these agents is still a remaining challenge because this virus may have numerous reservoirs over the time. It is also demonstrated that COVID-19 infection patients may temporarily or permanently have immunocompromised biological systems. Such-related adverse effects include risk of cardiac arrest, vision issues, weak respiratory system, neurological disorders (one of the serious issues because SARS-CoV-2 virus crosses the blood-brain barrier), etc. Therefore, a single therapeutic agent designed against the SARS-CoV-2 virus may not be enough to treat COVID-19 infected patients completely [1,8].
Thus, a manipulative therapy, a combination of optimized therapeutic agents, consisting of an anti-SARS-CoV-2 virus agent and immune-supportive agents will require to be optimized based on the patient infection profiling. Experts have thought about it and raised/dealing the following concerns 1) drug-to-drug interaction, 2) delivery of drug/drugs at the targeted site, 3) control over the release of drug/drugs from a therapeutic formulation, and 4) immune-supporting long-acting therapies. These tasks are challenging but needed to be managed; therefore, exploring aspects of nanomedicine could be a promising approach to develop novel therapies to manage COVID-19 infection and support the immune system along with SARS-CoV-2 virus affected organs .
Nanomedicine (10 to 200 nm) is a therapeutic cargo designed using an appropriate drug nanocarrier and a therapeutic agent [9–15]. Nowadays magnetic nanomedicine has performed to manage viral infection at various reservoirs even in the brain because nanomedicine is capable to cross any barriers in the body via adopting the following approaches 1) functionalization of nanomedicine with barriers specific receptors, 2) applying external stimulation like ultrasound, and 3) noninvasive guided approach like magnetically guided drug delivery system [10–12].
Besides drug delivery, magnetic nanomedicine could be formulated to deliver multiple drugs at a targeted site to achieve desired therapeutic performance due to 1) control over the release by applying external stimulation like an ac-magnetic field, 2) formulating a magnetic cargo to load multiple drugs without drug-to-drug interaction, for example, layer-by-layer (LBL) approach, and 3) the sequence of drug release can be tuned and planned according to a stage/requirement of disease condition [13–15]. The performance of such nanomedicine mainly depends on the selection of a multi-functional stimuli-response drug nanocarrier such as magneto-electric nanoparticles (MENPs) , opto-magnetic, opto-electromagnetic, magneto-LBL, magneto-liposome, and magneto-plasmonics nanosystem. These advanced nanomedicines not only deliver the drug/drug but also help in the recognition of drug distribution and disease progression.
Combining above mentioned salient features, manipulative magnetic nanomedicine (MMN) as one of the potential future therapy wherein control over delivery and performance if required. Such MMN has the capabilities to recognize and eradicate the SARS-CoV-2 virus to manage COVID-19 infection and symptoms. Besides, due to the flexibility of using the therapeutic agent of choice, these manipulative nanomedicines can be designed and developed as long-acting therapy for COVID-19 infection where anti-virus and immune-supportive agents can stay longer in the body without causing any side-effects. Such personalized MMN (Figure 1) is an urgently required therapy and its development should be the focus of future research with the following aims
Figure 1. Systematic illustration of manipulative nanomedicine projected as future COVID-19 pandemic/endemic therapyDisplay full size
Exploring stimuli-responsive magnetic nanosystems for on-demand-controlled delivery and release.
Image-guided therapy to recognize the delivery site and confirm drug release.
A magnetically guided approach to delivering drugs across the barriers like the gut, BBB, etc.
Magneto-LBL/liposomal approach to delivering multiple drugs to avoid drug-to-drug interaction and control over the drug release sequence. For example, an anti-virus drug should be released first then an immune-protective agent.
The MMN can be customized according to patient disease profile and medical history, for example, selection of anti-SARS-CoV-2 virus agent (antibody, ARV, CRISPR-Cas, etc.,) based on patient genomic profiling.
The MMN can also be customized as long-acting therapeutics that allows drug-releasing for a longer time (2–3 months), as must require therapy to manage post-COVID-19 infection effects.
The MMN can be explored as personalized precision therapy.
3. Expert opinion
Based on the experiences of developing MMN to eradicate neuroHIV/AIDS, under a project of getting into the brain, using MENPs as a drug nanocarrier, magnetically guided drug delivery, and ac-magnetic field stimulation dependent controlled drug release, my team and me believes that MMN can be a future therapy against COVID-19 infection pandemic/or endemic. As it is also known that the SARS-CoV-2 virus infection is a combination of several diseases and symptoms. During the infection treatment, even after the hospital discharge, the patient may have several diseases at the same time for a longer time. Such-complicated medical conditions are not easy to deal with using conventional antiviral drugs. Thus, experts feel the demand for a new therapy that can handle multiple tasks at the same time. Keeping advancements and potentials into consideration, manipulative nanomedicine can be one of the potential COVID-19 infection therapies.
Some of the advancements in this field has been reported, for example, micro-needle-based vaccine delivery to manage COVID-19 infection. Early outcomes are exciting, but a lot must be done in terms of animal model-based trials, and followed up with FDA approval, needed prior to suggest clinical implication. To promote MNM against COVID-19 successfully, a public-private involvement-based significant research needed to be conducted in this field to create a path from a lab (in-vitro) to in-vivo (appropriate animal model) to risk assessments to clinical trials to risk assessment to human trial to risk assessment to FDA approval for public utilization. In the process of developing an anti-COVID-19 infection therapy, careful and critical safety-related risk assessments will be a crucial factor to decide progression step-by-step. This introducing AI will be a good choice to gather bioinformatics, perform big data analysis, avoid unnecessary hit-&-trial approaches, establish a relation with a biological and pathological parameter, and projection of a potential approach. Besides AI, it is also suggested to design several projects focused on every aspect of pre/post-SARS-CoV-2 virus infection, and based on assessments and analytics a potential drug nanocarrier and therapeutics agents should be selected. Developing such an approach is a multidisciplinary research approach and experts of various expertise are needed to work on the same platform to investigate MMN to combat against SARS-CoV-2 virus infection. Projecting the above mention as a necessity, this editorial is a call to experts to join hands for investigating and promoting MMN as a potential future COVID-19 pandemic/endemic therapy. I believe that the MMN approach will be in more demand as new therapeutic agents, such BNT162b2, and mRNA1273 , vaccine as will be investigated over the time.
From author’s references, I want to highlight this study which shows that magnetism is also used to cross the Brain Blood Barrier -Silview
Magnetically guided non-invasive CRISPR-Cas9/gRNA delivery across blood-brain barrier to eradicate latent HIV-1 infection
CRISPR-Cas9/gRNA exhibits therapeutic efficacy against latent human immunodeficiency virus (HIV) genome but the delivery of this therapeutic cargo to the brain remains as a challenge. In this research, for the first time, we demonstrated magnetically guided non-invasive delivery of a nano-formulation (NF), composed of Cas9/gRNA bound with magneto-electric nanoparticles (MENPs), across the blood-brain barrier (BBB) to inhibit latent HIV-1 infection in microglial (hμglia)/HIV (HC69) cells. An optimized ac-magnetic field of 60 Oe was applied on NF to release Cas9/gRNA from MENPs surface and to facilitate NF cell uptake resulting in intracellular release and inhibition of HIV. The outcomes suggested that developed NF reduced HIV-LTR expression significantly in comparison to unbound Cas9/gRNA in HIV latent hμglia/HIV (HC69) cells. These findings were also validated qualitatively using fluorescence microscopy to assess NF efficacy against latent HIV in the microglia cells. We believe that CNS delivery of NF (CRISPR/Cas9-gRNA-MENPs) across the BBB certainly will have clinical utility as future personalized nanomedicine to manage neuroHIV/AIDS.
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When I first heard of blood clots in vaccinated people, I instantly recalled of a similar problem occurring while the mRNA platform was in study for a cancer therapy, by Moderna, I think, prior to Covid. I couldn’t find that piece of information again, but during the research I discovered something even more revealing.
Blood clots in subjects of Covid gene therapies are very likely caused by defective coatings in magnetic particles used for magnetofection, which leads to cell-clogging.
Silviu “Silview” Costinescu
It has been more than plausibly theorized that the explanation for the magnetism in vaxxers is magnetofection, a method of transfection using magnetic fields.
Magnetofection is a very effective way of transfecting plasmid DNA into a variety of primary cells including primary neurons which are known to be notoriously difficult to transfect and very sensitive to toxicity.
For coincidence theorists, let me just add that the inventor of transfection is one of mRNA jabs inventors, Dr. Robert Malone, who has warned FDA on the dangers of these technologies, according to himself.
Scientifically trained at UC Davis, UC San Diego, and at the Salk Institute Molecular Biology and Virology laboratories, Dr. Robert Malone is an internationally recognized scientist (virology, immunology, molecular biology) and is known as one of the original inventors of mRNA vaccination and DNA Vaccination. His discoveries in mRNA non viral delivery systems are considered the key to the current COVID-19 vaccine strategies. Dr. Malone holds numerous fundamental domestic and foreign patents in the fields of gene delivery, delivery formulations, and vaccines. Dr. Malone has close to 100 peer-reviewed publications and published abstracts and has over 11,477 citations of his peer reviewed publications, as verified by Google Scholar. His google scholar ranking is “outstanding” for impact factors. He has been an invited speaker at over 50 conferences, has chaired numerous conferences and he has sat on or served as chairperson on numerous NIAID and DoD study sections.
Magnetofection basically involves attaching DNA onto a magnetic nanoparticle coated with a cationic polymer like polyethylenimine (PEI) [254,255]. The magnetic nanoparticles are generally made up of a biodegradable substance like iron oxide, and its coating onto the polymeric particle is done by salt-induced colloidal aggregation. These prepared nanoparticles are then localized in the target organ by the application of an external magnetic field, which allows the delivery of attached DNA to the target organ, as shown in Figure 3.5. This method also increases the uptake of DNA into target cells as the contact time between the target organ and magnetic nanoparticles increases. In addition, the magnetic field pulls the magnetic nanoparticles into the target cells, which also helps to increase the uptake of DNA [256,257]. In addition, the standard transfection using viral or nonviral vectors is also increased by the magnetofection.
This is a more powerful method of controlled and targeted delivery for gene therapies, in layman terms.
The problem with it is that it’s been proven to be very dangerous for lab animals and it’s not authorized for human use.
From Dr. Jane Ruby m as well as from Pfizer and Moderna we find out how these particles are packaged into the injectable concocts:
“Stew Peters interviews Dr Jane Ruby who confirms the magnetic effects that Covid vaxxed people have experienced. She says it is a deliberately made substance added to the vaccines. This shows criminal intent. It was added because it is an aggressive delivery system to get it into EVERY cell of your body. The process is called ‘Magnetofection’ and is available in scientific literature such as Pubmed. It concentrates the mRNA into people’s cells and forces your body to make these synthetic mRNA instructions even in places where they shouldn’t be located within the body.
It is a ‘forced delivery system’ and is called by the acronym of SPIONS – Supramagnetic Iron Oxide Nanoparticles. These particles use a lipid nanoparticle envelope to gain entry into the cells. It is done this way to protect mRNA because mRNA is easily degraded and this is also why the Pfizer vaccines are refrigerated at -70 degrees Fahrenheit as another form of protection.
There is a German company on the internet called ‘Chemicell’ which sells different chemicals which can make these magnetic fields around your molecules. You can buy 200 microgram vials of their product called, ‘Polymag’. These are developed and sold for research purposes only and are not to be used for human diagnostic or as a component of any drug intended for humans.
However at least Pfizer and Moderna are using this substance in their vaccines. Therefore it is vital that anyone thinking of taking a shot, obtain a full ingredient list to have full informed consent and to postpone getting the Covid Jab, as each day brings further information into the public domain. Dr Ruby is asked if this was deliberate by the manufacturers and answers that this substance doesn’t occur naturally. It had to be added into the vaccine.
Many have spoken about the Polyethelene Glycol or PEG which enables the vaccines to get through water based cell membranes as this is lipophilic – attracted to fats – but there are other places in the body where ‘God and Nature’ hadn’t intended these substances to be, but by using this delivery system of supra nanoparticles, you are creating a super delivery system which forces these substances into areas where they are not meant to be.”
. 2019 Nov;13(9):1197-1209. doi: 10.1080/17435390.2019.1650969. Epub 2019 Aug 22.
Superparamagnetic iron oxide nanoparticles (SPIONs) modulate hERG ion channel activity
Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used in various biomedical applications, such as diagnostic agents in magnetic resonance imaging (MRI), for drug delivery vehicles and in hyperthermia treatment of tumors.
Although the potential benefits of SPIONs are considerable, there is a distinct need to identify any potential cellular damage associated with their use.
Since human ether à go-go-related gene (hERG) channel, a protein involved in the repolarization phase of cardiac action potential, is considered one of the main targets in the drug discovery process, we decided to evaluate the effects of SPIONs on hERG channel activity and to determine whether the oxidation state, the dimensions and the coating of nanoparticles (NPs) can influence the interaction with hERG channel.
Using patch clamp recordings, we found that SPIONs inhibit hERG current and this effect depends on the coating of NPs. In particular, SPIONs with covalent coating aminopropylphosphonic acid (APPA) have a milder effect on hERG activity. We observed that the time-course of hERG channel modulation by SPIONs is biphasic, with a transient increase (∼20% of the amplitude) occurring within the first 1-3 min of perfusion of NPs, followed by a slower inhibition. Moreover, in the presence of SPIONs, deactivation kinetics accelerated and the activation and inactivation I-V curves were right-shifted, similarly to the effect described for the binding of other divalent metal ions (e.g. Cd2+ and Zn2+).
Finally, our data show that a bigger size and the complete oxidation of SPIONs can significantly decrease hERG channel inhibition.
Taken together, these results support the view that Fe2+ ions released from magnetite NPs may represent a cardiac risk factor, since they alter hERG gating and these alterations could compromise the cardiac action potential.
MIT SAYS IT’S NOT JUST SPIONS, BUT ALSO LIONS:
HDT Bio, the biotechnology company in Seattle, has an alternative solution. Working with Deborah Fuller, a microbiologist at the University of Washington, it’s pioneering a different kind of protective bubble for the mRNAs. If it works, it would mean that an mRNA vaccine for covid-19 could be stable in a regular fridge for at least a month, or at room temperature for up to three weeks.
Their method: instead of encasing the mRNA in a lipid nanoparticle, they’ve engineered molecules called lipid inorganic nanoparticles, or LIONs. The inorganic portion of the LION is a positively charged metal particle—so far they’ve been using iron oxide. The positively charged metal would bind to the negatively charged mRNA, which wraps around the LION. The resulting particle is solid, which creates more stability and reduces the reliance on refrigeration.
A real-world study by the CDC backs up the clinical trial data from both mRNA vaccines—although the rise of the UK variant in the US is a cloud on the horizon.
“The cold chain has always been an issue for [the] distribution of vaccines, and it’s only magnified in a pandemic.”
HDT Bio initially developed LIONs to treat liver cancer and tumors in the head and neck, but when the pandemic hit, they pivoted to trying the particles with mRNA vaccines. Early preclinical trials in nonhuman primates showed that the LION, combined with an mRNA vaccine for covid-19, worked as they’d hoped.
Carter of HDT Bio says that in an ideal situation, LIONs could be sent to clinics worldwide in advance, to be stored at room temperature or in a regular refrigerator, before being mixed into vaccine vials at clinics. Alternatively, the two could be premixed at a manufacturing facility. Either way, this method would make doses stable for at least a month in a regular refrigerator.
Fuller says that some scientists have criticized the need for two vials—one for the LION and another for mRNA before they’re mixed together. “But I think the advantages of having an effective product more amenable to worldwide distribution outweighs those negatives,” she says.
HDT Bio is applying for permission to start human clinical trials in the US and is looking to start clinical trials in India this spring. In the US, it faces some unique challenges in FDA regulation, since the LION particles would be considered a drug separate from the vaccine. Regulators in Brazil, China, South Africa, and India—where HDT Bio is hoping to launch its product—don’t consider the LION a drug because it isn’t the active component, says Carter, meaning that there would be one less layer of regulation than in the US.
For now, it’s still very much an early-stage technology, says Michael Mitchell, a bioengineer at the University of Pennsylvania who works on drug delivery systems. He stresses that more research should reveal whether the iron oxide causes any side effects. – MIT Technology Review
Now here’s the bombshell:
This is no secret to experts, but it’s been revealed to me in the video presentation below, made in 2017 by reputed Prof Diana Borca, from Rensselaer Polytechnic Institute, who uses magnetic nanoparticles to treat diseases. In order to get the magnetic nanoparticles into the right places, scientists like Diana have to figure out what kind of coating the nanoparticles need. Coatings help the nanoparticles get to the cells they want to treat without hurting the healthy cells. And if the coating of the magnetic particles breaks, the result is “CLOGGING”, as Borca explains below. Which can translate as clotting, if in blood. Who knows what they lead to when in other organs, strokes maybe?
So I think the only thing we’re missing from the puzzle is official hard evidence that they used magnetofection or magnetogentic methods.
But if it walks like a duck and quacks like a duck, only the government needs government papers to confirm it’s a duck
What each and every one of you can do until we find that evidence?
On screens we’re sound. Please help with the statistical and empirical tests!
Please help finding out if there’s a strong data and empirical correlation between blood clots and magnetism. Anyone you know that has been jabbed and experienced blood clots, heart or circulatory problems needs to take the magnet challenge right now! A strong enough correlation indicates causation. If you make such a test, please reach us on our socials and communicate the result, whether positive or negative! Also VAERS is exploding with reports of magnetism, please help analyzing the data to see if it pairs with clotting. Thank you!
Also food for thought: isn’t this also related to the problems these GMO dupes experience during air-travel? I’ll investigate this in a soon coming report.
This chapter highlighted magnetofection, magnetic patterning of cells, and construction of 3D tissue-like structures. Among them, Mag-TE for constructing 3D structures has been extensively studied, and various kinds of other tissues such as retinal pigment epithelial cell sheets,102 MSC sheets,44 and cardiomyocyte sheets,46 have been already generated. Tubular structures consisting of heterotypic layers of endothelial cells, smooth muscle cells, and fibroblasts have also been created.43 In this approach, magnetically labeled cells formed a cell sheet onto which a cylindrical magnet was rolled, which was removed after a tubular structure was formed. If these processes can be scaled up, there is great potential for these techniques in the treatment of a variety of diseases and defects.
In the translational research, toxicology of functional magnetite nanoparticles is an important issue. The main requisite for a cell-labeling technique is to preserve the normal cell behavior. As for biocompatibility of MCLs, no toxic effects against proliferation of several cell types were observed within the range of magnetite concentrations tested (e.g., human keratinocytes,63 < 50 pg-magnetite/cell; HUVECs,41 HAECs,42 human dermal fibroblasts,41 human smooth muscle cells,43 mouse fibroblast cells,43 canine urothelial cells,43 human MSCs,44 and rat MSCs45 < 100 pg/cell). Moreover, MCLs did not compromise MSC differentiation44,45 or electrical connections of cardiomyocytes.46 In addition, an in vivo toxicity of magnetite nanoparticles has been extensively studied. As an MRI contrast agent, ResovistR was first applied clinically for detecting liver cancer, since ResovistR is taken up rapidly by the reticuloendothelial system such as Kupffer cells of the liver compared with the uptake by cancer cells of the liver. In a preliminary study,103 the authors investigated the toxicity of systemically administered MCLs (90 mg, i.p.) in mice; none of the 10 mice injected with MCLs died during the study. Transient accumulation of magnetite was observed in the liver and spleen of the mice, but the magnetite nanoparticles had been cleared from circulation by hepatic Kupffer cells in the spleen by the 10th day after administration.103
In conclusion, magnetic nanoparticles have been developed into “functional” magnetite nanoparticles which are highly promising tools for a wide spectrum of applications in tissue engineering. The proven lack of toxicity of the functional magnetite nanoparticles is expected to provide exciting tools in the near future for clinical tissue engineering and regenerative medicine.View chapter
One of the pioneers using magnetofection for in vitro applications was Lin et al.91 There are various cationic magnetic nanoparticles types that have the capacity to bind nucleotidic material on their surface. With this method, the magnetic nanoparticles are concentrated in the target cells by the influence of an external magnetic field (EMF). Normally, the internalization is accomplished by endocytosis or pinocytosis, so the membrane architecture stays intact. This is an advantage over other physical transfection methods. Other advantages are the low vector dose needed to reach saturation yield and the short incubation time needed to achieve high transfection efficiency. Moreover, with the application of an EMF, cells transfected with magnetic nanoparticles can be used to target the region of interest in vivo.
220.127.116.11 Iron Oxide Nanoparticles
The magnetic nanoparticles most used in magnetofection include the iron oxide nanoparticles (IONPs). IONPs are biodegradable and not cytotoxic and can be easily functionalized with PEI, PEG, or PLL. Poly-l-lysine-modified iron oxide nanoparticles (IONP–PLL) are good candidates as DNA and microRNA (miRNA) vectors because they bind and protect nucleic acids and showed high transfection efficiency in vitro. In addition, they are highly biocompatible in vivo.
Chen et al.92 used human vascular endothelial growth factor siRNA bound to superparamagnetic iron oxide nanoparticles (SPIONs) and it was capable of hepatocellular carcinoma growth inhibition in nude mice. Moreover, Li et al.93 demonstrated that the intravenous injection of IONP–PLL carrying NM23-H1 (a tumor suppressor gene) plasmid DNA significantly extended the survival time of an experimental pulmonary metastasis mouse model.
Another advantage of this kind of nanoparticles is that they can be used as MRI agents. Chen et al.94 bound siRNA to PEG-PEI SPIONs together to a gastric cancer-associated CD44v6 single-chain variable fragment. This bound permitted both cancer cell’s transfection and their visualization by MRI.
But those complexes might be used for cell therapies as well. Schade et al.95 used iron oxide magnetic nanoparticles (MNPs) to bind miRNA and transfect human mesenchymal stem cells. As the binding between the MNPs and PEI took place via biotin-streptavidin conjugation, these particles cannot pass the nuclear barrier, so they are good candidates to deliver miRNA, as it exerts its function in the cytosol. They functionalized the surface nanoparticles with PEI and were able to obtain a better transfection than PEI 72 h after transfection. Moreover, they demonstrated that magnetic polyplexes provided a better long-term effect, also when included inside of the stem cells.View chapter
Another attempt to apply magnetic IONPs is the so-called magnetofection (MF) approach. Key factors enabling this method are IONPs that are coupled to vector DNA and guided by the influence of an external magnetic field. By this means, DNA can be transfected into cells of interest. One possibility to enable enhanced binding capabilities of the negatively charged DNA to magnetic IONP beads is the coating IONPs with a positively charged material such as polyethylenimine. The efficiency of the vectors has hence shown to increase up to several thousand times (Scherer et al., 2002). The above depicted engagement of IONPs in MF has shown to be universally applicable to viral and nonviral vectors. This is mostly because it is very rapid and simple. Furthermore, it is a very attractive approach since it yields saturation level transfection at low-dose in vitro (Krotz et al., 2003). Fernandes and Chari (2016) have demonstrated an approach delivering DNA minicircles (mcDNA) to neural stem cells (NSCs) by means of MF. DNA minicircles are small DNA vectors encoding essential gene expression components but devoid of a bacterial backbone, thereby reducing construct size versus conventional plasmids. This could be shown to be very beneficial for the use of genetically engineered NSC transplant populations in regenerative neurology. The aim was to improve the release of biomolecules in ex vivo gene therapy. It could be demonstrated that MF of DNA minicircles is very safe and provided for sustained gene expression for up to 4 weeks. It is described to have high potential as clinically translatable genetic modification strategy for cell therapy (Fernandes and Chari, 2016). The last in vitro application for magnetic nanoparticles to be presented in this chapter will be tissue repair.View chapter
Two methods rely on the application of a magnetic field for gene transfer. Magnetofection uses magnetic nanoparticles coated with DNA in presence of a magnetic field. The nucleic acid-nanoparticle complexes are driven toward and into the target cells by magnetic force application. Gene transfer is enhanced by magnetofection as DNA-loaded particles are guided and maintained in close contact with the target cells. Cellular uptake through endocytosis is thus increased as well. The process has been mainly applied to cultured cells and has been proven more efficient than other chemical methods in some cases.8 The second method is magnetoporation in which membrane permeability is increased, triggered by the applied magnetic field.9View chapter
For gene therapy applications, magnetic particles are generally used for increasing the transfection efficiencies of cultured cells, a technique known as magnetofection [91–104] in which magnetic particles and nucleic acids are mixed together and then added to the cell culture media. The nucleic acid-bound magnetic particles then move from the media to the cell surface upon the application of an external magnetic force, as shown in Figure 9.1. The principle advantage of this approach is the rapid sedimentation of the gene-therapeutic agent onto the target area, thereby reducing the time and dose of vector to achieve highly efficient transfection, with lower cell cytotoxicity.
In in vivo magentofection, the magnetic field is focused over the target site. This method has the potential not only to enhance transfection efficiency but also to target the therapeutic gene to a specific organ or site, as shown in Figure 9.2.
Generally, magnetic particles carrying therapeutic genes are injected intravenously. As the particles flow through the bloodstream, they are captured at the target site using very strong, high-gradient external magnets. Once they are captured, the magnetic particles carrying the therapeutic gene are taken up by the tissue, followed by release of the gene via enzymatic cleavage of cross-linked molecules or degradation of the polymer matrix. If DNA is embedded inside or within the coating material, the magnetic field must be applied to heat the particles and release the gene from the magnetic carrier .View chapter
In an attempt to address the transient damage caused by the invasive methods mentioned above (i.e., hydrodynamic injection and electroporation), magnetofection techniques have been introduced. This technique uses the physical method of a magnetic field to direct the deliver of genetic material to the desired target site. The concept involves attaching DNA to a magnetic nanoparticle usually consisting of a biodegradable substance such as iron oxide and coated with cationic polymer such as PEI (Mulens, Morales, & Barber, 2013). These magnetic nanoparticles are then targeted to the tissue through a magnetic field generated by an external magnet. The magnetic nanoparticles are pulled into the target cells increasing the uptake of DNA. This technique is noninvasive and can precisely target the genetic material to the desired site while increasing gene expression. The drawback to magnetofection is the need to formulate magnetic nanoparticles complexed with naked DNA, as well as the need for strong external magnets.View chapter
Stimulus-guided delivery is a non-invasive and convenient approach for clinical applications. Several methods in this category, including electroporation, ultrasound and magnetofection, have been used to deliver siRNAs to specific tissue sites. Owing to constraints associated with application of external stimuli under in vivo conditions, most such studies have been done in vitro. However, in vivo applications of stimulus-guided delivery of anticancer siRNAs are increasingly being reported.
Electroporation has been studied as a means for facilitating in vivo delivery of anticancer siRNAs. Notably, an electroporation method employing a new type of ‘plate and fork’ type electrode has been applied in vivo in mice (Takei et al., 2008). In this application, a chemically modified form of VEGF-specific siRNA in phosphate-buffered saline was intratumorally administered at three doses of 0.08, 0.17 and 0.33 mg/kg, or intravenously administered at a single dose of 6.6 mg/kg. Then, an electronic pulse was applied to a pair of plate and fork electrodes pre-inserted into PC-3-xenografted tumour tissues. Application of electroporation inhibited tumour growth to a similar degree after 0.17 mg/kg intratumoral and 6.6 mg/kg intravenous doses, in each case producing a 40-fold greater inhibitory effect than a local dose. Notably, the duration of the antitumour effect was maintained for 20 days after a single injection via the local or systemic route.
Magnetically guided in vivo siRNA delivery has been investigated using magnetic crystal-lipid nanostructures (Namiki et al., 2009). In this study, a magnetitenanocrystal was coated with oleic acid and a cationic lipid shell, and complexed to EGFR-specific siRNA. Following intravenous administration to mice, siRNA complexed to the magnetic core-encapsulated cationic lipid shell showed a rank order of tissue distribution of spleen followed by liver and lung. For in vivo magnetofection, titanium nitride-coated magnets were internally implanted under the skin peripheral to tumour lesions or were externally placed onto the skin. Mice were intravenously given a total of eight 0.3 mg/kg doses of siRNA complexed to cationic nanoshells administered every other day. Both internal and external applications of a magnetic field reduced tumour (MKN-74 or NUGC-4) volume by 50% compared with the control group 28 days after the initiation of treatment.
Ultrasound-guided siRNA delivery has also been used to increase the in vivo delivery of siRNAs. Ultrasound can produce cavitation, thereby resulting in transient disruptions in cell membranes within tissues (Vandenbroucke et al., 2008). Few studies have addressed the in vivo antitumour effects of ultrasound-guided anticancer siRNAs. To date, most such studies have evaluated the feasibility of the method using siRNAs specific for reporter genes, such as enhanced green fluorescent protein (Negishi et al., 2008). In this latter study, PEG-modified cationic lipid nanobubbles entrapping the ultrasound imaging gas perfluoropropane were complexed with enhanced green fluorescent protein-specific siRNA and intramuscularly administered at a dose of 0.15 mg/kg to mice transfected 1 day prior with enhanced green fluorescent protein-encoding plasmid DNA. Three days after siRNA injection and ultrasound application, fluorescent protein levels at the injection sites were reduced.
Although the feasibility of in vivo applications of stimulus-guided delivery of anticancer siRNA has been demonstrated and positive results have been reported, the ultimate success of these delivery methods may depend on the development of devices capable of providing a sufficient stimulus to tumour tissues deep within the body. Moreover, for in vivosystemic administration, delivery systems that carry both external stimulus-responsive agents and siRNA must meet more general requirements, such as in vivo stability, low toxicity and enhanced tumour tissue accumulation. With the concurrent progress in medical device bioengineering and siRNA delivery technologies, it can be expected that stimulus-guided strategies will be used in more diverse in vivo applications to facilitate anticancer siRNA delivery.View chapter
Various physical methods of gene delivery have been developed, and each one has its own merits and demerits. EP is particularly important for introducing DNA to superficial areas, but to deliver DNA to particular organs, surgery is required. To overcome this problem and to enhance the introduction of gene vectors into cells , the new means of physical gene delivery is magnetofection, which delivers DNA to the target organ, using the magnetic field. Magnetofection basically involves attaching DNA onto a magnetic nanoparticle coated with a cationic polymer like polyethylenimine (PEI) [254,255]. The magnetic nanoparticles are generally made up of a biodegradable substance like iron oxide, and its coating onto the polymeric particle is done by salt-induced colloidal aggregation. These prepared nanoparticles are then localized in the target organ by the application of an external magnetic field, which allows the delivery of attached DNA to the target organ, as shown in Figure 3.5. This method also increases the uptake of DNA into target cells as the contact time between the target organ and magnetic nanoparticles increases. In addition, the magnetic field pulls the magnetic nanoparticles into the target cells, which also helps to increase the uptake of DNA [256,257]. In addition, the standard transfection using viral or nonviral vectors is also increased by the magnetofection.
The magnetofection has some drawbacks: a particle size below 50 nm renders it not suitable for magnetic targeting and too large a particle size (more than 5 μm) retards the entry of magnetic nanoparticles inside the blood capillaries. The blood flow rate also affects the transfection efficacy of this method; for example, the flow rate of around 20 cm/s in the human aorta makes the transfection tricky. The external magnetic flux density and gradient decreases at a distance from the magnetic pole, which also affects the transfection efficacy.
Primary endothelial cells are effectively transfected by magnetofection [254,258]. In addition, magnetofection is effective for in vitro and in vivo delivery of DNA to target cells like those in the GI tract and blood vessels , and for antisense ODNs delivery . Other applications include advances in ex vivo tissue engineering, development of tumor vaccines, localized therapy for cancer, and cardiovascular therapy . Significant enhancement in reporter gene expression in a short time has been observed in the ex vivo porcine airway model; this may be attributed to an increase in contact time with mucociliary cells, thereby reducing their clearance from the target site . A study carried out using magnetic albumin microspheres with entrapped doxorubicin in the rat model for tumors resulted in a high level of tumor remission in animals compared to animals treated with free doxorubicin, placebo microspheres, or nonlocalized doxorubicin microspheres, which resulted in considerable enlargement in tumor size associated with metastases and subsequent death [262,263]. The magnetic nanoparticles with doxorubicin are also under clinical trial . Magnetofection has been widely used for viral and nonviral vectors and also for the delivery of DNA, nucleic acids, and siRNA [260,265,266].
In conclusion, magnetofection is an efficient system for gene delivery and has the potential to bring in vitro and in vivo transgene transfection in the target organ. The limitations of this delivery system are overcome by the application of proper formulations and novel magnetic field skills.View chapter
Nonviral vectors group a heterogeneous variety of elements that can be classified as naked DNA or RNA, liposome-DNA complexes (lipoplexes), and polymer-DNA complexes (polyplexes). Since the beginning of the gene therapy field, nonviral vectors have received significant attention due to their reduced pathogenicity, lower immunotoxicity, and low cost and ease of production over viral approaches. To date, a myriad of delivery systems grouped as physical methods and chemical carriers have been reported. Physical methods such as direct injection, ballistic DNA, electroporation, sonoporation, photoporation, magnetofection, hydroporation, and mechanical massage, employ physical force to cross the cell membrane barrier. Chemical carriers such as (1) inorganic particles (calcium phosphate, silica, gold, but also magnetic nanoparticles, fullerenes, carbon nanotubes, quantum dots, and supramolecular systems); (2) lipid-based (cationic lipids, lipid-nano emulsions, solid lipid nanoparticles); (3) peptide-based; and (4) polymer-based (i.e., polyethylenimine, chitosan, dendrimers, and polymethacrylate) form small size complexes with nucleic acids to help them cross the cell membrane efficiently (see ref  for extensive review). However, despite the large number of different nonviral vectors still, there is poor transduction efficiency of the target cells as well as low and transient transgene expression. Due to it, nonviral vectors account for less than 25% of the clinical assays, mainly for cancer and cardiovascular diseases, being naked/plasmid DNA (452 clinical assays) and lipofection (119 clinical assays) the systems more frequently used, while all the rest of the nonviral vector account only for 3% of the assays.View chapter
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! Articles can always be subject of later editing as a way of perfecting them
Maybe you’ve been just like myself, too tired to be surprised or very concerned with the new wave of magneto-vaxxers. But we have to make the effort to take this as it most likely is: super-serious.
UPDATE JULY 2021: GRAPHENE OXYDE CONFIRMED AS MAIN INGREDIENT (99%) IN THE PFIZER VACCINE. AMONG OTHER DESASTRUOUS EFFECTS: BLOOD-CLOTTING and covid symptoms. HOW DID WE GET TO THIS REVELATION? READ THE FIRST INVESTIGATION INTO MAGNETOGENETICS EVER!
La Quinta Columna has recently made an urgent announcement that they hope will reach as many people as possible, especially those involved in health and legal services, as biostatistician Ricardo Delgado, Dr. José Luis Sevillano and the team of researchers and professors with whom they have been conducting their research have confirmed the presence of graphene oxide nanoparticles in vaccination vials.
In program nº63, the team showed some photos of the analyses carried out, specifically results obtained by optical and transmission electron microscopy observation, reserving the results of other techniques used for future programs. They also announced that the report based on all the techniques performed, which allowed determining the presence of graphene oxide, will be made official by the researchers who performed the analyses very soon….
There’s indications, if not full fledge proof, that masks being used and currently marketed contain graphene oxide. Not only the ones that were withdrawn at the time, as indicated by the media, the swabs used in both PCR and antigen tests also contain graphene oxide nanoparticles.
Graphene oxide can generates blood coagulation. Graphene oxide causes alteration of the immune system. By decompensating the oxidative balance in relation to the gulation reserves. If the dose of graphene oxide is increased by any route of administration, it causes the collapse of the immune system and subsequent cytokine storm.
Graphene oxide accumulated in the lungs generates bilateral pneumonias by uniform dissemination in the pulmonary alveolar tract. Graphene oxide causes a metallic taste. Perhaps this is starting to make sense to you now. Inhaled graphene oxide causes inflammation of the mucous membranes and thus loss of taste and partial or total loss of smell.
Graphene oxide acquires powerful magnetic propertiesinside the organism. This is the explanation for the magnetic phenomenon that billions of people around the world have already experienced after various routes of administration of graphene oxide. Among them the vaccine….
It is therefore absolutely essential and vital that you make this information available to your medical community.
So you have precisely 0 (zero) reasons for surprise if they find some type of graphene fibers in masks or swabs.
Older studies on graphene oxide below, now let’s see how we got here.
It all started with the courageous or desperate Pharma-dupes who got jabbed (yeah, vaxxers started it), and then had the guts to expose themselves on Internet with their weird magnetic symptoms. They got followed by courageous and persistent citizen-journalists like Tim Truth, who managed to capture attention from journalists like myself and a few others with bigger or smaller platforms, who, together, managed to push this as mainstream as Jimmy Kimmel.
The scientific method to debunk an experiment is to repeat it. If they really were serious about debunking it, they would’ve given everyone free magnets to test it. Instead…
UPDATE: SOMETHING BIG IS HAPPENING! Youtube censorship entered overdrive, they’ve deleted us a second video on this in 24h, this time it was THE Ben Swann investigation on DARPA’S MAGNETIC MIND CONTROL PROGRAM. both my channels are hanging on a thread now. PLEASE SPREAD THIS INFO LIKE FIRE! i’M NOT SAYING “SPREAD MY LINK,” BUT SPREAD THE INFO THAT SOUNDS RIGHT TO YOU AND DO IT NOW!
Proof that this is serious: as I was wrapping this report up, YouTube has just deleted my COMEDY take on this, proving that we struck a chord.
update #2: more examples of “magnetovaxxers” found and compiled
More and more people are taking the magnet challenge Thanks Tim Truth for sparking my investigation and following up! HERE you can watch his latest compilation of vaxxers turning into fridge doors
If next minute all vaxxtards turn into transformer drones, I’m not going to be very surprised, rather amused. But i should be concerned. I am concerned with sticky vaxxers because most likely there’s some magnetogenetics involved. It’s almost impossible that this is not the explanation for the new Internet sensation.
Earliest academic mention of magnetogenetics I found comes from China, but in the meantime I’ve learned this goes back to 2010 and beyond, more updates soon:
UPDATE #3 in just hours, youtube admits my appeal and reinstates the Ben Swann Video!
Can hardly keep up with myself lol What did the appeal say that was unprecedently persuasive? I don’t have the exact words, but the main ideas were: 1. Everything you’ve just claim is a lie, it’s offensive and defaming, but that’s ok because your words have no value. 2. Thanks for pointing out you’re especially sensitive about this topic, we’ll put it on turbo-boost!
UPDATE #4 mAY 20 2021: WE’VE ALREADY WON THE INFORMATION WAR AGAINST BIG TECH, THE KNOWLEDGE IS MAINSTREAM NOW, ICKE AND THE LAST AMERICAN VAGABOND ALL OVER IT
NOW ENTER THE SCIENCE
Nikhil Hajirnis tells us how cells developed strategies to detect light and magnetism with evolution of a class of proteins called the crytochromes. And now we use this understanding to alter magnetic fields around cells to image cells as well as to attempt changing the way they work. Source: CSIR – Centre For Cellular And Molecular Biology
Magnetogenetics: remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor
Viewing the body as a chemical system and treating maladies with pharmaceuticals is so 20th century. In 21st century medicine, doctors may consider the body as an electrical system instead, and prescribe therapies that alter the electrical pulses that run through the nerves.
That’s the premise of DARPA’s newest biomedical program, anyway. The ElectRx program aims to treat disease by modulating the activity of the peripheral nerves that carry commands to all the organs and muscles of the human body, and also convey sensory information back to the brain.
Yesterday, DARPA announced the first seven grants under the ElectRx program. The scientists chosen are doing fairly fundamental research, because we’re still in the early days of electric medicine; they’ll investigate mechanisms by which to stimulate the nerves, and map nerve pathways that respond to that stimulation. They’re working on treatments for disorders such as chronic pain, post-traumatic stress, and inflammatory bowel disease.
The proposed stimulation methods are fascinating in their diversity. Researchers will not only stimulate nerves with jolts of electricity, they’ll also use pulses of light, sound waves, and magnetic fields.
Three research teams using electrical stimulation will target the vagus nerve, which affects many different parts of the body. IEEE Spectrum explored the medical potential of vagus nerve hacking in a recent feature article, writing:
Look at an anatomy chart and the importance of the vagus nerve jumps out at you. Vagus means “wandering” in Latin, and true to its name, the nerve meanders around the chest and abdomen, connecting most of the key organs—heart and lungs included—to the brain stem. It’s like a back door built into the human physiology, allowing you to hack the body’s systems.
The light-based stimulation research comes from the startup Circuit Therapeutics. The company was cofounded by Stanford’s Karl Deisseroth, one of the inventors of optogenetics, the new technique that inserts light-sensitive proteins into neurons and then uses pulses of light to turn those neurons “on” and “off.” Under the DARPA grant, the researchers will try to use pulses of light to alter neural circuits involved in neuropathic pain.
To tweak the nervous system with sound waves, Columbia University’s Elisa Konofagou will use a somewhat mysterious ultrasound technique. In an e-mail, Konofagou explains that it’s already known that ultrasound can be used to stimulate neurons, but with the DARPA grant, she hopes to figure out how it works. Her hypothesis: As ultrasound propogates through biological tissue, it exerts mechanical pressure on that tissue, which stimulates specific mechanosensitive channels in neurons and causes them to “turn on.”
The final project will rely on magnetic fields to activate neurons, using a technique that could be called “magnetogenetics.” An MIT team led by Polina Anikeeva will insert heat-sensitive proteins into neurons, and will then deploy magnetic nanoparticles that bind to the surface of those neurons. When exposed to a magnetic field, these nanoparticles heat up and activate the neurons to which they’re attached.
Figuring out how to alter the activity of the nervous systems with these various tricks will be a pretty impressive accomplishment. But in the DARPA world, achieving that understanding is just step one. Next, the agency wants its grantees to develop “closed-loop” systems capable of detecting biomarkers that signal the onset of disease, and then respond automatically with neural stimulation. Spectrum covered the first such closed-loop neural stimulators in a recent feature article, stating:
The goal of all these closed-loop systems is to let doctors take their expert knowledge—their ability to evaluate a patient’s condition and adjust therapy accordingly—and embed it in an implanted device.
I bet all that goes great served with some trans-cranial magnetic brainwashing.
Military magnetic field breakthrough could lead to mind reading computers and Harry Potter ‘wands’ to check for head injuries
DARPA’s new project aims to focus on detecting superweak magnetic fields
The research could let medics rapidly diagnose concussions on the battlefield
It could also lead to brain-machine interfaces for controlling prosthetic limbs and external machines through the magnetic signals associated with thought
PUBLISHED: 22:35 BST, 20 March 2017 | UPDATED: 22:35 BST, 20 March 2017
Our own body generates electric currents that create ripples in the surrounding magnetic field.
These magnetic field variations allow medical professionals to use certain diagnostic tools for brain and heart conditions.
But now new research led by DARPA (Defense Advanced Research Projects Agency) aims to go beyond these diagnostic tests and develop magnetic field sensing for broader applications such as brain-machine interfaces (BMIs) for uses such as controlling prosthetic limbs and external machines through the magnetic signals associated with thought.
If scientists could give living cells magnetic properties, they could perhaps manipulate cellular activities with external magnetic fields. But previous attempts to magnetize cells by producing iron-containing proteins inside them have resulted in only weak magnetic forces. Now, researchers reporting in ACS’ Nano Letters have engineered genetically encoded protein crystals that can generate magnetic forces many times stronger than those already reported.
The new area of magnetogenetics seeks to use genetically encoded proteins that are sensitive to magnetic fields to study and manipulate cells. Many previous approaches have featured a natural iron-storage protein called ferritin, which can self-assemble into a “cage” that holds as many as 4,500 iron atoms. But even with this large iron-storage capacity, ferritin cages in cells generate magnetic forces that are millions of times too small for practical applications. To drastically increase the amount of iron that a protein assembly can store, Bianxiao Cui and colleagues wanted to combine the iron-binding ability of ferritin with the self-assembly properties of another protein, called Inkabox-PAK4cat, that can form huge, spindle-shaped crystals inside cells. The researchers wondered if they could line the hollow interiors of the crystals with ferritin proteins to store larger amounts of iron that would generate substantial magnetic forces.
To make the new crystals, the researchers fused genes encoding ferritin and Inkabox-PAK4cat and expressed the new protein in human cells in a petri dish. The resulting crystals, which grew to about 45 microns in length (or about half the diameter of a human hair) after 3 days, did not affect cell survival. The researchers then broke open the cells, isolated the crystals and added iron, which enabled them to pull the crystals around with external magnets. Each crystal contained about five billion iron atoms and generated magnetic forces that were nine orders of magnitude stronger than single ferritin cages. By introducing crystals that were pre-loaded with iron to living cells, the researchers could move the cells around with a magnet. However, they were unable to magnetize the cells by adding iron to crystals already growing in cells, possibly because the iron levels in cells were too low. This is an area that requires further investigation, the researchers say.
Genetically engineered ‘Magneto’ protein remotely controls brain and behaviour
“Badass” new method uses a magnetised protein to activate brain cells rapidly, reversibly, and non-invasively THE GUARDIAN, Thu 24 Mar 2016 14.30 GMT
Researchers in the United States have developed a new method for controlling the brain circuits associated with complex animal behaviours, using genetic engineering to create a magnetised protein that activates specific groups of nerve cells from a distance.
Understanding how the brain generates behaviour is one of the ultimate goals of neuroscience – and one of its most difficult questions. In recent years, researchers have developed a number of methods that enable them to remotely control specified groups of neurons and to probe the workings of neuronal circuits.
The most powerful of these is a method called optogenetics, which enables researchers to switch populations of related neurons on or off on a millisecond-by-millisecond timescale with pulses of laser light. Another recently developed method, called chemogenetics, uses engineered proteins that are activated by designer drugs and can be targeted to specific cell types.
Although powerful, both of these methods have drawbacks. Optogenetics is invasive, requiring insertion of optical fibres that deliver the light pulses into the brain and, furthermore, the extent to which the light penetrates the dense brain tissue is severely limited. Chemogenetic approaches overcome both of these limitations, but typically induce biochemical reactions that take several seconds to activate nerve cells.
The new technique, developed in Ali Güler’s lab at the University of Virginia in Charlottesville, and described in an advance online publication in the journal Nature Neuroscience, is not only non-invasive, but can also activate neurons rapidly and reversibly.
Several earlier studies have shown that nerve cell proteins which are activated by heat and mechanical pressure can be genetically engineered so that they become sensitive to radio waves and magnetic fields, by attaching them to an iron-storing protein called ferritin, or to inorganic paramagnetic particles. These methods represent an important advance – they have, for example, already been used to regulate blood glucose levels in mice – but involve multiple components which have to be introduced separately.
The new technique builds on this earlier work, and is based on a protein called TRPV4, which is sensitive to both temperature and stretching forces. These stimuli open its central pore, allowing electrical current to flow through the cell membrane; this evokes nervous impulses that travel into the spinal cord and then up to the brain.
Güler and his colleagues reasoned that magnetic torque (or rotating) forces might activate TRPV4 by tugging open its central pore, and so they used genetic engineering to fuse the protein to the paramagnetic region of ferritin, together with short DNA sequences that signal cells to transport proteins to the nerve cell membrane and insert them into it.
In vivo manipulation of zebrafish behavior using Magneto. Zebrafish larvae exhibit coiling behaviour in response to localized magnetic fields. From Wheeler et al (2016).
When they introduced this genetic construct into human embryonic kidney cells growing in Petri dishes, the cells synthesized the ‘Magneto’ protein and inserted it into their membrane. Application of a magnetic field activated the engineered TRPV1 protein, as evidenced by transient increases in calcium ion concentration within the cells, which were detected with a fluorescence microscope.
Next, the researchers inserted the Magneto DNA sequence into the genome of a virus, together with the gene encoding green fluorescent protein, and regulatory DNA sequences that cause the construct to be expressed only in specified types of neurons. They then injected the virus into the brains of mice, targeting the entorhinal cortex, and dissected the animals’ brains to identify the cells that emitted green fluorescence. Using microelectrodes, they then showed that applying a magnetic field to the brain slices activated Magneto so that the cells produce nervous impulses.
To determine whether Magneto can be used to manipulate neuronal activity in live animals, they injected Magneto into zebrafish larvae, targeting neurons in the trunk and tail that normally control an escape response. They then placed the zebrafish larvae into a specially-built magnetised aquarium, and found that exposure to a magnetic field induced coiling manouvres similar to those that occur during the escape response. (This experiment involved a total of nine zebrafish larvae, and subsequent analyses revealed that each larva contained about 5 neurons expressing Magneto.)
In one final experiment, the researchers injected Magneto into the striatum of freely behaving mice, a deep brain structure containing dopamine-producing neurons that are involved in reward and motivation, and then placed the animals into an apparatus split into magnetised a non-magnetised sections. Mice expressing Magneto spent far more time in the magnetised areas than mice that did not, because activation of the protein caused the striatal neurons expressing it to release dopamine, so that the mice found being in those areas rewarding. This shows that Magneto can remotely control the firing of neurons deep within the brain, and also control complex behaviours.
“Previous attempts [using magnets to control neuronal activity] needed multiple components for the system to work – injecting magnetic particles, injecting a virus that expresses a heat-sensitive channel, [or] head-fixing the animal so that a coil could induce changes in magnetism,” he explains. “The problem with having a multi-component system is that there’s so much room for each individual piece to break down.”
“This system is a single, elegant virus that can be injected anywhere in the brain, which makes it technically easier and less likely for moving bells and whistles to break down,” he adds, “and their behavioral equipment was cleverly designed to contain magnets where appropriate so that the animals could be freely moving around.”
‘Magnetogenetics’ is therefore an important addition to neuroscientists’ tool box, which will undoubtedly be developed further, and provide researchers with new ways of studying brain development and function.
Wheeler, M. A., et al. (2016). Genetically targeted magnetic control of the nervous system. Nat. Neurosci., DOI: 10.1038/nn.4265 [Abstract]
‘Magneto’ manipulates behavior of freely moving mice
Laws of attraction: Neurons expressing a magnetically sensitive protein (right) show a spike in calcium levels when exposed to a magnet.
A modified protein allows researchers to use a magnet to switch on neurons anywhere in the brain in freely moving mice and zebrafish. The tool, described in May in Nature Neuroscience, could shed light on neural circuits underlying autism-like behaviors in animal models of the condition1.
Scientists can already turn neurons on and off at will with a technique called optogenetics that renders the cells sensitive to light. But that method requires surgically implanting a light source near the cells they want to manipulate.
The researchers rendered an ion channel in neurons called TPRV4 magnetically sensitive by fusing it to ferritin, a protein rich in iron. TPRV4 is ordinarily heat- and pressure-sensitive, but the researchers reasoned that, when attached to ferritin, it would also open in the presence of a magnetic field. Opening the channel causes calcium to flow into the cell, prompting it to fire.
Placing a magnet near cultured kidney cells expressing the protein, dubbed ‘Magneto,’ causes a calcium-sensitive fluorescent probe inside them to light up within seconds. And placing a magnet next to brain slices from mice that had been ‘infected’ by a virus carrying the Magneto gene causes neurons in the slices to fire. This firing stops when the tissue is bathed in a drug that blocks TPRV4.
Coiling on cue: Zebrafish embryos injected with Magneto coil defensively in the presence of a magnetic field.
The team also inserted the protein into neurons in the mouse striatum, an interior brain region that processes rewards and is difficult to target using optogenetics. Placing the mice in a magnetized chamber triggered firing of these neurons. Mice injected with Magneto spent more time in the magnetized chamber than in an adjacent non-magnetized area, suggesting that they experience a ‘reward’ when the magnet activates the neurons.
Magneto is likely to be still sensitive to temperature and pressure, making it hard to precisely control. But the researchers say that flaw may be fixable. – Spectrum News
IN CASE YOU EVER WONDERED WHY TEMPERATURE IS SUCH AN ISSUE WHEN IT COMES TO THE MRNA INJECTIONS…
Like Magneto? Microcrystals give magnets superpower over living cells
These iron-rich protein crystals could be the future of how scientists study nerve cells
Imagine if you could control someone by using a magnet. It would be a bit like Magneto, the supervillain in X-Men. He can control anything magnetic. Even the iron inside someone’s body.
Controlling people with magnets sounds a little, well, wacky. But scientists have now done something close to that. They have engineered cells to make long, needle-like crystals rich in iron. Researchers can then use magnets to control cells containing these crystals.
Video recordings show these iron-rich crystals moving toward a strong magnet. The crystals pull the entire cell along with them.
Cui and her colleagues didn’t set out to give scientists superpowers like Magneto’s. Instead, their new protein crystals were designed to help scientists study which neurons control an animal’s movements and senses. The crystals provide something inside a cell that magnets can attract. This innovation fills a gap in the budding field of magnetogenetics (Mag-NEE-toh-jeh-NET-iks).
Scientists in this field genetically engineer cells so that they will respond to magnetic fields. Now researchers can remotely control specific neurons in the body using magnets. Those neurons could be ones that control how hungry an animal gets. Or they could be neurons that control leg muscles so a mouse starts running when a magnet is nearby.
Gaining magnetic control
A magnetic field can turn on neurons that contain proteins rich in iron. The field does this by heating or giving a mechanical push to those proteins.
Researchers had already been able to control neurons with light. That process is called optogenetics. To use it, scientists insert light-sensitive molecules into the neurons of living animals. The researchers can then turn the neurons on or off simply by shining a light on them. With this technique, neuroscientists have done some incredible things. They’ve made mice run in circles. They’ve even restored movement to an animal’s paralyzed leg.
But optogenetics has its downsides. Light, for example, can’t penetrate deeply into the body. There’s just too much bone, muscle and other tissue in the way. So researchers may implant optical fibers into the animal to deliver light to deep neurons. That makes the method cumbersome and even potentially dangerous.
The whole idea behind magnetogenetics is that you don’t have to implant anything, explains Jacob Robinson, who was not involved in the study. He’s a neuroengineer who works at Rice University in Houston, Texas.
Cells deep inside the body could be switched on with just a magnetic field. No fibers or surgery would be needed.
But there’s a snag. The only protein found naturally inside animal cells that’s even remotely magnetic is ferritin (FAIR-ih-tin). Each molecule can have as many as 4,500 atoms of iron. That may sound like a lot, but it’s not. The force that a magnet acting on ferritin generated would be only a billionth as strong as would be needed to turn on a neuron. So Cui’s team developed protein crystals that could carry enough iron to make their cells responsive to magnets.
Giant crystals with an iron heart
The team first extracted the gene to make ferritin from a microbe. They then made a circular piece of DNA that contained two human genes. Those genes make long, hollow crystals called inka-PAK4 (short for Inkabox-PAK4cat). The team introduced these circular pieces of DNA into human kidney cells that were growing in a petri dish. A day later, the first crystals appeared.
“When I first saw those crystals assemble in the cells by themselves, it was just amazing,” Cui recalls.
The crystals grew for three days until they were 45 millionths of a meter long. That’s about half the average thickness of a human hair. They’re the largest iron-containing protein crystals ever made in the lab — or in nature, Cui says. They were even longer than the cells they grew in. But the cells in which they formed never ripped. They just stretched to accommodate the crystals.
The researchers pried open the cells and removed the crystals. Then they loaded these with iron. The team estimates that it packed some 8 billion iron atoms into each crystal before inserting those crystals into human cells growing in a dish. Now they exposed the cells to a magnetic field and waited to see what would happen.
And the cells moved.
“The first time I actually saw [the cells] move toward the magnet, I was like, ‘Wow!’” Cui says.
Crystals started collecting close to the magnet. And the crystals pulled their cells with them. The team described this online September 25 in Nano Letters.
Robinson expressed excitement over this. “It’s an excellent step,” he said, “toward engineering cells to create their own magnetic nanoparticles.”
Scientists aren’t sure what will happen to the crystals afterward. But the cells have the genes for the crystals. So every cell reproduced from the original cells should be able to make the crystals, Cui says.
Iron not included
As promising as the results are, both Cui and Robinson emphasized that this isn’t the end.
“We still haven’t reached the goal,” Cui says.
Ideally, researchers would not need to first remove newly grown crystals to pack them full of the metal atoms. Instead, cells would enrich the crystals with iron as it built them. In fact, Cui’s group tried three different ways to get iron into its cells. They even drenched the cells in an iron-rich solution. Nothing worked.
Cells typically keep their iron levels low, Cui’s team notes. It’s estimated that cells naturally contain only 3 percent as much iron as the crystals would need to be effective.
We probably need to alter the cell’s outer membranes, Cui suspects. Then, she says, they might be able to transport more iron into a cell. Still, these magnetic crystals are a major leap forward in the young field of magnetogenetics. And the researchers are confident additional studies will overcome this iron-enrichment obstacle.
Graphene has unique mechanical, electronic, and optical properties, which researchers have used to develop novel electronic materials including transparent conductors and ultrafast transistors. Recently, the understanding of various chemical properties of graphene has facilitated its application in high-performance devices that generate and store energy. Graphene is now expanding its territory beyond electronic and chemical applications toward biomedical areas such as precise biosensing through graphene-quenched fluorescence, graphene-enhanced cell differentiation and growth, and graphene-assisted laser desorption/ionization for mass spectrometry. In this Account, we review recent efforts to apply graphene and graphene oxides (GO) to biomedical research and a few different approaches to prepare graphene materials designed for biomedical applications. Because of its excellent aqueous processability, amphiphilicity, surface functionalizability, surface enhanced Raman scattering (SERS), and fluorescence quenching ability, GO chemically exfoliated from oxidized graphite is considered a promising material for biological applications. In addition, the hydrophobicity and flexibility of large-area graphene synthesized by chemical vapor deposition (CVD) allow this material to play an important role in cell growth and differentiation. The lack of acceptable classification standards of graphene derivatives based on chemical and physical properties has hindered the biological application of graphene derivatives. The development of an efficient graphene-based biosensor requires stable biofunctionalization of graphene derivatives under physiological conditions with minimal loss of their unique properties. For the development graphene-based therapeutics, researchers will need to build on the standardization of graphene derivatives and study the biofunctionalization of graphene to clearly understand how cells respond to exposure to graphene derivatives. Although several challenging issues remain, initial promising results in these areas point toward significant potential for graphene derivatives in biomedical research.
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.
Magnetic fields pass through tissue undiminished and without producing harmful effects, motivating their use as a wireless, minimally invasive means to control neural activity. Here, we review mechanisms and techniques coupling magnetic fields to changes in electrochemical potentials across neuronal membranes. Biological magnetoreception, although incompletely understood, is discussed as a potential source of inspiration. The emergence of magnetic properties in materials is reviewed to clarify the distinction between biomolecules containing transition metals and ferrite nanoparticles that exhibit significant net moments. We describe recent developments in the use of magnetic nanomaterials as transducers converting magnetic stimuli to forms readily perceived by neurons and discuss opportunities for multiplexed and bidirectional control as well as the challenges posed by delivery to the brain. The variety of magnetic field conditions and mechanisms by which they can be coupled to neuronal signaling cascades highlights the desirability of continued interchange between magnetism physics and neurobiology.
Magnetic-Nanosensor-Based Virus and Pathogen Detection Strategies before and during COVID-19
This review covers the literature of magnetic nanosensors for virus and pathogen detection before COVID-19. We review popular magnetic nanosensing techniques including magnetoresistance, magnetic particle spectroscopy, and nuclear magnetic resonance. Magnetic point-of-care diagnostic kits are also reviewed aiming at developing plug-and-play diagnostics to manage the SARS-CoV-2 outbreak as well as preventing future epidemics. In addition, other platforms that use magnetic nanomaterials as auxiliary tools for enhanced pathogen and virus detection are also covered. The goal of this review is to inform the researchers of diagnostic and surveillance platforms for SARS-CoV-2 and their performances.
NOVEMBER 30, 2020
Molecule that promotes muscle health when magnetised
As people age, they progressively lose muscle mass and strength, and this can lead to frailty and other age-related diseases. As the causes for the decline remain largely unknown, promoting muscle health is an area of great research interest. A recent study led by the researchers from NUS has shown how a molecule found in muscles responds to weak magnetic fields to promote muscle health.
Led by Associate Professor Alfredo Franco-Obregón from the NUS Institute for Health Innovation and Technology (iHealthtech), the team found that a protein known as TRPC1 responds to weak oscillating magnetic fields. Such a response is normally activated when the body exercises. This responsiveness to magnets could be used to stimulate muscle recovery, which could improve the life quality for patients with impaired mobility, in an increasingly aging society.
“The use of pulsed magnetic fields to simulate some of the effects of exercise will greatly benefit patients with muscle injury, stroke, and frailty as a result of advanced age,” said lead researcher Assoc Prof Franco-Obregón, who is also from the NUS Department of Surgery.
The NUS research team collaborated with the Swiss Federal Institute of Technology (ETH) on this study, and their results were first published online in Advanced Biosystems on 2 September 2020. The work was also featured on the cover of the journal’s print edition on 27 November 2020.
Magnets and muscle health
The magnetic fields that the research team used to stimulate the muscle health were only 10 to 15 times stronger than the Earth’s magnetic field, yet still much weaker than a common bar magnet, raising the intriguing possibility that weak magnetism is a stimulus that muscles naturally interact with.
To test this theory, the research team first used a special experimental setup to cancel the effect of all surrounding magnetic fields. The researchers found that the muscle cells indeed grew more slowly when shielded from all environmental magnetic fields. These observations strongly supported the notion that the Earth’s magnetic field naturally interacts with muscles to elicit biological responses.
To show the involvement of TRPC1 as an antenna for natural magnetism to promote muscle health, the researchers genetically engineered mutant muscle cells that were unresponsive to any magnetic field by deleting TRPC1 from their genomes. The researchers were then able to reinstate magnetic sensitivity by selectively delivering TRPC1 to these mutant muscle cells in small vesicles that fused with the mutant cells.
In their previous studies, the researchers have shown that responses to such magnetic fields were strongly correlated to the presence of TRPC1, and it included the rejuvenation of cartilage by indirectly regulating the gut microbiome, fat burning and insulin-sensitivity via positive actions on muscle. The present study provided conclusive evidence that TRPC1 serves as a ubiquitous biological antenna to surrounding magnetic fields to modulate human physiology, particularly when targeted for muscle health.
Metabolic changes similar to those achieved with exercise have been observed in previous clinical trials and studies led by Assoc Prof Franco-Obregón. Encouraging benefits of using the magnetic fields to stimulate muscle cells have been found, with as little as 10 minutes of exposure per week. This tantalizing possibility, to improve muscle health without exercising, could facilitate recovering and rehabilitation of patients with muscle dysfunction.
Assoc Prof Franco-Obregón shared, “About 40 percent of an average person’s body is muscle. Our results demonstrate a metabolic interaction between muscle and magnetism which hopefully can be exploited to improve human health and longevity.”
This study represents a milestone in the understanding of how a key protein may developmentally react to magnetic fields.
Metabolic health such as weight, blood sugar levels, insulin, and cholesterol are strongly influenced by muscle health. As exercise is a strong modulator of metabolic diseases through the working of the muscles, and magnetic fields exert similar benefits of exercise, such magnetism may help patients who are unable to undertake exercise because of injury, disease, or frailty. As such, the NUS iHealthtech research team is now working to extend their study to reduce drug dependence for the treatment of diseases such as diabetes.
“We hope that our research can help alleviate side effects by reducing the use of drugs for disease treatment, and to improve the quality of life of the patients,” said Assoc Prof Franco-Obregón.
A Single Immunization with Spike-Functionalized Ferritin Vaccines Elicits Neutralizing Antibody Responses against SARS-CoV-2 in Mice
“The development of a safe and effective SARS-CoV-2 vaccine is a public health priority. We designed subunit vaccine candidates using self-assembling ferritin nanoparticles displaying one of two multimerized SARS-CoV-2 spikes: full-length ectodomain (S-Fer) or a C-terminal 70 amino-acid deletion (SΔC-Fer). Ferritin is an attractive nanoparticle platform for production of vaccines, and ferritin-based vaccines have been investigated in humans in two separate clinical trials. We confirmed proper folding and antigenicity of spike on the surface of ferritin by cryo-EM and binding to conformation-specific monoclonal antibodies. After a single immunization of mice with either of the two spike ferritin particles, a lentiviral SARS-CoV-2 pseudovirus assay revealed mean neutralizing antibody titers at least 2-fold greater than those in convalescent plasma from COVID-19 patients. Additionally, a single dose of SΔC-Fer elicited significantly higher neutralizing responses as compared to immunization with the spike receptor binding domain (RBD) monomer or spike ectodomain trimer alone. After a second dose, mice immunized with SΔC-Fer exhibited higher neutralizing titers than all other groups. Taken together, these results demonstrate that multivalent presentation of SARS-CoV-2 spike on ferritin can notably enhance elicitation of neutralizing antibodies, thus constituting a viable strategy for single-dose vaccination against COVID-19.”
THE STUDY IS FINANCED BY MARK AND PRISCILLA ZUCKERBERG THROUGH BIOHUB!
Mrinmoy Sanyal – Department of Biochemistry & Stanford ChEM-H, Stanford University, Stanford, California 94305, United States
Shaogeng Tang – Department of Biochemistry & Stanford ChEM-H, Stanford University, Stanford, California 94305, United States
Payton A. Weidenbacher – Department of Biochemistry & Stanford ChEM-H, Stanford University, Stanford, California 94305, United States; Department of Chemistry, Stanford University, Stanford, California 94305, United States
Shanshan Li – Department of Bioengineering & James H. Clark Center, Stanford University, Stanford, California 94305, United States
Tho D. Pham – Department of Pathology, Stanford University, Stanford, California 94305, United States; Stanford Blood Center, Palo Alto, California 94304, United States
John E. Pak – Chan Zuckerberg Biohub, San Francisco, California 94158, United States
Wah Chiu – Department of Bioengineering & James H. Clark Center, Stanford University, Stanford, California 94305, United States; Chan Zuckerberg Biohub, San Francisco, California 94158, United States; Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Menlo Park, California 94025, United States; http://orcid.org/0000-0002-8910-3078
The authors declare the following competing financial interest(s): A.E.P., P.A.W., and P.S.K. are named as inventors on a provisional patent application applied for by Stanford University and the Chan Zuckerberg Biohub on immunogenic coronavirus fusion proteins and related methods.
Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, & the State of California Partner to Track COVID-19 Spread Statewide
California COVID Tracker is the First Statewide SARS-CoV-2 Tracking Program of Its Kind in the United States — Will Help Local Health Officials Better Map the VirusTags: COVID-19, CZ Biohub, Science
Whole genome sequencing allows scientists to track mutations of the SARS-CoV-2 virus, which typically happens every 2-3 transmissions. These mutations are key to helping public health officials trace transmission sources.
Today, the Chan Zuckerberg Biohub (CZ Biohub), in partnership with the Chan Zuckerberg Initiative (CZI), announced that it will provide free whole genome sequencing and analysis of the SARS-CoV-2 virus to all California Departments of Public Health (DPH) and California local health jurisdictions through a newly-launched effort called the California COVID Tracker. By rapidly tracing how and where the virus is changing and spreading across the state, the California COVID Tracker aims to provide actionable viral genomic data to local public health jurisdictions and help ensure transmission remains low while we await a vaccine.
Under this new partnership, any California DPH may ship positive COVID-19 samples to the CZ Biohub, which will provide sequencing, analysis, and interpretation support, with an emphasis on making data actionable for public health surveillance and response. By tracing the emergence of SARS-CoV-2 virus mutations, genomic epidemiology can offer insights such as estimating the number of undetected cases in a community, identifying clusters of linked transmission events, and detecting new introductions of SARS-CoV-2 into a given area or community.
Connected in this way to local public health labs and county public health departments, this type of actionable genomic epidemiology program is not currently available anywhere else in the United States. The CZ Biohub will also offer training in bioinformatics and data interpretation to public health partners throughout the state, including those interested in building or augmenting sequencing and analytic capacity within their own departments. The groups will also work closely with the Centers for Disease Control and Prevention’s newly-launched SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology and Surveillance (SPHERES) consortium.
“Public health officials need accurate, timely information about how COVID-19 is spreading to make decisions that will help protect people,” said CZI co-founders and co-CEOs Dr. Priscilla Chan and Mark Zuckerberg. “Using genome sequencing, researchers can create viral family trees to track how the virus is spreading to help inform policy decisions. We hope that broader sequencing coverage across California will empower local health jurisdictions to better understand transmission dynamics and the corresponding action needed in their communities.”
As part of this effort, the CZ Biohub will deposit SARS-CoV-2 sequences into public repositories for COVID-19 genomics, including GISAID and NCBI. CZ Biohub and CZI will provide tools and analysis support to help California DPHs overlay epidemiological and demographic information onto this genomic data to better understand local SARS-CoV-2 transmission.
“Through the California COVID Tracker, researchers, epidemiologists, software engineers, and data scientists from CZI and CZ Biohub are working to provide critical SARS-CoV-2 genomic data to California public health officials and the broader scientific community so they can make smart decisions about public health actions like contact tracing and intervention strategies,” said Joe DeRisi, PhD, Co-President of the CZ Biohub, who contributed to the identification of the SARS coronavirus in 2003. “These data become increasingly more powerful with broader participation. We invite interested public health officials and universities to partner with us in the fight against this unprecedented pandemic — these efforts will go a long way to protect our state from future spikes as we continue to fight this pandemic.”
The California COVID Tracker expands upon the ongoing partnership between CZI, the CZ Biohub, and UCSF, which has provided free COVID-19 testing to all 58 California Departments of Public Health. For more information on how to become involved in the California COVID Tracker, please visit covidtracker.czbiohub.org or email firstname.lastname@example.org.
About the Chan Zuckerberg Initiative
Founded by Dr. Priscilla Chan and Mark Zuckerberg in 2015, the Chan Zuckerberg Initiative (CZI) is a new kind of philanthropy that’s leveraging technology to help solve some of the world’s toughest challenges — from eradicating disease, to improving education, to reforming the criminal justice system. Across three core Initiative focus areas of Science, Education, and Justice & Opportunity, we’re pairing engineering with grant-making, impact investing, and policy and advocacy work to help build an inclusive, just and healthy future for everyone. For more information, please visit www.chanzuckerberg.com.
About the Chan Zuckerberg Biohub
The Chan Zuckerberg Biohub is a nonprofit research organization setting the standard for collaborative science, where leaders in science and technology come together to drive discovery and support the bold vision to cure, prevent or manage disease in our children’s lifetime. The CZ Biohub seeks to understand the fundamental mechanisms underlying disease and to develop new technologies that will lead to actionable diagnostics and effective therapies. The CZ Biohub is a regional research endeavor with international reach, where the Bay Area’s leading institutions — the University of California, Berkeley, Stanford University and the University of California, San Francisco — join forces with the CZ Biohub’s innovative internal team to catalyze impact, benefitting people and partnerships around the world. To learn more, visit CZBiohub.org.
While the film “Transformers” introduced intelligent robots that morphed between shapes with multiple functionalities, researchers are developing intelligent soft transformers to significantly accelerate research applications in the lab. In a recent report now published in Advanced Intelligent Systems, Dachuan Zhang and a research team in materials science and chemical sciences in China, proposed a remotely controlled soft transformer based on a shape memory hydrogel system. The team obtained the hydrogel by embedding magnetite (Fe3O4) magnetic nanoparticles into a double network polymer structure of poly (N-(2-hydroxyethyl) acrylamide) containing gelatin.
The reversible coil-triple-helix transformation of the gelatin constituent imbued the hydrogel with shape memory and self-healing properties, while the magnetite nanoparticles gave photothermal heating and magnetic manipulation functions to deform the hydrogel for navigation in a magnetic field. The team could then restore the deformed shape via shape recovery using light irradiation. Zhang et al. remotely controlled the shape-memory processes through magnetically driven actuation and light-assisted shape memory. As proof of concept, they created a series of robots, including a hydrogel athlete that could do sit-ups, hydrogel transformers, a lotus in full bloom, and a hydrogel spacecraft that can be docked in air. The work will inspire the design and fabrication of new smart polymer systems with synchronized multiple functionalities.
Shape memory hydrogels
While the fictional transformers allowed hard robots to morph into any form including vehicles, soft transformers are of greater interest in fundamental research and applications in life sciences. In this work, Zhang et al. described a photothermally and magnetically controlled shape memory hydrogel. They combined a chemically crosslinked polymer and a reversibly crosslinked gelatin network embedded with magnetite nanoparticles to create a photothermal and flexible, self-healing construct that could be magnetically manipulated. Shape memory hydrogels (SMHs) have received increased attention as intelligent polymeric materials and researchers aim to remotely control such materials to establish diverse actuating behaviors.
For example, shape-memory polymers can fix temporary shapes and recover their architecture under external stimuli, with increasing interest across biomedical, textile, flexible electronics and data encryption disciplines. Magnetic nanoparticles are effective additives to introduce remotely controlled non-contact actuation. When hydrogels are illuminated with near-infrared (NIR) light, these magnetic nanoparticles will continuously convert light into heat, causing the hydrogel to be heated. This will cause reversible deformation of the hydrogel for applications as freely moving soft robots. This strategy will help promote the development of new shape memory hydrogel systems for applications as untethered robots.
Properties of shape memory hydrogels
Since shape memory hydrogels can stably and temporarily memorize their shape and recover the original shape perfectly under specific stimuli, the team conducted bending tests with the material, which they abbreviated as HG for its constituent polymers. They then immersed a sample in hot water (60 degrees Celsius) for 30 seconds to induce disaggregation to soften the hydrogel, removed it from the medium and recovered the shapes after re-immersing hydrogels in hot water (60 degrees Celsius). Zhang et al. conducted a series of controlled experiments to verify the factors affecting the shape memory performance of the hydrogel. As proof of concept, the team designed and developed a hydrogel flower to perfectly mimic the bloom of a lotus.
When the researchers introduced magnetite nanoparticles to form the HG-Fe3O4 hydrogel, the constituents could absorb and convert light to heat with light irradiation, causing the temperature of the hydrogel to increase. During light-to-heat conversion, the material achieved photo-activated self-healing. To demonstrate this phenomenon, the team created a HG-Fe3O4 hydrogel space station under a magnetic field and applied NIR to irradiate the connectors and dock the spacecraft-like construct with a space station-like connector to realize self-healing and reconnection in air.
Recovering shapes through photothermal effects and remotely controlling shape memory processes
The team could only achieve shape recovery for the HG-hydrogel by regulating the temperature to a specific value, in the absence of magnetite nanoparticles. The addition of magnetite conferred magnetic properties to the HG-Fe3O4 hydrogel to allow remotely controlled shape memory recovery cycles. As proof of concept, the team developed a shape-transition robot in the form of a hydrogel athlete to deform from 2-D to 3-D. In the absence of NIR and the presence of a magnet, the hydrogel athlete could ‘push up’ quickly, then recover its shape to the flat conformation on removal of the magnet. In the second setup, they turned-on NIR and lifted the hydrogel athlete with a magnet, then kept the magnet on for two minutes while switching off the NIR to allow the athlete to cool down. The team froze this gesture for a timeframe after which they allowed the robot to return to its original position by turning-on the NIR again. This technique can be used to develop soft grippers that are advantageous for applications as surgical robots in translational research.
Remote control of cells and single molecules by magnetic nanoparticles in nonheating external magnetic fields is a perspective approach for many applications such as cancer treatment and enzyme activity regulation. However, the possibility and mechanisms of direct effects of small individual magnetic nanoparticles on such processes in magneto-mechanical experiments still remain unclear. In this work, we have shown remote-controlled mechanical dissociation of short DNA duplexes (18–60 bp) under the influence of nonheating low-frequency alternating magnetic fields using individual 11 nm magnetic nanoparticles.
The developed technique allows (1) simultaneous manipulation of millions of individual DNA molecules and (2) evaluation of energies of intermolecular interactions in short DNA duplexes or in other molecules.
Finally, we have shown that DNA duplexes dissociation is mediated by mechanical stress and produced by the movement of magnetic nanoparticles in magnetic fields, but not by local overheating.
The presented technique opens a new avenue for high-precision manipulation of DNA and generation of biosensors for quantification of energies of intermolecular interaction.
MAY 18, 2021
New Material Could Create ‘Neurons’ and ‘Synapses’ for Computers
via University of Groningen
Classic computers use binary values (0/1) to perform. By contrast, our brain cells can use more values to operate, making them more energy-efficient than computers. This is why scientists are interested in neuromorphic (brain-like) computing. Physicists from the University of Groningen have used a complex oxide to create elements comparable to the neurons and synapses in the brain using spins, a magnetic property of electrons. Their results were published on 18 May in the journal Frontiers in Nanotechnology.
The operation of our brains can be simulated in computers, but the basic architecture still relies on a binary system. That is why scientist look for ways to expand this, creating hardware that is more brain-like, but will also interface with normal computers. ‘One idea is to create magnetic bits that can have intermediate states’, says Tamalika Banerjee, Professor of Spintronics of Functional Materials at the Zernike Institute for Advanced Materials, University of Groningen. She works on spintronics, which uses a magnetic property of electrons called ‘spin’ to transport, manipulate and store information.
In this study, her PhD student Anouk Goossens, first author of the paper, created thin films of a ferromagnetic metal (strontium-ruthenate oxide, SRO) grown on a substrate of strontium titanate oxide. The resulting thin film contained magnetic domains that were perpendicular to the plane of the film. ‘These can be switched more efficiently than in-plane magnetic domains’, explains Goossens. By adapting the growth conditions, it is possible to control the crystal orientation in the SRO. Previously, out-of-plane magnetic domains have been made using other techniques, but these typically require complex layer structures.
Schematic of the proposed device structure for neuromorphic spintronic memristors. The write path is between the terminals through the top layer (black dotted line), the read path goes through the device stack (red dotted line). The right side of the figure indicates how the choice of substrate dictates whether the device will show deterministic or probabilistic behavior. | Illustration Banerjee group
The magnetic domains can be switched using a current through a platinum electrode on top of the SRO. Goossens: ‘When the magnetic domains are oriented perfectly perpendicular to the film, this switching is deterministic: the entire domain will switch.’ However, when the magnetic domains are slightly tilted, the response is probabilistic: not all the domains are the same, and intermediate values occur when only part of the crystals in the domain have switched.
By choosing variants of the substrate on which the SRO is grown, the scientists can control its magnetic anisotropy. This allows them to produce two different spintronic devices. ‘This magnetic anisotropy is exactly what we wanted’, says Goossens. ‘Probabilistic switching compares to how neurons function, while the deterministic switching is more like a synapse.’
The scientists expect that in the future, brain-like computer hardware can be created by combining these different domains in a spintronic device that can be connected to standard silicon-based circuits. Furthermore, probabilistic switching would also allow for stochastic computing, a promising technology which represents continuous values by streams of random bits. Banerjee: ‘We have found a way to control intermediate states, not just for memory but also for computing.’
Above: Video abstract of an original research “Magnetically controlled protein nanocontainers as a drug depot for the hemostatic agent” published in the open access journal Nanotechnology, Science and Applications by Prilepskii, Schekina and Vinogradov.
Purpose: Currently, there is a number of successfully implemented local hemostatic agents for external bleedings in forms of wound dressings and other topical materials. However, little has been done in the field of intravenous hemostatic agents. Here, we propose a new procedure to fabricate biocompatible protein nanocontainers (NCs) for intravenous injection allowing magneto-controllable delivery and short-term release of the hemostatic agent ϵ-aminocaproic acid (EACA). Methods: The nanocontainers were synthesized by the desolvation method from bovine serum albumin (BSA) using methanol without any further crosslinking. Polyethylene glycol (PEG) was used both as a stabilization agent and for size control. Characterization of nanocontainers was performed by the transmission and scanning electron microscopy, dynamic light scattering, X-ray diffraction, and FTIR spectroscopy. Cytotoxicity was estimated using MTT assay. The dopant release from nanocontainers was measured spectrophotometrically using rhodamine B as a model molecule. The specific hemostatic activity was assessed by analyzing clot lysis and formation curve (CloFAL). Moreover, the ability for magneto targeting was estimated using the original flow setup made of a syringe pump and silicon contours. Results: Fabricated nanocontainers had an average size of 186±24 nm and were constructed from building blocks–nanoparticles with average size ranged from 10 to 20 nm. PEG shell was also observed around nanocontainers with thickness 5–10 nm. NCs were proved to be completely non-cytotoxic even at concentrations up to 8 mg BSA/mL. Uptake capacity was near 36% while release within the first day was 17%. The analysis of the CloFAL curve showed the ability of NCs to inhibit the clot lysis successfully, and the ability of magneto targeting was confirmed under flow conditions. Conclusion: The ability of synthesized NCs to deliver and release the therapeutic drug, as well as to accumulate at the desired site under the action of the magnetic field was proved experimentally. Read the full paper HERE
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