“Brain organoids can reproducibly make a large number of cell types that normally populate the endogenous brain. Although these neurons can extend axons and wire within circuits, at the moment, their connectivity is not organized like that of the actual brain,” Arlotta said. “By guiding axons of specific neurons to pre-defined targets, we would have an opportunity to engineer new connectivity, exactly as present in the intact organism. This is important for many reasons, not the least the possibility of understanding how diseases affect specific neurons and their networks to inform therapeutic progress.”This study was supported by the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, the National Institutes of Health, the Harvard Center for Biological Imaging, and the Harvard Stem Cell Institute. Harvard University researchers have developed an engineering technique to precisely control the direction that neurons grow their axons, cable-like structures that allow nerve cells to connect with each other. In a zebrafish model, researchers used the approach to correct defective neural connections and restore the neuron’s ability to cause muscle contractions.The findings, published in the journal Developmental Cell, represent a key step toward repairing nervous system damage in patients. They may also enable scientists to create more accurate models of the brain in a lab dish, by instructing the formation of precise neuronal connections resembling those of the actual brain.“The process of establishing connections between neurons mostly occurs during embryonic development, especially in mammals like us. After that point, if these connections are severed in situations such as spinal cord injury, the neurons typically do not regrow their connections, losing functionality. It would be a great achievement to be able to overcome these difficulties,” said Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology. “This study is a proof of principle that shows the potential of a noninvasive strategy to direct neuron growth.”Forming connectionsA neuron’s axon is a projection that emanates from the cell body and connects to other cells, often located a great distance away. In the developing embryo, a complex set of signals guide a specialized structure at the tip of the axon, called the growth cone, to its precise target to wire the nervous system.,“Nature has come up with this beautiful symphony of molecular signaling that allows a tissue as incredibly complex as the brain to wire appropriately. We’re learning more and more about how this happens, but we don’t yet have the ability to direct all these intricate processes,” said James Harris, a graduate student in the Arlotta lab and lead author of the study. “Instead, we created an extremely precise tool that allows us to override the molecular signals within the body and guide axonal growth, according to our own designs.”By controlling axonal growth directly, this strategy avoids disrupting critical biological signaling molecules or introducing chemicals that might alter the delicate developmental environment, which could potentially cause unintended consequences on neighboring cells. To make sure the tool was highly specific, the researchers took an engineering approach to the problem.A noninvasive engineering approachTo control axon growth, the researchers introduced a fusion protein into specific neurons that combined the functionality of two different proteins. The first protein is normally expressed in developing axons, and controls the machinery responsible for axonal outgrowth. The second protein is originally found in plants and helps them to sense light.“Much in the way that plants grow toward the sun, we engineered the axons so they grow toward our targeted illumination,” Harris said.When the researchers shone a specific type of light near the neurons, the axons grew toward the noninvasive stimulus.,The researchers tested the approach in a zebrafish model, in collaboration with the Leonard Zon lab. They were able to not only make the neurons grow in a specific chosen direction, but also make the neurons grow across repulsive developmental barriers that normally restrict axons to a very narrow body location.“There are specific molecules that are expressed in these developmental barriers that help guide axons correctly during normal development. Interestingly, many of these molecules are also present in damaged tissue and act as barriers to axonal regeneration in mammals,” Harris said. “In this particular context of a developing zebrafish embryo, our approach had the power to overcome these inhibitory signaling molecules.”The researchers also studied a zebrafish model with genetic mutations that prevented axons from growing correctly. Their illumination approach successfully rescued this defect by guiding axons to their targets. The guided axons were able to cause muscle contractions in the zebrafish, demonstrating that the repaired connections were functional.Applying the technologyAlthough applying this technology to repairing injured connections in patients will require substantial additional work, this study is a promising step in this important direction. More immediately, the new technique can help scientists create more accurate models of the brain.“We are really interested in using this technology to wire more specific connections within human brain organoids,” Arlotta said.Made from human stem cells, organoids replicate important features of the developing nervous system in a lab dish. In a first, researchers use base editing to correct recessive genetic deafness and restore partial hearing Related New technology helps dissect how it ignores or acts on information Getting the brain’s attention A promise to a friend Up close and personal with neuronal networks
Photo: Pexels.com By the way, it is good to know that Rent-a-car annually orders about 15-18 thousand new vehicles, with a total purchase value of approximately 250,000.000 euros, which includes large amounts of paid VAT and PPMV, as well as vehicle registration. Rent-a-car activity is one of the most important business segments for leasing companies and insurers, and in the last ten years the rent-a-car industry is responsible for 30-45% of all newly registered vehicles in Croatia, which is again very important for the functioning importers, distribution, transport, service and repairs. The following 4 emergency measures are needed to preserve the car rental industry: Rent-a-car The HUP Coordination therefore proposes the adoption of urgent additional assistance measures for the sector, in order to ensure the retention of employees and the preservation of rent-a-car companies until the normalization of operations. Also, Petreski emphasizes that due to the suspension of tourist arrivals, they demand that the collection of rent for counters and parking spaces at airports be suspended. In the financial aid package, it is extremely important to present to the Government of the Republic of Croatia the real illiquidity of tourism in the first part of the year and the positive cash flow where possible surplus (profit) is realized only at the end of summer. waiting until September 2021 because other options are not realistic, he points out Mladen Petreski, President of Rent-a-car Coordination of HUP He adds: The car rental industry in Croatia generates as much as 90 percent of its rental income, and due to the crisis, the entire sector is completely blocked. Rent-a-car annually orders about 15-18 thousand new vehicles “The consequences of this crisis will be much deeper and more far-reaching than anyone could have expected. It is difficult to predict the beginning of the normalization of business in tourism, so it is necessary to plan a new set of measures as soon as possible so that the tourism-dependent sector can preserve jobs and welcome 2021.”Concludes Petreski. “We welcome the April package of Government measures that have brought major shifts and help for the economy. We expect that significant relief in the area of parafiscal levies will be brought soon. As vehicles are our main means of work, it is important for our industry to relieve all vehicle-related benefits. Therefore, we hope to soon consider the proposal to postpone the obligation to register new vehicles and extend the validity of registrations during the time when the vehicles were out of order. Although Leasing is also included in the Government’s measures of moratorium and reprogramming, leasing obligations of leasing companies for now approve a delay of 3 months, which is not enough for our companies. It is necessary to ensure a moratorium of at least 18 months for the period of suspended revenues and low liquidity. ” The annual income of rent-a-car activities in Croatia is estimated at approx. 150,000.000 euros including VAT – most of the foreign currency collected directly from tourists and agents from abroad. Leasing moratorium should be agreed for a realistically feasible period of 18 months through changes in moratorium measures and loan repayment rescheduling of all those affected by the crisis Suspend the collection of rents at airports during the suspension of commercial flights and the percentage reduction after the start of passenger traffic (2019/20)Extension of the duration of vehicle registration for a period of 1 to 3 months as long as the vehicles are out of order and extension of the deadline within which a new vehicle must be registeredSuspension of payment of the RTV fee
The FCA’s comments echoed those made by the Bank of England – of which the FCA is a part – in 2014, when then-executive director for financial stability Andrew Haldane said it was viable to consider the risks to the wider economy of the collapse of an asset management company.The FCA also confirmed its plan to publish the final report into its asset management market study in the second quarter of 2017. As well as reiterating its findings from the market study, the regulator also highlighted other areas of concern, including asset managers overpaying for services and custody banks’ reluctance to invest in IT systems.Amanda Rowland, asset management regulation partner at PwC, said the regulator’s focus on liquidity management supported “broader operational concerns” linked to the UK’s imminent exit from the European Union. It also indicated that “some movement around enhanced stress testing and redemption disclosure is possible”, Rowland added.“While acknowledging that Brexit will require regulatory flexibility, the FCA has focused on asset management initiatives such as cost disclosure and liquidity management that have wider international support and will likely be successfully progressed regardless of where Brexit takes the UK and the FCA,” she said.In the immediate aftermath of the UK’s vote to leave the EU, several open-ended property funds were forced to temporarily close to redemptions due to a high level of withdrawals.Chris Cummings, chief executive of the Investment Association, the asset management trade body, welcomed the regulator’s approach and its willingness for industry dialogue. He added: “As we move into a post-Brexit world, it is vital that the UK regulatory framework continues to foster a globally competitive environment to set up and run an asset management business.” The failure or “disorderly wind-down” of one or several large asset managers could pose a financial stability risk to the UK’s system, the Financial Conduct Authority (FCA) has warned.Outlining its views of various sectors of the UK financial system as part of its annual mission statement and business plan, the FCA said: “Market stability could be affected by the failure or disorderly wind-down of a very large asset manager or several asset management firms as end-investors attempt to redeem their holdings on demand, creating a downward selling spiral.”In its business plan for 2017/18, the FCA said: “Following stakeholder feedback, we will review our policy options and the available tools that asset managers have to manage liquidity when facing redemptions and valuation issues, and assess how adequate they are in managing conduct risks and addressing financial stability concerns. This work should ensure that liquidity management in funds allows for a fair treatment of all customers, including those who remain invested, and does not amplify disruptions to the financial system in stressed market conditions.”International regulators such as the International Organisation of Securities Commissions and the Financial Stability Board have previously suggested treating large asset managers as systemically important, putting them at a similar regulatory priority level as the world’s biggest banks and insurers.