This stem cell startup is designing a therapy to restore and boost … – The Boston Globe

That bold vision has now attracted personal investments from several local life science leaders, including George Church, the Harvard University geneticist who has founded and advised dozens of biotech companies. Church told Wang a former postdoctoral researcher in his lab that his thymus cell therapy was one of the most exciting ideas hed come across, since it has the potential to impact almost every person on the planet.

Wangs startup recently raised $7 million in seed financing, bringing the total to $13 million, he said. Thymmunes investors include the biotech venture capital firm Pillar VC and NYBC Ventures, the investment arm of the New York Blood Center. Biotech entrepreneurs and investors Mark Bamforth, James Fordyce, John Maraganore, Judy Pagliuca, Philip Reilly, and Mark de Souza pitched in, too.

Maraganore, the former founding chief executive of Alnylam Pharmaceuticals, a genetic medicines company in Cambridge worth more than $23 billion, said he was fascinated by both the near-term and long-term goals of Wangs vision for what thymus cell therapies might do for rare and common conditions alike.

If successful, it could be pretty transformative, Maraganore said. At the end of the day, we all age and die due to our immune system falling apart, and if theres a way to reconstitute it, that would be pretty cool.

Physicians once thought that the thymus, a small gland situated behind the breastbone, between the lungs, and above the heart, was a dispensable organ. But it plays a vital role in developing immunity.

Its job is to basically be the schoolhouse for T cells, those critical cells in your immune system that help you fight everything from pathogens to cancer, Wang said. From a young age, the thymus also teaches T cells about the inventory of molecules normally found in people so that they dont attack their own body and cause an autoimmune disease.

The thymus is perhaps the most important organ youve never heard of. Many folks dont even know it exists, said Thomas de Vlaam, an investor at Pillar VC. If it works well, its unnoticeable, but once it starts failing for whatever reason, the effects are detrimental.

Thymmunes ambitions span the gamut of thymus biology, from replacing missing thymuses to bolstering shrinking ones, and its technology is largely based on work from a group of scientists at the University of California, San Francisco. In 2010, Audrey Parent, a postdoctoral researcher working with UCSF professors Matthias Hebrok and Mark Anderson, was trying to figure out how to make thymus cells in the lab for the first time.

Parent, now an assistant professor at UCSF, said the project involved a lot of trial and error to find a molecular recipe that could turn a stem cell into a thymus cell. There was no recipe to do that at the time, Parent said. We looked at how the embryo does it, we tried to replicate what nature has been doing really successfully, and then transferred that into a recipe that you can do in a dish.

Their results, published in 2013, used human embryonic stem cells to make thymus cells that were transplanted into mice that lacked a thymus. Crucially, the implants allowed the mice to make their own T cells. Thymmune has licensed patents from UCSF, and like many new startups in the stem cell field, it is forgoing difficult-to-source and ethically fraught embryonic stem cells in favor of induced pluripotent stem cells, or iPSCs, which can be made from adult skin cells.

Sometime in the next few years, Wang plans to start a clinical trial in children who are born without a thymus. Its a ticking time bomb where these kids usually dont survive past one or two years, Wang said.

The Food and Drug Administration approved the first therapy for the condition, called congenital athymia, in 2021. Slices of thymus obtained from organ donations, cultured in a lab and surgically implanted into an infants thigh, improved the chances of surviving the otherwise fatal condition to 76 percent after two years. The results there have been fantastic, Wang said. He hopes to replicate them and make an off-the-shelf product that doesnt require organ donations.

If that approach is successful, Wang wants to use his companys thymus cells as a therapy that helps people getting bone marrow or organ transplants recover more quickly and trains their immune systems to not reject the transplant. He also has plans to develop engineered thymus cells that can quell autoimmune diseases by retraining haywire immune cells to stand down and stop attacking the body.

Wangs ultimate vision, and the one thats especially invigorated investors like Church and Maraganore, is to inject thymus cells into aging people to bolster their immune response. To be clear, theres a lot more we need to do before getting to that point, Wang said. But that is the level of aspiration were aiming for. ... We want to provide everyone the opportunity for healthier aging.

Ryan Cross can be reached at ryan.cross@globe.com. Follow him on Twitter @RLCscienceboss.

More:
This stem cell startup is designing a therapy to restore and boost ... - The Boston Globe

How to generate new neurons in the brain – Science Daily

Some areas of the adult brain contain quiescent, or dormant, neural stem cells that can potentially be reactivated to form new neurons. However, the transition from quiescence to proliferation is still poorly understood. A team led by scientists from the Universities of Geneva (UNIGE) and Lausanne (UNIL) has discovered the importance of cell metabolism in this process and identified how to wake up these neural stem cells and reactivate them. Biologists succeeded in increasing the number of new neurons in the brain of adult and even elderly mice. These results, promising for the treatment of neurodegenerative diseases, are to be discovered in the journal Science Advances.

Stem cells have the unique ability to continuously produce copies of themselves and give rise to differentiated cells with more specialized functions. Neural stem cells (NSCs) are responsible for building the brain during embryonic development, generating all the cells of the central nervous system, including neurons.

Neurogenesis capacity decreases with age

Surprisingly, NSCs persist in certain brain regions even after the brain is fully formed and can make new neurons throughout life. This biological phenomenon, called adult neurogenesis, is important for specific functions such as learning and memory processes. However, in the adult brain, these stem cells become more silent or ''dormant'' and reduce their capacity for renewal and differentiation. As a result, neurogenesis decreases significantly with age.The laboratories of Jean-Claude Martinou, Emeritus Professor in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Science, and Marlen Knobloch, Associate Professor in the Department of Biomedical Sciences at the UNIL Faculty of Biology and Medicine, have uncovered a metabolic mechanism by which adult NSCs can emerge from their dormant state and become active.

''We found that mitochondria, the energy-producing organelles within cells, are involved in regulating the level of activation of adult NSCs,'' explains Francesco Petrelli, research fellow at UNIL and co-first author of the study with Valentina Scandella. The mitochondrial pyruvate transporter (MPC), a protein complex discovered eleven years ago in Professor Martinou's group, plays a particular role in this regulation. Its activity influences the metabolic options a cell can use. By knowing the metabolic pathways that distinguish active cells from dormant cells, scientists can wake up dormant cells by modifying their mitochondrial metabolism.

New perspectives

Biologists have blocked MPC activity by using chemical inhibitors or by generating mutant mice for the Mpc1gene. Using these pharmacological and genetic approaches, the scientists were able to activate dormant NSCs and thus generate new neurons in the brains of adult and even aged mice. ''With this work, we show that redirection of metabolic pathways can directly influence the activity state of adult NSCs and consequently the number of new neurons generated,'' summarizes Professor Knobloch, co-lead author of the study. ''These results shed new light on the role of cell metabolism in the regulation of neurogenesis. In the long term, these results could lead to potential treatments for conditions such as depression or neurodegenerative diseases'', concludes Jean-Claude Martinou, co-lead author of the study.

See original here:
How to generate new neurons in the brain - Science Daily

Enhanced mitochondrial biogenesis promotes neuroprotection in … – Nature.com

Reagents and resources

All the reagents including qPCR primers, antibodies, and software used are listed in Supplementary Table1

Human embryonic stem cell (H7-hESCs; WiCell, Madison, WI, https://www.wicell.org) reporter line with CRISPR-engineered multicistronic BRN3B-P2A-tdTomato-P2A-Thy1.2 construct into the endogenous RGC specific BRN3B locus was used for isogenic control20. CRISPR mutated H7-hESC reporter with OPTNE50K-homozygous mutation (H7-E50K) was done as explained previously25. Patient-derived induced pluripotent stem cells (iPSCs) with E50K mutation24 (iPSC-E50K), E50K mutation corrected to WT by CRISPR in the patient-derived iPSC (iPSC-E50Kcorr)25 with BRN3B::tdTomato reporter were obtained from the Jason Meyer lab. All the above cell lines were grown in mTeSR1 media (mT) at 37C in 5% CO2 incubator on matrigel (MG) coated plates. These cells were maintained by clump passaging using Gentle Cell Dissociation Reagent (GD) after 7080% confluency. Media was aspirated and GD was added to cells followed by incubation at 37C in 5% CO2 incubator for 5min. Next, mT was used to break up the colonies into small clumps by repeated pipetting and then seeded onto new MG plates.

For differentiation, stem cells were dissociated to single cells using accutase for 10min and then quenched with twice the volume of mT with 5M blebbistatin (blebb). The cells were centrifuged at 150xg for 6minutes and resuspended in mT with 5M blebb, then 100,000 cells were seeded per well of a 24-well MG coated plate. The next day, media was replaced with mT without blebb. After 24h, media was replaced with differentiation media (iNS) and further small molecule-based differentiation was carried out with iNS media as elucidated previously23. Differentiation of hRGCswas monitored by tdTomato expression and cells were purified during days 4555 using THY1.2 microbeads and magnetic activated cell sorting system (MACS, Miltenyi Biotec) as explained before20,23. Next, hRGCs were resuspended in iNS media, counted using a hemocytometer and seeded on MG-coated plates, coverslips, or MatTek dishes for experiments.

Purified hRGCs were seeded at 30,000 cells per well of a 96-well MG-coated plate and maintained for 3 days. For measuring mitochondrial mass, hRGCs were labeled with mitochondria-specific MTDR dye. To measure mitochondrial degradation, hRGCs were labeled with 10nM MTDR dye for 1h, washed, and then treated with 10M CCCP for a time course. To measure mitochondrial biogenesis, hRGCs were labeled with MTDR first, treated with 10M CCCP or equal amount of DMSO for 3h, then washed and incubated with fresh media with MTDR for the time course. After treatments, hRGCs were dissociated to single-cell suspension using accutase and analyzed using Attune NxT flow cytometer (Thermo Fisher).

Purified hRGCs were seeded at 500,000 cells per well of 24-well MG-coated plates and maintained for 3 days. Cells were then treated with indicated molecules and time points. DMSO was used as the control as the small molecules were dissolved in DMSO. The cells were lysed and collected in 100l of M-PER extraction buffer with 5mM EDTA and protease inhibitors. Protein quantification was done using a BSA standard following the DC Protein Assay Kit II (Bio-Rad) and measured on microplate reader. Loading samples were prepared with heat denaturation at 95C for 5minutes with laemmli sample buffer (1X). 1020g protein per sample were run on Bio-Rad Mini-PROTEAN TGX precast gels, in running buffer (Tris-Glycine-SDS buffer; Bio-Rad) at 100V until the dye front reached to the bottom. The transfer sandwich was made using PVDF membrane (activated in methanol) in Tris-Glycine transfer buffer (Bio-Rad) with 20% methanol and transferred for 2h at 30V, 4C. For the visualization of proteins, the membranes were blocked in 5% skim milk in TBST (TBS buffer with 20% Tween20) for 2h at room temperature and incubated overnight at 4C in 1:1000 dilution of primary antibodies for PGC1 (Abcam), Phospho-PGC1Ser571 (R&D Systems), PGC1 (Abcam), AMPK (Cell Signaling Technologies, CST), Phospho-AMPKThr172 (CST), LC3B (Sigma), GAPDH (CST), or ACTIN (CST). Membranes were then washed three times for 5minutes each in TBST, followed by 2h of incubation in 5% milk in TBST containing anti-rabbit HRP linked secondary antibody (CST) at 1:10,000 dilution. The membranes were again washed three times with TBST and then placed in Clarity Max Western ECL (Bio-Rad) substrate for 5min. The membranes were imaged in a Bio-Rad ChemiDoc Gel Imager, and the raw integrated density for each band was measured and normalized with respect to the corresponding GAPDH or actin loading control using Image J. Treatment conditions were further normalized to the corresponding DMSO control for each experiment. Complete blots of the representative western blot images, with protein molecular weight marker (Thermo Scientific), are provided in Supplementary Fig.6. Protein bands corresponding to the appropriate size were quantified following product datasheets and published literature.

Purified hRGCs were seeded on MG-coated coverslips (1.5 thickness) at a density of 30,00040,000 cells per coverslip and grown for 3 days. Next, hRGCs were treated with indicated molecules and time points. After treatment the media was aspirated, the cells were washed with 1 PBS, and then fixed with 4% Paraformaldehyde for 15min at 37C. Fixed cells were permeabilized with 0.5% Triton-X100 in PBS for 5min and then washed with washing buffer (1% donkey serum, 0.05% Triton-X100 in PBS) three times for 5min each. Cells were blocked with blocking buffer (5% donkey serum, 0.2% Triton-X100 in PBS) for 1h. After blocking, antibodies against TOM20 (Mouse, Santa Cruz), Tubulin 3 (mouse, Biolegend), RBPMS (rabbit, GeneTex) and Optineurin (Rabbit, Cayman Chemicals) were added (1:200 in blocking buffer) and the coverslips were incubated overnight at 4C. Next, coverslips were washed with washing buffer three times for 5min each and incubated for 2h at room temperature in the dark with fluorophore conjugated anti mouse or rabbit secondary antibodies (1:500). The coverslips were washed with washing buffer three times for 5min each, with 1.43M DAPI added to the second wash. The coverslips were then mounted onto slides with DAKO mounting medium. Visualization of above proteins and nucleus was done by confocal immunofluorescence microscopy using Zeiss LSM700 with 63x/1.4 oil objective. Analysis was carried out using ImageJ with maximum projections of DAPI channel (number of nuclei) and sum projections of TOM20 and OPTN channels for the corresponding confocal z-stacks. For OPTN aggregate size, we analyzed particles from 0.02 a.u. to infinity to account for the small and big aggregates.

Purified hRGCs were seeded at 300,000 cells per well of 24-well MG-coated plates and maintained for 3 days. Cells were then treated with indicated molecules and durations. Media was aspirated and cells were incubated in 200l accutase for 10min and then quenched with 400l iNS media. Cells were centrifuged at 150xg for 6min, media aspirated, and the cell pellets were stored at 20C. RNA was extracted from cell pellets following the kit protocol (Qiagen 74104). The RNA concentration was measured using Nanodrop 2000c (Thermo) and 6l of RNA was used to prepare cDNA following the kit protocol (Abm #G492). Primers were designed as detailed in TableS1 and qPCR were performed using BlasTaq qPCR MasterMix with 100ng total cDNA in a 20l reaction mixture using QuantStudio6 Flex RT PCR system (Applied Biosystems). GAPDH or actin was used as a housekeeping gene in every plate to calculate the Ct values. The Ct was calculated with respect to (w.r.t) the average Ct of the control sample. All conditions were measured by averaging three technical repeats for each biological repeat with total three biological replicates.

Purified hRGCs were seeded at 50,00075,000 cells per well of 96-well MG-coated plates and maintained for 3 days. Cells were then treated with indicated molecules for the designated durations. Media was aspirated and cells were incubated in 30l accutase for 10min and then quenched with 100l iNS media. Cells were centrifuged at 150xg for 6min, media aspirated, and the cell pellets were stored at 20C. DNA was extracted using DNeasy Blood & Tissue Kit (Qiagen) and eluted with 30l elution buffer. DNA concentration was measured using Nanodrop 2000c (Thermo). 10ng of DNA was used to measure both mitochondrial ND1 gene and internal control, human nuclear RNase P gene copy numbers, as done previously23.

hRGCs were seeded on MG-coated glass bottom (1.5 thickness)MatTek dishes at 40,000 cells per dish and maintained for 3 days. For the experiments in Fig.2ac, cells were incubated with 250l of JC1 media (1:100 in iNS) for 30min in the incubator, then an additional 1.75ml of dilute JC1 (1:1000 in iNS) was added to the dish. The dish was then transferred to the live cell chamber (5% CO2, 37C, Tokai Hit) and confocal z-stacks were acquired prior to (before) and 10minutes after CCCP (10M) treatment using Zeiss LSM700 with 63x/1.4 oil objective. For experiments in Fig.2df, cells were treated with 10M CCCP or equivalent DMSO for 30min. Next, cells were washed with iNS media, and then incubated with 250l of JC1 media (1:100 in iNS) for 30min in the incubator. The JC1 media was then removed, cells were washed again, and 2ml of new iNS was added to the dish. The dish was then transferred to the live cell chamber and imaged. Analysis was carried out using ImageJ with sum projections of red and green channels. The red fluorescence from the tdTomato expressed by the hRGCs was much less intense than the JC1 red staining of mitochondria, thus the red fluorescence measured from the cytoplasm was considered background and subtracted out of the measurements. For the green fluorescence, background was measured from outside the cell. Red-to-Green ratios were calculated by dividing the red intensity by green intensity. These values were then normalized to the control condition, hRGCWT-before (Fig.2c) or average DMSO ratio for each cell line (Fig.2f).

The 96-well seahorse plate was coated with MG and hRGCs were seeded at 250,000 cells per well and maintained for 2 days. 24h before measurements, media was exchanged with 100l iNS with 1g/ml BX795 or equivalent vehicle control DMSO. A day prior to the assay, the sensor cartridge was fully submerged with 200l of sterile water to hydrate it overnight in a non-CO2, 37C incubator. The next day, sterile water was replaced with pre-warmed XF calibrant buffer(Agilent) and the sensors were again submerged and incubated in the non-CO2, 37C incubator for 4560min. Seahorse media was made by adding stock solutions to XF DMEM to have final concentrations of 21.25mM glucose, 0.36mM sodium pyruvate, and 1.25 mM L-glutamine (Agilent), with pH adjusted to 7.387.42. Depending upon the assay, 20M Oligomycin (Oligo), 20M FCCP, 2.5g/ml Rotenone plus 5M Antimycin A (Rot/AA), and/or 175mM 2-deoxy-d-glucose (2-DG) solutions were then prepared in Seahorse media. In the Seahorse plate with hRGCs, iNS media was carefully exchanged to Seahorse media by removing, 60l iNS from all wells and adding 140l of Seahorse media. Next, 140l of the mixed media was removed by pipette and then an additional 140l seahorse media was added to each well to have a final volume of 180l. 180l of Seahorse media was then added to any empty wells. The plate was placed in Incucyte S3 (Sartorius) and one image of each well was taken for cell area normalization using brightfield and red fluorescence (tdTomato) channels. The hRGC seahorse plate was then placed into a non-CO2, 37C incubator for at least 45min. The reagents were added into their respective ports in the cartridge with the final concentrations in the wells as follows. For ATP rate assay, 2.0M Oligo and 0.25g/ml Rotenone plus 0.5M Antimycin A; for the glycolytic rate assay, 0.25g/ml Rotenone plus 0.5M Antimycin A and 17.5mM 2-DG; and for the Mito stress test, 2.0M Oligo, 2.0M FCCP (optimal concentration from FCCP titration), and 0.25g/ml Rotenone plus 0.5M Antimycin A. After loading all ports, the cartridge was placed into a non-CO2, 37C incubator while the experiment was setup in WAVE software (Agilent). The cartridge was then placed into the XFe96 analyzer (Agilent) and run for calibration. After the machine calibrations were successful, the hRGC seahorse plate was placed into the machine and the assay was run (ATP rate assay, glycolytic rate assay, or Mito stress test). Cell area from Incucyte images were measured using Image J and extrapolated for the total cell area in each well for normalization. The assay results were then exported into the appropriate excel macro using Seahorse Wave Desktop software (Agilent) for analysis.

hRGCs were seeded at 25,000 cells per well of a 96-well clear bottom black-walled plate and maintained for 3 days. The cells were then treated with indicated molecules for the designated time points. The caspase activity was measured using the ApoTox-Glo Triplex assay kit (Promega). 100l of Caspase-Glo 3/7 reagent was added to all wells and incubated for 30minutes at room temperature before measuring luminescence (Caspase). Measurements were normalized to DMSO control.

hRGCs were seeded at 250,000 cells per well on MG-coated 6-well plates and maintained for 3 days. The cells were then treated with 1 g/ml BX795 or equivalent DMSO for 24h. Media was aspirated, 500 l of fixative solution (3% Glutaraldehyde, 0.1M Cacodylate) was added, and the cells were incubated for 15min. Next, hRGCs were scraped and pelleted by centrifugation at 10,000xg for 20minutes. The pellets were fixed overnight at 4C, then rinsed the next day in 0.1M cacodylate buffer, followed by post fixation with 1% osmium tetroxide, 0.1M cacodylate buffer for 1h. After rinsing again with 0.1M cacodylate buffer, the cell pellets were dehydrated through a series of graded ethyl alcohols from 70 to 100%, and 2 changes of 100% acetone. The cell pellets were then infiltrated with a 50:50 mixture of acetone and embedding resin (Embed 812, Electron Microscopy Sciences, Hatfield, PA) for 72h. Specimen vial lids were then removed, and acetone allowed to evaporate off for 3h. Then the pellets were embedded in a fresh change of 100% embedding resin. Following polymerization overnight at 60C the blocks were then ready for sectioning. All procedures were done in centrifuge tubes including the final embedding. Sections with cut at 85nm, placed on copper grids, stained with saturated uranyl acetate, viewed, and imaged on a Tecnai Spirit (ThermoFisher, Hillsboro, OR) equipped with an AMT CCD camera (Advanced Microscopy Techniques, Danvers, MA). 49000X images were analyzed using Image J to measure mitochondrial parameters as explained in Fig.5.

Samples were treated with CCCP or BX795 at different time points as independent biological samples. Statistical tests between two independent datasets were done by Students t-test, each data point within a dataset is from an independent culture wellor cell (Figs.1cf, h, 1m; j, l, 2c, f, 3ad, fi, 4bd, fi, 5b, 6b, e, hl, Supplementary Figs.3b, 4bc). We used t-test rather than ANOVA because we did not want to assume that each group has the same variance. For non-normal data distribution, we performed MannWhitney U test to compare between two independent data sets (Fig.5ce, Supplementary Fig.5b). Graphs were made using GraphPad Prism 9.0 softwareand figures were made using Adobe Illustrator.

Further information on research design is available in theNature Portfolio Reporting Summary linked to this article.

Read the original:
Enhanced mitochondrial biogenesis promotes neuroprotection in ... - Nature.com

Will future computers run on human brain cells? Breaking ground on … – Science Daily

A "biocomputer" powered by human brain cells could be developed within our lifetime, according to Johns Hopkins University researchers who expect such technology to exponentially expand the capabilities of modern computing and create novel fields of study.

The team outlines their plan for "organoid intelligence" today in the journal Frontiers in Science.

"Computing and artificial intelligence have been driving the technology revolution but they are reaching a ceiling," said Thomas Hartung, a professor of environmental health sciences at the Johns Hopkins Bloomberg School of Public Health and Whiting School of Engineering who is spearheading the work. "Biocomputing is an enormous effort of compacting computational power and increasing its efficiency to push past our current technological limits."

For nearly two decades scientists have used tiny organoids, lab-grown tissue resembling fully grown organs, to experiment on kidneys, lungs, and other organs without resorting to human or animal testing. More recently Hartung and colleagues at Johns Hopkins have been working with brain organoids, orbs the size of a pen dot with neurons and other features that promise to sustain basic functions like learning and remembering.

"This opens up research on how the human brain works," Hartung said. "Because you can start manipulating the system, doing things you cannot ethically do with human brains."

Hartung began to grow and assemble brain cells into functional organoids in 2012 using cells from human skin samples reprogrammed into an embryonic stem cell-like state. Each organoid contains about 50,000 cells, about the size of a fruit fly's nervous system. He now envisions building a futuristic computer with such brain organoids.

Computers that run on this "biological hardware" could in the next decade begin to alleviate energy-consumption demands of supercomputing that are becoming increasingly unsustainable, Hartung said. Even though computers process calculations involving numbers and data faster than humans, brains are much smarter in making complex logical decisions, like telling a dog from a cat.

"The brain is still unmatched by modern computers," Hartung said. "Frontier, the latest supercomputer in Kentucky, is a $600 million, 6,800-square-feet installation. Only in June of last year, it exceeded for the first time the computational capacity of a single human brain -- but using a million times more energy."

It might take decades before organoid intelligence can power a system as smart as a mouse, Hartung said. But by scaling up production of brain organoids and training them with artificial intelligence, he foresees a future where biocomputers support superior computing speed, processing power, data efficiency, and storage capabilities.

"It will take decades before we achieve the goal of something comparable to any type of computer," Hartung said. "But if we don't start creating funding programs for this, it will be much more difficult."

Organoid intelligence could also revolutionize drug testing research for neurodevelopmental disorders and neurodegeneration, said Lena Smirnova, a Johns Hopkins assistant professor of environmental health and engineering who co-leads the investigations.

"We want to compare brain organoids from typically developed donors versus brain organoids from donors with autism," Smirnova said. "The tools we are developing towards biological computing are the same tools that will allow us to understand changes in neuronal networks specific for autism, without having to use animals or to access patients, so we can understand the underlying mechanisms of why patients have these cognition issues and impairments."

To assess the ethical implications of working with organoid intelligence, a diverse consortium of scientists, bioethicists, and members of the public have been embedded within the team.

Johns Hopkins authors included: Brian S. Caffo, David H. Gracias, Qi Huang, Itzy E. Morales Pantoja, Bohao Tang, Donald J. Zack, Cynthia A. Berlinicke, J. Lomax Boyd, Timothy DHarris, Erik C. Johnson, Jeffrey Kahn, Barton L. Paulhamus, Jesse Plotkin, Alexander S. Szalay, Joshua T. Vogelstein, and Paul F. Worley.

Other authors included: Brett J. Kagan, of Cortical Labs; Alysson R. Muotri, of the University of California San Diego; and Jens C. Schwamborn of University of Luxembourg.

See the rest here:
Will future computers run on human brain cells? Breaking ground on ... - Science Daily

Should we allow genome editing of human embryos? – University of Cambridge news

Andrea Reid-Kelly

I grew up in Leeds with my parents, my older brother and later on my foster brother Scott, who has Downs syndrome. I think growing up with a brother with Downs probably made me a better person. You develop a compassion and understanding for those whose experience is different from your own. This probably has something to do with me going into teaching and Ive taught children with special educational needs since the mid-1990s. I now live in Birmingham with my husband Martin and our daughters, Francesca and Claudia.

I was born with a significant heart condition, which we later learned was caused by Noonan syndrome. This is a genetic condition that can cause heart problems, distinctive facial features, small stature and specific learning difficulties such as dyslexia. But symptoms vary widely and so does its severity some people may never know that they have it. Its estimated that as many as one in 1000 people are born with Noonan syndrome. It can be hereditary or appear by chance, as it did in my case.

I have a couple of the more severe symptoms, I suppose. I had heart surgery when I was four years old and then again when I was 33 years old. My last surgery was three days after my daughters second birthday, which was hard. At four feet nine inches tall, I have proportionate short stature, a form of dwarfism. I also have dyslexia and wonder if I have other specific learning difficulties as well. Although the genetic cause of Noonan is known in many cases, in my case it remains a mystery.

Despite these challenges, I live a happy life and Im proud of what Ive achieved. My condition hasnt stopped me doing anything, except reaching the top shelf in the supermarket! I went through an angry phase when I was younger, but am at peace with who I am and I think dealing with Noonan has given me more confidence and strength to tackle lifes other challenges. I sometimes think my condition is harder on my family than it is on me they cant help worrying about me.

When my husband and I started thinking about having children, it was obviously a really serious decision. There was a 50-50 chance that my children would inherit Noonan syndrome. After a lot of soul searching, I decided that it was worth the risk. But I really pushed my husband to think long and hard about whether he wanted to have children with me. I didnt want him to just say yes because he loved me and hoped for the best.

So far as we know, neither of our daughters have Noonan syndrome. Because the gene that causes my case is unknown, we cant test them to know for sure. I wonder if Francesca has a very mild form, though. There are subtle signs, but then its easy to see what isnt there. Not every trait is necessarily linked to Noonan.

I first met another person with Noonan syndrome some years ago. Theres something powerful about meeting someone with the same genetic condition, you can identify with their experience and bond over challenges. I heard about the citizens jury via Genetic Alliance UK and decided to get involved.

Before the jury, I didnt really know much about editing of human embryos or have a strong opinion about it. Im a bit of a fence-sitter by nature. But by the end of the jury, I went from a neutral opinion to being in favour of parliamentary debate about potentially changing the law to allow editing of human embryos to treat genetic conditions. I felt well-informed and empowered after hearing from experts and others whose experience differed from mine.

One thing I feel very strongly now is that open and honest debate needs to happen about editing of human embryos, because it is incredibly complex. I think about my brother Scott and how the world would be less rich without people like him in it he is so much more than a person with Downs syndrome. We shouldnt automatically seek to remove difference, even if it scares us, because the less we see it the less compassionate we become as a society.

I think personal choice is key. If I could go back in time and had the option, I wouldnt chose to edit my embryos. But I understand that my daughters might want to have that choice, because theres a chance they have Noonan syndrome and could pass that on to their children.

The citizens jury has been an incredibly powerful and inspiring experience, its an amazing tool for debating complex issues. The danger, I think, is that nobody pays attention and that our thoughts have no influence in the end.

Continued here:
Should we allow genome editing of human embryos? - University of Cambridge news

Global Cell Dissociation Solution Market Size to Worth Around USD … – InvestorsObserver

Global Cell Dissociation Solution Market Size to Worth Around USD 872.8 Million by 2032

Chicago, March 01, 2023 (GLOBE NEWSWIRE) -- Markets N Research has recently released expansive research on Global Cell Dissociation Solution Market with 220+ market data Tables, Pie Chart, and Graphs & Figures spread through Pages and easy to understand detailed analysis. The report endows with wide-ranging statistical analysis of the markets continuous developments, capacity, production, production value, cost/profit, supply/demand and import/export. This market report provides best solutions for strategy development and implementation depending on clients needs to extract tangible results. This market research report serves the clients by providing data and information on their business scenario with which they can stay ahead of the competition in today's rapidly changing business environment.

As per the report titled "Cell dissociation solution Market Size, Share & COVID-19 Impact Analysis, By Type (Tissue Dissociation and Cell Detachment), By Product (Enzymatic Dissociation Products (Collagenase, Trypsin, Papain, Elastase, DNase, Hyaluronidase and Other Enzymes), Non-Enzymatic Dissociation Products and Instruments), By Tissue (Connective Tissues, Epithelial Tissues and Other Type Tissues (Skeletal and Muscles Tissues)), By End User (Pharmaceutical and Biotechnology Companies, Research and Academics and Other End Users), and Regional Forecasts, 2023-2030" observes that the market size in 2022 stood at USD 294.9 million and USD 872.8 million in 2030 . The market is expected to exhibit a CAGR of 14.90% during the forecast period.

Get Free Sample PDF of Cell Dissociation Solution Market Research Report: https://marketsnresearch.com/sample/1660

Cell Dissociation Solution Market Analysis:

The rising demand for R&D in biopharmaceutical businesses is one of the key factors anticipated to propel the growth of the cell dissociation market during the forecast period. Additionally, it is projected that the favourable funding environment for cancer research and the rising incidence and prevalence of infectious and chronic diseases will fuel the expansion of the cell dissociation market. Furthermore, the rising attention on customised treatment and increase in the government funding for cell-based research is further expected to cushion the growth of the cell dissociation market.

Recent Development:

Report Scope:

List Of Key Companies Profiled:

Symphogen (Denmark) And Thermo Fisher Scientific Collaborated To Further Their Strategic Partnership

In 2020, to improve the discovery and development of biopharmaceuticals, Thermo Fisher Scientific extended its strategic partnership with Symphogen (Denmark). QIAGEN N.V. (Germany) was purchased by Thermo Fisher Scientific in order to increase the scope of its specialty diagnostics offering.

Major Players Develop Acquisition Plans to Boost Brand Image

The leading businesses in the cell dissociation solution market plan acquisitions to improve their brand recognition globally. For instance, in 2021, a definitive merger agreement between Roche Diagnostics and GenMark Diagnostics was signed in order to have access to cutting-edge technologies for testing several infections in a single patient sample.

Enquiry For Buying @ https://marketsnresearch.com/buying-request/1660

Our Free Sample Report Consists of the following:

Driving Factors:

Cell-based therapies use cells to repair or regenerate tissues or organs that have been injured or afflicted by disease. These treatments have drawn a lot of attention recently because they offer the potential to treat a variety of illnesses that are currently difficult or impossible to treat using conventional methods. Cell-based therapies are in rising demand because they have various advantages over conventional therapies, including less side effects, greater efficacy, and the potential to have long-lasting effects. Stem cell therapy, for instance, is being researched as a potential cure for ailments like heart disease, Parkinson's disease, and spinal cord injury.

Players in the cell dissociation solutions market can expect to find significant growth prospects in emerging markets like China, India, and Brazil. The number of R&D initiatives in the life sciences sector has increased in these nations. For instance, Indian-based pharmaceutical companies are spending a lot of money on research and development to bring new medicines to market. An Indian pharmaceutical company named Cadila Healthcare Ltd. invested USD 113 million (or 13% more) in R&D in 2020 than it did in 2019. Similar to Biocon, another pharmaceutical business with headquarters in India, spent USD 58.79 million on R&D in 2020, a 52% increase from 2019. The country's demand for items involving cell dissociation solution is predicted to rise as a result of these investments.

Restraining Factors:

One of the biggest issues the market for cell dissociation solutions is high price. The high price of these goods is a result of a number of variables. First off, the ingredients required to make cell dissociation solutions can be pricey. Enzymes and other biological ingredients that are hard to get and expensive are used in many of these remedies. These materials could need to come from specialised vendors or go through intricate production procedures, which could raise the cost.

Challenging Factors:

Animals and humans must be employed in cell biology research because stem cell therapies and gene therapy studies that use gene recombination use both animal and human cells. In vivo drug toxicity and pharmacokinetic testing also uses these human and animal cells. This is due to the fact that direct testing on people or animals could be dangerous or even lethal. Furthermore, human embryos are often destroyed in stem cell research trials that employ them for medicinal purposes. In a number of nations around the world, strong restrictions have been developed by ethical authorities to regulate these operations. Cell biology research is being significantly constrained in many different countries due to these ethical issues and limitations on the use of cells for study.

To Gain More Insights into the Market Analysis, Browse Summary of the Cell Dissociation Solution Market Report @ https://marketsnresearch.com/report/1660/global-cell-dissociation-solution-market

Global Cell Dissociation Solution Market Segmentations:

Global Cell Dissociation Solution Market By Type:

Global Cell Dissociation Solution Market By Product:

Global Cell Dissociation Solution Market By Tissue:

Global Cell Dissociation Solution Market By End User:

Global Cell Dissociation Solution Market Regional Insights:

North America is projected to hold the largest share of the cell dissociation solution market over the forecast period due to the increase in the prevalence of chronic diseases like cancer. Furthermore, the emergence of significant key players and the rising industrial and academic interest in life sciences research and development would both support the growth of the cell dissociation market in the area throughout the course of the projected year.

Further Report Findings:

Access Full Report @ https://marketsnresearch.com/checkout/1660/1ecda5z5e4

Key questions answered in this report:

Key Offerings:

Table of Content

Chapter 1: Preface

Chapter 2: Report Summary

Chapter 3: COVID 19 Impact Analysis

Chapter 4: Global Cell Dissociation Solution Market, By Type Segment Analysis

Chapter 5: Global Cell Dissociation Solution Market, By Product Segment Analysis

Chapter 6: Global Cell Dissociation Solution Market, By Tissue Segment Analysis

Chapter 7: Global Cell Dissociation Solution Market, By End User Segment Analysis

Chapter 8: Cell Dissociation Solution Market Regional Analysis, 2023 2030

Chapter 9: Cell Dissociation Solution Market Industry Analysis

Chapter 10: Competitive Landscape

Chapter 11: Company Profiles

Chapter 12: Research Methodology

Chapter 13: Questionnaire

Chapter 14: Related Reports

Customize this Report @ https://marketsnresearch.com/customization-request/1660

Key Insights from Primary Research/Key Insights & Findings from the report:

Spectacular Deals:

Browse More Markets N Research Reports:

[Latest] Global Animation Market Size/Share Worth USD 528.8 Billion by 2030 at an 5.00% CAGR: Markets N Research (Analysis, Trends, Share, Segmentation, Background, Forecast, Growth, Growth Rate, Value): https://marketsnresearch.com/report/1653/global-animation-market

Global Continuous Positive Airway Pressure (CPAP) Devices Market Size/Share Worth USD 7.8 Billion by 2030, Emerging Trends, Business Strategies, Competitive Landscape and Regional Analysis: https://marketsnresearch.com/report/1647/global-continuous-positive-airway-pressure-cpap-devices-market

Global Autonomous Drone Market Size/Share Worth USD 56.5 Billion by 2030, Emerging Trends, Business Strategies, Competitive Landscape and Regional Analysis: https://marketsnresearch.com/report/1645/global-autonomous-drone-market

Global Sports Management Software Market Size/Share Worth USD 17.5 Billion by 2030, Emerging Trends, Business Strategies, Competitive Landscape and Regional Analysis: https://marketsnresearch.com/report/1643/global-sports-management-software-market

[Latest] Global Air Purification Market Size/Share Worth USD 22.1 Billion by 2030 at an 8.50% CAGR: Markets N Research (Analysis, Potential, Leaders, Strategy, Marketplace, Forecast, Segmentation): https://marketsnresearch.com/report/1640/global-air-purification-market

Hydropower Plant Market Size to Surpass USD 308.7 billion with Growing CAGR of 5.70% by 2030, Emerging Trends, Business Strategies, Competitive Landscape and Regional Analysis: https://marketsnresearch.com/report/1628/global-hydropower-plant-market

Retail POS Systems Market Size to Surpass USD 34.6 billion with Growing CAGR of 13.50% by 2030, Emerging Trends, Business Strategies, Competitive Landscape and Regional Analysis: https://marketsnresearch.com/report/1642/global-retail-pos-system-market

About Markets N Research

When it comes to investing and money matters, you need the leading market research consultancy firm to help you make the right decisions during the toughest business questions and decisions. Markets N Research is the leading research company offering both tactical and strategic support to all our customers. Customer satisfaction is our goal and that is why, we have a team of skilled and experienced specialist with the ability to do data mining, information management, and revenue enhancement solutions to ensure that our clients make informed decisions when coming to investing in the market.

Markets N Research team is comprised of well skilled and equipped personnel ready to concur any upcoming challenges in the market sector for both individual people and organization around the world. We know time is money, and therefore we ensure we solve your problem within the shortest time possible to prevent delays or missing any opportunities. We use globally accepted techniques with a little innovation from our staff in solving all your market research related challenges.

Contact Us: Markets N Research US: +1-773-649-1529 Email:- sales@marketsnresearch.com Website: https://marketsnresearch.com/ Follow on Linkedin: https://www.linkedin.com/company/markets-n-research Follow on Twitter: https://twitter.com/marketsnr

Read the original post:
Global Cell Dissociation Solution Market Size to Worth Around USD ... - InvestorsObserver

In review: the life sciences regulatory regime in United Arab Emirates – Lexology

All questions

Introduction

The United Arab Emirates (UAE) biotechnology and pharmaceutical industries are subject to stringent regulation primarily by rules and regulations at the federal level and, to a lesser degree, at the individual emirate level. Abu Dhabi and Dubai have the most developed rules and regulations of the seven emirates with respect to biotechnology and pharmaceutical matters, and the other emirates usually follow their respective cues as regards policy and legislation.

As the UAE has now evolved as a member of the globalised economy, it has endeavoured to make itself a global destination for healthcare. Accordingly, much of its new legislation reflects the influence and direction of jurisdictional trends of international market players in the pharmaceutical and medical industries. There has been a growth phase in the healthcare sector in the past few years, which has helped the UAE move towards becoming a hub for medical tourism. The nation's strategy also aims to guide and support the industry by building sustainable publicprivate partnership models in the healthcare sector.

The regulatory regime

To be supplied in the UAE, therapeutic goods must be vetted by the Registration and Control Department (RCD) of the Ministry of Health and Prevention (MOHP). The importer, exporter, manufacturer or seller of medicine or medical devices must satisfy the requirements of the RCD before they can be disseminated for public consumption within the UAE.

The RCD regulates medication and medical devices (which includes a delineation for devices that include a pharmaceutical component). The RCD further oversees the examination and registration of dietary supplements (including vitamins and herbal extracts), medicated cosmetics, antiseptics and disinfectants, and all other products that contain a pharmaceutical component or medical claim that cannot otherwise be appropriately classified as a medication. Foodstuffs and general consumer products are not regulated by the RCD, provided they assert no medical or therapeutic value or claims.

The RCD and the MOHP have the unilateral right to pull or ban any products that they may later deem to be unsafe for public consumption based on studies or recent cases within the UAE.

UAE Federal Law No. 16 of 2007 (on animal protection) states, at Article 12, that the use of animals for scientific purposes must be approved by the applicable governmental authority. Further, animals are protected from neglect, abuse and cruel treatment by applicable UAE law.

The law specifically states 'scientific purposes', which seems to implicate medical or pharmaceutical testing and does not directly address or contemplate the use of animals for the testing of (non-medicated) cosmetics or household products. The governmental approval process is always at the discretion of the concerned director, who may reject any request deemed excessive, unnecessary or generally harmful.

Effective 1 January 2020, a new law has been enacted in the UAE whereunder fertility centres are now permitted to freeze human embryos, as well as unfertilised eggs and sperm for a period of five years (extendable upon request).

In vitro fertilisation (IVF) clinics are regulated pursuant to Cabinet Decision 64 of 2020 regarding the executive regulations of Federal Law No. (7) of 2019 regarding medical assistance for childbearing. Governmental approvals are contingent upon satisfaction of numerous requirements, including facilities, equipment and staffing with appropriate professional personnel. There are numerous IVF clinics throughout the UAE.

In 2010, the MOHP licensed its first stem cell practitioner, a specialist in spinal cord and brain injuries, and a facility to perform stem cell therapies within the UAE. There have been reports of autologous stem cell treatment on two patients with degenerative diseases. However, general stem cell transplants have been permitted on a restricted, alternative basis, although the storage of stem cells has been permitted. The Dubai Health Authority (DHA) approved the first stem cell and regenerative medical centre in Dubai in 2018. Abu Dhabi and Dubai are the two Emirates in the UAE that now have established public guidelines for the regulated sector of stem cell therapies. The rules and standards to be applied during the granting, collection, testing, processing, preservation, storage, distribution, import, export and implementation of procedures related to cord blood and stem cells, and other nuclei cells derived from blood-forming cells such as the bone marrow, peripheral blood, and cord blood are regulated under the Cabinet Decision No. 6/2020 on endorsement of the regulations of cord blood and stem cells storage centres.

We understand a number of memoranda of understandings have been signed regarding stem cell therapy treatments with the regulators in the UAE.

The UAE federal law permitting organ transplantation became effective in March 2017. The law allows the transplant of tissue or organs from either live or deceased patients for the care of patients in need of the same. However, the law prohibits the sale of human tissue or organs, the funding of transplantation if this results from such sale, and the unlicensed advertising of transplantation services.

All clinical and research trials within the UAE require human subject consent, as well as the written approval of the MOHP, or other concerned governmental authorities, after a review of an application for such trials.

The Guidance of the Drug Control Department of the MOHP states that the sponsor of a specific clinical trial or experimental protocol is required to secure all the necessary agreements between the concerned parties.

Designated clinical trial centres should establish independent institutional ethics committees (IECs), which are then tasked with reviewing the relevant proposals of the sponsors. These IECs will review the proposals for clinical trials and experimental protocols, taking into consideration the soundness of the objectives and the medical protocols and practices.

The IECs will render recommendations as whether or not to commence a clinical trial based upon the information provided. The findings and recommendation will then be provided to the applicable governmental authorities for their final, official approvals.

In the respective proposal, the sponsor is to set forth the compensation (if any) for the investigators and the subjects of a clinical trial in its proposal to the IEC. Furthermore, the IEC is to review and approve the proposal of the sponsor with respect to insurance coverage, indemnities or other forms of compensation in case of subject injury.

The investigator may also be the sponsor of a clinical trial, provided it independently plans, conducts and assumes full responsibility for the clinical trial.

All amendments to protocols and all unexpected or serious adverse reactions to drugs administered during the clinical trial are to be reported immediately to the Ethics Committee.

While the clear letter of the law states that no unregistered drugs may be used within the UAE, there are certain circumstances where the MOHP or other governmental departments have approved the use of unregistered drugs (discussed in further detail in Section II.iv).

The Guidance further states that all clinical trials should follow the Helsinki Declaration to safeguard the rights of individuals subject to a clinical trial.

In exceptional circumstances, governmental authorities in the UAE have permitted the importation and use of unregistered medicine into the country. The MOHP has put forth an approval process that allows such importation, under any of the following circumstances:

Because of the nature of the UAE's regulated market, applications to obtain or use unregistered medication or devices must be tailored for specific patients, trials or protocols, and exigent circumstances. As a result, the quantity of unregistered medication should be limited to a specific hospital or clinic capacity, and for existing or anticipated patients per the application. The MOHP has the discretion to reject, approve, or approve with modifications any application for unregistered medication.

Furthermore, the application to the MOHP must include the following documents or information: (1) a signed undertaking letter from the concerned hospital or clinic that it shall bear all liability for the use of the unregistered medicine; (2) a certification that the medicine is registered in the country of origin or an approved jurisdiction, such as the United States, the European Union or the Gulf Cooperation Council; and (3) a registration certificate from the manufacturer listing the chemical components of the medication.

To be supplied in the UAE, medication, pharmaceuticals and medical devices must be vetted and cleared by the MOHP. A foreign manufacturer of medication, pharmaceuticals and medical devices must establish a local presence and appoint a local representative or a local agent (which may be the same person) for the sale and distribution of these products within the UAE.

Unless there are exigent circumstances (as described in Section II.iv), there are virtually no exceptions to expedite or accelerate the approvals process. The approval of a new medication, for example, would take, on average, no less than two years from submission of an application to the relevant authorities.

The UAE is a signatory to international conventions on narcotics and psychotropic substances. When a medication is approved and registered for use in the UAE, the method of dispensation is also agreed. This is based on the level of control in the source country, as well as the level of control of the active ingredient pursuant to UAE law.

Pricing for medications is fixed by UAE law, and the MOHP provides an updated pricing list for these periodically. Attempts by manufacturers and agents to circumvent the fixed pricing may be subject to fines, bans or other legal recourse by the UAE government.

Medical devices must also be approved by the MOHP before they can be sold or distributed in the UAE. The law defines a medical device as any such device that is used to diagnose, monitor or treat an illness. UAE laws and regulations make a distinction between devices that provide therapeutic benefit through purely mechanical or non-pharmaceutical means and those devices that have a pharmaceutical component (i.e., devices that dispense a drug therapy). The latter may be subject to pricing controls similar to those of medication.

Currently, the UAE is largely dependent on the import of sophisticated medical equipment. However, recently, there has been development in the nascent medical products industry. In the near future, the UAE may play a leading role in 3D printing in the medical products sector, which could involve developing 3D-printed teeth, bones, artificial organs, medical and surgical devices, and hearing aids.

Patents in the UAE are registerable for pharmaceuticals for a period of up to 20 years, with no extension period allowed.

The UAE recognises the patentability of second-use medical inventions under the law and has registered a number of these.

There are no remarkable regulatory incentives within the UAE with respect to the marketing, developing or production of pharmaceuticals at this time.

Under the UAE law, the foreign manufacturer of a drug must appoint a local authorised representative within the UAE. The representative may also be the distributor of the medication within the UAE. The representative will be tasked with handling all complaints or recalls relating to the medication, as well as fulfilling all requirements with respect to placing the product in the market. The post-market obligations include the obligation to maintain distribution records, complaint-handling procedures and incident-reporting processes, and implement processes to execute investigations and recalls in respect of defective or potentially defective products promptly.

The RCD or MOHP have the discretion to recall any medication based on any information or incident reports directed to them.

The MOHP newly established a decree in June 2021 for a system wherein pharmaceutical products within the UAE and those entering the UAE are tracked and traced for authenticity and legality. This decree applies to all standard pharmaceutical products traded in the UAE. To develop a centralised platform, MOHP, in partnership with EVOTEQ, is developing the track-and-trace platform Tatmeen, which will be used to track individual events in the drug supply chain and confirm their authenticity.

The relevant governmental authorities must approve a pharmaceutical manufacturing plant within the UAE.

The proposed facility must be approved as far as its layout, infrastructure, manufacturing capacities, and its storage and handling of chemicals. The government reserves the right for site inspections and for assessing penalties upon non-compliant facilities.

The UAE has repealed the Commercial Companies Law (Federal Law No. 2 of 2015, CCL) by issuing Federal Decree Law No. 32 of 2021 (Decree Law) and thereby overhauling the entire corporate legal framework by removing the requirement to have 51 per cent share capital owned by majority UAE national shareholders or a company wholly owned by UAE nationals (except for certain activities of strategic importance). The said changes are effective from 2 January 2022.

Healthcare and medical advertising are strictly regulated by governmental authorities and there are stringent guidelines to ensure transparency and honesty, and to stamp out misleading marketing practices. All forms of medical and pharmaceutical advertising require governmental pre-approval before publication. Comparative advertising is usually not permitted and, given other considerations (mainly relating to potential criminal liability for libel or harm to business reputation), most companies steer clear of any advertising pitting themselves against their competitors. Even advertisements on discount websites for businesses such as laser hair removal or dermal fillers require MOHP approval and carry a requisite warning to customers relating to efficacy or potential risks of such procedures.

Additionally, advertisements must not violate public morals, decency, UAE customs or Islamic values and traditions. Medical advertising cannot be false, deceptive or misrepresent the quality or type of medical treatment or product presented. Further, it cannot mislead potential patients regarding the efficacy of certain medication treatment, therapy or protocol, or that the aforementioned will have no potential side effects.

Advertising for telemedicine companies should clearly state what services they are and are not authorised or licensed to provide. Advertisements geared towards children are prohibited.

Incentives to healthcare workers for the sale of specified medications, procedures or devices are not permitted by any medical or healthcare advertisement.

The UAE has a number of provisions within its Agency Law, Civil Code and Commercial Code that provide a number of protections to local agents and distributors. Some pharmaceuticals or medical equipment may, in certain circumstances, require a registered 'commercial agent' to be the importer on record. Such registered commercial agents enjoy wide protections under the UAE's Agency Law, including exclusivity within the UAE market.

A registered agency under the Agency Law makes it difficult for a foreign principal to terminate. Often, a registered agency will only agree to deregister a registered agency (and, hence, allow the principal to distribute products through other agents or resellers) upon an agreed and substantial financial settlement. A new draft Agency Law was discussed in mid-2022 in which a commercial agency can be terminated by mutual agreement of the parties or on the expiry of its term. The criticism of the current law of Agency Law as biased in favour of UAE national commercial agents (i.e., cannot be easily terminated even at the expiry of the contractual term) over foreign principals may be put to rest if the draft law is released in the format discussed in the press.

In addition to the basic definition of 'prescription' medication, the MOHP recognises the following three classifications: narcotics, CDA and CDB.

Narcotics are defined based upon their active ingredients and composition. Additionally, CDA medications are defined by their active ingredients, as well as their potential for abuse or diversion for illegal use. CDB medications are defined as those that are used for psychiatric conditions, avoid narcotic controls and restrictions owing to their chemical formulation, or require stricter control than simply those medications that are designated as 'prescription'.

Medical devices are classified in order of risk:

That being said, the vast majority of medication or medical devices that fall outside the categories of stricter scrutiny are available for sale and distribution over the counter.

To import medicine or medical devices into the UAE, a UAE company must obtain a medical warehouse licence or a UAE national must obtain a medical importer licence with the relevant government authorities. The law was amended to permit companies with mixed UAE and foreign shareholding to obtain a medical import licence.

Re-exportation of imported goods can occur within six months of importation, provided the goods are in unused and otherwise exportable condition and the applicable documentation relating to the goods is current.

The UAE abolished the Boycott of Israel Law in 2020 and subsequently revoked all trade restrictions that were previously in place with Israel.

Controlled substances are heavily regulated and monitored in the UAE. In most circumstances, narcotics or psychotropic substances can only be administered within the confines of a hospital or clinic, or dispensed exclusively from a government hospital upon submission of a valid prescription.

The MOHP has a list of controlled substances that cannot be brought into the UAE by people visiting or entering the country, regardless of whether the person has a valid prescription for the medication in the country of origin. UAE residents and travellers are allowed to import narcotic medicines and psychotropics (controlled medicine) for personal use to the country upon the issue of a permit from the MOHP official portal.

The UAE governmental authorities have broad powers of regulation and sanction for the violation of any laws or regulations relating to medication and medical devices. These include: warning, fining, banning of distribution of certain products, blacklisting of manufacturers or medication, suspension or deregistration of local representatives or agents, and closing operations of pharmaceutical plants. The fines may be substantial, and imprisonment may be warranted in cases of intentional criminal activity.

The UAE has enacted the Health Data Protection Law (UAE Federal Law No. 2 of 2019), with the objective of addressing the protection of health data originating in the UAE. This law derives principles from the European Union's General Data Protection Regulation, including purpose limitation, accuracy, integrity and confidentiality. Any health-related information and data that originates in the UAE may not be stored, processed, generated or transferred outside the UAE certain exceptions to this rule were clarified in an amendment to the law in 2021. This has a direct effect on foreign companies that provide cloud-based services, in addition to local companies that use these services. With regard to enforcement, healthcare providers that violate certain provisions of the Health Data Protection Law may face fines ranging from 1,000 to 1 million dirhams, effective from May 2019. Although the legislation has the clear intent of enforcement, it is not clear whether the MOHP and relevant authorities will take immediate action.

Pricing and reimbursement

Pricing of medication is fixed and regulated by applicable laws, with specified margin limits. Hospitals and clinics must sell medication to the public at the prices specified by the MOHP and cannot give discounts on medication outside the margins fixed by law. Bonus schemes between manufacturers and distributors are strongly discouraged (if not prohibited by law).

Since 2010, and under the direction of Abu Dhabi, the UAE has been moving towards a diagnostic rate group (DRG) system for insurance billing and reimbursement. One of the intended purposes of switching to the DRG system is to lower medical costs in the UAE (where the vast majority of medication is imported).

The DRG system requires new billing systems within hospitals and clinics, and the requisite staff training for documenting and coding applicable medical services. One potential benefit of the installation and implementation of the DRG system UAE-wide is providing transparency and avoiding excess payments or overbilling.

Administrative and judicial remedies

The UAE Medical Liability Law (UAE Federal Law No. 4 of 2016 read together with the implementing regulation of 2019) gives patients the right to report any form of medical malpractice or medical negligence by their service providers or by pharmaceutical companies directly to the MOHP, or its applicable departments. The complaints are to be referred to medical liability commissions, formed by the MOHP, or the chairman of the local health authority.

The relevant commission will review the complaint with all the applicable documentation and make an adjudication on the existence of malpractice and, if applicable, the causes and results of that malpractice.

The decisions made by the commissions are appealable by the patients, doctors or providers within 30 days to a higher liability commission, formed by the UAE Cabinet. After review of the file, the decisions of this higher commission are final and binding upon all parties.

Financial relationships with prescribers and payers

The Emirates of Abu Dhabi and Dubai have instituted mandatory health insurance schemes upon all employers. Additionally, the Department of Health Abu Dhabi (DOH) introduced a standard provider contract mandating that all contracts between insurers and providers meet required standards. One such requirement is that reimbursement of healthcare fees is made in accordance with a mandatory tariff, which specifies the price for basic services. Ideally, such requirement is an attempt to discourage or stop commissions or kickbacks between providers.

The DOH previously issued a directive relating to kickbacks in medical laboratory services and testing. This directive was the result of complaints from patients who were often directed to a medical laboratory that a specific doctor had an agreement with, to be billed for examinations, diagnostics or treatments that were unnecessary. The doctor was given a portion of any fees generated from such visits.

Additionally, local insurers have recently taken a novel approach in requiring that providers sign an undertaking letter to the effect that providers would comply with the spirit and letter of contractual requirements of their binding contract, with a sworn statement that no volume incentives or commissions are being paid for obtaining services. Violation of the undertaking letter could result not only in a material breach of the underlying contract justifying termination, but would allow the insurer to petition the DOH or another concerned governmental authority for redress.

Efforts to stem the flow of kickbacks are much more likely to have a significant impact on smaller secondary care providers (e.g., medical laboratory service providers or specialist diagnostic centres) that generate much of their revenue from larger hospitals or clinics. One way to ensure referrals is the payment of kickbacks. If kickbacks are no longer available through this route, companies will need to become more competitive.

The DRG billing system (as discussed in Section III) may be a further tool in the future to combat kickbacks and illegal commissions.

Special liability or compensation systems

Other than the remedies delineated in Section IV, there are no special liability or compensation systems contemplated in applicable law.

Transactional and competition issues

UAE Federal Law No. 4 of 2012 on the regulation of competition (the Competition Law) became effective in 2013 and regulates competition within the UAE market. The production and distribution of pharmaceuticals are specifically exempted from the Competition Law. Further, as stated elsewhere, the pricing of medication and pharmaceuticals is fixed by UAE law.

With respect to the sale of pharmaceutical manufacturing plants, companies or patents in the UAE, generally, these would follow the rules and requirements contained in the UAE Commercial Companies Law or Commercial Transactions Law. Approval of the relevant health department (DOH or DHA) or the Ministry of Health may be required depending on the specific activity on the licence of the company.

With respect to patent licensing, a patent licence cannot be transferred to a third party unless ownership of the licensed item has been assigned and approved by the respective court.

Current developments

Many of the legal and regulatory reforms contemplated herein strongly convey the desire of the UAE to be at the forefront of medical care. The ultimate objective of the UAE (the Emirates of Abu Dhabi and Dubai in particular) is to be able to manufacture or provide medication and healthcare that rivals that of any country around the world. This also includes a renewed focus on research and development and attracting qualified medical professionals and researchers.

During the past few years, the UAE has ramped up its investment strategy in the pharmaceutical industry. The UAE has witnessed significant deals in terms of mergers, acquisition and strategic tie-ups between healthcare stakeholders and public and private entities to enhance the healthcare industry in the recent years. The UAE pharmaceutical sector is expanding rapidly and is expected to reach almost 11.1 million by 2030, according to the World Bank. The Dubai Industrial Strategy 2030 and the Abu Dhabi vision 2030 consider the pharmaceutical industry as one of the main sub-sectors to develop with its future growth prospects, export potential and mid-term to long-term economic impact. This augmented investment strategy is propelled to focus on one of the significant national agenda items (i.e., to achieve a world-class healthcare system in the UAE and reduce reliance on imported pharmaceuticals and manufacture locally).

Outlook

Here is the original post:
In review: the life sciences regulatory regime in United Arab Emirates - Lexology

Targeting p53 pathways: mechanisms, structures, and advances in … – Nature.com

Kastenhuber, E. R. & Lowe, S. W. Putting p53 in context. Cell 170, 10621078 (2017).

Article CAS PubMed PubMed Central Google Scholar

Levine, A. J. p53: 800 million years of evolution and 40 years of discovery. Nat. Rev. Cancer 20, 471480 (2020).

Article CAS PubMed Google Scholar

ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 578, 8293 (2020).

Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495501 (2014).

Article CAS PubMed PubMed Central Google Scholar

Bykov, V. J. N., Eriksson, S. E., Bianchi, J. & Wiman, K. G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer. 18, 89102 (2018).

Article CAS PubMed Google Scholar

Sullivan, K. D., Galbraith, M. D., Andrysik, Z. & Espinosa, J. M. Mechanisms of transcriptional regulation by p53. Cell Death Differ. 25, 133143 (2018).

Article CAS PubMed Google Scholar

Sager, R. Tumor suppressor genes: the puzzle and the promise. Science 246, 14061412 (1989).

Article CAS PubMed Google Scholar

Muller, P. A. J. & Vousden, K. H. p53 mutations in cancer. Nat. Cell Biol. 15, 28 (2013).

Article CAS PubMed Google Scholar

Meek, D. W. Tumour suppression by p53: a role for the DNA damage response? Nat. Rev. Cancer 9, 714723 (2009).

Article CAS PubMed Google Scholar

Wong, K. B. et al. Hot-spot mutants of p53 core domain evince characteristic local structural changes. Proc. Natl. Acad. Sci. USA 96, 84388442 (1999).

Article CAS PubMed PubMed Central Google Scholar

Kitayner, M. et al. Structural basis of DNA recognition by p53 tetramers. Mol. Cell 22, 741753 (2006).

Article CAS PubMed Google Scholar

Joerger, A. C. & Fersht, A. R. Structural biology of the tumor suppressor p53 and cancer-associated mutants. Adv. Cancer Res. 97, 123 (2007).

Article CAS PubMed Google Scholar

Loh, S. N. Arsenic and an old place: rescuing p53 mutants in cancer. Cancer Cell 39, 140142 (2021).

Article CAS PubMed Google Scholar

Linzer, D. I. & Levine, A. J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17, 4352 (1979).

Article CAS PubMed Google Scholar

Lane, D. P. & Crawford, L. V. T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261263 (1979).

Article CAS PubMed Google Scholar

Parada, L. F. et al. Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature 312, 649651 (1984).

Article CAS PubMed Google Scholar

Eliyahu, D., Michalovitz, D. & Oren, M. Overproduction of p53 antigen makes established cells highly tumorigenic. Nature 316, 158160 (1985).

Article CAS PubMed Google Scholar

Lane, D. P. & Benchimol, S. p53: oncogene or anti-oncogene? Genes Dev. 4, 18 (1990).

Article CAS PubMed Google Scholar

Nigro, J. M. et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 342, 705708 (1989).

Article CAS PubMed Google Scholar

Cunningham, J. et al. Expression of p53 and 17p allelic loss in colorectal carcinoma. Cancer Res 52, 19741980 (1992).

CAS PubMed Google Scholar

Hinds, P., Finlay, C. & Levine, A. J. Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J. Virol. 63, 739746 (1989).

Article CAS PubMed PubMed Central Google Scholar

Eliyahu, D. et al. Meth A fibrosarcoma cells express two transforming mutant p53 species. Oncogene 3, 313321 (1988).

CAS PubMed Google Scholar

Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215221 (1992).

Article CAS PubMed Google Scholar

Olivero, C. E. et al. p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis. Mol. Cell. 77, 761774 (2020).

Article CAS PubMed PubMed Central Google Scholar

Yonish-Rouach, E. et al. The role of p53 as a transcription factor in the induction of apoptosis. Behring Inst. Mitt. 97, 6071 (1996).

CAS Google Scholar

Wei, C.-L. et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124, 207219 (2006).

Article CAS PubMed Google Scholar

Bieging, K. T., Mello, S. S. & Attardi, L. D. Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer 14, 359370 (2014).

Article CAS PubMed PubMed Central Google Scholar

Lakin, N. & Jackson, S. Regulation of p53 in response to DNA damage. Oncogene 18, 76447655 (1999).

Article CAS PubMed Google Scholar

Gu, B. & Zhu, W. Surf the post-translational modification network of p53 regulation. Int. J. Biol. Sci. 8, 672684 (2012).

Article PubMed PubMed Central Google Scholar

DeHart, C., Chahal, J., Flint, S. & Perlman, D. Extensive post-translational modification of active and inactivated forms of endogenous p53. Mol. Cell Proteom. 13, 117 (2014).

Article CAS Google Scholar

Chen, L., Liu, S. & Tao, Y. Regulating tumor suppressor genes: post-translational modifications. Signal Transduct. Target Ther. 5, 90 (2020).

Article CAS PubMed PubMed Central Google Scholar

Kruse, J.-P. & Gu, W. SnapShot: p53 posttranslational modifications. Cell 133, 93030 (2008).

Article CAS PubMed PubMed Central Google Scholar

Aubrey, B. et al. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 25, 104113 (2018).

Article CAS PubMed Google Scholar

Vaddavalli, P. & Schumacher, B. The p53 network: cellular and systemic DNA damage responses in cancer and aging. Trends Genet 38, 598612 (2022).

Article CAS PubMed Google Scholar

Ma, M. et al. p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521. Signal Transduct. Target Ther. 7, 290 (2022).

Article CAS PubMed PubMed Central Google Scholar

Mihara, M. et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell. 11, 577590 (2003).

Article CAS PubMed Google Scholar

Chipuk, J. E. et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 10101014 (2004).

Article CAS PubMed Google Scholar

Miyashita, T. & Reed, J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293299 (1995).

Article CAS PubMed Google Scholar

Seoane, J., Le, H.-V. & Massagu, J. Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature 419, 729734 (2002).

Article CAS PubMed Google Scholar

Engeland, K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ. 29, 946960 (2022).

Article CAS PubMed PubMed Central Google Scholar

Hafner, A., Bulyk, M., Jambhekar, A. & Lahav, G. The multiple mechanisms that regulate p53 activity and cell fate. Nat. Rev. Mol. Cell Biol. 20, 199210 (2019).

Article CAS PubMed Google Scholar

Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103112 (2002).

Article CAS PubMed Google Scholar

Sancar, A. DNA repair in humans. Annu. Rev. Genet. 29, 69105 (1995).

Article CAS PubMed Google Scholar

Sancar, A., Lindsey-Boltz, L. A., Unsal-Kamaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 3985 (2004).

Article CAS PubMed Google Scholar

Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 5762 (2015).

Article CAS PubMed PubMed Central Google Scholar

Liu, Y. & Gu, W. The complexity of p53-mediated metabolic regulation in tumor suppression. Semin. Cancer Biol. 85, 432 (2021).

Article PubMed Google Scholar

Blagih, J., Buck, M. D. & Vousden, K. H. p53, cancer and the immune response. J. Cell Sci. 133, jcs237453 (2020).

Article CAS PubMed Google Scholar

Spike, B. T. & Wahl, G. M. p53, stem cells, and reprogramming: tumor suppression beyond guarding the genome. Genes Cancer 2, 404419 (2011).

Article CAS PubMed PubMed Central Google Scholar

White, E. Autophagy and p53. Cold Spring Harb. Perspect. Med. 6, a026120 (2016).

Article PubMed PubMed Central Google Scholar

Mrakovcic, M. & Frhlich, L. p53-mediated molecular control of autophagy in tumor cells. Biomolecules 8, 14 (2018).

Article PubMed PubMed Central Google Scholar

Williams, A. B. & Schumacher, B. p53 in the DNA-damage-repair process. Cold Spring Harb. Perspect. Med. 6, a026070 (2016).

Original post:
Targeting p53 pathways: mechanisms, structures, and advances in ... - Nature.com

Kanazawa University research: Biomolecular sliding at the nanoscale – StreetInsider.com

KANAZAWA, Japan, Feb. 28, 2023 /PRNewswire/ -- Researchers at Kanazawa University report in Nano Letters the discovery of a biomolecular dynamical process likely relevant to gene expression. The process, revealed by means of high-speed atomic force microscopy, involves DNA and its packaging molecules.

In organisms whose cells have a nucleus, like plants and animals, the basic packaging units of DNA are the so-called nucleosomes. A nucleosome consists of a segment of DNA wound around eight proteins known as histones. Gene expression, which lies at the basis of protein production, requires 'reading' DNA, for which DNA needs to be temporarily unwrapped. Detailed studies, and especially visualizations, of DNAhistone and nucleosome dynamics are crucial for better understanding DNA unwrapping and related processes. Mikihiro Shibata from Kanazawa University and colleagues have now succeeded in making video recordings of the nucleosome dynamics of H2A.Z, a histone variant associated with various biological processes. The videos reveal the spontaneous sliding of H2A.Z nucleosomes on a substrate.

Histone variants, such as H2A.Z, differ from the canonical forms (like H2A) encountered in stable nucleosome packaging. They form unstable nucleosomes with particular biological functions; H2A.Z is believed to play a role in early embryonic development and stem cell differentiation. The dynamics of the H2A.Z nucleosome under physiological conditions are mostly unknown. Shibata and colleagues used high-speed atomic force microscopy (HS-AFM) to investigate H2A.Z nucleosome dynamics, as the method is a powerful nanoimaging tool for visualizing molecular structures and their dynamics at high spatiotemporal resolution.

To observe DNAhistone dynamics in HS-AFM experiments, the nucleosome needs to be put onto a substrate. The DNA should adsorb easily to the substrate, but at the same time, substrateDNA interactions should still be weak enough to avoid suppressing dynamical processes. The scientists therefore prepared substrates by putting pillar[5]arenes onto a mica surface. The pillar[5]arenes, molecules with a pentagonal tubular structure, form a thin film on the mica, and provide the ideal surface for nucleosome dynamics observations.

The researchers looked at the time evolution of a system consisting of a nucleosome particle put on a DNA strand. Experiments with canonical H2A histones confirmed the stability of H2A nucleosomes: no significant changes over time were observed. Observations for H2A.Z histone variants showed a different picture, however. HS-AFM with a time resolution of 0.3 s revealed sliding events, in which a nucleosome particle slides along the DNA strand.

The findings of Shibata and colleagues may lead to a better understanding of the biochemical mechanisms behind gene expression. Quoting the researchers: "[t]he single-molecule imaging by HS-AFM presented here could help unveil the relationship between nucleosome dynamics and gene regulation in the near future."

Background

High-speed atomic force microscopyThe general principle of atomic force microscopy (AFM) is to make a very small tip scan the surface of a sample. During this horizontal (xy) scan, the tip, which is attached to a small cantilever, follows the sample's vertical (z) profile, inducing a force on the cantilever that can be measured. The magnitude of the force at the xy position can be related to the z value; the xyz data generated during a scan then result in a height map providing structural information about the investigated sample. In high-speed-AFM (HS-AFM), the working principle is slightly more involved: the cantilever is made to oscillate near its resonance frequency. When the tip is moved around a surface, the variations in the amplitude (or the frequency) of the cantilever's oscillation resulting from the tip's interaction with the sample's surface are recorded, as these provide a measure for the local 'z' value. AFM does not involve lenses, so its resolution is not restricted by the so-called diffraction limit as in X-ray diffraction, for example.

HS-AFM results in a video, where the time interval between frames depends on the speed with which a single image can be generated (by xy-scanning the sample). Researchers at Kanazawa University have in recent years developed HS-AFM further, so that it can be applied to study biochemical molecules and biomolecular processes in real-time. Mikihiro Shibata and colleagues have now applied the method to study nucleosome dynamics, revealing a sliding process of nucleosome particles along a DNA strand.

Related figurehttps://nanolsi.kanazawa-u.ac.jp/wp-content/uploads/2023/02/H2AZ_thumbnail.png

Caption: High-speed atomic force microscopy visualization of the sliding of a H2A.Z nucleosome along a DNA strand. 2023 Morioka, et al., Nano Letters

Reference

Shin Morioka, Shoko Sato, Naoki Horikoshi, Tomoya Kujirai, Takuya Tomita, Yudai Baba, Takahiro Kakuta, Tomoki Ogoshi, Leonardo Puppulin, Ayumi Sumino, Kenichi Umeda, Noriyuki Kodera, Hitoshi Kurumizaka, and Mikihiro Shibata. High-Speed Atomic Force Microscopy Reveals Spontaneous Nucleosome Sliding of H2A.Z at the Subsecond Time Scale, Nano Letters (2023).

DOI: doi=10.1021/acs.nanolett.2c04346

https://pubs.acs.org/doi/abs/10.1021/acs.nanolett.2c04346

ContactHiroe YonedaVice Director of Public AffairsWPI Nano Life Science Institute (WPI-NanoLSI)Kanazawa UniversityKakuma-machi, Kanazawa 920-1192, JapanEmail: [emailprotected]Tel: +81 (76) 234-4550

About Kanazawa Universityhttp://www.kanazawa-u.ac.jp/e/As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.

The University is located on the coast of the Sea of Japan in Kanazawa a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas.

View original content:https://www.prnewswire.com/news-releases/kanazawa-university-research-biomolecular-sliding-at-the-nanoscale-301757624.html

SOURCE Kanazawa University

Read the original here:
Kanazawa University research: Biomolecular sliding at the nanoscale - StreetInsider.com

Automating iPSC generation to enable autologous photoreceptor … – Journal of Translational Medicine

Starzl TE. The early days of transplantation. JAMA. 1994;272(21):1705.

Article CAS PubMed PubMed Central Google Scholar

Vanholder R, Dominguez-Gil B, Busic M, Cortez-Pinto H, Craig JC, Jager KJ, et al. Organ donation and transplantation: a multi-stakeholder call to action. Nat Rev Nephrol. 2021;17(8):55468.

Article PubMed PubMed Central Google Scholar

Aubert O, Yoo D, Zielinski D, Cozzi E, Cardillo M, Durr M, et al. COVID-19 pandemic and worldwide organ transplantation: a population-based study. Lancet Public Health. 2021;6(10):e709e19.

Article PubMed PubMed Central Google Scholar

Zhang Y, Klassen HJ, Tucker BA, Perez MT, Young MJ. CNS progenitor cells promote a permissive environment for neurite outgrowth via a matrix metalloproteinase-2-dependent mechanism. J Neurosci. 2007;27(17):4499506.

Article CAS PubMed PubMed Central Google Scholar

Luo J, Baranov P, Patel S, Ouyang H, Quach J, Wu F, et al. Human retinal progenitor cell transplantation preserves vision. J Biol Chem. 2014;289(10):636271.

Article CAS PubMed PubMed Central Google Scholar

Han IC, Bohrer LR, Gibson-Corley KN, Wiley LA, Shrestha A, Harman BE, et al. Biocompatibility of Human Induced Pluripotent Stem cell-derived retinal progenitor cell grafts in immunocompromised rats. Cell Transpl. 2022;31:9636897221104451.

Article Google Scholar

Tucker BA, Park IH, Qi SD, Klassen HJ, Jiang C, Yao J, et al. Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS ONE. 2011;6(4):e18992.

Article CAS PubMed PubMed Central Google Scholar

Mandai M, Fujii M, Hashiguchi T, Sunagawa GA, Ito SI, Sun J, et al. iPSC-Derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice. Stem Cell Reports. 2017;8(1):6983.

Article PubMed PubMed Central Google Scholar

Lin B, McLelland BT, Aramant RB, Thomas BB, Nistor G, Keirstead HS, et al. Retina organoid transplants develop photoreceptors and improve visual function in RCS rats with RPE dysfunction. Invest Ophthalmol Vis Sci. 2020;61(11):34.

Article CAS PubMed PubMed Central Google Scholar

McLelland BT, Lin B, Mathur A, Aramant RB, Thomas BB, Nistor G, et al. Transplanted hESC-Derived retina organoid sheets differentiate, integrate, and improve visual function in retinal degenerate rats. Invest Ophthalmol Vis Sci. 2018;59(6):2586603.

Article CAS PubMed PubMed Central Google Scholar

Zerti D, Hilgen G, Dorgau B, Collin J, Ader M, Armstrong L, et al. Transplanted pluripotent stem cell-derived photoreceptor precursors elicit conventional and unusual light responses in mice with advanced retinal degeneration. Stem Cells. 2021;39(7):88296.

Article CAS PubMed Google Scholar

Santos-Ferreira T, Volkner M, Borsch O, Haas J, Cimalla P, Vasudevan P, et al. Stem cell-derived photoreceptor transplants differentially integrate into mouse models of cone-rod dystrophy. Invest Ophthalmol Vis Sci. 2016;57(7):350920.

Article CAS PubMed Google Scholar

Gagliardi G, Ben M, Barek K, Chaffiol A, Slembrouck-Brec A, Conart JB, Nanteau C, et al. Characterization and transplantation of CD73-Positive photoreceptors isolated from human iPSC-Derived retinal organoids. Stem Cell Reports. 2018;11(3):66580.

Article CAS PubMed PubMed Central Google Scholar

Chao JR, Lamba DA, Klesert TR, Torre A, Hoshino A, Taylor RJ, et al. Transplantation of human embryonic stem cell-derived retinal cells into the Subretinal Space of a non-human primate. Transl Vis Sci Technol. 2017;6(3):4.

Article PubMed PubMed Central Google Scholar

Zhu J, Cifuentes H, Reynolds J, Lamba DA. Immunosuppression via loss of IL2rgamma enhances long-term functional integration of hESC-Derived photoreceptors in the mouse retina. Cell Stem Cell. 2017;20(3):37484. e5.

Article CAS PubMed Google Scholar

Lamba DA, McUsic A, Hirata RK, Wang PR, Russell D, Reh TA. Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS ONE. 2010;5(1):e8763.

Article PubMed PubMed Central Google Scholar

Lamba DA, Gust J, Reh TA. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in crx-deficient mice. Cell Stem Cell. 2009;4(1):739.

Article CAS PubMed PubMed Central Google Scholar

Lingam S, Liu Z, Yang B, Wong W, Parikh BH, Ong JY, et al. cGMP-grade human iPSC-derived retinal photoreceptor precursor cells rescue cone photoreceptor damage in non-human primates. Stem Cell Res Ther. 2021;12(1):464.

Article CAS PubMed PubMed Central Google Scholar

Aboualizadeh E, Phillips MJ, McGregor JE, DiLoreto DA Jr, Strazzeri JM, Dhakal KR, et al. Imaging transplanted photoreceptors in living Nonhuman Primates with single-cell resolution. Stem Cell Reports. 2020;15(2):48297.

Article CAS PubMed PubMed Central Google Scholar

Kruczek K, Gonzalez-Cordero A, Goh D, Naeem A, Jonikas M, Blackford SJI, et al. Differentiation and transplantation of embryonic stem cell-derived cone photoreceptors into a mouse model of end-stage retinal degeneration. Stem Cell Reports. 2017;8(6):165974.

Article CAS PubMed PubMed Central Google Scholar

Gonzalez-Cordero A, West EL, Pearson RA, Duran Y, Carvalho LS, Chu CJ, et al. Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nat Biotechnol. 2013;31(8):7417.

Article CAS PubMed Google Scholar

Ballios BG, Cooke MJ, Donaldson L, Coles BL, Morshead CM, van der Kooy D, et al. A Hyaluronan-Based Injectable Hydrogel improves the survival and integration of stem cell progeny following transplantation. Stem Cell Reports. 2015;4(6):103145.

Article CAS PubMed PubMed Central Google Scholar

Klassen H, Sakaguchi DS, Young MJ. Stem cells and retinal repair. Prog Retin Eye Res. 2004;23(2):14981.

Article CAS PubMed Google Scholar

Eberle D, Santos-Ferreira T, Grahl S, Ader M. Subretinal transplantation of MACS purified photoreceptor precursor cells into the adult mouse retina.J Vis Exp. 2014(84):e50932.

Lakowski J, Gonzalez-Cordero A, West EL, Han YT, Welby E, Naeem A, et al. Transplantation of photoreceptor precursors isolated via a cell surface Biomarker Panel from embryonic stem cell-derived self-forming retina. Stem Cells. 2015;33(8):246982.

Article CAS PubMed Google Scholar

Semo M, Haamedi N, Stevanato L, Carter D, Brooke G, Young M, et al. Efficacy and safety of human retinal progenitor cells. Transl Vis Sci Technol. 2016;5(4):6.

Article PubMed PubMed Central Google Scholar

Aftab U, Jiang C, Tucker B, Kim JY, Klassen H, Miljan E, et al. Growth kinetics and transplantation of human retinal progenitor cells. Exp Eye Res. 2009;89(3):30110.

Article CAS PubMed Google Scholar

Meyer JS, Shearer RL, Capowski EE, Wright LS, Wallace KA, McMillan EL, et al. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2009;106(39):16698703.

Article CAS PubMed PubMed Central Google Scholar

Meyer JS, Howden SE, Wallace KA, Verhoeven AD, Wright LS, Capowski EE, et al. Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. Stem Cells. 2011;29(8):120618.

Article CAS PubMed Google Scholar

Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10(6):77185.

Article CAS PubMed Google Scholar

Capowski EE, Samimi K, Mayerl SJ, Phillips MJ, Pinilla I, Howden SE, et al. Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines. Development. 2019. https://doi.org/10.1242/dev.171686.

Article PubMed PubMed Central Google Scholar

Phillips MJ, Perez ET, Martin JM, Reshel ST, Wallace KA, Capowski EE, et al. Modeling human retinal development with patient-specific induced pluripotent stem cells reveals multiple roles for visual system homeobox 2. Stem Cells. 2014;32(6):148092.

Article CAS PubMed Google Scholar

Wiley LA, Burnight ER, DeLuca AP, Anfinson KR, Cranston CM, Kaalberg EE, et al. cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness. Sci Rep. 2016;6:30742.

Article CAS PubMed PubMed Central Google Scholar

Reichman S, Terray A, Slembrouck A, Nanteau C, Orieux G, Habeler W, et al. From confluent human iPS cells to self-forming neural retina and retinal pigmented epithelium. Proc Natl Acad Sci U S A. 2014;111(23):851823.

Article CAS PubMed PubMed Central Google Scholar

Zhong X, Gutierrez C, Xue T, Hampton C, Vergara MN, Cao LH, et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun. 2014;5:4047.

Article CAS PubMed Google Scholar

Kuwahara A, Ozone C, Nakano T, Saito K, Eiraku M, Sasai Y. Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue. Nat Commun. 2015;6:6286.

Article CAS PubMed Google Scholar

Mellough CB, Collin J, Khazim M, White K, Sernagor E, Steel DH, et al. IGF-1 signaling plays an important role in the formation of Three-Dimensional laminated neural retina and other ocular structures from human embryonic stem cells. Stem Cells. 2015;33(8):241630.

Article PubMed Google Scholar

Singh RK, Mallela RK, Cornuet PK, Reifler AN, Chervenak AP, West MD, et al. Characterization of three-dimensional retinal tissue derived from human embryonic stem cells in adherent monolayer cultures. Stem Cells Dev. 2015;24(23):277895.

Article CAS PubMed PubMed Central Google Scholar

Lowe A, Harris R, Bhansali P, Cvekl A, Liu W. Intercellular adhesion-dependent cell survival and ROCK-Regulated actomyosin-driven forces mediate self-formation of a retinal organoid. Stem Cell Reports. 2016;6(5):74356.

Article CAS PubMed PubMed Central Google Scholar

Gonzalez-Cordero A, Kruczek K, Naeem A, Fernando M, Kloc M, Ribeiro J, et al. Recapitulation of human Retinal Development from Human pluripotent stem cells generates transplantable populations of cone photoreceptors. Stem Cell Reports. 2017;9(3):82037.

Article PubMed PubMed Central Google Scholar

Wahlin KJ, Maruotti JA, Sripathi SR, Ball J, Angueyra JM, Kim C, et al. Photoreceptor outer segment-like structures in long-term 3D retinas from human pluripotent stem cells. Sci Rep. 2017;7(1):766.

Article PubMed PubMed Central Google Scholar

Ovando-Roche P, West EL, Branch MJ, Sampson RD, Fernando M, Munro P, et al. Use of bioreactors for culturing human retinal organoids improves photoreceptor yields. Stem Cell Res Ther. 2018;9(1):156.

Article CAS PubMed PubMed Central Google Scholar

Hallam D, Hilgen G, Dorgau B, Zhu L, Yu M, Bojic S, et al. Human-Induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient-dependent efficiency. Stem Cells. 2018;36(10):153551.

Article CAS PubMed Google Scholar

Luo Z, Zhong X, Li K, Xie B, Liu Y, Ye M, et al. An optimized system for effective derivation of three-dimensional retinal tissue via wnt signaling regulation. Stem Cells. 2018;36(11):170922.

Article CAS PubMed Google Scholar

NIH human embryonic stem cell registry. https://grants.nih.gov/stem_cells/registry/current.htm. Accessed 27 Feb 2023.

Guha P, Morgan JW, Mostoslavsky G, Rodrigues NP, Boyd AS. Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell. 2013;12(4):40712.

Article CAS PubMed Google Scholar

Singh VK, Kalsan M, Kumar N, Saini A, Chandra R. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 2015;3:2.

Article PubMed PubMed Central Google Scholar

Mantripragada VP, Luangphakdy V, Hittle B, Powell K, Muschler GF. Automated in-process characterization and selection of cell-clones for quality and efficient cell manufacturing. Cytotechnology. 2020;72(5):61527.

Article CAS PubMed PubMed Central Google Scholar

Wiley LA, Anfinson KR, Cranston CM, Kaalberg EE, Collins MM, Mullins RF, et al. Generation of Xeno-Free, cGMP-compliant patient-specific iPSCs from skin biopsy. Curr Protoc Stem Cell Biol. 2017. https://doi.org/10.1002/cpsc.30.

Article PubMed PubMed Central Google Scholar

Bohrer LR, Wiley LA, Burnight ER, Cooke JA, Giacalone JC, Anfinson KR, et al. Correction of NR2E3 associated enhanced s-cone syndrome patient-specific iPSCs using CRISPR-Cas9. Genes (Basel). 2019. https://doi.org/10.3390/genes10040278.

Article PubMed PubMed Central Google Scholar

Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184(13):3573-87e29.

Article CAS PubMed PubMed Central Google Scholar

Continued here:
Automating iPSC generation to enable autologous photoreceptor ... - Journal of Translational Medicine