Cell atlases of the human brain – Science Daily

In two parallel projects, researchers at Karolinska Institutet have been involved in creating the most comprehensive atlases of human brain cells to date. The two studies, which are published in Science, provide clues on different brain diseases and give hope for medical advancements in the future, such as new cancer drugs.

Knowing what cells constitute the healthy brain, where different cell types are located and how the brain develops from the embryo stage is fundamental to the ability to compare and better understand how diseases arise. There are at present advanced atlases of the mouse brain, but not for the human brain. Until now.

A brain-cell census

"We've created the most detailed cell atlases of the adult human brain and of brain development during the first months of pregnancy," says Sten Linnarsson, professor of molecular system biology at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet in Sweden. "You could say that we've taken a kind of brain-cell census."

The first project was led by Kimberly Siletti from Linnarsson's group. It was conducted in close collaboration with Ed Lein at the Allen Institute for Brain Science in Seattle, USA, as part of the international Human Cell Atlas initiative, and based on three donated human brains from adults. The researchers analysed more than three million individual cell nuclei using the technique of RNA sequencing, which reveals each cell's genetic identity. All in all, the researchers studied cells from just over a hundred brain regions and found over 3,000 cell types, some 80 per cent of which were neurons, the remainder being different kinds of glial cells.

"A lot of research has focused on the cerebral cortex, but the greatest diversity of neurons we found in the brainstem," says Professor Linnarsson. "We think that some of these cells control innate behaviours, such as pain reflexes, fear, aggression and sexuality."

Groundwork for medical advances

The researchers could also see that the cells' identity reflects the place in the brain where they first developed in the fetus, which links to the second project. Here, Emelie Braun and Miri Danan-Gotthold from Sten Linnarsson's group collaborated with the Swedish consortium for the Human Developmental Cell Atlas to analyse over a million individual cell nuclei from 27 embryos at different stages of development (between 5 and 14 weeks of fertilisation). The study enabled the researchers to show how the entire brain develops and is organised over time.

Even though the results are examples of molecular biological basic research, the new knowledge generated can also lay the groundwork for medical advances. Professor Linnarsson's research group has used similar methods to examine different kinds of brain tumours, one of which was a glioblastoma -- a cancer with a poor prognosis.

"The tumour cells resemble immature stem cells and it looks like they're trying to form a brain, but in a totally disorganised way," he explains. "What we observed was that these cancer cells activated hundreds of genes that are specific to them, and it might be interesting to dig into whether there is any potential for finding new therapeutic targets."

Freely available brain atlases

The brain atlases will be freely available to researchers around the world so that they can compare the brain diseases they are researching with what a normally developed brain looks like.

The studies are part of a larger package of articles published simultaneously in the scientific journal Science. The study on the adult brain was supported by a grant from the National Institutes of Health, while the embryo study was financed by the Knut and Alice Wallenberg and Erling-Persson foundations.

Sten Linnarsson is a scientific advisor at Moleculent, Combigene and Oslo University Center of Excellence in Immunotherapy. He and co-authors Alejandro Mossi Albiach and Lars E. Borm also hold shares in EEL Transcriptomics AB, which owns the intellectual property rights to the EEL method ("Spatial RNA localization"). Co-authors aneta Andrusivov and Joakim Lundeberg are scientific consultants for 10x Genomics, which holds the intellectual property rights to the Spatial Transcriptomics (Visium) technique.

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Cell atlases of the human brain - Science Daily

Adipose stromal cells bioproducts as cell-free therapies … – Journal of Translational Medicine

Cell culture

ASC from lipoaspirates from three donors were processed by the group of Prof. Karen Bieback (University of Heidelberg, Heidelberg, Germany) after informed consent. The Mannheim Ethics Commission II approved the study (vote 2011-215N-MA). The ASC were cultured using MEM- media, Gibco, ThermoFisher Scientific, 2,561,029) and 10% Fetal Bovine Serum (FBS, 10270-106, Gibco, MA, USA) at 37 with 5% CO2 and controlled humidity. These three ASC batches (referred to a N=3 biological replicates in the figure legends) were shipped as cryo-aliquots to the other two centers to be cultured under identical harmonized culture conditions from passage 46 as detailed previously [29]. Bioproducts were derived from the conditioned medium of either 3D cultured ASC, processed by size exclusion chromatography to yield (1) EV-SEC or the (2) protein-rich fraction, or 2D-cultured cells, processed by ultracentrifugation to yield (3) EV-UC or after concentration to yield (4) the conditioned medium (CM) or (5) the respective wash-off (CM-WO) (Fig.1).

At 80% confluence, ASC were passaged and seeded in a hollow-fibber bioreactor at a concentration of 14106 cells/cartridge (20kDa MWCO, 450cm2, C2025D, FiberCell System-KD Bio, France). Prior to injecting the cells, a pre-culture step was carried out to initiate and activate the bioreactor, first Dulbeccos phosphate-buffered saline (PBS) for 24h, followed by fibronectin coating over-night. After the pre-culture process, ASC were seeded in serum-free MEM- in the extra-capillary space, at 37 with 5% CO2 and controlled humidity for 7days without harvesting the supernatant, with continuous monitoring of glucose levels. Serum-containing medium was used as circulating medium, given that EVs and high molecular weight proteins cannot cross the 20 kD MWCO filter fiber and thus do not contaminate the cell-derived EVs harvested from the extra-capillary-space (according to the Hollow Fiber Bioreactor Protocol for Mesenchymal Stem Cells by fibercellsystems.com) ASC were cultured for 4weeks in the bioreactor and during this period, the supernatant was collected daily. Following centrifugation to remove cell debris (5min at 420g), the supernatant was stored at 80 until EV isolation by size exclusion chromatography (see below) was performed. Cells were harvested and counted to calculate the bioproduct per producer cell concentration.

The secretome obtained in vitro, also named conditioned media (CM), was generated from ASC at passage 4 to 6. Upon reaching 80% confluence, cells were washed with PBS and incubated for 24h in serum-free MEM- medium. The supernatant was collected and centrifuged for 5min at 400g to remove cell debris before being placed in centrifugal concentrator units of 3KDa molecular weight cut-off (UFC9003, Merck Millipore, USA). The CM was centrifuged for 90min at 3,000g, 4 using an Eppendorf 5810 R Centrifuge to achieve tenfold concentration. The flow-through resulted from the concentration step (thereafter named wash-off, CM-WO) was kept and used as a control. Concentrated conditioned media samples were stored at 80 until further use. Cells were harvested and counted to calculate the bioproduct per producer cell concentration.

When the cells reached 80% confluence, they were starved for 1624h in serum-free medium. The supernatant was collected and centrifuged for 20min at 3000g to remove cell debris and apoptotic cells. The supernatant was then ultracentrifuged for 2h at 100,000g, 4 using Beckman Coulter Optima L-100K Ultracentrifuge (Beckman Coulter, CA, USA) with the rotor type 70Ti. The EV pellet was resuspended in PBS supplemented with 1% DMSO. The suspension of EVs (EV-UC) was then stored at80 until further use. EVs were collected from ASC at 4-6th passage. Cells were harvested and counted to calculate the cell equivalents used for cell treatments.

After thawing at 4, samples were centrifuged for 10min at 300g and 20min at 4000g. After, the supernatant was filtered through a 0.2m syringe filter and concentrated with a 100kD MWCO concentration filter to a final volume of 10mL. The qEV10-IZON column 35mm was initially washed with sterile PBS, and then 10mL of the sample was added to concentrate it to the final volume of 1.5mL (Vivaspin 20, 100,000 MWCO PE, Sartorius). Each EV sample (EV-SEC) and the resultant supernatant containing the protein fraction (Protein-Rich Fraction) were collected, concentrated (Vivaspin 20, 100,000 MWCO PE, Sartorius) and stored at 80 until further use.

ASC derived bioproducts were used at a ratio of 2:1 and 20:1 relative to recipient cells. To do so, we counted the number of ASC after harvesting and used it to relate the number of particles/volumes generated of EVs and CM respectively for each bioproduct.

After the isolation, the concentration of all the samples was measured (a) by Nanosight NS300 or (b) ZetaView.

After the isolation, the concentration of all the samples was measured (a) by Nanosight NS300 (Malvern Instruments Ltd., Malvern, UK) equipped with a 488nm laser module that utilizes Brownian motion and refraction index. The particle size scatters 10nm to 1000nm, although the optimized size range is 70300nm. It uses the scattered light to detect a particle and tracks its motion as a function of time. The particles scattered light was recorded with a light-sensitive camera under a 90 angle to the irradiation plane. This angle allows the Brownian motion of the EVs. Samples were diluted 1:100 in physiologic solution. For each sample, 3 videos of 60s at camera level 15 and threshold 5 were captured using a syringe pump 30. All the samples were characterized with NTA 3.2.16 Analytical software. The NTA settings were kept constant between samples.

After the isolation, the concentration of all the samples was measured b) by ZetaView (Particle Metrix GmbH, Germany). 1L of concentrated EVs was diluted in sterile-filtered PBS in a dilution 1:1,000 and visualized using the ZetaView (sensitivity 80%, shutter 100, 11 positions, 2 cycles; Particle Metrix, Germany).

Super-resolution microscopy pictures of EVs were obtained using a temperature-controlled Nanoimager S Mark II microscope from ONI (Oxford Nanoimaging, Oxford, UK) equipped with a 100 , 1.4NA oil immersion objective, an XYZ closed-loop piezo 736 stage, and 405nm/150mW, 473nm/1W, 560nm/1W, 640nm/1W lasers and triple emission channels split at 640/and 555nm. For sample preparation, we followed the manufacturers protocol using EV profiler Kit ONI (Alfatest, Rome, Italy). Before each imaging session, bead slide calibration was performed for aligning the channels, to achieve a channel mapping precision smaller than 12nm. Images were taken in dSTORM mode using 50% laser power for the 647nm channel, 30% laser power for the 488nm laser channel, and 30% for the 555 channel. Three-channels (2000 frames per channel) (647, 555 and 488) were acquired sequentially at 30Hz (Hertz) in total reflection fluorescence (TIRF) mode. Single-molecule data was filtered using NimOSsoftware (v.1.18.3, ONI) based on the point spread function shape, photon count and localization precision to minimize background noise and remove low-precision and non-specific colocalization. Data has been processed with the Collaborative Discovery (CODI) online analysis platform https://www.alto.codi.bio/ from ONI and the drift correction pipeline version 0.2.3 was used. Clustering analysis was performed on localizations and BD clustering-constrained parameters were defined (photon count 300-max, sigma 0200nm, p-value 01, localization precision 020nm). Colocalization was defined by a minimum number of localizations for each fluorophore/protein within a distance of 100nm or a distance used from the centroid position of a cluster.

MACSPlex Exosome Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) containing fluorescent labeled (FITC-PE) capture beads coupled to 37 exosomal surface epitopes and 2 isotope controls was used, following the manufacturers instructions (in detail: CD3, CD4, CD19, CD8, HLA-DR, CD56, CD105, CD2, CD1c, CD25, CD49e, ROR1, CD209, CD9, SSEA-4, HLA-ABC, CD63, CD40, CD62P, CD11c, CD81, MCSP, CD146, CD41b, CD42a, CD24, CD86, CD44, CD326, CD133-1, CD29, CD69, CD142, CD45, CD31, REA control, CD20, CD14, mIgG1 control). Briefly, 15L of beads were added to 120L of buffer or sample, including a total of 1109 EVs, and the complex was then incubated on a rotor overnight at 4. After the incubation and washing steps, a cocktail of APC fluorescent antibodies against tetraspanins (CD9, CD63 and CD81) was added (allowing the detection of beads bound EVs) and set on the rotor for 1h at room temperature. After washing, samples were detected using BD FACSCelestaTM Flow Cytometer (BD Bioscience, NJ, USA). Median background values of buffer control were subtracted, and samples were normalized to the median fluorescence intensity of tetraspanins.

Proteins extracted from Hela cells were used as cellular control, the pellet was resuspended in RIPA buffer (50mM TrisHCl, pH7.4, 150mM NaCl, 1% Triton X-100, 1% Na-deoxycholate, 0.1% SDS, 0.1mM CaCl2, and 0.01mM MgCl2 supplemented with protease inhibitor cocktail (Thermo Fisher Scientific), incubate 30min in ice vortexing every 10min and centrifuge 20min at 20,000g. An equal volume of bioproducts (38L) was loaded and separated on 415% Mini-PROTEAN TGX Precast Gels (Bio-Rad, USA). Bioproducts and cell lysates were treated with protein loading dye (Laemmli sample buffer; Bio-Rad) with freshly added -mercaptoethanol 10%; v/v; Sigma, Germany) and boiled for 5min at 95 before SDS-PAGE. Proteins were subsequently blotted to a nitrocellulose blotting membrane (0.2m; 1,060,000; GE Healthcare, USA). Membranes were blocked in 5% BSA (Carl Roth, Germany) in 0.1% Tween in TBS (TBS-T). After blocking, blots were probed with the following primary antibodies diluted in 5% BSA/TBS-T: Calnexin (1:500 dilution, E-10, Santa Cruz Biotechnology). After overnight incubation at 4, membranes were washed 3 times with TBS-T and subsequently incubated with the secondary antibody dilution: Polyclonal Goat anti-mouse HRP (1:5000 dilution; P0447) for 1h at room temperature followed by washing. Blots were then developed using Western Bright ECL (541,004; Biozym Scientific, Germany) and protein bands were detected using the FusionCapt Advanced Solo 4 (Vilber, Germany).

The capacity of ASC or their bioproducts to inhibit induced proliferation of peripheral blood mononuclear cells (PBMCs) was analyzed as described before [27]. PBMCs were isolated from leukapheresis samples from healthy donors, provided by the German Red Cross Blood Donor Service in Mannheim (Mannheim Ethics Commission; vote number 2018-594N-MA). To assess their proliferation, PBMCs were labelled with proliferation dye Cytotell Green (ATT Bioquest, 22,253) (1:500 dilution) and seeded at a 1:10 ASC/bioproduction:PBMCs ratio in RPMI, supplemented with 10% FBS, 2% l-glutamine (PAN Biotech, P04-80100), 1% Penicillin/Streptomycin (PAN Biotech, P06-07100), and 200U/mL IL-2 (Promokine, C61240). PBMC proliferation was stimulated with phytohemagglutinin-L (PHA, 4.8g/mL (Biochrom, Merck Millipore, M5030)). PBMCs cultured alone without ASC in the absence and presence of PHA served as negative and positive controls, respectively. After 5days, PBMC proliferation was measured based on the dilution of Cytotell Green dye using a FACS Canto II (BD Biosciences) and the data were analyzed with FlowJo Software.

THP-1 monocyte-like cell line (ATCC, Manassas, VA, USA) were cultured in RPMI-1640 growth medium with l-Glutamine (Sigma-Aldrich Ireland Ltd. Wicklow, Ireland) supplemented with 10% FBS (Sigma-Aldrich), 1% penicillin G (100U/mL) and streptomycin (100g/mL) solution (Sigma-Aldrich). In vitro assessment of phagocytic activity was done as described before [30]. THP-1 cells were seeded at a density of 5104 cells/well in dark 96 well-plates (Perkin Elmer Ireland Ltd. Dublin, Ireland) and exposed to 1g/mL of para-methoxyamphetamine (PMA, Sigma-Aldrich, St. Louis, MO, USA) for 48h to induce a macrophage-like phenotype. Cultures were washed with DPBS and fed with growth media for 24h. Afterwards, cells were activated with 100ng/mL of lipopolysaccharide (LPS, Sigma-Aldrich) for 24h. To measure the phagocytic capacity, Zymosan A FITC BioParticles (Thermo Fisher Ltd.) were used. Particles were opsonized with human serum (2mg/mL per 2107 particles, Sigma-Aldrich) for 1h and added to the cells in experimental media containing ASC bioproducts and growth media for 4h. Then, cells were washed twice with DPBS, fixed with 4% PFA for 15min and stained with Hoechst 33,342 (Invitrogen, Thermo Fisher Ltd). Images were taken on the Cytation 1 Imaging Reader at 20X (BioTek, with Gen5 Version 3.04 software, Swindon, UK). Six replicates were undertaken per condition and particle analysis was done by counting particle opsonization in a minimum of 200 cells per well.

HUVEC were seeded in 48-well plates at 84,000 cells/cm2 and cultured overnight. Subsequently, a p200 tip was used to create a scratch in each monolayer. Cultures were washed with DPBS before adding EVs/CM as described before. Complete EndoGRO-LS medium was used as a positive control, while EndoGRO-LS without FBS and VEGF served as a negative control. Scratches were imaged immediately after the addition of CM (0h) and after 8- and 24-h incubation using the automated Cytation 1 Imaging Reader at 4X. Six replicates were undertaken, and the total area of each scratch was measured using Image J. The percentage of closure was calculated relative to time 0h.

20,000 ASC were seeded in a 96-well Essen ImageLock plate and cultured overnight. Then, a 96-pin WoundMaker was used to create precise and reproducible wounds in all the wells. After the wound, the cells were washed 2 times with DPBS and ASC bioproducts added in different concentrations. Plates were then cultured in an IncuCyte ZOOM incubator and every 3h were taken a picture with the software. The results were analyzed after 24h. Relative Wound Density algorithm was used to report data.

Human umbilical vascular endothelial cells (HUVEC) either from Lonza or prepared as described before [31] and cultured until the 6th passage in EndoGRO-LS Complete Culture Media Kit (SCME001, Sigma-Aldrich, St. Louis, MO, USA). In vitro formation of capillary-like structures was performed on growth factorreduced Matrigel (356,231, Corning, NY, USA, center 1 and 3) or geltrex (Geltrex LDEV-free reduced growth factor matrix; Thermo Fisher Scientific, United States, center 2) HUVEC cells were treated with EVs or CM as described before, seeded at a density of 10103cells/well on a 48-well plate. Positive control was full EndoGro-LS medium, negative control medium without VEGF and FBS (as used for all the conditions). Cells were periodically observed with a Nikon TE2000E inverted microscope (Nikon, Tokyo, Japan), and experimental results were recorded after 16h; 3 images were taken per well. Image analysis was performed with the ImageJ software v.1.53c, using the Angiogenesis Analyzer (center 1,3). The data from three independent experiments were expressed as the meanSD of tube length in arbitrary units per field. Center 2 used live cell imaging (Incucyte Zoom) to assess network formation as described before [32].

Presence of vascular endothelial growth factor (VEGF) on ASC bioproducts was determined by solid phase sandwich ELISA using the human VEGF DuoSet ELISA (R&D Systems, USA) according to manufacturers instructions. The samples were read immediately at 450nm with a wavelength correction at 570nm using a VICTOR X4 multilabel plate reader (Perkin Elmer, Waltham, Massachusetts, USA). Levels of cytokines were quantified against an eight-point standard curve using twofold serial dilutions in reagent diluent.

The Pierce BCA Protein Assay Kit (ThermoFisher Scientific, UK) was used to determine protein concentration. In order to quantify the total amount of protein, samples were first lysed with RIPA buffer 4:1 (ThermoFisher Scientific, UK) for 30min on ice. The assay was carried out as per manufacturers instructions. The absorbance values were read in a VICTOR X4 plate reader (Perkin Elmer) at a 550nm wavelength, and the protein concentrations of the samples were quantified against the standard curve.

Statistical analysis was performed using GraphPad prism v9.4.2 (GraphPad software, USA). Data are expressed as meanstandard deviation (SD). N indicates biological replicates; n indicates technical replicates. Statistical differences among groups were calculated using ordinary two-way analysis of variance (ANOVA) and Tukeys post-hoc test when group distributions were normal (ShapiroWilks test) and variances of populations were equal (Bartletts test). When either or both assumptions were violated, non-parametric analysis was conducted; KruskalWallis test used to perform multiple comparison analysis and Dunns multiple comparison test for pairwise comparison. Results were considered statistically significant when p>0.05.

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Adipose stromal cells bioproducts as cell-free therapies ... - Journal of Translational Medicine

Bayer Opens First Cell Therapy Manufacturing Facility to Advance … – BioSpace

BERLIN, Germany & BERKELEY, Calif.--(BUSINESS WIRE)-- Bayer AG announced today the opening of its first Cell Therapy Launch Facility in Berkeley, California to create the capacity to bring cell therapies to patients on a global scale. The $250 million (USD), 100,000-square-foot facility will supply the material required for late-stage clinical trials and potential commercial launch of BlueRock Therapeutics bemdaneprocel (BRT-DA01), an investigational cell therapy currently in evaluation for treating Parkinsons disease. In addition, it includes space for a second module of production suites to support additional cell therapies as Bayers portfolio advances. BlueRock Therapeutics LP is a clinical stage, cell therapy company and wholly owned, independently operated subsidiary of Bayer AG.

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Cell therapy represent a groundbreaking class of medicines and is an area where Bayer is making a significant investment to research potentially transformative treatment approaches for people with unmet medical needs, said Sebastian Guth, President of Bayer U.S.A. and Pharmaceuticals North America, and member of the Pharmaceutical Executive Committee. Our new cell therapy facility represents true innovation in product development and manufacturing in addition to contributing to Bayers sustainability goal as our first fully electric pharmaceutical manufacturing plant.

The new Cell Therapy Launch Facility is part of a transformation at the companys dedicated biotechnology site in Berkeley, where Bayer has invested nearly USD 500 million in infrastructure over the past five years.

Our teams are driving innovation in late-stage development and manufacturing with a goal of bringing transformational cell and gene therapies to patients on a global scale, and this facility will enable us to make it real, said Jens Vogel, Sr. Vice President and Global Head of Biotech for Bayers Pharmaceutical Division. Bayer is collaborating with biotech innovators, academia, and equipment and automation suppliers to establish platforms that would help bring more therapies to patients faster.

Bayers global biotech organization recognizes the importance of helping innovators transfer their product candidates from the laboratory bench to the clinical study and commercial launch settings. The Biotech team provides its biologic development and manufacturing capabilities for Bayers larger biotherapeutics portfolio, including commercial products and late-stage protein and cell therapies in development. As part of Bayers larger mission of Health for All, the company is now also helping early-stage U.S. and European companies to enable patient trials and commercial launches through its BioPartnering Solutions offerings.

Having access to this Cell Therapy Launch Facility is central to our goal to deliver impactful cell therapies from our pipeline to patients in need, said Seth Ettenberg, President & CEO of BlueRock Therapeutics. Our team is excited to be working shoulder to shoulder with Bayers biotech scientists and manufacturing experts as we look to scale up manufacturing for our first investigational therapy, bemdaneprocel for Parkinsons disease, as it advances through clinical trials.

The new Cell Therapy Launch Facility, launched in conjunction with manufacturing day in the United States, is among several recent investments to advance Bayers biologic pipeline of protein therapeutics, cell and gene therapies including a new Cell Culture Technology Center and Cell Therapy Labs. The new Cell Therapy Launch Facility features flexible, modular space for cell culture, viral transduction and automated filling of cell therapies leveraging Biotech@Bayer expertise in iPSC and CAR-T characterization, process development, analytics and clinical to commercial production.

Beyond Berkeley, the companys global biotech network includes biologic development, manufacturing science, industrialization and advanced manufacturing engineering teams in Wuppertal and Leverkusen, Germany; and Basel, Switzerland; with a full complement of labs and clinical production suites.

About bemdaneprocel and Parkinsons Disease

Bemdaneprocel (BRT-DA01) is an investigational cell therapy designed to replace the dopamine producing neurons that are lost in Parkinsons disease. These dopaminergic neuron precursors are derived from pluripotent stem cells (PSC) that are human embryonic stem cells. In a surgical procedure, these neuron precursors are implanted into the brain of a person with Parkinsons disease. When transplanted, they have the potential to reform neural networks that have been severely affected by Parkinsons and restore motor and non-motor function to patients. Planning is underway for BlueRock Therapeutics Phase II study that is expected to begin enrolling participants in H1 (first half) 2024.

Parkinsons disease is a progressive neurodegenerative disorder caused by the death of nerve cells in the brain, leading to decreased dopamine levels. At diagnosis, it is estimated that patients have already lost 50-80% of their dopaminergic neurons. The loss of these neurons leads to a progressive loss of motor function and symptoms such as tremors, muscle rigidity, and slowness of movement. Even with medication, the symptoms of Parkinsons disease can fluctuate during the course of the day. According to the Parkinsons Foundation, more than 10 million people worldwide suffer from Parkinsons disease, with approximately one million living in the United States. There is no cure, and the effectiveness of current treatments decreases over time.

About BioPartnering Solutions for Biotech Innovators in U.S. and Europe

Through Bayers BioPartnering Solutions, innovators can leverage industry-leading biotech process development and biomanufacturing capabilities to make their therapeutic candidates a reality. Bayers highly skilled Biotech teams and infrastructure which includes preclinical, clinical and commercial launch scale manufacturing are available to advance promising cell therapy, monoclonal antibody and protein therapeutic candidates from the discovery bench to patients. Through BioPartnering Solutions, Bayer provides early-stage companies with a single source of IND- and BLA-enabling development; bioprocess and biochemical engineering; clinical and commercial manufacturing. A range of complementing support service functions such as supply chain management, procurement, quality, and CMC strategy support for regulatory filings are also available. For more information visit: https://www.bayer.com/en/us/BioPartneringSolutions.

About Bayers Biotech Campus in Berkeley, CA

Innovation happens in communities which foster it. Bayer has a 46-acre site located in Berkeley, CA where a team of about 1,000 employees drives the development and manufacturing of traditional protein therapeutics as well as novel cell and gene therapies. It has also served as the global commercial supply center for manufacturing and supplying Bayers biotherapeutics for people living with hemophilia A around the world for 30 years.

During todays event, Bayer celebrated its continuing relationship with the City of Berkeley through a 30-year extension of its Development Agreement which will support up to one million square feet of additional infrastructure. Through the agreement, Bayer will invest more than $30 million in the local community in career technical education; initiatives focused on health equity, economic resiliency and climate action; and more. For more information visit: https://www.bayer.com/en/us/berkeley-site-updates.

About Bayer

Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to http://www.bayer.com.

Find more information at https://pharma.bayer.com Follow us on Facebook: http://www.facebook.com/bayer Follow us on Twitter: @BayerPharma

Forward-Looking Statements

This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayers public reports which are available on the Bayer website at http://www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

View source version on businesswire.com: https://www.businesswire.com/news/home/20231009274687/en/

Bayer U.S.-based Media Contacts: Cathy Keck, +1-206-249-5191 Email: cathy.keck@bayer.com

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Bayer Opens First Cell Therapy Manufacturing Facility to Advance ... - BioSpace

SIRT2 Works Against Cardiac Aging in Mice and Monkeys – Lifespan.io News

Working with non-human primates, scientists have discovered that the protein SIRT2, a member of the sirtuin family, might play an important role in slowing cardiac aging [1].

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The heart is arguably the hardest worker among the organs, constantly pumping enormous amounts of blood without ever skipping a beat (well, almost). This marvel of evolution works for decades before it begins to show its age. Heart aging happens due to all the usual culprits, including chronic inflammation, mitochondrial dysfunction, oxidative stress, and telomere damage [2].

In this study published in Nature Aging, the researchers used long-tailed macaques to elucidate the molecular aspects of cardiac aging using multi-omics analysis. Unlike short-lived mice and rats, non-human primates like these have hearts that closely resemble those of humans and, due to their relatively long lifespan, suffer from spontaneous heart conditions as well.

The researchers compared the hearts of eight young (4-6 years) and eight aged (18-21 years) monkeys, which roughly translates to 16 and 65 human years. In aged monkeys, hearts exhibited all the familiar signs of aging: they contained more senescent cells and more fibrotic areas, and their heart muscle cells were significantly enlarged with structural abnormalities. The levels of several inflammatory factors were elevated as well.

Using proteomic analysis, the researchers identified 126 upregulated and 43 downregulated aging-associated differentially expressed proteins (DEPs).Further analysis showed that the upregulated DEPs were mainly related toinflammation, blood clotting, and fibrosis, while protein synthesis, mitochondrial function, and lipid metabolism DEPs were downregulated.

The researchers then compared those DEPs to genes known to be involved in age-related cardiovascular diseases. SIRT2, a SIRT family protein that often pops up in studies of aging [3],was the only protein that was downregulated in aged monkey hearts and was also linked to all four types of cardiovascular diseases. It was also the only downregulated DEP that overlapped with the aging-related genes from the Aging Atlas database.

The scientists then generated human SIRT2-deficient cardiomyocytes from embryonic stem cells. The resulting cells resembled old cardiomyocytes, including hypertrophy and an increased percentage of senescent cells. They also showed signs of mitochondrial dysfunction.

Transcriptomic analysis showed that many genes were either upregulated or downregulated in SIRT2-deficient cardiomyocytes compared to young healthy cells. The researchers were able to identify the transcription factor (a gene that regulates expression of other genes) STAT3 as a major driver of those changes. STAT3 is also a well-known mediator of inflammation.

Notably, STAT3 was the only transcription factor that controlled changes in gene expression in both SIRT2-deficient human cardiomyocytes and in aged hearts of monkeys of both sexes. The researchers then confirmed via a technique called co-immunoprecipitation that STAT3 was one of the few transcription factors to interact with SIRT2.

SIRT2 acts by deacetylating proteins (removing an acetyl group from lysine residues, which alters the proteins function). Overexpression of SIRT2 led to decreased levels of acetylated STAT3, suggesting that SIRT2 recognizes STAT3 as a substrate. STAT3 levels did not react to overexpression of a SIRT2 mutant that lacked deacetylation ability. Aged monkey hearts had more acetylated STAT3 than young ones, showing impaired deacetylation.

Since transcription factors act by changing the expression of other genes, the researchers searched for downstream targets that would be relevant to the cardiac aging phenotype. They identified the gene CDKN2B, which encodes the senescence-related protein p15, as an important target. Apparently, acetylated STAT3 induces the transcription of CDKN2B, which, in turn, induces cellular senescence in cardiomyocytes. By deacetylating STAT3, SIRT2 intervenes in this process and ameliorates cardiac aging.

The researchers tested this hypothesis by injecting the hearts of aged mice with viral vectors containing SIRT2. Decreased ejection fraction and fractional shortening, two major markers of cardiac aging observed in old mice, were partially reversed by the treatment, as was the age-related enlargement of cardiomyocytes, indicating a possible cardioprotective role for SIRT2.

In this study, we systemically surveyed the multi-dimensional profiles of the NHP heart and unveiled a panel of critical biological pathways that shifted during primate heart aging. We identified SIRT2 as a key mediator of geroprotection in primate heart aging and showed that SIRT2-deficient human cardiomyocytes recaptured key senescence features of aged primate hearts. We also found that SIRT2 formed complexes with STAT3 and deacetylated it on Lys685, which, in turn, transcriptionally inactivated the senescence inducer CDKN2B. Thus, our results suggest a SIRT2STAT3CDKN2B axis, regardless of sex, in the regulation of primate cardiomyocyte senescence.

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[1] Ye, Y., Yang, K., Liu, H., Yu, Y., Song, M., Huang, D., & Liu, G. H. (2023). SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B. Nature Aging, 1-19.

[2] Li, H., Hastings, M. H., Rhee, J., Trager, L. E., Roh, J. D., & Rosenzweig, A. (2020). Targeting age-related pathways in heart failure. Circulation research, 126(4), 533-551.

[3] de Oliveira, R. M., Sarkander, J., Kazantsev, A. G., & Outeiro, T. F. (2012). SIRT2 as a therapeutic target for age-related disorders. Frontiers in pharmacology, 3, 82.

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SIRT2 Works Against Cardiac Aging in Mice and Monkeys - Lifespan.io News

Stem Cell Treatment Discussed with Cerebral Palsy Community – Mirage News

Exploring the boundaries of stem cell therapy, scientists consulted the cerebral palsy community to understand their perspectives.

Dr Courtney McDonald and Dr Madeleine Smith, in collaboration with researchers at the Cerebral Palsy Alliance, surveyed people in the Australian cerebral palsy community to better understand the acceptability of NSC treatment.

They distributed an online survey and received responses from 232 Australians with cerebral palsy, their parents and/or carers.

Cerebral palsy is the most common physical disability of childhood and currently has no known cure. Researchers at Hudson Institute of Medical Research have been investigating neural stem cell (NSC) treatment for cerebral palsy, but not without considering important ethical and practical considerations for the use of NSCs.

Various stem cell therapies are currently being explored for the treatment of cerebral palsy, including some in clinical trials. Advancing stem cell research is a priority for the cerebral palsy community and neural stem cells offer potential as a future regenerative treatment.

The researcher's rationale was that it's much better to engage with the community early in their research, rather than down the track, during clinical implementation.

"NSC treatment for cerebral palsy is complex, and researchers need to consider the therapeutic source of NSCs and how they are administered as a treatment.," Dr Smith said. "For instance, NSCs need to be administered directly into the brain via neurosurgery in order to replaced damaged brain cells. Another significant factor is that they can be obtained from both adult donors as well as embryonic and fetal sources."

This procedure also needs to be accompanied by strong drugs, called immunosuppressants, that help to ensure the NSCs stay in the brain and are not rejected by the body. However, both the invasiveness of neurosurgery and the use of these drugs present treatment risks.

"Via a research survey, we wanted to better understand, given all the complexities, if NSC treatment for cerebral palsy is an acceptable treatment." Dr Smith said.

Natasha Garrity, Research Assistant at Cerebral Palsy Alliance Research Institute and Co-Chair of the CPA Stem Cell Reference Group, welcomed this research as an important opportunity for people living with cerebral palsy and their families to provide their perspectives.

"It is critically important to respect the lived experience of the people with CP receiving this potential treatment and the views of their support network. By involving consumer stakeholders early on in the research process, the treatment can both be better understood by the community and targeted to the groups that are willing to use the treatment option," she said.

"Cerebral Palsy Alliance is committed to and passionate about involving people with a disability and their families in research for the benefit of researchers, clinicians and the CP community."

"Overall, the survey results showed that NSC therapy is deemed acceptable in the community," Dr Smith said. "even with the known complexities of neurosurgery and the need to use immune suppressing drugs."

"The survey also provided important insights into community expectations of NSC treatment there was some hesitancy reported, which is to be expected and we can learn from the various opinions in the community to inform our future research."

Some of the responses from survey participants are listed below:

"If my brother can help himself get ready or be able to transport himself even a little bit without assistance from the family, that would be great."

"I'd love to be able to have better days than worse days. To wake up with no pain."

"It would mean inclusion. And validation to her that she is a valuable asset. Currently she is spoken over, ignored, or spoken down to."

(Anonymous participant quotes)

The findings from this study informs the work that scientists are conducting in the lab so that new treatments are acceptable to the cerebral palsy community. Additionally, this study is a great example of how early collaboration could aid in moving towards timely treatments for the people that need it the most.

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Stem Cell Treatment Discussed with Cerebral Palsy Community - Mirage News

Is Fasting the Secret to a Longer Life? – Men’s Health UK

Youre probably familiar with the idea, not always concrete, that fasting precipitates good health. Maybe youve been tempted to give the

Game-changing research has proven that short diets that mimic the act of fasting can trigger powerful natural healing and regenerative processes lying dormant in our bodies. Processes that not only burn fat but also fight heart disease, slow ageing, lower cholesterol, reboot the immune system and extend lifespan.

It doesnt stop there: the most recent studies have shown that fasting can kill forms of human cancer in mice and enhance the effects of chemotherapy. In some trials, fasting itself proved as effective as chemotherapy. In short, science is telling us that going hungry could prevent and treat some of the biggest killers of men.

The man behind this research and the structured, prescriptive diet that Im following is Dr Valter Longo. A professor of gerontology at the University of Southern California, he embarked upon this line of inquiry when he first noticed that yeast cells simple organisms that predate humans by millions of years respond to periods of fasting by protecting cells and fighting toxins. Yeast that had been fed a low-calorie diet, Longo discovered, lived up to 10 times longer than the control group.

Longos latest findings show that humans have similar self-healing mechanisms buried deep in our DNA and that periodically fasting on low-calorie diets has a wholesale regenerative effect on the body. Some of the reasons behind this are understood; others remain a mystery. It is believed that fasting kills cancer cells by starving them of glycogen (on which they depend for fuel more than regular cells), thus tricking them into releasing damaging free radicals that spark cellular suicide.

But fastings more general healing powers derive from a different mechanism. Longo has shown that fasting triggers the creation of new stem cells, which repair the body by regenerating tissues, organs and blood, and re-booting the immune system. It sounds too good to be true, I tell Longo when I call him at his California lab. Well, the regeneration that fasting triggers is remarkable, he says. During abstention, organs like the liver, as well as the entire immune system, shrink because they are deemed less necessary. When the body rebuilds these systems, however, it activates the release of healthy stem cells which regenerate newer, younger, more functional versions.

Its akin to pressing the reset button on your bodys operating system, he says. The rebuilding is so massive its probably the closest humans can get to the original embryogenesis process the growth of an embryo during weeks one to eight of human development, he reveals. This is not just a proliferation of new cells but a very coordinated one. It is an evolved programme that has been around for billions of years because organisms starved all the time. For the earliest Homo sapiens, devoid of Smeg fridges and Tesco, periods of feast and famine were the norm. All we need to do, maintains Longo, is rediscover this primitive state of being.

Theres a catch. Its not merely a case of not eating for five days. You have to severely restrict calories, yes, but Longos research shows that those you do eat must have the right balance of nutrients to trigger a natural process called autophagy, which encourages your body to cannibalise waste cell debris. Think of it as your own natural recycling process, removing damaged cells that could cause disease or ill health. Crucially, autophagy also shuts down the enzyme PKA the absence of which has been linked to extended lifespan and the proliferation of healthy stem cells and decreases the hormone IGF-1, which is associated with ageing and cancer risk.

Longos findings could well enrich our lives, but not before they enrich the coffers of L-Nutra, a specially established spin-off company of the University of Southern California. Together with L-Nutra, Professor Longo has developed ProLon: the pre-packaged, off the (pharmacists) shelf Fasting Mimicking and Enhancing Diet (FMED). This five-day menu of all-natural soups, nut bars and snacks provides enough calories to minimise cravings (at least theoretically) without jeopardising the miracles apparently brought about by abstinence. ProLon works by cheating your body into thinking youre literally starving, even though youre just hungry.

Day one is 1090 calories (10 per cent protein, 56 per cent fat, 34 per cent carbs), with days two to five dropping to 725 calories (9 per cent protein, 44 per cent fat and 47 per cent carbs). The first priority when designing the food was that it had to mimic fasting, explains Longo. The food is 20 years of painstaking work: removing, adding, substituting. If I add that ingredient, will it interfere with the PKA effect? Will this one affect the IGF-1 changes? Hunger is also an issue so we tried to make people feel relatively full.

Human trials of ProLon are ongoing, but L-Nutra expects to be able to launch the FMED kits imminently, priced at around 150 for a five-day pack. The healthier among us will be advised to undergo a course of FMED every four months or so, while obese people might benefit from a monthly cycle.

In the name of science, journalism and a little bit of weight management thrown in, I ask Professor Longo to send me a five-day course of ProLon. A mere 48 hours later I am tucking into the contents of my first little white box. The packets within look like space food but taste better than expected. The minestrone soup is watery yet filling, and the choco-crisp bar a surprising treat. Another pack contains olives, which I hate, so I throw them away. I am evidently not starving.

Day two is a different matter. Hunger haunts me all day. I eat my soup with a teaspoon to make it feel more substantial. It doesnt work. I want to stop but Longos words echo around my head: The regeneration of cells and the autophagy only start in days three, four and five, he says. Thats when you push the system to an extreme and back.

My trip to the newsagent on day three almost derails my efforts entirely. When, by the evening, my symptoms have still not subsided, I decide to contact Longo again. What I am experiencing is not only natural but beneficial, I am assured. Our brains are energy-sapping organs that normally run on 100 per cent glucose. But while fasting, our livers produces the ketone body B-hydroxybutyrate, a kind of emergency energy source for the mind, saving energy derived from fat and muscle for other organs.

At this stage in the fast your brain switches to the ketone body utilisation mode, possibly for the first time in your life, says Longo. This can cause a mild headache. I mention my own brain feels like its at the business end of a pneumatic drill, but this is batted away with yet more good news: studies have shown that ketones fight inflammation associated with type 2 diabetes, MS and Alzheimers. To the converted, there is apparently no end to fastings list of fortunes.

Not everyone is similarly convinced, however. Professor Kieran Clarke, from University of Oxfords Department of Physiology, Anatomy and Genetics, thinks fasting could be a smokescreen for the real message. A lot of the benefits [of fasting] relate to extending life, and its possible, but we dont know if its the fasting per se that achieves that, he says. It could just be related to the benefits of helping people reach normal bodyweight. If you look at the records, healthy people invariably do not fast.

Dr Tim Woodman, medical director at Bupa UK, goes further. He believes that fasting could actually have reverse health effects. Losing weight too quickly means that you also tend to lose muscle and water, he says. As a result, your body starts to work more slowly and needs fewer calories to function. So when you resume eating normally, the extra calories will be stored as fat.

One of the most vocal opponents to fasting being seen as a magic bullet is Dr Joel Fuhrman, author of The End of Dieting and Super Immunity. Fuhrman is the man behind so-called nutritarianism, the theory that the key to longevity lies in maximising the number of micronutrients per calorie consumed. Fasting, he holds, is a mere distraction. The modern diet is so nutrient-poor that to discuss fasting without framing it within a normal diet is inappropriate. Our diets are too deficient in micronutrients, phytochemicals and antioxidants to maintain normal immune system function.

If you want to live longer and healthier, says Fuhrman, forget fasting: just eat raw greens; a 30g portion of walnuts; chia seeds and flax seeds; a dish containing mushrooms, beans and onions; plus three portions of fruit like cherries, plums and oranges every single day. A nutritarian diet is the most effective way to not get heart disease, cancer or dementia, and to push the envelope of human longevity closer to 100 years old, he says.

Oh, and ditch the meat. The real impediment to our lifespan, claims Fuhrman, is animal protein. It may be essential for building muscle, burning fat, maintaining a healthy metabolism and supplying a range of important vitamins, but in Fuhrmans eyes it ultimately does your immune system no favours. Huge studies following people for 15-24 years prove that eating more animal products causes cancer, heart disease and shorter lifespans, he says. There is no controversy here. All nutritional scientists agree.

Indeed, the World Health Organisation has recently added red and processed meats to its list of carcinogens. These studies are not new some date back to 2010 but such is our cultural fascination with increasing our protein intake that weve just been ignoring them.

I advocate up to 10 per cent of your diet from animal products, with the other 90 per cent from plants, says Fuhrman. A few days of fasting wont help unless you change you regular diet, too. Animal protein elevates IGF-1, which speeds up the ageing process and negatively affects lifespan. Yes, calorific restriction might briefly restrict IGF-1, but if you then eat a lot of animal products after, it wont actually drop. If you both restrict animal protein and eat a more vegan diet, however, you get the benefits of fasting without actually having to fast.

To eat or not to eat? It would have been naive to expect a clear-cut consensus on such a radical concept. But the arguments made by Fuhrman and Longo arent too dissimilar. Fuhrman acknowledges that fasting is effective; he just takes issue with best practice when temporary abstainers start eating again. And in spite of cases made by critics of fasting, the research into its potential is still compelling.

An extensive review in Research in Complementary Medicine concluded that there was large empirical and observational evidence that medically supervised modified fasting combats high blood pressure, diabetes and obesity. This is simply too significant to ignore.

Were never going to say that fasting is so effective that it means people can smoke and eat badly as soon as they stop, says Professor Longo. The fact is if somebody has a vegan, low-protein diet, a BMI of 23, and regularly exercises, then they will benefit from fasting, just not as much as someone who is unhealthy.

Following an undeniably difficult midpoint, day four of my own experiment is something of an epiphany. I experience a surge of mental energy owing, I am told, to an increase in the levels of noradrenaline and dopamine in my brain. On the first two to three days of your fast you tend to sleep a lot, explains Raimund Wilhelmi of the famous German fasting clinic Buchinger Wilhelmi. Then, like a phoenix, you rise, and after four or five days you feel very positive.

Unfortunately my final rise is less phoenix-like, more vodbull hangover. Day five is tough. With mixed feelings I note that I have lost 1.7kg in just five days not the main purpose of the fast, but also not insignificant. On day six, with the fast finally over, the Toffee Crisps Ive been fantasising about are back on the menu, but my cravings have faded. My appetite has changed, as has my appreciation of portions and flavours. What I can say with some conviction is that fasting will rewire your mind.

There is yet some way to go. Professor Longo believes we are only just beginning to understand the potential power of fasting. Think about this, he says. If you are a 50-year-old man, you have a new child, and that baby is born perfect, it proves your cells know exactly how to build perfection again. How do they know? And is it possible that this can be done within an organism itself, without having to generate a new one? Longo sounds excited, verging on giddy. That is what we are chasing here.

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Is Fasting the Secret to a Longer Life? - Men's Health UK

SightCare Reviews – Legit Ingredients or Negative Scam Complaints … – Seattle Weekly

Everyone wishes to have optimal eye health because without it the world can turn bleak. People cannot function or do everyday tasks that seemed so easy once in their lives. Maybe, that is why so many people are supplementing their diet with vision supplements.

One such supplement is Sight Care. The blend of natural ingredients with no side effects is a popular choice in the United States. The official website of Sight Care says that they have helped thousands of people restore their vision naturally.

But is it really as effective as the makers claim? The official website says that you will not need any surgery or feel the need to wear glasses. They even go on to say that it can reverse blindness! That is really shocking and if true, miraculous! To get to the truth, we did exhaustive research.

In this Sight Care review, you will discover everything about the dietary supplement. We will tell you everything we discovered in our research about this vision supplement.

First, lets take a look at the summary:

Category:

Dietary Supplement

Quantity:

Each bottle of SightCare contains 60 capsules

Side Effects:

Customer reviews did not reveal any side effects (See what people are saying!)

Characteristics:

Ingredients:

Bilberry Extract, Eyebright, N-Acetyl-L-Cysteine, Quercetin, L-Lysine, Astaxanthin, Lutein and Zeaxanthin, and others

Money-Back Guarantee:

A 180-day money-back guarantee is available

Free Shipping:

On Select Purchase

Price:

Starts at $69 (Official Website)

Poor eyesight can be caused by several factors. Some of the most common ones are age-related macular degeneration, glaucoma, cataracts, eye infection, etc. Exposure to blue light and hereditary eye conditions can also be the leading causes of poor eye health.

Sight Care supplement was manufactured after Shinya Yamanaka discovered the power of adult repair stem cells. Scientists in the United Kingdom were using stem cell therapy to regenerate eye cells to treat blindness and age-related diseases like cataracts and other eye health problems.

This scientific discovery repaired the retinas of a man in his 80s and a woman in her 60s. Earlier, the test subjects could not even read or see clearly due to poor eye health. But, after the trials, they could read up to 80 words in a minute.

When David and his friend, Mark read this research in the journal they decided to make Sight Care.

The unique feature of SightCare vision health supplement is that despite being a supplement that helps in maintaining healthy vision, it does not stop at eye health benefits only. The vision supplement also promotes your overall well-being.

The health benefits of SightCare vision health formula are innumerable. Well, not literally but they are too many for us to discuss all of them here. You can write books on each ingredients benefits if you wish. That is how many benefits Sight Care supplement has to offer!

SightCare: Try it now, you wont be disappointed!

David Lewis is the creator of the Sight Care eye health supplement. He is an eye specialist and has over 37 years of experience in helping people support healthy eye function.

In his later years, David struggled with blurred and poor eyesight. The cause was age-related macular degeneration. This made David search for a solution along with his friend, Mark. Together they created this blend of natural ingredients to support vision health naturally.

The eye health formula is made in an FDA-approved and GMP-certified facility in the USA. The makers have tested the formula multiple times to ensure that it is clean and effective.

Before you get tempted to buy this supplement to support healthy vision, you should know if it is even made for you. You do not need to make unnecessary purchases and include something in your diet that you do not need.

The official website of the SightCare vision formula claims that anyone between the ages of 19 and 90 can take the supplement. As the ingredients are plant-based, the vision supplement will have no side effects on users.

So, if you are struggling with vision impairment or age-related eye diseases, say age-related macular degeneration, SightCare will be the right choice for you. You are suitable to use it if you want to maintain healthy vision.

SightCare takes a multi-action approach to protect the eyes and promote healthy eye function. Let us give you an overview of how it works in a simple way.

First of all, the SightCare eye supplement works to boost the growth of adult repair stem cells. Adult repair stem cells are free agents which means they have no assigned role. The major function of adult repair stem cells is to assume the role of cells wherever our body or organs require them. In the case of age-related macular degeneration, adult repair stem cells assume the role of eye cells to enhance vision.

Moreover, Sight Care has ingredients with anti-inflammatory properties that induce a healthy inflammatory response to reduce inflammation caused by eye diseases and support healthy vision. The ingredients in the formula protect the eyes from free radicals and blue light to prevent any damage from occurring.

To support healthy eye function and rectify age-related macular degeneration, the Sight Care pills promote blood circulation and keep your blood vessels healthy.

Click here to get all the details about SightCare >>>

Sight Care dietary supplement brings multiple health benefits to you. From the official website and Sight Care reviews, we have gleaned the following health benefits of the Sight Care supplement:

The ingredients in the Sight Care eye formula support healthy vision. As supported by the SightCare reviews, the formula supports overall eye health. The blend of natural ingredients nourishes your eyes and prevents free radicals from damaging your eye tissue. Thus, you get healthy eyes.

The vision supplement also has cell regeneration ability to regenerate eye cells and prevent age-related eye diseases like macular degeneration. This helps in regenerating eye tissues to maintain healthy eyes with clear vision.

Sight Care formula supports liver health. SightCare eye formula has n-acetyl which has antioxidant and anti-inflammatory properties. A healthy inflammatory response protects your liver from inflammation damage and reduces the risk of liver diseases. It helps in detoxifying your body and prevents free radical damage to support a healthy liver.

By promoting healthy liver function, Sigh Care optimizes your overall well-being.

Sight Care also helps improve brain health as supported by the official website and SightCare reviews. N-acetyl has anti-inflammatory properties that protect your brain from inflammation and oxidative stress to improve brain health.

Brain Health supports healthy vision and overall eye health.

Sight Cares natural ingredients also enhance vision to support night vision. Now, you do not have to fumble around or squint hard to see things in the dark.

Sight Care is scientifically proven to specifically target age-related macular disease or macular degeneration which is the leading cause of poor eyesight in older people. Thus, it supports your overall eye health despite your age.

Click here to order your supply of SightCare now and start enjoying its benefits!

SightCare is a revolutionary product that combines the power of Bilberry Extract, Eyebright, N-Acetyl-L-Cysteine, Quercetin, Astaxanthin, Lutein, and Zeaxanthin into one powerful formula.

Its designed to help support healthy eyesight and promote clearer vision so you can get the most out of life with the help of powerful natural ingredients:

A study conducted on the effects of bilberry extract on eye health supports its inclusion in SightCare. In a randomized, double-blind, placebo-controlled trial published in the Journal of Science of Food and Agriculture, researchers looked at the impact of bilberry extract supplementation on visual function in 120 participants with early-stage AMD.

The study found that after six months of bilberry extract supplementation, there was a significant improvement in visual acuity, contrast sensitivity, and macular pigment optical density compared to the placebo group.

According to the study, participants who took the bilberry extract supplement experienced a 25% improvement in visual acuity compared to only 9% in the placebo group. Additionally, their contrast sensitivity increased by 33%, while the placebo group only showed a 13% increase.

At a microscopic level, eyebright contains various bioactive compounds such as flavonoids, iridoids, and tannins. These compounds possess antioxidant and anti-inflammatory properties, which play a key role in maintaining and improving eye health.

Another vital mechanism by which eyebright aids in visual acuity and eyesight protection is its ability to promote blood circulation to the ocular region. The tiny capillaries and blood vessels within the eyes deliver the necessary nutrients and oxygen to maintain the optimal functioning of ocular tissues.

By enhancing blood flow, eyebright ensures that these vital nutrients reach the cells of the eyes, including the retinal cells responsible for signaling and visual perception.

A study conducted by Babizhayev et al. (2016) examined the effects of NAC in patients with early cataracts. The study involved 49 individuals who were divided into two groups: one receiving NAC eye drops and the other receiving placebo eye drops.

The researchers measured various indicators of eye health, including visual acuity, glare sensitivity, and lens transparency, before and after the intervention. The results showed that the group receiving NAC eye drops experienced significant improvements in all measured parameters compared to the placebo group.

Visual acuity improved by 35%, glare sensitivity decreased by 27%, and lens transparency increased by 41%.

Place your order today by clicking here before stock runs out! >>>

Quercetin is a flavonoid compound found in various plant-based foods such as onions, apples, and berries. On a molecular level, quercetin consists of three rings and several hydroxyl groups, which contribute to its antioxidant and anti-inflammatory properties. When it comes to improving visual acuity and protecting eyesight, quercetin plays a crucial role in several core mechanisms.

By inhibiting the production of inflammatory molecules such as cytokines and chemokines, quercetin helps to reduce inflammation in the eyes. This anti-inflammatory action not only alleviates discomfort but also preserves the integrity of ocular tissues and improves visual acuity.

Moreover, quercetin aids in reducing oxidative stress in the eyes. Oxidative stress occurs when there is an imbalance between the production of harmful free radicals and the bodys ability to neutralize them with antioxidants. In the eyes, this oxidative stress can lead to the development of various eye conditions such as cataracts and age-related macular degeneration (AMD).

Astaxanthin is a naturally occurring red pigment that belongs to the carotenoid family. Its chemical composition consists of a central polyene chain with alternating single and double bonds and several end groups called keto and hydroxyl groups. This unique structure gives astaxanthin its powerful antioxidant properties.

When it comes to vision functioning, astaxanthin demonstrates remarkable benefits. It has a strong affinity for the retina and accumulates in the macula, a small area responsible for central vision. Astaxanthin protects the eyes from harmful ultraviolet (UV) radiation and filters out harmful blue light.

It also acts as a potent antioxidant, neutralizing free radicals that can damage the delicate structures of the eye. Furthermore, astaxanthin enhances blood flow to the retina, improving nutrient delivery and oxygenation, which in turn supports optimal vision functioning.

Numerous scientific studies have provided evidence for the effectiveness of lutein and zeaxanthin in supporting eye health and improving night vision. One specific study published in the Journal of the American Medical Association in 2016 examined the effects of these antioxidants on participants with intermediate AMD.

The study found that a combination of lutein and zeaxanthin supplements significantly reduced the progression of AMD and improved visual acuity compared to a placebo group. Specifically, the lutein and zeaxanthin group had a 10% reduction in the risk of progression to advanced AMD, highlighting the powerful protective effects of these antioxidants.

Furthermore, studies have shown that higher levels of lutein and zeaxanthin in the macula are associated with a lower risk of cataracts and improved contrast sensitivity, especially in low-light conditions.

In a study published in the Journal of Optometry in 2017, researchers found that individuals with higher macular pigment optical density (indicating higher levels of lutein and zeaxanthin) had better night vision and were less affected by glare.

Dont miss out on this limited-time offer!

The advantages of purchasing the Sight Care formula are as follows:

The following are the disadvantages of purchasing Sight Care vision health formula:

We compared Sight Care dietary supplement with other eye health supplements to see how it stands apart from them and we were not disappointed. Take a look at the comparison below:

Ocusil is a dietary supplement that supports healthy eyesight. It provides crystal-clear vision and prevents free radicals from damaging your retina.

In terms of pricing, both Ocusil and Sight Care are the same. You can purchase the basic pack for $69 plus shipping charges.

If we talk about the manufacturing of both supplements then like Sight Care, the Ocusil dietary supplement is also made in an FDA-approved and GMP-certified facility ensuring its effectiveness and quality.

However, both supplements have different list ingredients and target different causes of vision loss to help you in maintaining healthy eyesight. You can go through the ingredient list of both supplements and decide which dietary supplement is better in case you are allergic to any ingredient.

Comparing the money-back guarantee, we found that Ocusil offers a 60-day money-back guarantee only. On this parameter, Sight Care is better as it is covered with a 180-day money-back guarantee.

Overall, both Ocusil and Sight Care can help you maintain healthy eyes. You can make your decision after talking to your physician.

Vision20 is another dietary supplement that supports healthy vision. The supplement fights free radicals and promotes night vision.

Comparing the ingredients of both supplements, we found that they are more or less similar. Except for a few ingredients, that is. Also, both Vision20 and Sight Care are manufactured in an FDA-approved and GMP-certified facility.

Coming to the pricing of Vision20, we found that it is cheaper than Sight Care. People living in the United States can purchase Vision20 for $59 only.

Both the supplements are manufactured by doctors. However, Vision20 is manufactured by Zenith Lab whereas, Sight Care does not mention anything like that. This gives Vision20 more credibility if we test their brands.

Another common thing between Vision20 and Sight Care is that both offer a 180-day money-back guarantee which is a great thing but makes it really impossible to choose one brand between the two.

Again, you can select the supplement based on ingredients. But we think Sight Care will be a good choice because it brings multiple health benefits in comparison to Vision20.

Place your order right here for the best prices available!

First and foremost, SightCare is designed for anyone between the ages of 19 and 90. If you find yourself struggling with vision impairment, whether due to age-related macular degeneration or other eye-related issues, SightCare might just be your solution. Its specifically formulated to combat various eye health problems, making it a versatile option for a wide range of people.

But what exactly can SightCare help with? The supplement is crafted to address a multitude of eye health issues. If youre battling age-related macular degeneration, glaucoma, cataracts, or even eye infections, SightCare could offer relief. Its a natural, plant-based solution that promotes overall eye health and prevents further damage caused by free radicals and blue light exposure.

Moreover, SightCare doesnt stop at eye health; it promotes your overall well-being. By supporting healthy vision, SightCare indirectly benefits other aspects of your health. For instance, its anti-inflammatory properties protect not only your eyes but also your liver and brain, enhancing your overall vitality.

So, if youre tired of fumbling for glasses or struggling with poor eyesight, SightCare might be your ticket to clear vision. Its natural ingredients, coupled with a 180-day money-back guarantee, offer you a risk-free opportunity to experience the potential benefits.

Getting a healthy vision has become affordable and if you have made up your mind to buy SightCare vision supplement to tackle age-related eye diseases or vision impairment, let us tell you about the pricing structure of the supplement.

You can buy SightCare vision supplement in the following range of bundles from the official website:

Basic Bundle: The basic bundle consists of one bottle of SightCare. You can purchase it for $69.

Popular Bundle: The popular bundle consists of three bottles of Sight Care. It will cost you $177.

Best Value Bundle: The price of this six-bottle bundle is $294.

The Basic bundle will come with a standard shipping charge. So, your total charge will change on this order accordingly. However, for the Popular and Best Value bundles free shipping is available.

Order SightCare today and be glad you did!

The makers will not leave you hanging once you have purchased the Sight Care Formula or have placed an order. You can visit customer support (getSightCare.com) if you have any questions about the order, ingredients, or anything. Their team will be available to guide you and answer all your questions.

This is one of the most frequently asked questions and for all the right reasons. No one wants to make a risky purchase and lose their money over something that will not help them get a crystal clear vision.

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SightCare Reviews - Legit Ingredients or Negative Scam Complaints ... - Seattle Weekly

Trajectory of the Changing GA Treatment Landscape – AJMC.com Managed Markets Network

Ryan Haumschild, PharmD, MS, MBA: Now I would like to really transition into the future considerations of geographic atrophy [GA]. Obviously, theres been a lot of excitement here recently around complement inhibitors, and I feel like the treatment of the future landscape is even more exciting. And were going to have more options for our patients to really improve outcomes, give durable responses, and ultimately, improve the quality of life. Dr Lally, I would like to start with you. What are you most excited about in the treatment landscape of GA in the next 5 years? And what are some final thoughts that you want to share with our viewing audience from todays discussion?

David Lally, MD: I think the take-home message that Im excited about is there has really been an explosion of clinical trials and different strategies of trying to tackle this disease of GA. Blocking complement is one very important part of the puzzle. But as we have seen and we have talked about earlier, complement inhibition is really just the tip and just the start of what is to come. And really our goal is we want to prevent GA from even developing, or if it develops, we want to stop it in its track. These new therapies are really the first step of showing a slowing progression, but the disease is still progressing. We do not want it to progress. We want to stop it or prevent it from even developing. There are a lot of different strategies out there beyond complement [inhibitors] looking to try to accomplish this goal. Something we look at is neuroprotection, which is a big umbrella term thats kind of even hard to define what neuroprotection means. But I think neuroprotective medicines that can protect the retina; the retina is like an outpouching of the brain. We consider it like neural tissue, an outpouching of the brain. Any medication that can really preserve neuronal health, I think is going to be an exciting place to look. I think what is exciting is there is a lot of work going into trying to design and figure out end points that can be used to see the effects of treatments at the intermediate stage of dry AMD [age-related macular degeneration] before GA develops. And I think, again, if we can find really good clinical trial outcome measures, for the development of GA, in a reasonable time frame to run a clinical trial, I think we are really going to see the field move forward. There are a lot of people working on functional outcome measures, on structural outcome measures, to really try to help us hone in there. I think regenerative medicine is interesting. Some strategies are looking at replenishing the atrophic area with pluripotent embryonic stem cells. And theres some work that is actually getting into the later stages of development. Stem cells, although we are not all the way there yet, I think are starting to make some progress in the development of hopefully getting to an FDA-approval someday, and actually restoring the loss of the photoreceptors. But to me, the most encouraging if we look at these complement inhibitors is I hope someday we have gene therapy for these complement inhibitors. Wouldnt it be wonderful if we could give one intravitreal injection with a gene therapy that went into the cells, and we had our own retina cells make the complement inhibitors themselves where it went on forever? Because, as I mentioned earlier, these patients live with this disease for the rest of their lives. The way its looking right now, in the current state, they are going to be receiving intravitreal injections, either monthly or every other month, indefinitely. I think gene therapy is a place to be watching in the future. But the take-home message is its a really exciting time if you are a patient with GA. This is really a hallmark time in our field, having our first FDA-approved treatment. Hopefully, we may have a second soon in the summertime. The knowledge is really exponentially moving forward, and I really think in 5 years we are going to have even a lot more knowledge and we are going to have a lot better treatments coming for our patients.

Ryan Haumschild, PharmD, MS, MBA: Absolutely. Great final comments. And a lot more real-world evidence to make more informed decisions. Dr Lopes, curious what are your thoughts on how you expect the treatment landscape to change in the next 5 years, and upon that, what are your final thoughts from todays discussion?

Maria Lopes, MD, MS: Its certainly an exciting time to be in this disease space and going from no treatments to several, with 1 already approved and more in the pipeline. I guess until there is a cure, there is an unmet need. Exciting to see not just slowing disease progression, but that were looking at different mechanisms of action that hopefully make a very significant impact on preserving vision and potentially, halting progression as well as maybe even reversing disease, which is really exciting and innovative. [I would] love to see maybe more personalized medicine around predictive tools because as we have more treatment options, how do we sequence those options? How do we define what success looks like in this disease state if were just looking at a rate of growth? [I would] love to see more about any predictive tools that help us, not just identify, but then have the right shared decision approach that hopefully has and meets patient expectations, as well as payer needs and budget impact, and ultimately, making a significant impact on a clinically meaningful difference, which is about vision preservation.

Ryan Haumschild, PharmD, MS, MBA: Excellent. Clinical meaningful difference is really whats going to carry us forward, I feel like, from a treatment selection standpoint. Dr Khanani, we couldnt end without your thoughts on the evolving treatment landscape in the next 5 years. And also, what are some of your final thoughts and takeaways for our viewing audience?

Arshad Khanani, MD: Ryan, thank you again for moderating this great discussion. I really enjoyed it. I think the bottom line for me is that GA is a devastating disease that progresses 100% of the time, in 100% of the patients. And its a really severe disease that can take your independence away. It puts our patients in really tough situations. They cannot function and they go into depression. It really impacts the quality of life, and it leads to other comorbidities because the patients cannot see. Now, its a really exciting time to have the first FDA-approved treatment in pegcetacoplan [Syfovre], and hopefully, avacincaptad pegol coming in August. As physicians, there are still big unmet needs in this space. Obviously, complement inhibitors are a great start. Its chapter 1 of a really thick book that we will write together over the next 1 to 2 decades. In the next 5 years or so, I think we have both of these approved treatments, hopefully, that we utilize in an appropriate fashion to help our patients. And I think having artificial intelligence to help us with finding the right patients, doing the right treatment interval, monitoring the growth will be important. Now, its exciting because we have so many things in the pipeline. Gene therapy programs, some of them are in phase 2 trials, where you are actually enriching a complement factor I, and kind of modulate the overactive complement system in bringing it towards normal complement activity. We have to wait for the data to see if that pans out. Treatment burden will likely be a big problem with frequent injections. Gene therapy, as Dr Lally said, with one-time treatment targeting the complement system in one way or another, whether in the operating room or in clinic, will be exciting. We have some other novel drugs and mechanisms of action that are in the pipeline. We saw some promising data from elamipretide to preserve mitochondrial function. There are other pathways we are looking at. But at this point, over the next 5 years, I think we will have to utilize the complement inhibitors in a fashion to help our patients preserve their vision. Final comments from me, it was very depressing over the last 15 years of practice for me to give the bad news of blindness to our patients with GA. Now I can give them some hope. They will be able to preserve their vision longer. Yes, we cannot reverse the disease. Yes, we cannot stop the disease. But slowing the disease down can have meaningful outcomes in the future because the treatment effect is greater the longer you treat these patients. And then, hopefully, we will have more treatments come down the pipeline and treat this disease early at the intermediate stage so we can actually tell our patients that you are not going to go blind.

Ryan Haumschild, PharmD, MS, MBA: Complement inhibitors sure are going to be a game changer in the field of GA. Thank you all so much. Thank you to our expert panelists for this rich and informative discussion, and to our viewing audience, we hope that you found this AJMC Peer Exchangeto be useful and informative.

Transcript edited for clarity.

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Trajectory of the Changing GA Treatment Landscape - AJMC.com Managed Markets Network

Brain cells are starved of energy when autophagy malfunctions, new … – University of Birmingham

Research has major implications for neurodegenerative disease treatments

Neurodegeneration in brain cells may be happening when the natural cellular cleaning process malfunctions due to falling levels of a niacin-related coenzyme and leaves cells starved of energy, new research shows.

Brain cells die from malfunction of autophagy, a process by which cells get rid of cellular waste and generate energy for their survival. In new research published in Cell Reports, researchers have found that a metabolic failure arising from loss of autophagy is detrimental to brain cells called neurons. When autophagy stops working, the levels of a coenzyme called nicotinamide adenine dinucleotide (NAD) falls, causing the cells to not be able to get enough energy to maintain normal function and to survive.

Researchers led by Dr Sovan Sarkar at the University of Birmingham along with his PhD students, Ms Congxin Sun and Dr Elena Seranova, and in collaboration with Prof. Rudolf Jaenisch at the Whitehead Institute for Biomedical Research, developed a human embryonic stem cell (hESC) model with deletion of a key gene involved in autophagy.

They generated neurons from these hESCs to understand how loss of autophagy kills brain cells. In autophagy-deficient neurons, depletion of NAD was identified to mediate cell death. The researchers found that upon loss of autophagy, NAD was consumed by hyperactivation of naturally occurring enzymes such as Sirtuins and PARPs.

Critically for brain health, dropping NAD levels resulted in undesirable electrical changes to mitochondria, leading to them not being able to function effectively and cells arent able to metabolise energy to continue to maintain homeostasis.

The researchers say that the findings of this neurotoxic pathway provide new clues about a way to combat neurodegenerative diseases, by showing that compounds boosting NAD levels can improve the survival of neurons with loss of autophagy.

....identifying that NAD levels are being depleted when autophagy malfunctions is a very important step in thinking about a way to manage decline in brain health both in older age and among at-risk populations.

Dr Sovan Sarkar, a Birmingham Fellow in the Institute of Cancer and Genomic Sciences at the University of Birmingham and lead senior author of the paper said:

We have shown a new mechanism of how brain cells are dying when autophagy stops working properly by using a hESC-derived neuronal model of autophagy deficiency. Autophagy is a critical process across all cells, especially in neurons, and identifying that NAD levels are being depleted when autophagy malfunctions is a very important step in thinking about a way to manage decline in brain health both in older age and among at-risk populations.

NAD can be boosted through the use of targeted therapeutics such as supplementation with NAD precursors like nicotinamide (NAM), nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), as well as through the consumption of vitamin B3 also called niacin.

Our research also identifies the potential for drugs that slow down the NAD-eating enzymes in the PARP and Sirtuin families, all of which could support healthy ageing and reduced risk of neurodegeneration.

The results suggest that among the many roles that autophagy plays, helping maintain the levels of NAD that supports cell metabolism is an important process for staving off neurodegeneration. It also provides new potential targets for future treatments for neurodegenerative diseases, both by targeting the enzymes (SIRT1 and 2 and PARP1 and 2) that ate up NAD and by supplementing NAD precursors.

Dr Viktor Korolchuk, Associate Professor at Newcastle University and a senior co-author of the paper said:

Both autophagy and NAD levels decline in our cells and tissues as we get older contributing to age-related diseases. Our study helps to explain how these processes are interlinked: loss of autophagy also causes depletion of NAD.

Our recent paper demonstrated this in yeast and mouse cells, and the current study in human cells unequivocally shows that this intimate link between autophagy and NAD can trigger the death of human neurons. This finding significantly adds to our understanding of ageing and age-related neurodegeneration and opens new avenues to explore.

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Brain cells are starved of energy when autophagy malfunctions, new ... - University of Birmingham

Developing cells likely can ‘change their mind’ about their destiny – Phys.org

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A neural crest cell (a type of stem cell) begins with the ability to differentiate into any number of specialist cell types, but it also appears to retain the capacity to "change its mind" and differentiate anew when the circumstances are right, according to new research from the University of Bath. As a result of this hyper-flexibility, the possibilities for these cells in replacing damaged human tissue is likely to be even greater than previously thought.

Neural crest cellsfound in very young embryos, and vital for determining the color of hair and skinare highly flexible by nature, giving rise to many different types of vital cells, including neurons. New research from the University of Bath suggests their flexibility remains greater than previously thought, a finding that has significant implications for regenerative medicine.

Until now, it was assumed that neural crest cells became committed to becoming a particular cell type very early, after which their fate was sealed. However, studies led by Professor Robert Kelsh from the Department of Life Sciences at Bath suggest they retain their adaptability even after they have become visibly differentiated.

This newly discovered flexibility helps explain why neural crest stem cellsan important type of stem cell that can also be readily isolated from adult skinhave immense potential as treatments to replace and repair damaged body tissue in many parts of the body.

The finding that even after choosing a destiny (for instance, developing into skin pigment cells), neural crest cells might be able to "change their mind" and choose a new destiny (perhaps becoming cartilage cells) reconciles a long-standing debate among biologists over the nature of neural crest cell differentiation.

In humans, neural crest cells are multipotent, meaning they are capable of developing into many different types of cell, including cells of the peripheral nervous system, cardiac muscle, and cartilage, as well as pigment cells in the skin and hair. These are all cells with highly specific functions.

Until now, two rival theories have sought to explain how, exactly, they pull this off.

"The question of how the fate of these cells becomes decided and restricted has been unclear and much debated for over 40 years," said Professor Kelsh.

According to the first theory, neural crest cells begin to commit to a specific role in the young embryo before leaving the place from which they arisethe neural tube (which develops into the brain and spine). The thinking goes that by the time they start migrating to their final destinationbe that the gut, skin, or connective tissuetheir destiny is already partially limited (i.e., some options are already off the table) and that more and more options become eliminated as they migrate.

The second theory posits that neural crest cells remain multipotent when they leave the neural tube and only commit to a specific differentiation path once they reach their destination.

There has been a general feeling in the field that the first model was the more accurate of the two. The new study published in Nature Communications, however, finds that neither of these "static" theories is correct.

"It would appear that these cells are choosing their fate in a much more dynamic, mobile way and are not narrowing their options irreversibly until much later than we previously thought," said Professor Kelsh. "This provides experimental biologists with a new, updated model to help them understand the behavior of neural crest cells."

It has long been known that neural crest cells use molecular signals from their environments to turn into one type of cell or another. However, Professor Kelsh's genetic work on zebrafisha freshwater fish with many genetic similarities to humansshows these steps are likely reversible: remove the signals and the cells revert to a more primitive state, where their potential to differentiate differently is restored.

Professor Kelsh said, "Our work shows these cells become biased by their environment. Take them out of that environment and they relax back to a more broadly competent state, likely capable of becoming anything."

He added, "Our findings will be of interest to other stem-cell researchers, as they give us a theoretical understanding of how neural crest cells might be used in medicine to repair any number of defects, from skin-pigmentation defects such as vitiligo to defects of the nervous system."

More information: Tatiana Subkhankulova et al, Zebrafish pigment cells develop directly from persistent highly multipotent progenitors, Nature Communications (2023). DOI: 10.1038/s41467-023-36876-4

Journal information: Nature Communications

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Developing cells likely can 'change their mind' about their destiny - Phys.org