Bold new therapy delivery method shows initial promise as treatment for Duchenne muscular dystrophy – Medical Xpress

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Graphical abstract. Credit: Cell (2023). DOI: 10.1016/j.cell.2023.03.033

Doug Millay, Ph.D., a scientist with the Division of Molecular Cardiovascular Biology at Cincinnati Children's has dedicated his career to revealing the most fundamental mechanisms of skeletal muscle development. He has been a leader in characterizing how two "fusogens" called Myomaker and Myomerger mediate the entry of stem cells into mature muscle cells to build the tissue that humans depend upon for movement, breathing, and survival.

Now, some of the basic discoveries made by Millay and colleagues are translating into a potential treatment for people living with Duchenne muscular dystrophy (DMD). Their latest research, published April 12, 2023, in the journal Cell, reveals that in mice, modified viruses, engineered with Myomaker and Myomerger, result in specific fusion with muscle cells. These viruses can therefore be used as a vector to deliver a vital gene needed for muscle function that is mutated in people with DMD.

A key unknown prior to this work was whether proteins like Myomaker and Myomerger, which mainly function on cells, could even work on viruses. First author Sajedah Hindi, Ph.D., also with the Division of Molecular Cardiovascular Biology at Cincinnati Children's and a leading member of the research team, took on the challenge to test this idea.

Hindi first designed a strategy to place Myomaker and Myomerger on the surface of viruses and showed that they were functional in cultured cells. She went on to leverage her extensive experience in skeletal muscle biology to test the efficacy of these novel vectors in mice.

"This modified viral vector appears to be a promising tool for delivering a potential lifelong supply of the gene that is absent in people with DMD," Millay says. "The unique advantages of this vector provide an opportunity to significantly impact gene therapy for a myriad of muscle diseases."

DMD is a rare and fatal genetic muscle disease characterized by the lack of a critical membrane-stabilizing protein called dystrophin, which results in progressive muscle degeneration and weakness. DMD primarily strikes boys, occurring in about 1 of every 3,500 male births worldwide.

Doctors often diagnose the disease between ages 3 and 6 when children show early signs of significant muscle weakness, such as delayed ability to sit, stand, or walk and difficulties learning to speak. Over time, DMD becomes fatal as muscle degeneration disrupts lung and heart function.

There is no cure. However, lifespans have been extended and quality of life has been improved for many through physical therapy and medications to address certain symptoms. Some gene therapy clinical trials are evaluating the use of adeno-associated virus (AAV) as the delivery vector, and there is hope that these strategies work. However, novel vectors, such as the lentiviruses described by Millay and colleagues, have the potential to improve long-term delivery of therapeutic material for muscular dystrophies.

Conducting the numerous experiments involved in this study took Hindi and collaborators about four years to complete. A significant collaborator who helped initiate the project was Benjamin Podbilewicz, from the Technion-Israel Institute of Technology, Haifa, Israel. Their findings include:

Much more research will be needed to further develop this discovery into a treatment that could someday benefit people with DMD. Even more work will be needed to determine which other muscle diseases might be treated with this lentivirus vector.

"We envision that this concept, transferring a naturally occurring process within muscle to membrane vehicles, could revolutionize delivery of therapeutic material to skeletal muscle to improve genetic conditions such as muscular dystrophy and conditions associated with muscle loss and weakness," Millay says.

More information: Sajedah M. Hindi et al, Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery, Cell (2023). DOI: 10.1016/j.cell.2023.03.033

Journal information: Cell

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Bold new therapy delivery method shows initial promise as treatment for Duchenne muscular dystrophy - Medical Xpress

Cell and Tissue Preservation Market To Deliver Greater Revenues … – Digital Journal

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Published April 28, 2023

Polaris Market Research endeavors to present the most relevant and admirable research on Cell and Tissue Preservation Market: By Size, Trends, Share, Growth, Segments, Industry Analysis and Forecast, 2032 based on the needs of the business. The report examines the constant changes taking place in the market, and such dynamics are helping the industry in growing its operations. The primary goal of this report is to highlight the growing potential of the market and its growth-promoting variables. The report also examines the Cell and Tissue Preservation Market growth rate and valuation. The study provides a thorough analysis of current industry trends and developments, as well as a complete predictive and prescriptive analysis.

According to the research report, the global cell and tissue preservation market was valued at USD 3.47 billion in 2021 and is expected to reach USD 8.32 billion by 2030, to grow at a CAGR of 10.5% during the forecast period.

The cell and tissue preservation market refers to the industry that develops and provides products and services for the storage, transport, and preservation of biological samples such as cells, tissues, and organs. The preservation of these samples is essential for research, drug development, and clinical applications.

The report determines the upcoming trends and the competitive landscape of the industry that helps companies make insightful decisions and manage business growth effectively. It contains history analysis, key developments in the market, projected growth, geographical analysis, Cell and Tissue Preservation Market share, revenue, industry variable, key segmentation, and forecast scenario. Segmentation is prominently performed by type, application, players, and region. Furthermore, the regional and country-level section assesses the market in each geography and Cell and Tissue Preservation Market size by region and country.

The market for cell and tissue preservation has been growing in recent years due to the increasing demand for biobanking, regenerative medicine, and personalized medicine. Biobanking refers to the collection and storage of biological samples for future research, while regenerative medicine aims to develop new treatments by using cells and tissues to repair or replace damaged tissues or organs.

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Parse Biosciences and Human Cell Atlas Partner to Help Map … – PR Web

The HCA has already provided transformational work to the single cell community. Parses technology will assist this important work with unprecedented scale, opening up new possibilities for what is achievable in scientific research.

SEATTLE (PRWEB) April 27, 2023

Parse Biosciences, a leading provider of accessible and scalable single cell sequencing solutions, today announced the company has partnered with the international Human Cell Atlas (HCA) consortium, a global collaboration of researchers developing comprehensive reference maps of all human cells as a basis for understanding human health and diagnosing, monitoring, and treating disease.

Parses EvercodeTM technology for single cell transcriptomics and single cell immune profiling enables million-cell experiments without the need for expensive instrumentation. Through the partnership, HCA members gain more access to Parses technology. Parse will also provide support to HCA members for experimental design, assay execution, and bioinformatic support in applying the Evercode technology to their research.

The Human Cell Atlas project is an enormous undertaking and will transform our understanding of the 37 trillion cells in the human body, noted Dr Sarah Teichmann, co-Chair of the HCA Organizing Committee and Head of Cellular Genetics at Englands Wellcome Sanger Institute. Our global community of researchers is charting the cell types in the body, across time from development to adulthood and eventually to old age, and effective large-scale technologies are needed to enable this.

An open global initiative, the HCA was founded in 2016 and has grown to more than 2,900 members from over 1,500 institutes and 94 countries around the world. Bringing together an international community of biologists, clinicians, technologists, physicists, computational scientists, software engineers and mathematicians, HCA membership is open to the entire scientific community worldwide.

The HCA has already provided transformational work to the single cell community. Parses technology will assist this important work with unprecedented scale, opening up new possibilities for what is achievable in scientific research, noted Parse co-founder and CEO Alex Rosenberg, Ph.D. Were proud and excited to help support researchers worldwide to reach the ambitious goal of the HCA.

About the Human Cell AtlasThe Human Cell Atlas (HCA) is an international collaborative consortium which is creating comprehensive reference maps of all human cellsthe fundamental units of lifeas a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA is likely to impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine.

The HCA was co-founded in 2016 by Dr. Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr. Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now more than 2,900 HCA members, from 94 countries around the world. https://www.humancellatlas.org

About Parse BiosciencesParse Biosciences mission is to accelerate progress in human health and scientific research. At the core of our company is our pioneering approach for single cell sequencing. Single cell sequencing has already enabled groundbreaking discoveries which have led to new understandings of cancer treatment, tissue repair, stem cell therapy, kidney and liver disease, brain development, and the immune system. At Parse Biosciences, we are providing researchers with the ability to perform single cell sequencing with unprecedented scale and ease. To learn more, please visit https://www.parsebiosciences.com/.

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Regulation of synaptic connectivity in schizophrenia spectrum by … – Nature.com

The methods were performed in accordance with relevant guidelines and regulations and approved by the Ethics Committee of the University Hospital and Faculty of Medicine Tuebingen. We confirm that participants provided a written informed consent to take part in the study. Inclusion and exclusion criteria for the selection of patients diagnosed with SCZ are described in Supplementary Table1. iPSCs were generated and fully characterized as described elsewhere (Table1; refs. 22,23). All experiments were carried out with all lines in parallel.

Patient-derived human fibroblasts were reprogrammed by nucleofection of non-integrative, episomal vectors encoding for OCT3/4, SOX2, LIN28, KLF4, c-MYC, p53 and EBNA1 (Addgene, catalog no. 41813, 41814, 41855, 41856, 41857). Electroporated fibroblasts were seeded onto Matrigel (Corning, catalog no. 354277) coated well plates and expanded in a feeder-free culture system for 2128 days until first iPS colonies appeared. iPS clones were manually picked and expanded on Matrigel in mTeSR Plus medium (STEMCELL Technologies, catalog no. 05825). Passaging was routinely performed non-enzymatically using Gentle Cell Dissociation Reagent (STEMCELL Technologies, catalog no. 100-0485) in early passage numbers or later enzymatically by using accutase (Sigma Aldrich, catalog no. A6964). All expanded iPS clones were routinely tested for expression of stem cell marker on protein and RNA level and pluripotency. All iPS clones used in this study were chromosomally intact.

For microglia differentiation, we modified a previously published protocol for the differentiation of iPSC into monocytes and macrophages55. iPSCs were dissociated using accutase and seeded at a density of 5104 cells per cm (day -2). Only wells containing equally distributed iPSC colonies of 1020 cells were considered for differentiation. For all differentiation steps, a 1:1 mix of IMDM without phenol red (Thermo Fisher Scientific, catalog no. 21056023) and Hams F12 Nutrient Mix (Thermo Fisher Scientific, catalog no. 21765029) was used. The basal medium was supplemented with 10g/mL poly vinyl alcohol (Sigma Aldrich, catalog no. P8136), 64g/mL ascorbic acid 2 phosphate (Sigma Aldrich, catalog no. A8960), 0.1x chemically defined lipid concentrate (Thermo Fisher Scientific, catalog no. 11905031), 2x ITS-X (Thermo Fisher Scientific, catalog no. 51500056), 0.0039% -Monothioglycerol (Sigma Aldrich, catalog no. M6145), 1x GlutaMAX (Thermo Fisher Scientific, catalog no. 35050061) and 1x non-essential amino acids. Additional growth factors and cytokines were always added freshly before usage. For mesoderm induction at day 0, the basal medium was supplemented with 50ng/mL BMP4 (Peprotech, catalog no. 120-05ET), 15ng/mL Activin A (Miltenyi Biotec, catalog no. 130-115-008) and 1.5M CHIR99021 (Axon Medchem, catalog no. 1386) for mesoderm induction. For the suppression of self-renewal in favor of stem cell differentiation at day 2, 10M of SB431542 and SCF (Peprotech, catalog no. 300-07), VEGF (Peprotech, catalog no. 100-20) and bFGF (Bio-Techne, catalog no. 233-FB) were added to the medium at a final concentration of 50ng/ml each. For hematopoietic patterning at day 5, 10ng/ml of IL-3 (Peprotech, catalog no. 200-03) and 50ng/ml of IL-6 (Peprotech, catalog no. 200-06), 50ng/ml of TPO (Miltenyi Biotec, catalog no. 130-095-747), 50ng/ml of bFGF, 50ng/ml of SCF and 50ng/ml of VEGF were supplemented to the basal medium. Medium was refreshed at day 7. At day 9, differentiated cells grew to full confluence with hematopoietic stem cells emerging into the supernatant. Adherent cells were dissociated by accutase treatment and added to non-adherent cells collected from the supernatant. After centrifugation at 300xg for 3min, cells were resuspended in microglia medium containing 100ng/ml of IL-34 (Peprotech, catalog no. 200-34), 50ng/ml of TGF-1 (Peprotech, catalog no. 100-21) and 25ng/ml of GM-CSF (Peprotech, catalog no. 300-03). Cells were subsequently plated on ultra-low attachment plates that were pretreated with Anti-Adherence Rinsing Solution for at least 5min and afterwards rinsed twice with DPBS. Microglia differentiation was allowed to proceed for further seven days with medium changes every other day.

Microglia were routinely characterized regarding expression of key markers like IBA1, SPI1 and TMEM119. Functionality was proven by active uptake of pHrodo-labelled bacteria and response to LPS as a pro-inflammatory stimulus. Microglia identity was confirmed by RNA sequencing. Transcriptome analysis and bioinformatical evaluation was performed by CeGaT GmbH (Germany) as previously described15. For characterization of microglial phenotypes, microglial genes were chosen according to previously published literature that identified panels of highly specific microglia signature genes21,56,57,58,59,60.

Secretion of the pro-inflammatory cytokine TNF was quantified by a standard sandwich-ELISA (human TNF-alpha DuoSet ELISA kit, R&D Systems, catalog no. DY210) according to the manufacturers instructions. Briefly, 96-well plates were coated with the capture antibody and incubated over night at room temperature. Wells were washed three times and blocked for at least 1h at room temperature. Wells were again washed and 100l of culture supernatant or standards were added and incubated for 2h at room temperature. After washing, detection antibody was added and incubated at room temperature for 2h. Wells were washed and the streptavidin / horse radish peroxidase (HRP) mix was added for 30min at room temperature. Afterwards, wells were washed again and substrate solution was added for 20min at room temperature in the dark, stop solution was added and the plate was tapped for mixing. Immediately afterwards, the optical density was determined using a microplate reader (Tecan Spark) set to 450nm with wavelength corrections set to 540nm.

Flow cytometry measurements were performed using BD FACS Chorus software on a BD FACS Melody and analyzed using FlowJo 10.6.1 (FlowJo Engine, Becton Dickinson & Company). Cells were detached, washed three times with DPBS and stained with conjugated antibodies for 30min at 4C. Subsequently, cells were washed three times with DPBS and resuspended in PBS+1% FCS for immediate analysis. The following conjugated antibodies were used: anti-human SSEA-4 PE-Vio770 (Miltenyi Biotech, catalog no. 130-105-081), anti-human CD11b FITC (Thermo Fisher Scientific, catalog no. 11-0118-42) and anti-human CD45 VioBlue (Miltenyi Biotech, catalog no. 130-110-775). Doublets were excluded in FSC and SSC. Unstained cells served as negative population.

Day 19 microglia were plated at a density of 1105 cells/cm on Matrigel-coated 96 well plates. Cells adhered within 24h and were subsequently fixed and stained against NFB p65 (Cell Signaling, catalog no. 6956T), Phalloidin CruzFluor 488 Conjugate (Santa Cruz Biotechnology, catalog no. sc-363791) and Hoechst (Sigma-Aldrich, catalog no. 911004450). Using confocal laser scan microscopy with a 63x plan-apochromatic oil immersion objective, at least ten 3D Z-stacks were acquired of microglia were taken within each experiment. During acquisition, all settings such as exposure time, laser intensity and gain were kept constant. Z-stacks were further processed using Imaris software (Bitplane, version 8.2.0). Therefore, a surface for the nucleus was generated covering the Hoechst signal. Within this mask, the mean fluorescence intensity of NFB p65 was determined and quantified.

Caspase-1 activity was determined using the Caspase-Glo 1 Inflammasome Assays (Promega, catalog no. G9951) according to the manufacturers instructions. Briefly, day 19 microglia were plated at a density of 1.2105 cells/cm on Matrigel-coated 96 well plates and incubated overnight. The next day, cells were treated with 100ng/ml of LPS (Sigma Aldrich, catalog no. L6529) for 3h and subsequently with 5mM ATP (Sigma Aldrich, catalog no. A2383) for 30min at 37C and 5% CO2. The culture supernatant was transferred into a white 96 well plate and Caspase-Glo 1 Reagent was added. The mixture was incubated at room temperature in the dark for 1h and luminescence was measured on a Tecan Spark microplate reader.

Day 19 microglia and nave iPSC as control were plated at a density of 2104 cells per well of a 96 well plate and cells adhered within 24h. pHrodo Red E. coli BioParticles (Thermo Fisher Scientific, catalog no. P35361) were resuspended in 2ml PBS to generate a stock suspension with a concentration of 1mg/ml. Bioparticles were vortexed rigorously to generate a homogenous suspension. 10l of pHrodo Red E. coli BioParticles were added to the wells. Cells were incubated at 37C and 5% CO2 for 4h in the Incucyte S3 live-cell imaging system (Sartorius). 9 images per well were acquired every 15min at x20 magnification. Finally, the relative red fluorescent units per image were analyzed over time.

For lentivirus production, HEK293FT were cultured at 37C and 8 % CO2 in culture medium consisting of DMEM (Thermo Fisher Scientific, catalog no. 10566016), 10% FCS (Thermo Fisher Scientific, catalog no. 10270106), 500g/ml G418 (Carl Roth, catalog no. 2039), 1% non-essential amino acids (Thermo Fisher Scientific, catalog no. 11140035) and passaged using 0.25% Trypsin/EDTA (Thermo Fisher Scientific, catalog no. 25200056) once or twice a week. For lentivirus production, cells were dissociated and seeded at a density of 3000 cells per cm. After four days of incubation, medium of HEK293FT cells was changed to a serum-reduced transfection medium of Opti-MEM (Thermo Fisher, catalog no. 11058021) supplemented with 5% FCS. 27g of pC-Pack2 Lentiviral Packaging Mix (Cellecta, catalog no. CPCP-K2A) were mixed with 108l of Lipofectamine 2000 Reagent (Thermo Fisher Scientific, catalog no. 11668019) in 4.5mL Opti-MEM, incubated at room temperature for 20min and added to the cells for further incubation at 37C and 5% CO2. After 24h, medium was changed, while after 48h and 72h post-transfection the supernatant was removed and stored at 80C. Lentiviral suspensions were filtered through a 22nm filter, transferred into ultracentrifugation buckets and centrifuged at 19,600rpm and 4C for 80min. Pellets were air dried for a few minutes and remaining liquid was removed with sterilized soft tissue papers. Finally, 100l of DPBS+1% BSA were added per tube without pipetting or resuspending. Tubes were sealed with Parafilm and left overnight at 4C. The next day, pellets were resuspended by pipetting several times and aliquoted for storage at 80C. Titer determination was performed using the Lenti-X p24 Rapid Titer Kit (Takara Bio, catalog no. 632200) according to the manufacturers instructions. Lentiviral suspensions were diluted 10-fold and 100-fold and quantified against a p24 standard curve. Yields ranged from 51010 to 51011 particles/ml.

Ectodermal patterning was induced using the STEMdiff Neural Induction Kit (STEMCELL Technologies, catalog no. 05835) according to the manufacturers instructions. iPSC were dissociated using accutase and 2106 iPSC were seeded into ultra-low attachment AggreWell 800 well plates (STEMCELL Technologies, catalog no. 34815) pretreated with Anti-Adherence Rinsing Solution (STEMCELL Technologies, catalog no. 07010). After cultivation at 37C and 5% CO2 for seven days with daily medium changes, embryoid bodies were harvested using 37m reversible strainers (STEMCELL Technologies, catalog no. 27215). Prior to seeding, 6-well plates were pretreated with 20% poly-L-ornithine (PLO, Sigma-Aldrich, catalog no. P4957) in Dulbeccos phosphate-buffered saline (Thermo Fisher Scientific, catalog no. 14190094), incubated for 2h at room temperature and washed three times with DMEM/F12 (Thermo Fisher Scientific, catalog. no. 21331020). Subsequently, wells were treated with 10g/ml laminin (Lam, Sigma-Aldrich, catalog no. L2020) diluted in DMEM/F12 and incubated overnight at 37C and 5% CO2. Harvested embryoid bodies were washed to remove remaining single cells and seeded onto PLO/Lam pre-coated well plates in STEMdiff Neural Induction Medium with daily medium changes. Neural rosettes were selected using the STEMdiff Neural Rosette Selection Reagent (STEMCELL Technologies, catalog no. 05832), resuspended in STEMdiff Neural Induction Medium supplemented with 1M Dorsomorphin dihydrochloride (Bio-Techne, catalog no. 3093), 10M SB 431542 (Bio-Techne, catalog no. 1614), 500ng/ml recombinant Human Noggin Fc Chimera Protein (Bio-Techne, catalog no. 719-NG) and cultivated in PLO/Lam coated 6-well plate. After the first passage, cultivation medium was changed to STEMdiff Neural Progenitor Medium (STEMCELL Technologies, catalog no. 05833). NPCs were passaged up to passage 10. All generated NPCs were routinely tested for progenitor marker expression, such as PAX6, NESTIN or SOX1.

Neuronal differentiation was achieved by lentiviral overexpression of human Neurogenin 2 following previously published protocols61,62. 3.15104 NPC were dissociated by accutase treatment and seeded in PLO/Lam-coated well plates at a density of 3104 cells per cm in STEMdiff Neural Progenitor Medium. For induction of neuronal differentiation62, NPC were co-infected with lentiviral vectors pLV-TetO-hNGN2-Puro (Addgene, catalog no. 79049), and FUdeltaGW-rtTA (Addgene, catalog no. 19780) at a final concentration of approximately 10ng/ml or 2108 particles/ml per lentivirus. After 24h, doxycycline (Sigma Aldrich, catalog no. D9891) was added to a final concentration of 10g/ml to induce tetracycline-dependent expression of the reverse tetracycline transactivator (rtTA) and hNGN2. 24h later, 2g/ml of puromycine (Thermo Fisher Scientific, catalog no. 11113803) was added to the medium to select for transduced NPC. After removal of selection medium at day 2 post transduction, cells were supplied with neuronal differentiation medium consisting of Neurobasal Plus Medium (Thermo Fisher Scientific, catalog no. A3582901) supplemented with 1x B27 Plus supplement (Thermo Fisher Scientific, catalog no. A3582801), 1x N2 supplement (Thermo Fisher Scientific, catalog no. 17502048), 1g/ml Laminin, 20ng/mL BDNF (Peprotech, catalog no. 450-02), 20ng/mL GDNF (Peprotech, catalog no. 450-10), 500g/mL dibutyryl cyclic adenosine monophosphate (Sigma Aldrich, catalog no. D0627), 35g/mL L-Ascorbic Acid (Sigma Aldrich, catalog no. A2078) and 10g/ml doxycycline. At this point, 3104 murine primary astrocytes per cm were added a 50% medium change was performed every other day until neurons were assayed or fixed after 1421 days in vitro.

Neuronal and microglial differentiation started separately from each other for 16 days. Subsequently, microglia were lifted from the ultra-low attachment plates, washed with DPBS, centrifuged and finally resuspended in microglia medium. In case of pretreatment, microglia were primed using 100ng/ml of LPS or 10M of Minocycline (STEMCELL Technologies, catalog no. 74112) at 37C and 5% CO2 for 60min. Subsequently, microglial cells were washed with DPBS and added to the neuronal cultures. For a final microglia:neuron ratio of approximately 1:5, microglia were seeded at a density of 5104 microglial cells per cm combined with 3104 initially seeded NPCs per cm. The co-culture plate was transferred to the incubator and left for 72h at 37C and 5% CO2. Co-cultures were maintained in microglia medium throughout the experiments.

iPSC-derived neurons and microglia, cultured in 96-well clear plates (Greiner Bio, catalog no. 655090), were fixed using paraformaldehyde (4% in PBS, Sigma Aldrich, catalog no. P6148) for 15min at room temperature. After fixation, cells were washed three times with PBS and then blocked and permeabilized at room temperature in 0.1% Triton X-100/PBS containing 1X Blocking Reagent for ELISA (Merck, catalog no. 11112589001) for 30min. After overnight incubation at 4C with primary antibodies diluted in blocking solution, cells were washed three times in PBS and exposed to fluorescently labeled secondary antibodies (1:500; Cy3 anti-rabbit (Jackson ImmunoResearch, catalog no. 111-165-144) or Cy5-coupled goat anti-mouse secondary antibodies (Jackson ImmunoResearch, catalog no. 115-175-146) and Alexa Fluor 488-coupled goat anti-chicken or 647-coupled goat anti-rat antibodies (Thermo Fisher Scientific, catalog no. A21247, A11039). Secondary antibodies were dissolved in blocking solution and incubated at room temperature for 2h. Nuclei were stained using Hoechst Dye 33258 (1:1,000 in PBS, Sigma-Aldrich, catalog no. 911004450). The following primary antibodies were used: mouse monoclonal anti-Beta-Tubulin III (STEMCELL Technologies, catalog no. 60100, 1:250), mouse monoclonal CX3CR1 (BioLegend, catalog no. 355701, 1:500), rabbit polyclonal anti-IBA1 (FUJIFILM Wako Chemicals, catalog no. 019-19741, 1:1000), CD11b monoclonal antibody (ICRF44), eBioscience (#14-0118-82), rat monoclonal anti-LAMP1 (Santa Cruz Biotechnology, catalog no. sc-19992, 1:100), chicken polyclonal anti-MAP2 (Invitrogen, catalog no. PA1-10005; 1:2500), mouse monoclonal anti-NFB p65 (Cell Signaling, catalog no. 6956), mouse monoclonal anti-PAX6 (BioLegend, catalog no. 862001, 1:200), Phalloidin CruzFluor# 488 (Santa Cruz Biotechnology, catalog no. sc-363791), rabbit monoclonal recombinant anti-PSD95 (Synaptic Systems, catalog no. 124008, 1:500), mouse monoclonal anti-SPI1 (PU.1, BioLegend, catalog no. 658002, 1:100), rabbit polyclonal anti-SOX1 (Abcam, catalog no. ab22572, 1:500), mouse monoclonal anti-Synapsin1 (Synaptic Systems, catalog no. 106011, 1:1000), rabbit polyclonal anti-Synaptophysin1 (Synaptic Systems, catalog no. 101002, 1:500), rabbit anti-TMEM119 (Synaptic Systems, catalog no. 400002, 1:400), rabbit monoclonal anti-TREM2 (Cell Signaling, catalog no. 91068, 1:400), mouse monoclonal anti-VGlut1 (Synaptic Systems, catalog no. 135511, 1:300), mouse monoclonal anti-Nestin (Synaptic System, catalog no. 312011, 1:1000). Antibody specificity was confirmed by analysis on differentiated cells and nave iPSC, and by secondary antibody only stainings.

To determine microglial pruning of synaptic structures, Z-stacks of neuronal networks were acquired with a confocal laser scan microscopy Cell Observer SD with a x63 plan-apochromatic oil immersion objective. Z-stacks were retrieved from regions of comparable fibre density, while the settings for acquisition (such as exposure time, laser intensity and gain) were unchanged for all conditions. Each image is a 3D reconstruction of a z-stack.

Images of neuronal cultures or neuron-microglia co-cultures were further processed by imaging using Imaris software. A surface was generated covering all MAP2 signals present in the whole stack. Next, the surface was masked using the Synapsin 1 (SYN1) signal creating a new channel for SYN1. After spot detection in the new SYN1 channel, SYN1-positive synaptic structures were counted after thresholding and referred to the volume of MAP2-positive structures to provide the density of SYN1-positive presynaptic terminals. The threshold for SYN1 spot detection was kept constant for each replicate. Data from multiple images were averaged to give yield to one datapoint for each biological replicate. The number of biological replicates is indicated in the figure legends. Within each image 2-3 microglial cells were analyzed on average. Within individual biological replicates, samples were normalized to the mean of CTR1.

Microglial uptake of synaptic structures was quantified by determination of the mean fluorescence intensity of SYN1 within IBA1 positive microglia. To this end, Z-stacks of microglia were acquired as described above and further processed using Imaris. A first surface was generated using the IBA1 signal to cover whole microglial cells and was subsequently masked with the signal for SYN1. Mean fluorescence intensities were measured for SYN1-positive spots identified within microglia. At least three independent experiments were performed for each donor combination.

Statistical analysis was performed using GraphPad Prism 9.2.0 (GraphPad Software Inc.). For non-Gaussian distribution in pairwise comparisons, the unpaired MannWhitney U test was performed and for group comparisons, KruskalWallis test with Dunns post-hoc multiple comparisons test was used. The type of statistical tests used and results are reported in the figure legends or main text.

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

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Regulation of synaptic connectivity in schizophrenia spectrum by ... - Nature.com

College of Science faculty and staff recognized at 2023 Galileo … – University of Arizona News

The College of Science recently recognized its 2023 Galileo Circle Awards recipients. These awards recognize some of the college's most exceptional faculty and staff and are one of the highest honors the college can bestow. The Galileo Circle Awards are made possible by the generosity of ourGalileo Circle members.

At the annual Galileo Circle Awards Dinner on Thursday, April 27, 2023, College of Science Dean Carmala Garzione and members of the CoS administration recognized the 2023 awardees and the Galileo Circle members who greatly support their efforts. Here are the award recipients:

Fellowsare the College's most distinguished faculty. They have a deep understanding of a broad range of science, a willingness to think in a truly interdisciplinary way, and an ability to inspire colleagues and students alive.

Dr. Shufang Su earned her bachelors degree in physics at the University of Science and Technology of China and her Ph.D. from the Massachusetts Institution of Technology. She was the John A. McCone Postdoc Fellow at the California Institute of Technology and joined the University of Arizona (UArizona) faculty in 2003. Her primary research interests are in theoretical particle physics, focusing on important connections between theory and experiments as well as links between particle physics, astrophysics, and cosmology. She was elected as the American Physics Society (APS) Fellow in 2014 for her fundamental contributions to the phenomenology of Higgs bosons, dark matter, supersymmetry, and other physics beyond the Standard Model, which have stimulated and guided experimental search programs. Shufang served as Chair of the APS Four Corners Section and Chair of APS Committee on Scientific Publications. She is the faculty advisor for Women in Physics Club at UArizona, mentor for UArizona Steps in the Scholar Journey Program, as well as mentor for the UArizona Mentor Institute of the Faculty Development Communities for Promotion program.

The Curie Awardwas created for rising stars among junior tenure-track faculty in the College of Science. Their innovative work advances science and adds diversity within the scientific community.

Born in Marseille, south of France, Dr. Gianetti received his bachelors and masters education at CPE Lyon in 2009. In 2014, he received his doctoral degree from University of California, Berkeley, followed by a three-year post-doctoral position at ETH Zrich. His research has largely focused on discovering ways to efficiently store electricity, and in 2020, he co-founded the startup company CarbeniumTec that strives to develop a metal-free battery for long-term energy storage. In his time as an Assistant Professor at UArizona, Thomas has published research articles in major outlets, filed invention disclosures and patent applications with TechLaunch Arizona. As an educator, Thomas is part of the UArizona Vertically Integrated Projects (VIP) and KEYS Research Internship Programs, and he has developed an interdisciplinary class with the College of Law that brings together students from Science and Law to study policy issues related to climate change, pollution, renewable energy, and more.

Dr. Hamden received her bachelors degree in astrophysics at Harvard University, then pursued her doctoral studies at Columbia. For her postdoctoral research, she joined California Institute of Technology to develop the FIREball-2 telescope. She specializes in building telescopes that go into space and the stratosphere and develops technology to make telescopes better. The FIREball-2 telescope is designed to observe huge clouds of hydrogen gas that are thought to flow into and out of galaxies. Erika is a leader in the field of space astrophysics and has developed programs to teach early career scientists how to develop their own space missions. She is the deputy principal investigator of Aspera, a NASA orbiting telescope in development. She has won numerous awards from NASA, including a Presidential Early Career Award for Scientists and Engineers, the highest honor the US Government can bestow on a young scientist. She is a former chef, a TED Fellow, an AAAS If/then Ambassador, an aspiring astronaut, and is working on her pilots license.

Dr. Megha Padi is an Assistant Professor in the department of Molecular and Cellular Biology, and she serves as a Co-Director of the Biostatistics and Bioinformatics Shared Resource at the Arizona Cancer Center. She completed her bachelors degrees in physics and biology at the Massachusetts Instituteof Technology and pursued her Ph.D. in high-energy physics at Harvard University. Motivated by the genomics revolution, Megha switched her focus to modeling Big Data in biology during her postdoctoral training at the Harvard School of Public Health.In her lab at UArizona, she integrates genomics, network theory, and cell culture experiments to understand how cellular networks are disrupted in disease. She predicts how cells will respond to therapeutic interventions and validatesher hypotheses in the lab.By incorporating insights from molecule biology, she is developing smarter algorithms for identifying drivers of disease. Megha applies these tools to tackle challenging health issues like early-onset colorectal cancer and the evolution of drug resistance.

The Copernicus Awardrecognizes the extraordinary accomplishments of College of Science non-tenure-eligible faculty or staff. The efforts of these individuals significantly advance the mission of their department and the knowledge base of their discipline.

For the last 20 years, Mark has led Steward Observatorys business activity that includes the management of contracts and grants resulting in over 1.2 billion dollars in research expenditures. His strong oversight of the financial operations of Astronomy and Steward Observatory has contributed to UArizona being number one in the National Science Foundation Higher Education Research and Development Rankings for 33 years. Marks remarkable leadership empowers highly innovative and entrepreneurial groups of researchers, academic faculty, and professionals to be highly successful in their education, research, and outreach missions. Mark has developed close relationships with local and national industrial partners and has mentored other managers. He has brought creative solutions and developed teams to respond to business, financial, human resource, safety, facility, and organizational challenges. This work directly enables the successful, safe, and cost-effective operation of the department, projects, and facilities, including telescopes operated with local and international sponsors and partners.

Dr. Graham attended the College of Wooster from 1996-2000 then came to UArizona to earn her Ph.D. in Analytical Chemistry. Amy has been engaged in innovative teaching for over a decade and has a passion for using active learning strategies and inclusive teaching practices in a collaborative learning environment. She has been involved in facilitating Faculty Learning Communities, fostering an enthusiasm for enhancing teaching practices. Amy has expertise in training Learning Assistants and works as a Graduate College Faculty Fellow, creating resources for supporting and training Graduate Teaching Assistants across campus. She recently created the podcast PEP Talks: Productive Educational Practices, which offers conversations celebrating instructors across campus, along with their journeys and their methods. Amy was awarded the College of Science Distinguished Achievement in Science Education Award in 2017, and the AAU STEM Undergraduate STEM Education Teaching Excellence Award in 2015.

The Postdoc Awardwas created for the substantial and invaluable contributions postdocs make to the research, mentoring, and outreach missions of both the College and University.

Originally from Romina, Dr. Stoica earned a BA in Psychology from East Carolina University, an MS in Neuroscience from University of Hartford, and her Ph.D. in Translational Neuroscience from the University of Louisville. Her research focus is an interdisciplinary approach to understanding the relationship between neuroarchitecture and emotional functioning, specifically pertaining to the aging brain and neurodegenerative diseases. In addition to her research contributions, she is an incredibly active science writer on her blog, CuriousCortex.com, and for Scientific American. As a mentor, she has helped establish Louisville Science Pathways, an award-winning summer research program for at-risk and underrepresented high school students through the University of Louisville. During her appointment as a dual postdoctoral researcher in emotion and memory labs, Teodora created Mentally Minded, an evidence-based Q&A website aimed at answering the publics pressing mental health questions.

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The Galileo Circle is a community of engaged individuals whose support is vital to the continued excellence of the College of Science at the University of Arizona. As a member, you will be supporting established and budding scientists at the College of Science. Your gifts provide crucial scholarship support to outstanding students and facilitate groundbreaking research by our distinguished faculty. The Galileo Circle creates a meaningfulconnection between our patrons and ourscientists.If you would like to learn more about the Galileo Circle and join as a member, pleaseclick here.

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College of Science faculty and staff recognized at 2023 Galileo ... - University of Arizona News

Preliminary Results for the Year Ended 31 December 2022 – GlobeNewswire

28 April 2023

Biodexa Pharmaceuticals PLC(Biodexa or the Company or, together with its subsidiaries, the Group)

Preliminary Results for the Year Ended 31 December 2022

Biodexa Pharmaceuticals PLC (Nasdaq: BDRX), a clinical-stage biopharmaceutical company developing a pipeline of products aimed at primary and metastatic cancers of the brain, announces its audited preliminary results for the year ended 31 December 2022.

For more information, please contact:

Biodexa Pharmaceuticals PLC

Stephen Stamp, CEO, CFO

Tel: +44 (0)29 2048 0180

http://www.biodexapharma.com

Edison Group (US Investor Relations)

Alyssa Factor

Tel: +1 (860) 573 9637

Email: afactor@edisongroup.com

Biodexa Pharmaceuticals PLC (listed on NASDAQ: BDRX) is a clinical stage biopharmaceutical company developing a pipeline of products aimed at primary and metastatic cancers of the brain. The Companys lead candidate, MTX110, is being studied in aggressive rare/orphan brain cancer indications including recurrent glioblastoma and diffuse midline glioma.

MTX110 is a liquid formulation of the histone deacetylase (HDAC) inhibitor, panobinostat. This proprietaryformulation enables delivery of the product via convection-enhanced delivery (CED) at potentially chemotherapeutic doses directly to the site of the tumour, by-passing the blood-brain barrier and avoiding systemic toxicity.

Biodexa's headquarters and R&D facility is in Cardiff, UK. For more information, please visit http://www.biodexapharma.com

Forward-Looking Statements

Certain statements in this announcement may constitute "forward-looking statements" within the meaning of legislation in the United Kingdom and/or United States Private Securities Litigation Reform Act. All statements contained in this announcement that do not relate to matters of historical fact should be considered forward-looking statements.

Reference should be made to those documents that Biodexa shall file from time to time or announcements that may be made by Biodexa in accordance with regulations promulgated by the US Securities and Exchange Commission, which contains and identifies other important factors that could cause actual results to differ materially from those contained in any projections or forward-looking statements. These forward-looking statements speak only as of the date of this announcement. All subsequent written and oral forward-looking statements by or concerning Biodexa are expressly qualified in their entirety by the cautionary statements above. Except as may be required under the relevant law in the United States, Biodexa does not undertake any obligation to publicly update or revise any forward-looking statements because of new information, future events or otherwise arising.

INTRODUCTION

Headquartered in Cardiff, UK, and quoted on NASDAQ in the US, Biodexa is a clinical-stage biotechnology company with three enabling drug delivery technologies. The Company de-listed from the AIM market as of 26 April 2023.

STRATEGY

Since the Strategic Review, and throughout 2022, we pursued a strategy of broadening our R&D pipeline by initiating internal programmes, collaborating with third party pharmaceutical companies on their proprietary active pharmaceutical ingredients, or APIs, and adding new indications to MTX110. New internal programmes were selected and prioritised based on the expected time to deliver proof-of-concept data for potential partnering.

Other than adding a second R&D collaboration with Janssen Pharmaceutica NV, for reasons not always within our control, we were not successful in finding partners for our internal Q-Sphera pipeline. As our cash runway ran down, and the market for biotech financing worsened in 2022, we considered the opportunities for refinancing the Company as a drug delivery company were limited. Accordingly, we concluded that repositioning the Company as a therapeutics company, focused on rare and orphan products in a merger with Bioasis Technologies, Inc. (Bioasis) with an attendant $10.0 million financing was the optimal solution for the Company. Although the merger and financing did not proceed, we were successful in raising $6.0 million, repositioning the Company as a clinical-stage therapeutics company supported by enabling technologies. In line with that repositioning, we undertook a restructuring in March 2023 including a cost reduction programme and termination of our internal Q-Sphera programmes. These initiatives are described more fully in the Chief Executives Review.

Following the repositioning of the Company, our priorities for 2023 reflect our modified strategy as follows:

Finalise recruitment of our second Phase I study in DIPG and report safety data.

Accelerate recruitment of our Phase I study in medulloblastoma.

We completed our assignment under our first R&D collaboration with Janssen, including optimising drug loading of Janssens proprietary large molecule using our Q-Sphera technology.

Explore opportunities for MTX110 in combination therapy for brain and metastatic CNS cancer.

Expand further our patent portfolio to cover new inventions and divisionals to strengthen existing patent families.

Seek a partner to develop, or co-develop, MTX110 once preliminary data from our Phase I study in recurrent GBM become available.

We added a new research programme coded MTD217 focused on developing new therapeutics options for metastatic cancers including leptomeningeal disease.

Initiate additional preclinical studies to assess the potential for MTD217 inhibitors in leptomeningeal disease.

During the year, we introduced a new COSHH assessment procedure to better quantify the safety of chemicals and third parties APIs being deployed in our laboratories.

Develop individualised learning programmes for staff members through participation in conferences, webinars and/or training programmes.

BUSINESS MODEL

Following our Strategic Review in March 2020, we reverted to a traditional biotech business model. We aimed to deploy our proprietary technologies to develop proof-of-concept formulations and then enter into licensing agreements with third party pharmaceutical companies.

In order to make the Company more investable and secure additional financing, the Board decided to reposition the Company as a therapeutics (as opposed to drug delivery) company in early 2023. As a result, the delivery of proof-of-concept clinical data is the primary focus of our business model going forward.

Development

Our intention is to build a balanced portfolio of clinical-stage development assets, ideally focused on oncology and on rare/orphan indications. Our only current clinical-stage asset, MTX110 is in Phase I development for three rare/orphan brain cancers.

Our R&D programmes may, like MTX110, be based on one or more of our enabling technologies.

Our aim is to enter into R&D collaborations with third parties to develop proof-of-concept formulations of their proprietary compounds using our proprietary drug delivery technologies. We will not be expanding our internal pipeline of drug delivery based programmes.

Manufacturing

To establish proof-of-concept in pre-clinical studies for potential licensees, we are able to manufacture non-GMP Q-Sphera products at pilot scale at our Cardiff facility. Upon securing a license partner who wishes to start clinical studies, our intention would be to technology transfer GMP manufacture of clinical trial supplies and ultimately full GMP commercial manufacture to a third party CMO. We would expect a licensee to assume the cost of manufacturing GMP product and commercial scale-up pursuant to a technology transfer agreement.

MTX110 is currently being manufactured to GMP standards at a CMO.

Commercialisation

Once proof-of-concept has been established, we intend to seek to license our products to a partner who would complete the clinical development and subsequently market and sell them in the licensed territory. In addition to reimbursement of development costs, the partner would be expected to make milestone payments based on sales targets and royalty payments.

Our development pipeline includes six projects of which one is partnered with Janssen:

CLINICAL-STAGE ASSETS

MTX110

Using our MidaSolve technology in combination with panobinostat, an otherwise insoluble drug, MTX110 is designed for direct-to-tumour treatment of intractable brain cancers. Panobinostat is currently marketed under the brand Farydak which is used orally in combination therapy for the treatment of multiple myeloma. We are currently researching the utility of MTX110 to proof-of-concept stage in three indications:

Glioblastoma Multiforme (GBM):GBM is the most common and aggressive form of brain cancer in adults, usually occurring in the white matter of the cerebrum. Treatments include radiation, surgical resection and chemotherapy, although in almost all cases tumours recur. There are approximately 2-3/100,000(1) population diagnoses of GBM per annum. Survival with standard of care treatment ranges from approximately 13 months in unmethylated MGMT patients to approximately 30 months in highly methylated MGMT patients(2).

Following IND approval in December 2021, we are in the process of recruiting patients in a Phase I study to assess the utility of MTX110 in recurrent GBM. The Phase I study is an open-label, dose escalation study designed to assess the feasibility and safety of intermittent infusions of MTX110 administered by convection enhanced delivery (CED) via implanted refillable pump and catheter. The study aims to recruit two cohorts, each with a minimum of four patients; the first cohort will receive MTX110 only and the second cohort will receive MTX110 in combination with lomustine.

Diffuse Intrinsic Pontine Glioma (DIPG):DIPG tumours are located in the pons (middle) of the brain stem and are diffusely infiltrating. Occurring mostly in children, approximately 1,000 patients(3) worldwide are diagnosed with DIPG per annum and median survival is approximately 10 months(4). There is no effective treatment since surgical resection is not possible. The standard of care is radiotherapy, which transiently improves symptoms and survival. Chemotherapy does not improve survival and one likely reason is that many anti-cancer drugs cannot cross the blood-brain barrier to access the tumour.

In October 2020, we reported the first-in-human study by the University of California, San Francisco (UCSF) of MTX110 in DIPG using a convection enhanced delivery (CED) system. The Phase I study established a recommended dose range for Phase II, a good safety and tolerability profile but also encouraging survival data in the seven patients treated.

Medulloblastoma:Medulloblastomas are malignant embryonal tumours that start in the cerebellum. They are invasive and, unlike most brain tumours, spread through thecerebrospinal fluid(CSF) and frequentlymetastasizeto different locations in the brain and spinal cord. Treatments include resection, radiation and chemotherapy. Approximately 350 patients(5) are diagnosed with medulloblastoma per annum and 3,800 people are living with the disease in the US. The cumulative survival rate is approximately 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively(6); however, recurrence is nearly always fatal with no established standard of care.

The University of Texas is undertaking a Phase I exploratory study in recurrent medulloblastoma patients using direct administration of MTX110 into the fourth ventricle, enabling it to circulate throughout the CSF.

(1)American Association of Neurosurgeons(2)Radke et al (2019). Predictive MGMT status in a homogeneous cohort of IDH wildtype glioblastoma patients. Acta Neuropathologica Communications 7:89 Online: https://doi.org/10.1186/s40478-019-0745-z(3)Louis DN, Ellison DW, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131:803820 (4)Jansen et al, 2015. Neuro-Oncology 17(1):160-166(5)Aboian et al (2018). Neuro-Oncology Practice, Volume 5, Issue 4, December 2018(6)Smoll NR (March 2012). "Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs)".Cancer.118(5): 131322

TECHNOLOGIES

Q-Sphera

Our Q-Sphera technology employs 3-D printing techniques to encapsulate medicines in polymer-based bioresorbable microspheres. The microspheres may be injected to form depots in the body which release drug over predictable, sustained periods from one week up to several months. The features and benefits of Q-Sphera technology offer numerous potential advantages to patients and payors compared with immediate release products and other polymer-based technologies.

MidaSolve

Our MidaSolve technology increases the aqueous solubility of certain classes of anti-cancer drugs using complexes that solubilize these agents in water, thereby enabling them to be injected in liquid form directly into tumours.

The MidaSolve complexation agents (cyclodextrins) comprise a hydrophobic inner surface and a hydrophilic outer surface, and as a result are capable of forming host-guest complexes with normally water-insoluble molecules. The hydrophobic, poorly water-soluble drug associates with the inner, more hydrophobic surface of the MidaSolve host, while the hydrophilic outer surface allows the complex to dissolve at biological pH.

MidaCore

Our MidaCore technology platform is based on ultra-small gold nanoparticle (GNP) drug conjugates, which at 2-4nm are among the smallest particles in biomedical use. They are composed of a core of gold salts decorated with an array of therapeutic and/or targeting ligands. The small size and multi-functional arrangement around the gold core underpin the ability to improve biodistribution and target tumour and/or immune sites.

MidaCore design and synthesis GNP technology enables the production of nano-medications, which we believe are five-to-tenfold smaller than any other delivery vehicle in medical use.

CHIEF EXECUTIVES REVIEW

Introduction

With probably the most challenging market backdrop since the financial crisis in 2008/09 for financing biotech companies, 2022 was dominated by efforts to refinance the Company before its cash runway was due to expire in the first quarter of 2023. These efforts included our proposed acquisition of Bioasis and financing which was voted down by a group of shareholders followed by a successful, smaller financing and shift in strategic focus in early 2023.

Commercial Update

We made some incremental steps with our commercial strategy in 2022. In January we announced that Janssen had extended our R&D collaboration to optimise the drug loading and in vitro dissolution of a proprietary Janssen protein using our Q-Sphera technology. In March we announced that Janssen had further extended the collaboration to include the optimisation of drug loading and in vitro dissolution of a second protein. We have met our objectives with the first assignment and continue to work on the second.

R&D Update

MTX110

Employing our MidaSolve technology, MTX110 solubilises panobinostat, a histone deacetylase (HDAC) inhibitor currently used in the treatment of multiple myeloma. In a liquid formulation as MTX110, panobinostat can be delivered directly to a patient's tumour under constant pressure via a catheter system (Convection Enhanced Delivery, or "CED"), thereby bypassing the blood-brain barrier and allowing for high drug concentrations and broader drug distribution in and around the tumour while simultaneously minimising systemic toxicity and other side effects.

During 2021, following receipt of promising pre-clinical data from tumour models and in vitro patient-derived cell lines, we reprioritised our development of MTX110 in favour of GBM, potentially a very significant opportunity with annual diagnoses of 2-3/100,000 population and global market potential of US$3-5 billion. In December 2021 we received an IND to proceed with an open label, dose escalation study designed to assess the feasibility and safety of intermittent infusions of MTX110 administered by CED via implanted refillable pump and catheter. The study aims to recruit two cohorts, each with a minimum of four patients; the first cohort will receive MTX110 only and the second cohort will receive MTX110 in combination with lomustine. We announced our first patient enrolled in the trial in November 2022 and the Data Safety Monitoring Board recommended the dose be escalated to 90M, the expected optimal dose for patients. We are aiming for preliminary safety and efficacy data (in the form of Progression Free Survival data) for the first cohort in the third quarter of 2023.

We initially began developing MTX110 for DIPG, the ultra-rare, highly aggressive and inoperable form of childhood brain cancer. We have an ongoing Phase I study in the US with one more patient required for completion. We are also evaluating the utility of MTX110 in medulloblastoma in a pilot study at the University of Texas.

Q-Sphera

Development programmes in our internal Q-Sphera pipeline are designed to address large markets but also offer significant clinical benefits compared with current therapies and, importantly for reimbursement, savings to the healthcare system.

MTD211 (Q-brexpiprazole)

We have developed a long-acting formulation of brexpiprazole. In in vivo studies, MTD211 demonstrated that a single dose is expected to deliver therapeutic blood levels of brexpiprazole over a period of approximately three months. Marketed under the brand name Rexulti, brexpiprazole is indicated for the treatment of schizophrenia and adjunctive treatment of major depressive disorder (MDD) and is currently only available as an immediate release oral tablet. The market for anti-psychotic drugs has shifted towards long-acting formulations for reasons of improved patient compliance and lowering of payor costs associated with patient hospitalisation events. MTD211 is available for licensing.

MTX223 Q-Protein, partnered with JanssenWe are continuing to collaborate with Janssen on a second large molecule to optimize drug loading and in vitro dissolution profiles.

MidaSolveMTD217 (MTX110 plus an oxphosphorylation inhibitor)

Our recently initiated MTD217 programme explores simultaneous inhibition of aerobic glycolysis and oxphosphorylation, key metabolic pathways for cancer cells. Our programme is centred around a number of new water-soluble drug formulations that can be easily infused or injected simultaneously, or sequentially, directly into the cancer microenvironment, disrupting metabolic functions in a highly localised manner and limiting off-target toxicity. We have already demonstrated up to a six-fold synergistic effect of administering MTX110, with an oxphosphorylation inhibitor in vitro in three patient-derived cell lines. On the back of those data, we have established new patent positions to protect these combination formulations.

Our initial target is treatment of leptomeningeal disease, a lethal complication in which metastatic cancer cells invade the cerebrospinal fluid and central nervous system. In collaboration with several large academic centres, we are now accelerating preclinical studies to generate proof of concept data that can support a future clinical trial application.

MidaCore

We are using our GNP technology to engineer a formulation of methotrexate for the topical treatment of psoriasis. Pre-clinical data have shown that MTX114 normalises skin thickness in mouse psoriatic skin models. There are estimated to be over 100 million(2) people who suffer from psoriasis worldwide. MTX114 is available for licensing.

(1)Jansen et al, 2015. Neuro-Oncology 17(1):160-166(2)Psoriasis.org

Strategic Repositioning in 2023

Since our 9.0 million (net) fundraise in July 2021 we had consistently forecast that our cash resources would fund operations into the first quarter of 2023. As our cash runway ran down, and the market for biotech financing worsened in 2022, we found the opportunities for refinancing as a drug delivery company were, for practical purposes, non-existent.

Bioasis

In response to the lack of appetite to refinance a drug delivery platform company, the Board looked for opportunities to merge or acquire other companies to create a more investable therapeutics company. Accordingly, the Board proposed an acquisition of Bioasis, a multi-asset company listed on the TSX-V exchange with two platform technologies that had been validated by partnerships and licenses with pharmaceutical companies with potential milestone payments totalling in excess of US$200 million. The enlarged, merged company would have been repositioned as a therapeutics company with an internal pipeline focused on rare and orphan products. Importantly, we had secured a $10.0 million financing conditional upon the acquisition. One shareholder corralled sufficient votes to ensure the requisite Special Resolutions to approve the acquisition and financing were not approved and, accordingly, the acquisition and financing did not proceed.

Financing

After the General Meeting on 23 January 2023 at which the Bioasis acquisition and financing were voted down, we had only a short time to secure funding, failing which the Directors would have no option other than to place the Group in Administration. At this time, the Company engaged Quantuma Advisory Limited, a specialist business advisory firm, to advise the Board on its obligations to creditors, in particular. Ultimately, we were successful in raising $6.0 million using a cashbox structure which did not require shareholder approval but on terms materially more dilutive than those of the conditional financing originally proposal alongside the Bioasis acquisition. At the time, in early February, the Board had considered it had no actionable alternatives to Administration other than the $6.0 million financing. The financing is expected to allow the Group to fund operations into the fourth quarter of 2023 and progress its clinical-stage asset MTX110, in particular.

Repositioning the Company as a Therapeutics Company

In the course of raising additional finance for the Company in late 2022 and early 2023, it became clear that a therapeutics company was more investable than a drug delivery platform company. Accordingly, the Board determined that the Company should be repositioned as a therapeutics company supported by three enabling technologies. Going forward, our priority will be moving our development programmes into the clinic and generating clinical data to demonstrate proof-of-concept. We intend to continue our existing, and seek new, R&D collaborations for our drug delivery technologies but we will not be expanding our internal drug delivery platform.

De-listing from AIM

The Board decided to cancel the Companys AIM listing for a number of reasons including: an increasingly smaller proportion of trading in the Ordinary Shares is conducted on AIM compared to NASDAQ; improved liquidity through concentration of trading in the Companys securities on a single market; and the cost, management time commitment and the burden of complying with the AIM Rules and maintaining a quotation on AIM is duplicative of that for complying with the NASDAQ rules. In addition, the Company intends to seek opportunities to expand its pipeline through the acquisition and/or in-licensing of additional development programmes. Given the Companys market capitalisation, transactions are likely to be deemed reverse takeovers under AIM rules, requiring suspension and relisting via a new Admission Document which is both time-consuming and costly.

Change of Name

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Preliminary Results for the Year Ended 31 December 2022 - GlobeNewswire

Scientific discoveries: Recent breakthroughs that could change the world – The Week

Scientists in many fields have been getting little attention over the last two years or so as the world focused on the emergency push to develop vaccines and treatments for COVID-19. But labs and researchers have remained busy, recently reporting a dizzying series of major discoveries and achievements:

Scientists at the Lawrence Livermore National Laboratory in California announced in December that they had produced the first fusion reaction that created more energy than was used to start it. The long-elusive achievement marked a major breakthrough in harnessing the process that fuels the sun. "This milestone moves us one significant step closer" to "powering our society" with zero-carbon fusion energy, Energy Secretary Jennifer Granholm said.

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Fusion involves pushing together two nuclei of a lightweight element, such as hydrogen, at a colossal speed, forcing them to fuse. The leftover mass is converted into an enormous amount of energy, according to Einstein's formula E = mc2. Unlike fission, in which atoms are split, fusion requires small amounts of ordinary fuel the amount of hydrogen in a glass of water could provide enough energy for one person's lifetime and does not create much radioactive waste, which is why it's been called "the holy grail for the future of nuclear power."

Popular Science magazine this year named NASA's James Webb Space Telescope the Innovation of the Year in aerospace technology. Unlike the Hubble space telescope, which scanned the heavens from low Earth orbit, the Webb telescope is camped hundreds of thousands of miles farther out, sitting in Earth's shadow, where it ispermanently blocked from sunlight. Its view further protected by a multi-layer sunshield, it sits at the temperature (-370 degrees Fahrenheit) best suited for its infrared sight.

As a result, Popular Science says, the $10 billion JWST "can see deep into fields of forming stars. It can peer 13 billion years back in time at ancient galaxies, still in their nursery. It can peek at exoplanets, seeing them directly where astronomers would have once had to reconstruct meager traces of their existence. It can teach us about how those stars and galaxies came together from primordial matter, something Hubble could only glimpse."

A group of Yale scientists reported in the journal Nature this summer that they succeeded in reviving cells in the hearts, liver, kidneys, and brains of pigs that had been lying dead in a lab for an hour. The researchers accomplished the feat by using a device much like a heart-lung machine to pump a custom-made solution, dubbed OrganEx, into the pigs' bodies. The pigs' hearts started beating and sent the solution through their veins.

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The pigs weren't revived, but their organs started functioning again, and they "never got stiff like a typical dead pig," The New York Times reported. The researchers, according to the Times, hope their breakthrough eventually will help increase the supply of human organs available for transplant by letting doctors get viable organs from bodies long after death. The technology also might be useful in limiting damage to hearts from heart attacks, and to brains from strokes.

The researchers say their goals are to one day increase the supply of human organs for transplant by allowing doctors to obtain viable organs long after death. And, they say, they hope their technology might also be used to prevent severe damage to hearts after a devastating heart attack or brains after a major stroke.

U.S. public health officials have long warned Americans to brace for another possible COVID-19 surge as winter hits and families gather for the holidays. Indeed, the nation is facing a "tripledemic," with COVID-19 cases rising, respiratory syncytial virus (RSV) overloading many hospitals, and the 2022-23 flu season building into what could be the worst in a decade. As of early December, the Centers for Disease Control and Prevention had already recorded 4,500 flu deaths.

Fighting the flu represents a new challenge every year because influenza viruses are constantly evolving. Some years, the vaccines are effective. Sometimes they miss the mark. But now Scott Hensley at the University of Pennsylvania and his colleagues have created a flu vaccine based on mRNA molecules the same technique Moderna, and Pfizer, along with its partner BioNTech, used to make their widely used COVID-19 vaccines. The vaccine has produced antibody responses against all 20 known strains of influenza A and B in tests on mice, with the effectiveness lasting four months. The results were similar in tests on ferrets, fueling hopes the universal vaccine could work in humans, too.

If you've watched Armageddon or Deep Impact or some other movie about an asteroid threatening to wipe out life on Earth, relax. NASA this year proved with its Double Asteroid Redirection Test (DART) mission that it has the ability to deflect a giant space rock off a collision course with our planet. NASA sent the 1,100-pound DART spacecraft slamming into a 525-foot-diameter asteroid, Dimorphos, at 14,000 miles per hour to see whether the impact force would be enough to change its trajectory.

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Dimorphos, which didn't actually threaten Earth, was orbiting around a larger parent asteroid, Didymos, every 11 hours and 55 minutes before the crash. After DART slammed into Dimorphos on Sept. 26, astronomers clocked its orbit time at 11 hours and 23 minutes, 32 minutes shorter than before, signaling a significant change in its path. "All of us have a responsibility to protect our home planet. After all, it's the only one we have," said NASA Administrator Bill Nelson. "This mission shows that NASA is trying to be ready for whatever the universe throws at us."

Artificial intelligence is opening up new possibilities for businesses and households, and now new text-to-image generators are giving everyone from artists to urban planners to reconstructive surgeons a new tool to help them visualize ideas. DALL-E 2, which Open AI released in July, looks at hundreds of millions of captioned images to turn text prompts written by users into images.

Mark Chen, the lead researcher on DALL-E 2, told The Atlantic that image generators like DALL-E 2 aim to "democratize" art. "This is the most exciting new technology in the AI space since natural-language translation," Atlantic deputy editor Ross Anderson said.

Malaria, found in more than 90 countries, kills an estimated 627,000 people every year. Vaccines could help reduce or eliminate the toll, but scientists have struggled to develop a highly effective one. This year, though, the technology used to create mRNA vaccines against COVID-19 has helped a research team led by George Washington University develop two experimental mRNA vaccine candidates that are highly effective in reducing malaria infection and transmission, according to a study published in December in npj Vaccines, an open-access scientific journal in the Nature Portfolio.

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"Malaria elimination will not happen overnight but such vaccines could potentially banish malaria from many parts of the world," says Nirbhay Kumar, a professor of global health at the George Washington University Milken Institute School of Public Health.

Scientists reported progress on several fronts in the battle against cancer. A team led by Chris Jones, a professor of Pediatric Brain Tumor Biology at the Institute of Cancer Research, worked with the company BenevolentAI touse artificial intelligence tools to come up with a new drugcombination to fight diffuse intrinsic pontine glioma, an incurable childhood brain cancer. The proposed combination extended survival in mice by as much as 14 percent and has been tested in a small group of children.

In another potential breakthrough, Dr. Luis A. Diaz Jr. of Memorial Sloan Kettering Cancer Center wrote a paper published in June in the New England Journal of Medicinedescribing a treatment that resulted in complete remission in all 18 rectal cancer patients who took the drug. "I believe this is the first time this has happened in the history of cancer," Dr. Diaz said.

Scientists from Stanford University successfully injected human nerve cells into the brains of newborn lab ratsand found that they formed connections with the animals' own brain cells, guiding their behavior, according to a study published in the journal Nature. The human cells wound up making up one-sixth of the rats' brains. The cluster, known as a brain organoid, then develops in ways similar to a human brain, which could help researchers understand more about schizophrenia, autism spectrum disorder, bipolar disorder, and other neuropsychiatric disorders. "It's definitely a step forward," says Paola Arlotta, a prominent Harvard University brain organoid researcher who wasn't involved in the study.

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Some bioethicists are uneasy about the implications of putting human cells into rats. "It raises the possibility that you're creating an enhanced rat that might have cognitive capacities greater than an ordinary rat," said Julian Savulescu, a bioethicist at the National University of Singapore. But Dr. Sergiu Pasca, a professor of psychiatry and behavioral sciences at Stanford who developed the transplant technique, says the human brain organoids, made from stem cells, stop developing after a few months. "No matter how long we keep them in a dish, they still do not become as complex as human neurons would be in an actual human brain," Pasca says.

In experiments at the Weizmann Institute of Science in Israel, researchers created mouse embryos inside a bioreactor that were made up of stem cells cultured in a Petri dish no egg, no sperm. The embryos developed normally, starting to elongate on day three and developing a beating heart by day eight. It was the first time scientists ever managed to grow fully synthetic mouse embryos outside the womb.

The experiment marked a leap in the study of how stem cells form various organs, and how mutations result in developmental diseases. "It also raises profound questions about whether other animals, including humans, might one day be cultured from stem cells in a lab," according to STAT News. "As soon as the science starts to move into a place where it's feasible to go from a stem cell population in a Petri dish all the way through to organ development which suggests one day it will be possible to go all the way to creating a living organism it's a pretty wild and remarkable time," said Paul Tesar, a developmental biologist at Case Western Reserve University School of Medicine who wasn't involved in the study.

A 53-year-old man became the fifth personto be cured of HIV followinga stem cell transplant he received shortly after being diagnosed with the disease. The "Dusseldorf patient," who was also diagnosed with a severe form of blood cancer, received a bone marrow transplant 10 years ago that gave him HIV-resistant stem cells, according toThe Washington Post. He has been off anti-retroviral medication for four years with no trace of the virus in his body.

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"It's really cure, and not just, you know, long-term remission," saidDr. Bjorn-Erik Ole Jensen. Stem cell transplants are considered high-risk and normally reserved for people diagnosed with cancer. The Dusseldorf patient was only the third to receive the treatment and be cured of HIV. For now, the treatment will likely continue to be reserved for cancer patients,but it "shows it's not impossible it's just very difficult to remove HIV from the body."

With five cases of HIV having been cured, scientists are hopeful for the future."Following our intensive research, we can now confirm that it is fundamentally possible to prevent the replication of HIV on a sustainable basis by combining two key methods," including anti-retroviral medication and stem-cell transplants,Jensen said.

Scientists have found a way to capture atmospheric carbon dioxide and convert it to baking soda to be stored in the sea. In a recent study, researchers also found a way to make carbon capture more efficient by using a hybrid of existing methods. "This material can be produced at very high capacity very rapidly," according to the study's lead authorArup SenGupta. "This simple ability to capture CO2 at a high quantity, in a small volume of material, is a unique aspect of our work."

Baking soda is also safe to store in the ocean. "Higher alkalinity also means more biological activity; that means more CO2 sequestration," SenGupta explained. In turn, the ocean can act as an "infinite sink" with an "immense capacity for accessible CO2 storage lasting hundreds to thousands of years," as described byStuart Haszeldinefrom the University of Edinburgh.

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However, to truly be effective carbon capture needs to be expanded.Myles Allenfrom the University of Oxford added that it will only reach "the scale it needs to happen is if it's made a licensing condition of continuing to sell fossil fuels."

Researchers successfully created live baby mice withtwo male parents. According to new research, this was done by manipulating the chromosomes of a male stem cell, turning it into a female egg cell."This is the first case of making robust mammal oocytes from male cells," remarkedKatsuhiko Hayashiof Kyushu University, who lead the research.

While the vast majority of the mice pups did not survive, the few that did grew up normally and were fertile adults. The genetic manipulation required to create the embryos is "a significant advance with significant potential applications," according toKeith Latham, a developmental biologist at Michigan State University. It could be used to treat or prevent genetic disorders, or even help same-sex couples have biological children. "What I can say is only about the technological side,"Hayashi toldNew Scientist. I think in theory it is possible."

Updated April 28, 2023: This article has been updated throughout to reflect the most recent advancements.

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Scientific discoveries: Recent breakthroughs that could change the world - The Week

Have a second cup: Coffee provides health benefits – AgriLife Today – AgriLife Today

Having that second cup may actually be good for coffee drinkers, according to a discussion of coffees preventive and therapeutic benefits to human health in a recent review paper by Texas A&M University researchers.

The paper, Health Benefits of Coffee Consumption for Cancer and Other Diseases and Mechanisms of Action, was published recently in the International Journal of Molecular Sciences.

Some of the coffee research reported in the review was conducted by Texas A&M AgriLife Research scientists in Texas A&Ms College of Agriculture and Life Sciences Department of Nutrition and Department of Biochemistry and Biophysics in collaboration with researchers in the School of Veterinary Medicine and Biomedical Sciences Department of Veterinary Physiology and Pharmacology.

Coffee is one of the most widely consumed beverages worldwide, and epidemiological studies have associated higher coffee consumption with decreased rates of mortality, as well as decreased rates of neurological and metabolic diseases, including Parkinsons disease and Type 2 diabetes.

There is also evidence that higher coffee consumption is associated with lower rates of colon and rectal cancer, as well as breast, endometrial and other cancers, although there are conflicting reports on its benefit for some of these cancers, said Stephen Safe, Ph.D., a coauthor of the review paper.

Safe is a Distinguished Professor and Regents Professor of toxicology in the Department of Veterinary Physiology and Pharmacology. He has conducted research on the anti-inflammatory and anti-cancer properties in coffee.

Among the studies noted in the review was an examination of the Role of the aryl hydrocarbon receptor (AhR) in mediating the effects of coffee in the colon, originally published in Molecular Nutrition and Food Research. The research was conductedin the Safe Lab and Chapkin Lab, in collaboration with Arul Jayaraman, Ph.D., of the Texas A&M College of Engineering.

The Chapkin Laboratory is led by Robert Chapkin, Ph.D., University Distinguished Professor andAllen Endowed Chairin theDepartment of NutritionandDepartment of Biochemistry and Biophysics. Chapkin also is the National Cancer Institute R35 Outstanding Investigator Awardee, leads the Program in Integrative Nutrition and Complex Diseases and is the recently named deputy director of the Cancer Prevention and Research Institute of Texas Regional Center of Excellence in Cancer Research at Texas A&M.

Chapkin and Laurie Davidson, Ph.D., a Department of Nutrition research scientist who works in the Chapkin Lab, were two of the primary contributors to the study.

The mechanisms associated with the chemopreventive or chemotherapeutic effects of over 1,000 individual compounds in roasted coffee are complex and may vary with different diseases, Chapkin said.

Some of these mechanisms may be related to pathways that target oxidative stress or pathways that induce reactive oxygen species to kill diseased cells, he said. There is also evidence for the involvement of receptors in addition to contributions from epigenetic pathways and the gut microbiome.

As part of our study using genetically modified cell lines, mouse colonic organoids and transgenic mouse models, we wanted to further elucidate the mechanisms that would facilitate the potential future clinical applications of coffee extracts, Chapkin said.

The review noted that although roasted coffee beans and brewed coffee contain high levels of caffeine, there are several hundred individual phytochemical-derived compounds that include chlorogenic acid/lignans, alkaloids, polyphenolics, terpenoids, melanoidins, vitamins and metals. Some of these also include flavonoid quercetin, chlorogenic acid, caffeine, the alkaloid norharman also called beta-carboline, and the terpenoid cafestrol.

Research showed the mechanisms of action of coffee are complex and dependent on the effects of its constituents, including chlorogenic acids, polyphenolics, terpenoids, alkaloids and other phytochemicals.

We also found evidence that the antioxidant activity of coffee, which activates the nuclear factor erythroid 2-related factor 2, or Nrf2, may be an important mechanism of action, Davidson said. But since Nrf2 exhibits both health-protective and drug-resistant activities, other cell context-dependent factors may also be important.

Davidson said they also found evidence that the protective effects of coffee in the gut decreased colon cancer risk, which may be due to its activity as an aryl hydrocarbon ligand. The aryl hydrocarbon receptor, AhR, is a transcription factor that regulates gene expression.

The collaborative study also demonstrated that roasted coffee-derived extracts function in part by activating the AhR.In the mouse model, coffee induced several AhR-dependent responses in the intestine. These included gene expression, inhibition of intestinal stem cell-enriched organoid growth and inhibition of intestinal barrier damage.

Overall, these mechanisms, in concert with possible epigenetic pathways and the modulation of gut microbiota and microbial metabolites, contribute to the health benefits of higher coffee consumption, Chapkin said.

Their research also found that some coffee components bind the orphan nuclear receptor NR4A1 to the interactions with the AhR receptor. The NH4A1 receptor is a key factor in multiple diseases, such as arthritis, inflammation, cancer and cardiovascular diseases, and a high NR4A1 expression is associated with breast cancer.

The recently published paper also refers to research from the Safe Laboratory focused on developing and discovering compounds for mechanism-based drug development to target both cancer and non-cancer endpoints.

A major target for cancer chemotherapy includes specific protein transcription factors, the aryl hydrocarbon receptor, the estrogen receptor and orphan nuclear receptors NR4A1, Safe said.

He said research from the Safe Lab has included collaboration with Chapkin and others to investigate the role of the aryl hydrocarbon ligand and its microbial metabolites on intestinal function and disease.

We also have ongoing collaborations focused on endometriosis, Parkinsons Disease, and learning and memory, Safe said. We have been very interested in the therapeutic impact of coffee consumption on many of these diseases and how it may improve human health.

While much of the research conducted on the human health benefits of coffee was performed using preclinical models, Safe and Chapkin said the mechanistic findings will support future translational studies in humans.

This suggests that clinical applications of coffee extracts, particularly for treating some cancers, should be considered, Safe said.

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Have a second cup: Coffee provides health benefits - AgriLife Today - AgriLife Today

Research Associate job with KINGS COLLEGE LONDON | 338029 – Times Higher Education

Job description

We are seeking a highly motivated, scientifically curious, and creative postdoctoral research associate with a strong interest in mammalian brain development, specifically the role of posttranscriptional modifications in neuronal and glial subtype specification to join Setsuko Sahara in collaboration with Engene Maleyev lab at Kings College London (https://devneuro.org/cdn/group-overview.php?groupID=87). This 3 year-post is funded by the Leverhulme Trust.

The Sahara lab studies the mechanisms regulating the self-renewal potential of cortical progenitors and the ability of multipotent cells to differentiate into different types of progenitors, neurons and glia (Ramos et al 2020). The successful applicant will pursue research projects to understand how a vast diversity of cortical projection neurons and glia emerge from a limited number of progenitors during development. We will address this question by interrogating the molecular mechanisms in mouse cortical development. These include RNA biology, in vivo manipulation of gene expression, cell and molecular biology, imaging and bioinformatics.

Applicants should have an undergraduate degree and a PhD (awarded or soon to be awarded) in neuroscience, stem cells, development, or RNA biology. Prior experience with transcriptomics, related bioinformatics and cell sorting techniques, ES cell-based neuronal differentiation (2D or 3D), or RNA biology-related techniques is an advantage. Candidates from other disciplines or model organisms but are motivated to switch to the field of mammalian neuroscience/neurogenesis will be welcomed to apply if they demonstrate high flexibility and a good track record.

The lab is based at the Centre for Developmental Neurobiology (CDN) and the MRC Centre for Neurodevelopmental Disorders at King's College London (KCL), with easy access to various areas of expertise from molecular and stem cells biology, synapse biology, in vivo imaging, behavioural studies and clinical research. This provides a stimulating environment and extensive training opportunities for the proposed project.

For more information, please contact setsuko.sahara@kcl.ac.uk.

This post will be offered ona fixed-termcontract to 30/09/2025 (or theend of the project date)

This is a full-time post 100 % full time equivalent

Key responsibilities

The above list of responsibilities may not be exhaustive, and the post holder will be required to undertake such tasks and responsibilities as may reasonably be expected within the scope and grading of the post.

Skills, knowledge, and experience

Essential criteria

Desirable criteria

Please note that this is a PhD level role but candidates who have submitted their thesis and are awaiting award of their PhDs will be considered. In these circumstances the appointment will be made at Grade 5, spine point 30 with the title of Research Assistant. Upon confirmation of the award of the PhD, the job title will become Research Associate and the salary will increase to Grade 6.

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Research Associate job with KINGS COLLEGE LONDON | 338029 - Times Higher Education

A novel Alzheimer’s disease prognostic signature: identification and … – Nature.com

Alzheimers disease (AD) is often regarded as one of the primary causes of dementia and frailty. The signs of the illness begin with mild memory issues and proceed to cognitive impairment, dysfunctions in complex daily tasks, and several other domains of cognition. By the time AD is clinically recognized, neuronal loss and neuropathologic abnormalities have devel- oped in several brain locationst1,2. AD is a degenerative and irreversible brain disease that impairs memory, cognition, and, eventually, the ability to perform even the most basic activities. Injury appears to begin in the hippocampus and entorhinal cortex, two areas of the brain critical for memory formation3. Additional brain regions are harmed as more neurons die, and brain tissue is substantially reduced in the latter stages of AD. While numerous variables, like as genetics and lifestyle, impact a persons risk of acquiring AD, age is by far the most important4. The condition is rare before the age of 65, and the recurrence grows in subsequent decades, with a 2433% probability of having the disease by the age of 855.Given the pessimistic projections for the AD population and its associated socioeconomic costs between 2030 and 2050, scientific and clinical research in the field of AD is currently focusing on the early detection of the transitional phase between normal aging, moderate cognitive impairment, and dementia6,7. Throughout the preceding three decades, much has been learnt about the molecular basis of the condition, stressing the potential for developing biomarkers for diagnosis, risk assessment, clinical trials, therapeutic targeting, and discovering novel pharmaceutical targets8,9.

AD is a complex disease that is unlikely to be successfully treated with a single medication or other intervention. Modern pharmacotherapeutic strategies are focused on supporting patients in maintaining mental capacities, regulating behavioral manifestations, and delaying development, hence decreasing the appearance of sickness symptoms10,11. All currently known treatments work by altering the levels of particular neurotransmitters in the brain, principally acetylcholine (ACh) and glutamate. Although this helps with symptoms, it is not a total cure for the condition12. With the growth of bioinformatics, a lot of evidence-based evidence has been gathered. Computation and prediction based on relevant information can give certain alternative suggestions for future clinical diagnosis and therapy and drug research.

Because glutamine (Gln) is the most prevalent amino acid in circulation, cultured tumor cells use it quickly. Gln is commonly used in cellular aerobic glycolysis to maintain TCA flux or as a source of citrate for lipid synthesis in reductive carboxylation13. Furthermore, glutaminolysis enhances proliferative cell survival by decreasing oxidative stress and preserving the integrity of the mitochondrial membrane. Gln serves as an energy source for both tumor and immunological cells14. However, it appears that inflammatory antitumor immune cells, particularly macrophages, do not rely on or even reject Gln metabolism. M2 macrophages are more dependent on Gln than naive macrophages, but decreased Gln metabolism can generate pro-inflammatory M1 macrophages15. As a result, Gln metabolism may be a target for converting tumor-associated macrophages from M2 to M1, hence increasing the anti-tumor inflammatory immune response.

Furthermore, Gln metabolism is important in Th1 cell differentiation and effector T cell activation. These data imply that inhibiting Gln metabolism may be able to restructure TME and boost immunotherapy effectiveness. Some pattern recognition receptors in AD can form huge multiprotein complexes known as inflammasomes. When inflammasomes combine, they create membrane holes and process proinflammatory cytokines, resulting in pyroptosis, a kind of inflammatory cell death16. Innate immune signaling and inflammasome activation are important preventive mechanisms against AD17. Their activation, however, must be strictly managed, since excessive activation can cause neuroinflammation and brain injury. Potential treatment methods for AD have included balancing the hosts innate immune response18. Although targeting Gln metabolism in conjunction with immunotherapy is incredibly promising in AD, the landscape of Gln metabolism in tumor microenvironment (TME) is yet unknown. As a result, we conducted this work to conduct a comprehensive review of GlnMgs and immunotherapy in AD.

In biological research, gene expression analysis is becoming increasingly significant. The Accelerating Medicines Partnership- AD programs availability of high-throughput transcriptome sequencing data and clinical annotation allows us to investigate the altered transcriptional and related molecular pathways implicated in AD. Several research have used gene expression information acquired from the Gene Expression Omnibus (GEO) to investigate the molecular pathways involved in the development of AD19,20. The results of these bioinformatics analyses provide intriguing insights for understanding the pathophysiology and processes of AD from several perspectives. However, no study has used bioinformatics to determine whether GlnMgs are im- portant for AD development. As a result, the goal of this work was to examine the AD-related GEO via the lens of the GlnMgs (Fig.1).

Framework. The data of AD patients were obtained from GEO databases, and then the GlnMgs were matched to carry out difference analysis and risk model construction, respectively.aGSE132903 was used as the main body and GSE63060 was used to verify the model with good grouping, and GlnMgs related to the prognosis of AD patients were obtained.aThen, GO, KEGG and GSEA analyses were performed with multiple databases to obtain the functions related to GlnMgs.aLast, the immune cells, function and RNA changesawere analyzed.

Among the 26 GlnMgs, all were significantly different except for CPS1, GLUD1, CAD, SLC38A1,GMPS (Fig.2a). Some genes cluster in the treat group and some in the control group. Treat: PHGDH, CTPS2, LGSN, GLYATL1, GLUL, ASL, ARHGAP11B. Control: MECP2, NR1H4, NIT2, PFAS, GLS2, GLS, ASNS, PPAT, GFPT1, ASNSD1 (Fig.2b) (Table S2).

Principal component analysis. (a) GlnMgs. (b) Expression of GlnMgs in clusters.

We calculated the chromosomal positions of GlnMgs and visualized them in circles (Fig.3a) (Table S3).aThen, in order to clarify the expression of these genes, we conducted correlation analysis of these genes (Fig.3b,c).

Expression of GlnMgs. (a) Expression of GlnMgs on sequences. (b,c) The correlation between GlnMgs and related genes.

The immune environment is extremely essential in the onset and progression of AD. CIBERSORT was used to examine the immune cell components in adipose tissue. We built barplot and corplot to show the results of immune cells (Fig.4a,b). Then, in order to clarify the expression of these genes, we conducted correlation analysis of these genes and immune cells (Fig.4c).

Expression of Immune cells. (a,b) Expression of immune cells in different clusters. (c) Correlation between GlnMgs and immune cells.

When the clustering variable (k) was set to 2, the intragroup correlations were the strongest and the intergroup correlations were the smallest, indicating that AD patients could be divided into two groups based on GlnMgs (Fig.5a). Based on this cluster, we also discussed the expression of the GlnMgs in different clusters. CTPS2, ARHGAP11B, and NR1H4 were not significantly different between the two groups (Fig.5b,c). According to the PCA results, patients with varying risks were divided into two groups (Fig.5d). Based on the previous results, we also analyzed the results of immune cell infiltration according to different clusters (Fig.5e,f).

Cluster analysis. (a) Consensus clustering matrix. (b,c) Expression of the GlnMgs in different clusters. (d) PCA. (e,f) Immune cell infiltration of different clusters.

The GlnMgs were used to conduct the enrichment analysis. The MF mainly involves atp dependent dna dna annealing activity, beta galactoside cmp alpha-2-3-sialyltransferase activity, gomf phosphatidylinositol-3-4-5-trisphosphate binding. The BP mainly involves cell fate specification, atrioventricular canal development, neuron fate specification (Fig.6a). The pathways analysis showed that the notch signaling pathway, primary immunodeficiency, renin angiotensin system were enriched (Fig.6b).

Enrichment analysis for DEGs. (a) GO. (b) KEGG. (a) Barplot graph for GO enrichment (the longer bar means the more genes enriched; q-value: the adjusted p-value). (b) Barplot graph for KEGG pathways (the longer bar means the more genes enriched).

To establish an approximation scale-free topology for the network, a soft-thresholding power was applied (Fig.7a). The genes with the highest variance were grouped and integrated into nine co-expression modules (Fig.7b). The relationship between module eigengene and clinical characteristics was investigated using Pearsons correlation analysis (Fig.7c). The turquoise module was shown to be highly connected with the Group attribute (i.e. AD and ND) and to have the greatest association (Fig.7d) (Table S4).

Co-expression module construction. (a) Soft threshold power mean connection and scale-free fitting index anal- ysis. (b) Clustering of dendrograms According to dynamic tree cutting, the genes were sorted into distinct modules using hierarchical clustering with a threshold of 0.25. Each color represents a separate module. (c) Heatmap of correlations between module eigengenes and clinical characteristics. (d) Gene scatterplot in the turquoise module.

To establish an approximation scale-free topology for the network, a soft-thresholding power was applied (Fig.8a). The co-expression modules were formed by clustering the variance genes (Fig.8b). Pearsons correlation analysis was used to investigate the relationship between module eigengene and clinical characteristics (Fig.8c). The module was shown to be strongly linked with the Group characteristic (i.e. AD and ND) and to have the greatest association (Fig.8d) (Table S5).

Cluster construction of co-expression modules (a) Soft threshold power mean connection and scale-free fitting index analysis. (b) Dendrogram clustering (c) Heatmap of correlations between module eigengenes and clinical characteristics. (d) Gene scatterplot in the grey module.

DEGs, grey module genes (WGCNA), and GlnMgs overlapping as well. A total of 34 genes were crossed (Fig.9a) (Table S6). The Boxplots depicted the residual expression patterns of these genes in AD (Fig.9b).aThere are some differences in the proportions of the four different modes (Fig.9c). As seen in Fig.6e, the GlnMgs diagnostic capacity in distinguishing AD from control samples revealed a satisfactory diagnostic value, with an Areas under the curve (AUC)aof RF: 0.784, SVM: 0.759, XGB: 0.788, and GLM: 0.666 (Fig.9d). An AUC of 0.784 (95% CI 0.6550.896) in GSE132903, an AUC of 0.815 (95% CI 0.7340.895) in GSE63060 (Fig.9e) (Table S7).

(a) Identification of GlnMgs with a venn diagram. (b,c) Residualaexpression patterns. (d) AUC of train group. (e) AUC of test group.

The hub gene in the XGB model predicted three drugs. These include ME-344, METFORMIN HYDROCHLORIDE, NV-128(Table 1). In addition, we predicted all interacting genes for drug and gene relationships (Table 2).

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A novel Alzheimer's disease prognostic signature: identification and ... - Nature.com