LAP3

Researchers succeed at generating 3D visualizations of chloroplasts' copying machines. For life on Earth, it is essential that plants carry out photosynthesis and ultimately produce oxygen and chemical energy with the help of sunlight. Researchers from Göttingen and Hannover have now succeeded for the first time in visualising the copying machine of chloroplasts, the RNA polymerase PEP, in high-resolution 3D. The detailed structure provides new insights into the function and evolution of this complex cellular machine, which plays a central role in reading the genetic instructions for photosynthesis proteins. Without photosynthesis, there would be no air to breathe -- it is the basis of all life on Earth. This complex process allows plants to convert carbon dioxide and water into chemical energy and oxygen using light energy from the sun. The conversion takes place in the chloroplasts, the heart of photosynthesis. Chloroplasts developed in the course of evolution when the ancestors of today's plant cells absorbed a photosynthetic cyanobacterium. Over time, the bacterium became increasingly dependent on its "host cell," but maintained some significant functions such as photosynthesis and parts of the bacterial genome. The chloroplast therefore still has its own DNA, which contains the blueprints for crucial proteins of the "photosynthesis machinery." With PEP to energy "A unique molecular copying machine, an RNA polymerase called PEP, reads the genetic instructions from the chloroplasts' genetic material," explains Prof. Dr. Hauke Hillen, research group leader at the Max Planck Institute (MPI) for Multidisciplinary Sciences, professor at the University Medical Center Göttingen and member of the Göttingen Cluster of Excellence "Multiscale Bioimaging" (MBExC). It is essential for activating the genes required for photosynthesis, Hillen emphasises. Without a functioning PEP, plants cannot photosynthesise and remain white instead of turning green. Not only the copying process is complex, but also the copying machine itself: It consists of a multi-subunit core complex, whose protein parts are encoded in the chloroplast genome, and at least twelve associated proteins, called PAPs. The nuclear genome of the plant cell provides the blueprints for these. "So far, we have been able to characterise some individual parts of the chloroplast copying machine structurally and biochemically, but we lacked a precise insight into its overall structure and the functions of the individual PAPs," says Prof. Dr. Thomas Pfannschmidt, professor at the Institute of Botany at Leibniz University Hannover. Detailed snapshot in 3D In close collaboration, researchers led by Hauke Hillen and Thomas Pfannschmidt have now succeeded for the first time in visualising a 19-subunit PEP complex in 3D at a resolution of 3.5 angstroms -- 35 million times smaller than a millimetre. "We isolated intact PEPs from white mustard, a typical model plant in plant research," describes Frederik Ahrens, a member in Pfannschmidt's team and one of the first authors of the study now published in the journal Molecular Cell. Using cryo-electron microscopy, the scientists then created a detailed 3D model of the 19-part PEP complex. For that, the samples were flash-frozen ultra-fast. The researchers then photographed the copying machine thousands of times and down to the atomic level from numerous angles and combined them into an overall image using complicated computer calculations. "The structural snapshot showed that the PEP core is similar to those in other RNA polymerases, such as in bacteria or the cell nucleus of higher cells. However, it contains chloroplast-specific features that mediate the interactions with the PAPs. The latter we find only in plants and they are unique in their structure," explains Paula Favoretti Vital do Prado, PhD student at the MPI, member of the MBExC's Hertha Sponer College, and also first author of the study. Scientists had already assumed that the PAPs fulfil individual functions in reading the photosynthesis genes. "As we could show, the proteins arrange themselves in a special way around the RNA polymerase core. Based on their structure, it is likely that the PAPs interact with the core complex in various ways and are involved in the gene reading process," Hillen adds. Understanding the evolution of photosynthesis The research collaboration also used databases to search for evolutionary clues. They wanted to find out whether the observed architecture of the copying machine is similar in other plants. "Our results indicate that the structure of the PEP complex is the same in all land plants," says Pfannschmidt. The new findings on the copying process of chloroplast DNA help us better understand the fundamental mechanisms of the photosynthesis machinery's biogenesis. They might also be valuable for biotechnological applications in the future. The study was funded by the German Research Foundation (FOR2848, SFB1565, PF323-7 and SPP 2237 MadLand (PF323-9)) and within the framework of the Excellence Strategy (EXC 2067/1 -- 390729940) via the Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC) as well as by the European Research Council (ERC) within the framework of the EU Horizon 2020 programme with the ERC Starting Grant MitoRNA (Grant agreement no. 101116869).

NEW YORK and LONDON, May 26, 2021 (GLOBE NEWSWIRE) -- Tiziana Life Sciences plc (NASDAQ: TLSA, LSE: TILS) (“Tiziana” or the “Company”), a biotechnology company focused on innovative therapeutics for inflammatory diseases and cancers, today provided an update on further analysis of lymphocyte subsets from blood samples from a Phase 1 study with nasally administered Foralumab in healthy volunteers. Results exhibiting statistically significant immunomodulatory effects on CD8 cytotoxic T-lymphocytes and other inflammatory biomarkers were observed. This Phase 1 trial, conducted at the Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, was a single-site, double-blind, placebo-controlled, dose-ranging study with nasally administered Foralumab at 10, 50 and 250 mcg per day, consecutively for 5 days in healthy volunteers. The treatment was well-tolerated at all doses and there were no apparent symptoms of severe toxicity. Importantly, the treatment showed significant positive effects at 50 mcg/day dose (compared to other dose and placebo groups) on T-cell subsets and inflammatory biomarkers. These data support other clinical and pre-clinical studies showing that this route of administration is capable of inducing site-targeted immunomodulation and anti-inflammatory effects. Furthermore these pharmacodynamic data point to a clinical dose range that Tiziana intends to test in further clinical development among MS patients. Highlights of clinical and immunologic data Nasally administered Foralumab was well tolerated and there were no apparent symptoms of severe toxicity or cytokine release syndrome. Systemic levels of Foralumab were below the lower quantitation limit of 8 ng/mL suggesting that nasally administered Foralumab appears to exert its effects via nasal epithelium utilizing local and lymphatic immune systems directly. Most prominent effects among cytotoxic T-cell subsets were observed in the 50mcg group compared to 10mcg, 250mcg and placebo groups. The observed effects in the 50mcg dose group were the following: Statistically significant reductions from baseline in CD8_Tem cytotoxic T-cell subset through 14 days and CD8_TEMRA, CD8_GranzymeB, CD8_Perforin subsets through 21 days Statistically significant increase from baseline in CD8_naive subset through day 21 Statistically significant stimulation in production of anti-inflammatory cytokine IL-10 along with suppressed production of pro-inflammatory cytokine IFN-γ, suggested a positive trend for immunomodulation and anti-inflammatory effect. These observed clinical responses on biomarkers, indicative of immunomodulation and anti-inflammatory, are consistent with the positive clinical data observed with nasally administered Foralumab in COVID-19 patients in Brazil. Results from this clinical study demonstrated that nasally administered Foralumab at 100 mcg/day for 10 consecutive days was not only well-tolerated but it also showed significant reduction of lung inflammation along with statistically reduced levels of interleukin-6 (IL-6) and C-reactive protein (CRP), in the blood samples taken from patients (). “Nasal administration of Foralumab is a unique approach to treat patients with neurodegenerative diseases such as progressive MS, amyotrophic lateral sclerosis (ALS) and Alzheimer’s Disease (AD). This study demonstrates for the first-time that nasally administered Foralumab, at the identified optimal dose of 50 mcg/day, induces immunomodulatory effects capable of providing clinical benefit to treated subjects. These data along with results from our recently completed trial in COVID-19 patients in Brazil suggest a dose-range of 50 mcg-150 mcg could be used for future clinical development of nasally administered Foralumab. This is a major accomplishment providing the scientific rationale to move forward with further clinical development of nasally administered Foralumab in patients with neurodegenerative diseases,” commented Dr. Howard L. Weiner, Chair of the Scientific Advisory Board of Tiziana Life Sciences and Professor of Neurology at Harvard Medical School. He added that “both oral and nasal administration routes are physiologic approaches to stimulate the mucosal immune system to induce disease modifying immunomodulation. Our immediate focus is on developing Foralumab for treatment of progressive MS.” “The demonstration of the positive immunomodulatory effects providing a recommended dose-range is important to move forward with further studies in the progressive MS population,” stated Dr. Tanuja Chitnis, the study PI at the Brigham and Women’s Hospital. The person who arranged for the release of this announcement on behalf of the Company was Dr Kunwar Shailubhai, CEO & CSO of Tiziana. THIS ANNOUNCEMENT CONTAINS INSIDE INFORMATION FOR THE PURPOSES OF ARTICLE 7 OF REGULATION 2014/596/EU (WHICH FORMS PART OF DOMESTIC UK LAW PURSUANT TO THE EUROPEAN UNION (WITHDRAWAL) ACT 2018) ("UK MAR"). UPON THE PUBLICATION OF THIS ANNOUNCEMENT, THIS INSIDE INFORMATION (AS DEFINED IN UK MAR) IS NOW CONSIDERED TO BE IN THE PUBLIC DOMAIN. About Foralumab Foralumab (formerly NI-0401), the only entirely human anti-CD3 mAb, shows reduced release of cytokines after IV administration in patients with Crohn's disease with decreases in the classic side effects of cytokine release syndrome (CRS) and improves the overall safety profile of Foralumab. In a humanized mouse model (NOD/SCID IL2γc-/-), it was shown that while targeting the T cell receptor, orally administered Foralumab modulates immune responses of the T cells, enhances Tregs and thus provides therapeutic benefit in treating inflammatory and autoimmune diseases without the occurrence of potential adverse events usually associated with parenteral mAb therapy (Ogura M. et al., 2017). Based on animal studies, the nasal and oral administration of Foralumab offers the potential for the immunotherapy of autoimmune and inflammatory diseases in a safe manner by the induction of Tregs. Preclinical studies on nasal and oral administration with Anti-CD3 mAbs Preclinical and clinical studies have shown that mucosal induction of Tregs by oral or nasal administration of anti-CD3 mAbs is an innovative approach to treat autoimmune and anti-inflammatory diseases (Kuhn and Weiner 2016). Nasally administered anti-CD3 mAbs were shown to ameliorate disease in an animal model of multiple sclerosis by inducing IL-10+LAP+ (latency-associated peptide) T cells, demonstrating nasal anti-CD3 mAbs as a new approach to treat progressive forms of multiple sclerosis and other types of chronic CNS inflammation. Additionally, nasally administered anti-CD3 mAbs suppressed lupus in lupus-prone mice (BWF1) by inducing IL-10 and TGF-β dependent mechanisms associated with a suppression of IL-17 and IL-21 pro-inflammatory cytokines. About Tiziana Life Sciences Tiziana Life Sciences plc is a UK biotechnology company that focuses on the discovery and development of novel molecules to treat human disease in oncology and immunology. In addition to Milciclib, the Company is also developing Foralumab for liver diseases. Foralumab is the only fully human anti-CD3 monoclonal antibody in clinical development in the world. This Phase 2 compound has potential application in a wide range of autoimmune and inflammatory diseases, such as multiple sclerosis, crohn’s disease, COVID-19, type-1 diabetes (T1D), ulcerative colitis, psoriasis and rheumatoid arthritis, where modulation of a T-cell response is desirable. Forward-Looking Statements Certain statements made in this announcement are forward-looking statements. These forward-looking statements are not historical facts but rather are based on the Company’s current expectations, estimates, and projections about its industry; its beliefs; and assumptions. Words such as ‘anticipates,’ ‘expects,’ ‘intends,’ ‘plans,’ ‘believes,’ ’seeks,’ ‘estimates,’ and similar expressions are intended to identify forward-looking statements. These statements are not guarantees of future performance and are subject to known and unknown risks, uncertainties, and other factors, some of which are beyond the Company’s control, are difficult to predict, and could cause actual results to differ materially from those expressed or forecasted in the forward-looking statements. The Company cautions security holders and prospective security holders not to place undue reliance on these forward-looking statements, which reflect the view of the Company only as of the date of this announcement. The forward-looking statements made in this announcement relate only to events as of the date on which the statements are made. The Company will not undertake any obligation to release publicly any revisions or updates to these forward-looking statements to reflect events, circumstances, or unanticipated events occurring after the date of this announcement except as required by law or by any appropriate regulatory authority. 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€1.5 million guaranteed by the French government (PGE) and granted by BNP bank €1.5 million innovation and R&D loan granted by Bpifrance Funding will allow for acceleration of R&D programs PARIS, April 28, 2021 (GLOBE NEWSWIRE) -- Quantum Genomics (Euronext Growth - FR0011648971 - ALQGC), a biopharmaceutical company specializing in the development of a new class of drugs that directly targets the brain to treat difficult-to-treat/resistant hypertension and heart failure, today announced it has secured €3 million in non-dilutive financing through grants from the French government and BNP bank and an R&D loan from Bpifrance. BNP bank has granted a €1.5 million loan, guaranteed by the French government (PGE) with an initial 12 months maturity, at a rate of 0.25%. The Company has been given the option to request 5 years’ amortization. Bpifrance has granted a €1.5 million innovation and R&D loan for a period of 7.6 years at an interest rate of 0.72%. First reimbursement is scheduled on December 31, 2023. “We would like to thank the French government, Bpifrance and our banking partners for their support in this financing. This additional non-dilutive financing, which processes were initiated last November 2020, secured our treasury in a context which remain uncertain. This comes at an important time for our Company, following our recent capital raise in December 2020 and the signing of various partnerships with various strategic partners in 2020, all of which will serve to strengthen and accelerate our R&D programs,” said Jean-Philippe Milon, Chief Executive Officer of Quantum Genomics. About Quantum GenomicsQuantum Genomics is a biopharmaceutical company specializing in the development of a new class of cardiovascular medications based on brain aminopeptidase A inhibition (BAPAI). Quantum Genomics is the only company in the world exploring this innovative approach that directly targets the brain. The company relies on 20 years of academic research from the Paris-Descartes University and the laboratory directed by Dr. Catherine Llorens-Cortes at the Collège de France (French National Institute of Health and Medical Research (INSERM)/the Scientific Centre for National Research (CNRS)). The goal of Quantum Genomics is to develop innovative treatments for complicated, or even resistant, cases of hypertension (around 30% of patients have poor control of their condition or receive ineffective treatment) and for heart failure (one in two patients diagnosed with severe heart failure dies within five years). Based in Paris and New York, Quantum Genomics is listed on the Euronext Growth exchange in Paris (FR0011648971- ALQGC) and trades on the OTCQX Best Market in the United States (symbol: QNNTF). For more information, please visit , or follow us on Twitter and LinkedIn Contacts