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Learn about the mechanisms of enzyme action (lock-and-key and induced fit theories). Each enzyme has an unambiguous (and often long) systematic name that specifies the substrate of the enzyme (the substance acted on), the functional group acted on, and the type of reaction catalyzed. The cofactor may also be an inorganic ion (usually a metal cation, such as Mg2+, Zn2+, or Fe2+). Since humans obtain folic acid from their diet rather than by manufacturing it, it is not harmful to the patient. This allows the concentration of the product to be maintained within very narrow limits. Increasing the number of enzymes molecules present through genetic mechanisms is one way to increase production of needed products. The coupling of genetic control and allosteric regulation allows for very tight control of cellular processes. If they are found in the bloodstream, it indicates damage to that tissue; the extent of cell damage can sometimes be estimated from the magnitude of serum concentration increase above normal levels. Although all forms of a particular isoenzyme catalyze the same reaction, their structures are slightly different and their location within body tissues may vary. Acceleration of Biopharma Partnering Activity into China Evolving Marketplace Favorable to Drug Development and Western Partners December 2019 1 Table of Contents 1. Preface & Executive Summary Recent market and regulatory changes Reimbursement Policy Changes Recent Regulatory Policy Changes New Policies on Rare Diseases and Pediatrics in China Cross-Border Licensing Activities Typical Deal Structures Licensing Deal Values Out-licensing from China Outlook of cross-border transactions Torreya China Team and Capabilities 3 6 10 15 20 26 33 36 45 48 49 2 Preface & Executive Summary 3 Preface We at Torreya are engaged in providing strategic advice to companies in the life sciences industry. Torreya has a four person team covering Chinese pharmaceutical companies that is in China at least six times a year. China Market and Recent Changes 6 China is the second largest healthcare market in the world. The new company has renamed itself as Viatris, moved its executive team to Shanghai and has indicated that its plans include "building a meaningful presence in China". Disease 1 2 3 4 5 6 7 8 9 21-Hydroxyulase Deficiency Albinism Alport Syndrome Amyotrophic Lateral Sclerosis Angleman Syndrome Arginase Deficiency Asphyxiating Thoracic Dystrophy (Jeune Syndrome) Atypical Hemolytic Uremic Syndrome Autoimmune Encephalitis No. Encouragement of licensing over M&A following the 19th Party Congress Strong stock market valuations of companies that are licensing in many Western drugs Drop in activity in 2019 versus huge boom year in 2018 (but 2019 still the second strongest year in history) 29 Source: Torreya China Deal Database, November 2019. Dollar Volume of Investment and Upfronts in China Licensing Deals Volume of Upfronts, Milestones and Investment in China Deals, 2004-2019 ($mm) $3,202 $2,525 $1,666 $837 $581 $216 $0 2004 $379 $162 2012 $0 2005 $0 2006 $0 2007 $5 2008 $38 2009 $7 2010 2011 $155 2013 2014 2015 2016 2017 2018 2019 Key factors behind the jump in funds committed in recent years. Encouragement of licensing over M&A following the 19th Party Congress BeiGene / Amgen deal a key driver for 2019 *Data for 2019 shown from Jan 1 to November 22, 2019 and annualized. The highest total deal averages have been associated with Hematology and Gastrointestinal medicines. The greatest area of licensing activity has been for approved products (24% of deals). Chinese pharmaceutical companies have robust R&D capabilities and are willing to collaborate with their Western counterparts on interesting science. Distribution of China In-Licensing Deals by Phase of Development Pre-approval 2% Phase 3 15% Approved 24% Phase 2 22% Phase 1 14% Discovery 3% Source: Torreya China Deal Database, November 2019. The difference is a reflection, of course, of the economic value of products in each territory. We do expect to see the gap in deal economics between the territories narrow in the years ahead. Japan Territory In-Licensing Deal Statistics Phase Approved Pre-approval Phase 3 Phase 2 Phase 1 Preclinical Average Japan vs.

The purpose of this study is to evaluate the effect of Slc7a11 on the redox state of intracellular proteins. Slc7a11 over-expression restored global age-dependent trend of oxidation of cysteine residues in multiple peptides. Specifically, redox states of 151 proteins were changed in old fibroblasts compared to young fibroblasts. Cell death and survival were predicted to be the most affected with necrosis being on the top. This study finds that aging results in changes of redox states of multiple proteins, including those involved in protein turnover and cell survival, and that targeting Slc7a11 can restore the redox states of these proteins. Products of unsaturated fatty acid peroxidation by O3 have been proposed to mediate some of the functional and inflammatory effects of O3 exposure. These findings may have implications for dietary recommendations for populations exposed to O3. In contrast to pancreatic endpoints, embryos were most sensitive to pro-oxidants at 72 hpf. Overall, this study contributes to understanding the role of exogenous pro-oxidants and antioxidants in shaping pancreatic organogenesis and embryonic development. The objective is to investigate their exact mechanisms via chemical proteomics by employing an alkyne-modified iodoacetamide chemical probe for in-gel fluorescence imaging. Of the modified proteins, a recurring theme was the covalent binding of anti-oxidant enzymes such as peroxiredoxins. We validated our proteomics results via enzyme kinetic assays of anti-oxidant enzymes. Altered development of the pancreas by toxicant exposure can lead to altered pancreas morphology that has been linked to later-life diabetes. In this study, zebrafish (Danio rerio) is used as a model to compare critical windows of exposure to redox modulators for pancreas organogenesis and embryonic survival. Both chemical-, stage-, and celltype specific effects of redox modulation were observed on the endocrine pancreas. These findings are significant given the recent reports that zebrafish embryos and fish Channa punctatus have higher levels of lipid peroxidation products. Subepithelial mucoserous glands in nasal airways may contribute to compensatory protective mechanism of Muc5ac-/- mice. The exposome is a measure of all exposures of an individual and how those exposures relate to health. Important components of the exposome include lifestyle (diet), environmental and occupational exposures, and individual genetic predisposition. Mapping of the exposome could improve the understanding of disease and aid in prevention strategies and possible cures of many diseases. The goal was to develop an experimental model of the exposome by collecting biological samples during critical life stages of an exposed animal that are applicable to worker populations. An animal model can be useful in the study of the exposome as external lifetime exposures can be easily controlled and adverse health outcomes measured. Pulmonary and nasal airway injuries were assessed by bronchoalveolar lavage and histopathologic analyses. Electron micrograph determined reduced storage of goblet cell secretory granules and increased contents of subepithelial mucoserous glands in Muc5ac-/- relative to Muc5ac+/+. After 2-3 days of ozone exposure, nasal airways of Muc5ac-/- mice developed more severe epithelial sloughing and hypertrophy in septum, expansion of subepithelial mucous glands, and lateral wall congestion, compared to those in Muc5ac+/+ nasal airways. Ozone significantly increased mid-septal intraepithelial mucus in Muc5ac+/+ but not in Muc5ac-/-. Results indicate that lack of Muc5ac impaired the nasal and pulmonary 2014 Nitroreduction Bioremediation of 3-Nitrobenzanthrone via Bacterial Metabolism M. Field, American Association for Cancer Research 3-Nitrobenzanthrone, the most potent mutagen currently known, is currently being produced in significant quantities, mostly from the emissions of diesel-fueled engines and industry. While this compound was previously thought to be too non-volatile to be degraded, certain types of bacteria can bioremediate this carcinogen via nitro-reduction. In order to remediate this compound, dozens of bacteria samples were tested for their bioremediation ability. After the bacteria were allowed to grow in this solution, the solution would turn pink (from yellow), and its wavelength absorbance would show peaks resembling those of 3-Aminobenzanthrone. Future studies are planned to investigate the pneumotoxicity of Cu-Ni fume in A/J mice.

Also Serine Phosphoglyceride Quenching of chlorophyll fluorescence by oxidised Q, the electron acceptor of photosystem 2; includes qQ-quenching. Phycoerythrin is the metal-free red phycobilin pigment in a conjugated chromoprotein of red algae. They are found in plants, fungi, nematodes and all groups of algae including cyanobacteria. Phytochelatins act as chelators, and are important for heavy metal detoxification. Two molecules of the 20 carbon geranylgeranyl pyrophosphate are condensed in a tail-to-tail configuration to give the forty carbon phytoene, the first committed step in carotenoid biosynthesis. A member of the class of pterocarpans that is the 3-O-methyl ether of (+)-6a-hydroxymaackiain (the 6aR,12aR stereoisomer). A phytoalexin found in pods of garden peas (Pisum sativum) and other plants of the pea family, including Tephrosia candida. Platelets are disk-shaped, contain no hemoglobin, and are essential for the coagulation of blood and in maintenance of hemostasis. This class of compounds includes many substances that play important roles in both eukaryotic and prokaryotic cells, such as putrescine, cadaverine, spermidine, and spermine. A carbohydrate polymer that is formed from three or more molecules of simple carbohydrates. Examples of polysaccharides are dextrin, starch, glycogen, cellulose, gums, and inulin. Any of various heterocyclic compounds, derived from pyrrole, that occur universally in protoplasm, contain a central metal atom, and provide the foundation structure for hemoglobin, chlorophyll, and certain enzymes. Physiologically inactive substances that can be converted to active enzymes, specific precursor form is referred to as a procarboxypeptidase A. In the case of pancreatic carboxypeptidase A, the inactive zymogen form, pro-carboxypeptidase A, is converted to its active form - carboxypeptidase A - by the enzyme enteropeptidase. In the case of pancreatic carboxypeptidase B, the inactive zymogen form, pro-carboxypeptidase B, is converted to its active form - carboxypeptidase A - by the enzyme enteropeptidase. This mechanism ensures that the cells wherein procarboxypeptidase A is produced are not themselves digested. A protein that may play a role in the regulation of both apoptosis and cell proliferation. A cyclic, nonessential amino acid occurring in proteins; it is a major constituent of collagen. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. Also: Malonic acid, Dicarboxymethane, Carboxyacetic acid, Methanedicarboxylic acid. The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Markers of oxidative stress measured as 2,4dinitrophenylhydrazine incorporated into protein Protein: any of a group of complex organic compounds containing carbon, hydrogen, oxygen, nitrogen, and sulfur. Proteins, the principal constituents of the protoplasm of all cells, are of high molecular weight and consist of -amino acids joined by peptide linkages. Twenty different amino acids are commonly found in proteins, each protein having a unique, genetically defined amino acid sequence that determines its specific shape and function. Their roles include enzymatic catalysis, transport and storage, coordinated motion, nerve impulse generation and transmission, control of growth and differentiation, immunity, and mechanical suppport. Any of a group of complex organic compounds which contain carbon, hydrogen, oxygen, nitrogen and usually sulphur, the characteristic element being nitrogen and which are widely distributed in plants and animals. In this case: Insoluble proteins Total amount of protein in a sample A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. A crystalline acid C7H6O4 produced from various resins and found in combination in many plant products A phenolic acid derivative. An immediate precursor of chlorophyll a, which lacks the phytol side-chain of chlorophyll.

Lipids were extracted via a modification of the method of Bligh and Dyer (1959) and lipid mass was determined gravimetrically. The lipid content of Boekelovia was 27% of the organic mass in N-sufficient cells, increasing to 42% and 59% after 2 days and 10 days of N-deficiency, respectively. There was less effect of N starvation on the lipid content of Ankistrodesmus; the lipid content only increased from 23% in N-sufficient cells to 29% in cells that were N-deficient for 10 days. Numerous strains were characterized with respect to growth at several temperatures and salinities using these new media. A Look Back at the Aquatic Species Program-Technical Review 11 National Renewable Energy Laboratory Publications: Barclay, W. Formulas for these media were developed by statistical analysis of saline groundwater data for the state of New Mexico. Examples of growth contour plots generated from data obtained by the use of a temperature-gradient table. The contour lines represent interpolated values indicating where a particular combination of temperature and salinity would result in a given growth rate. Each point represents the mean of at least five separate daily growth rate determinations. The cultures that exhibited substantial algal growth were further treated to isolate the predominant strains as unialgal (clonal) isolates. These strains were then tested for growth using the temperature-salinity matrix described earlier. This time collecting trips were also made to New Mexico and Nebraska, in addition to Colorado and Utah. Eighty-six sites were sampled during the year, 53 of which were sampled in the spring. An analysis was conducted comparing the results of the new protocol with those that would have resulted from the protocol used in prior years. This analysis indicated that the revised protocol was in fact superior to the older protocol. For example, only six of the 17 strains selected via the new protocol would also have been selected using the old protocol. Only three of the 17 strains grew best in the artificial medium type that most closely resembled the collection site water; in fact, only six strains were even considered to grow well in the collection site water relative to growth in at least one of the artificial medium. This analysis clearly indicated the value of performing the initial screening and enrichment in a variety of relevant media. The results suggest that the shallow saline environments sampled probably contain a large number of species whose metabolism is arrested at any given time. In other words, the water quality of such sites varies greatly, depending on precipitation and evaporation, so probably only a few of the many species present are actively growing at any given time. This also may explain the wide range of salinities and temperatures tolerated by many of these strains. Bicarbonate and divalent cation concentrations were found to be important determinants in controlling the growth of Boekelovia sp. These results make sense, since media enriched in bicarbonate would have more dissolved carbon available for photosynthesis. These results indicate that matching the chosen strain for a particular production site to the type of water available for mass cultivation will be important. The lipid contents of several strains were determined for cultures in exponential growth phase and for cultures that were N-limited for 7 days or Si-limited for 2 days. In general, nutrient deficiency led to an increase in the lipid content of the cells, but this was not always the case. However, these experiments did not provide information on actual lipid productivity in the cultures, which is the more important factor for developing a commercially viable biodiesel production process. Therefore, there was no basis for designing experiments to estimate lipid productivity potential. Second, because the desert southwest sites targeted for biodiesel production facilities can be quite cool during the winter, a new effort to collect strains from cold-water sites was initiated. Finally, a strategy was developed and implemented to reduce the number of strains that had accumulated as a result of in-house and subcontracted research efforts, which allowed researchers to focus on the most promising strains. Eight additional strains collected previously from warm-water sites that grew well during the initial screening procedures were characterized with respect to temperature and salinity tolerances, growth rates, and lipid content under various conditions.