Journal articles: 'Scripps Research Institute'

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WILSON, ELIZABETH K. "Scripps Research Institute Thrives At Interface Of Chemistry And Biology." Chemical & Engineering News 74, no. 21 (1996): 39–44. http://dx.doi.org/10.1021/cen-v074n021.p039.

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Shigenaga, Akira. "Looking Back on Study Abroad at The Scripps Research Institute." YAKUGAKU ZASSHI 139, no. 2 (2019): 221–28. http://dx.doi.org/10.1248/yakushi.18-00169-4.

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Castagnetto, J. M. "MDB: the Metalloprotein Database and Browser at The Scripps Research Institute." Nucleic Acids Research 30, no. 1 (2002): 379–82. http://dx.doi.org/10.1093/nar/30.1.379.

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Kawamata, Yu, and Phil S. Baran. "Cluster Preface: Electrochemical Synthesis and Catalysis." Synlett 30, no. 10 (2019): 1147–48. http://dx.doi.org/10.1055/s-0039-1689970.

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Yu Kawamata was born in Japan in 1988, and he completed his undergraduate education at Kyoto University. He obtained his master’s degree and his Ph.D. at the same university under the supervision of Professor Keiji Maruoka, and he undertook a short-term internship at The Scripps Research Institute working on natural product synthesis with Professor Phil S. Baran. Upon completion of his doctoral studies, he returned to the Baran laboratory as a research associate and currently is pursuing his postdoctoral studies on organic electrochemistry.Phil S. Baran was born in New Jersey in 1977 and completed his undergraduate education at New York University in 1997. After earning his Ph.D. at The Scripps Research Institute (TSRI) in 2001, he pursued postdoctoral studies at Harvard University until 2003, at which point he returned to TSRI to begin his independent career. He was promoted to the rank of professor in 2008 and is currently the Darlene Shiley Professor of Chemistry. The mission of his laboratory is to educate students at the intersection of fundamental organic chemistry and translational science.

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Jiang, Xuefeng. "Cluster Preface: Perspectives on Organoheteroatom and Organometallic Chemistry." Synlett 32, no. 13 (2021): 1260–61. http://dx.doi.org/10.1055/s-0040-1720387.

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Xuefeng Jiang is a professor at East China Normal University. He received his B.S. degree in 2003 from Northwest University (China). He then joined Professor Shengming Ma’s research group at the Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences, where he received his Ph.D. degree in 2008. From 2008 to 2011, Xuefeng worked as a postdoctoral researcher on the total synthesis of natural products in the research group of Professor K. C. Nicolaou at The Scripps Research Institute (TSRI). His independent research interests have focused on green organosulfur chemistry and methodology-oriented total synthesis.

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Liu, Lei. "Cluster Preface: Recent Advances in Protein and Peptide Synthesis." Synlett 28, no. 15 (2017): 1895–96. http://dx.doi.org/10.1055/s-0036-1591237.

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Lei Liu received undergraduate training at the University of Science and Technology of China. He obtained his PhD degree at Columbia University in 2004 under the supervision of Prof. Ronald Breslow. He carried out post-doctoral studies at Scripps Research Institute from 2004 to 2007 in the laboratory of Prof. Chi-Huey Wong. He has been working at Tsinghua University since 2007. His research group studies chemical protein synthesis.

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Cordell, Geoffrey A. "Volume 4. Amino Acids, Peptides, Porphyrins, and Alkaloids Edited by Jeffery W. Kelly (Scripps Research Institute). xl + 429 pp." Journal of Natural Products 63, no. 2 (2000): 289–90. http://dx.doi.org/10.1021/np990772c.

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Kochevar, Randall E., Ruth Krumhansl, Kira Krumhansl, et al. "Inspiring Future Marine and Data Scientists Through the Lure of Ocean Tracks." Marine Technology Society Journal 49, no. 4 (2015): 64–75. http://dx.doi.org/10.4031/mtsj.49.4.4.

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AbstractThe Oceans of Data Institute (ODI) at the Education Development Center (EDC), Inc.; Stanford University; and the Scripps Institution of Oceanography have been collaborating, with the support of three National Science Foundation grants over the past 5 years, to bring large scientific data sets into secondary and postsecondary classrooms. These efforts have culminated in the development of a Web-based student interface to marine science data called Ocean Tracks (<ext-link ext-link-type="uri" xlink:href="http://oceantracks.org">http://oceantracks.org</ext-link>), which incorporates design principles based on a broad range of research findings in fields such as cognitive science, visual design, mathematics education, and learning science. The Ocean Tracks interface was tested in high school classrooms in spring and fall of 2013 with a total of 195 high school students. These tests indicate that students appeared to find many aspects of the interface simple and intuitive to use. Teachers and students indicated that working with real data was highly engaging, pointing to the tremendous potential for “big data” to transform the way science is taught. Interest among college faculty in Ocean Tracks indicates a need in undergraduate classrooms for similar tools that allow students to interact with data. So in the fall of 2014, we began to collect baseline data on students attending undergraduate oceanography classes at the Scripps Institution of Oceanography (Scripps) and Palomar College, where we will also be developing curricula and conducting classroom tests. Preliminary results from this work are presented here.

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Bhat, Vikas, Andrew J. Gale, John H. Griffin, Laurent O. Mosnier, and Annette von Drygalski. "Reversal of Novel Oral Anticoagulant (NOAC)-Induced Bleeding in Mice By Engineered superfactor Va." Blood 124, no. 21 (2014): 695. http://dx.doi.org/10.1182/blood.v124.21.695.695.

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Abstract Introduction and Objectives: Novel oral anticoagulants (NOACs), such as Factor (F) Xa inhibitors (Rivaroxaban and Apixaban) or the direct thrombin inhibitor (Dabigatran), are used for prevention of venous thromboembolism and ischemic strokes. However, conventional hemostatic reversal strategies in case of bleeding or surgery are ineffective, posing a major unmet clinical need. We recently demonstrated that superFVa, a novel FVa variant engineered with mutations of 3 activated protein C (APC) cleavage sites and a disulfide bond between the A2 and A3 domains, has enhanced biological activity and APC resistance. SuperFVa provided efficient normalization of hemostasis in hemophilia A mice and in animal models of APC-induced bleeding. Moreover, superFVa synergistically reduced bleeding in combination with recombinant human (rh) FVIIa in hemophilia mice. Thus, superFVa fits the criteria for a prohemostatic biologic. Therefore, the in vitro and in vivo effects of superFVa alone and in combination with other prohemostatic agents such as rhFVIIa or 4-Factor prothrombin complex concentrates (4F-PCC) as a novel hemostatic reversal strategy for NOAC-induced bleeding were determined. Materials and Methods: In vitro procoagulant properties of superFVa alone and in combination with rhFVIIa or 4F-PCC were studied using thrombin generation assays in normal human plasma (NHP) in the presence of FXa inhibitors (Rivaroxaban, Apixaban) or the direct thrombin inhibitor (Dabigatran, active form). In vivo prevention of blood loss by superFVa after intravenous injection of Rivaroxaban, Apixaban, or Dabigatran was studied using the tail clip model in BalbC mice. Results: Rivaroxaban and Apixaban each dose-dependently reduced thrombin generation in NHP and reduced the Endogenous Thrombin Potential (ETP) by ~60% at therapeutic concentrations (200 nM). Addition of either superFVa (50 nM) or rhFVIIa (40 nM, equivalent to a 90 µg/kg therapeutic dose in hemophilia patients), increased thrombin generation to some extent. However, ETP and thrombin peak height increased dose-dependently when increasing concentrations of superFVa (6.25 to 400 nM) were added with rhFVIIa (40 nM). superFVa effects appeared synergistic, with a plateau reached at 25-50 nM superFVa and ETP restored to ~93% of normal. Synergistic effects of superFVa were also present and even more pronounced in combination with 4F-PCC (1.35 U/ml; therapeutic plasma concentration). In the presence of Dabigatran (1 µM), superFVa (0.1 nM-100 nM) in combination with rhFVIIa (40 nM) or 4F-PCC (1.35 U/ml) showed a concentration dependent reduction of the lag time of thrombin generation. However, in contrast to the FXa inhibitors, in the presence of Dabigatran, no effects on ETP and thrombin peak height were observed for the addition of superFVa or combinations of superFVa and rhFVIIa or 4F-PCC. The in vivo efficacy of superFVa to reduce NOAC-induced bleeding was determined by blood loss after tail transection in BalbC mice injected i.v. with Rivaroxaban (40 mg/kg), Apixaban (20 mg/kg), or Dabigatran (0.4 mg/kg). Mean blood loss in mice injected with Rivaroxaban (16 µL/g), Apixaban (16.5 µL/g) or Dabigatran (14.5 µL/g) was significantly higher than baseline bleeding (4 µL/g, p<0.001). superFVa reduced blood loss after Rivaroxaban or Apixaban administration significantly in a dose dependent manner, e.g., superFVa at 40 U/kg significantly reduced bleeding to the baseline control level (5 µL/g). RhFVIIa (1 mg/kg) was able to reduce bleeding caused by Rivaroxaban but not by Apixaban. Neither superFVa nor rhFVIIa was able to reduce bleeding caused by Dabigatran. Conclusion: superFVa alone or in combination with rhFVIIa significantly improved in vitro thrombin generation in the presence of FXa inhibitors and to some extent in the presence of a direct thrombin inhibitor. SuperFVa alone consistently reduced bleeding in mice treated with FXa inhibitors, whereas a mixed response dependent on the type of FXa inhibitor was obtained with rhFVIIa. None of the agents was able to decrease bleeding in mice induced by Dabigatran. Because superFVa exerts a potent class effect as a hemostatic reversal strategy for FXa inhibitor-induced bleeding, it deserves further consideration for potential development as a hemostatic agent. Disclosures Gale: University of California, San Diego: University of California, San Diego Patents & Royalties. Griffin:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties. Mosnier:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties. von Drygalski:University of California, San Diego: University of California, San Diego Patents & Royalties.

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Sinha, Ranjeet Kumar, Laurent Burnier, Naveen Gupta, et al. "Novel R41Q-PAR1-Modified Mice Enable Proof-of-Concept Studies for in Vivo Mechanisms of Action for Thrombin (IIa) and Activated Protein C (APC)." Blood 124, no. 21 (2014): 99. http://dx.doi.org/10.1182/blood.v124.21.99.99.

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Abstract Introduction: Thrombin (IIa) and activated protein C (APC) are serine proteases involved in coagulation and inflammatory responses that affect many cell types in the body. IIa employs the GPCR, protease activated receptor 1 (PAR1), to promote endothelial barrier disruption, vascular leakage, and inflammation. In contrast, APC requires PAR1 for its opposing actions to stabilize endothelial barriers and to provide anti-inflammatory and anti-apoptotic activities. Studies of murine in vivo injury models using PAR1 knockout mice show that APC requires PAR1 to reduce sepsis-induced mortality and to provide robust neuroprotection following ischemic stroke. Extensive in vitro studies support the hypothesis that IIa’s cleavage at R41 in PAR1 initiates its signaling. Although APC was long thought, paradoxically, to act also via cleavage at R41, we recently proposed that APC’s cleavage at R46 initiates its endothelial barrier-protective and cytoprotective signaling via biased signaling. Since PAR1 knock-out mice cannot provide mechanistic data for testing these hypotheses in vivo, mice carrying the point mutation of R41 to Q in PAR1 were generated to enable mechanistic studies to test whether or not IIa and APC require Arg41 for their PAR1-dependent effects. Methods: Using C57BL/6-derived embryonic stem cells and standard gene targeting methods, we prepared C57BL/6 mice carrying the PAR1 mutation of R41 to Q. IIa-induced and APC-induced signaling, detected as phosphorylation of ERK1/2 or Akt in Brain Microvascular Endothelial Cells (BECs), was quantified using immunoblotting. BECs were obtained from homozygous 41QQ-PAR1 mice and wild type 41RR-littermates. Endothelial barrier disruption of cultured BECs was assayed using Trans-Endothelial Resistance (TER) assays (iCelligence, Acea, San Diego). Mortality of wild type and 41QQ-PAR1 mutant mice that was caused by live E. coli-induced pneumonia and to endotoxin was determined using standard methods. The ability of a cytoprotective-selective murine APC mutant (5A-APC) to reduce mortality of E.coli-challenged wild type and homozygous mutant mice was determined. Results: Upon breeding of R41Q-PAR1 heterozygous mice, the progeny did not fit a Mendelian pattern and yielded only 14% rather than 25% homozygous 41QQ mice. This reduced yield of homozygous mutant mice was similar to the previously reported low yield of homozygous PAR1 knockout mice. Homozygous 41QQ-PAR1 mice showed normal protein expression in BECs for PAR1 and endothelial cell protein C receptor (EPCR) antigens. When BECs from homozygous mutant mice were compared to those from wild type littermates, the IIa-induced vascular disruption in TER assays was greatly reduced by the mutation. Intracellular Ca2+ release, a hallmark of IIa-induced signaling, was greatly impaired (>90%) in BECs from homozygous mutant mice compared to wild type controls. IIa-induced phosphorylation of ERK1/2 in BECs was also significantly reduced by the mutation whereas APC-induced phosphorylation of Akt was not significantly affected. In murine sepsis-induced mortality studies, homozygosity for the R41Q-PAR1 mutation conveyed considerable resistance to death induced by either E. coli pneumonia or endotoxin in female mice but not in male mice. Tests to determine whether 5A-APC rescued male mice from sepsis-induced lethality showed that homozygous 41QQ-PAR1 mice were entirely responsive to 5A-APC therapy because 5A-APC treatment reduced mortality from 50 % to 0 % (see Figure). Wild type control mice also showed a beneficial response with reduced mortality in response to 5A-APC therapy, as previously described. Conclusions: These studies show that mutation of Arg41 to Gln in murine PAR1 diminishes or eliminates signaling induced by IIa but not by APC. Moreover, the ability of cytoprotective-selective 5A-APC to reduce bacteria-induced septic mortality in 41QQ-PAR1 mutant mice provides strong in vivo proof-of-concept data for PAR1 activation caused by non-canonical cleavage by APC. In summary, the 41QQ-PAR1 mutant mouse provides a unique and powerful tool to define in vivo requirements for cleavage sites that enable PAR1 signaling activities induced by IIa, APC or other proteases. Figure 1 Figure 1. Disclosures Mosnier: The Scripps Research Institute : The Scripps Research Institute Patents & Royalties. Griffin:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties.

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Wu, Yanqi, Yuehua Wan, and Fengzhi Zhang. "Characteristics and Trends of C-H Activation Research: A Review of Literature." Current Organic Synthesis 15, no. 6 (2018): 781–92. http://dx.doi.org/10.2174/1570179415666180426115417.

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Background: C-H activation has attracted great interests over the past two decades, which resulted in an explosive growth in both quality and quantity of published papers related to this topic. Objective: In this review, a bibliometric analysis was performed to evaluate the publications in this field from 1996 to 2015 based on the Science Citation Index (SCI) Expanded database. This work presented a detailed overview of C-H activation from aspects of types of articles, citations, h-indices, languages, years, journals, institutions, countries and author keywords. Conclusion: The results showed that the USA took the leading position in this research field, followed by P. R. China and German. Chinese Academy of Science had the most publications and the highest h-index, Scripps Research Institute won the first place as far as the highest average citation per paper is concerned. Organometallics, Angewandte Chemie International Edition and Journal of the American Chemical Society were the most productive journals in this field, and Chemistry was the most frequently used subject category. Keywords analysis indicated that most research focused on the Palladium, Rhodium and Copper catalyzed cross-coupling synthetic method development for the heterocycle synthesis. The research about exploring the asymmetric C-H functionalization, mechanism investigation and solving the regioselectivity issue is the development trend in this area.

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Tan, Choon-Hong, and Benjamin List. "Cluster Preface: Asymmetric Brønsted Base Catalysis." Synlett 28, no. 11 (2017): 1270–71. http://dx.doi.org/10.1055/s-0036-1590548.

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Choon-Hong Tan is a professor at the Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore. He received his BSc (Hons) First Class from the National University of Singapore (NUS) and his Phd from the University of Cambridge. He underwent postdoctoral training at the Department of Chemistry and Chemical Biology, Harvard University and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School. He began his independent career at the Department of Chemistry, National University of Singapore in 2003. Choon Hong has focused on the development of organocatalytic Brønsted base reactions that can be catalyzed with chiral guanidines. He has also demonstrated that pentanidiums (conjugated guanidiniums) are efficient phase-transfer catalysts. Recently, he described the use of chiral organic cations such as bisguanidiniums to modulate and activate anionic metallic salts. Benjamin List has been a director at the Max-Planck-Institut für Kohlenforschung since 2005. He obtained his Ph.D. in 1997 (Frankfurt). From 1997 until 1998 he conducted postdoctoral research at The Scripps Research Institute in La Jolla (USA) and became an assistant professor there in January 1999. In 2003 he joined the Max-Planck-Institut für Kohlenforschung. He has been an honorary professor at the University of Cologne since 2004. Ben List’s research focuses on organic synthesis and catalysis. He has contributed fundamental concepts to chemical synthesis including aminocatalysis, enamine catalysis, and asymmetric-counteranion-directed catalysis (ACDC). His latest work deals with chiral counteranions in asymmetric catalysis. This remarkably general strategy for asymmetric synthesis has recently found widespread use in organocatalysis, transition-metal catalysis, and Lewis acid catalysis.

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Bhat, Vikas, Annette von Drygalski, Andrew J. Gale, John H. Griffin, and Laurent O. Mosnier. "Synergistic Effect in Bleed Reduction By superfva and Recombinant Human FVIIa in Vivo Suggests a Novel Bypassing Strategy for Hemophilia Patients with Inhibitors." Blood 124, no. 21 (2014): 692. http://dx.doi.org/10.1182/blood.v124.21.692.692.

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Abstract Introduction: In Hemophilia patients with inhibitors, recombinant human (rh)FVIIa-based bypassing strategy does not always achieve hemostasis indicating a clinical need for improved treatment strategies. We engineered an activated FVa variant (superFVa) with mutations at 3 activated protein C cleavage sites (R506, R306 and R679) and an engineered interdomain disulfide bond (H609C-E1691C) connecting the A2 and A3 domains. SuperFVa resisted inactivation and showed superior hemostatic properties in FVIII-deficient plasma and in mouse models of Hemophilia A compared to wild type rhFVa. Therefore, the hemostatic effects of superFVa alone and in combination with rhFVIIa in hemophilia with inhibitors were determined in more detail. Materials and Methods: Procoagulant and clot stabilizing properties of superFVa, rhFVIIa, and combinations thereof were studied in thrombin generation (endogenous thrombin potential (ETP) and peak height) and clot lysis assays in hemophilia A and normal plasma with or without high titer inhibitors. In vivo efficacy of superFVa alone and in combination with rhFVIIa for bleed reduction in hemophilia was tested in FVIII-deficient mice using a tail clip model. Results: Extensive dose-response titrations of superFVa, rhFVIIa, and combinations thereof in hemophilic or normal plasma with inhibitors indicated synergistic responses for normalization of thrombin generation or clot stabilization. For instance, at 0.4 nM rhFVIIa (1/100 of the therapeutic plasma level), the concentration of superFVa required to normalize thrombin generation was reduced 10-fold. Vice versa, rhFVIIa tested up to 40 nM only marginally improved thrombin generation, however, rhFVIIa in the presence of a low concentration of superFVa (3 nM) normalized thrombin generation at concentrations 50-fold below the therapeutic plasma level. Saturation of the synergistic effect between superFVa and rhFVIIa was evident as thrombin generation reached a plateau at ~110% of normal plasma at higher concentrations of superFVa and rhFVIIa. Similar synergistic normalization of clot lysis time was observed when superFVa and rhFVIIa were used together at low concentration. Beneficial effects of superFVa and rhFVIIa combinations were also observed in 5 individual plasma samples of hemophilia A patients with inhibitors (41-280 BU/ml). ETP and peak height improved ~1.5-3 fold when both superFVa (3 nM) and rhFVIIa (2 nM) were present compared to the individual 10 to 20-fold higher concentrations of superFVa (30 nM) or rhFVIIa (40 nM). Also, a therapeutic dose of rhFVIIa administered to 2 hemophilia patients with inhibitors (32 & 64 BU/ml) provided unremarkable improvements of thrombin generation in plasma taken before and 10 minutes post-infusion, whereas thrombin generation was fully restored upon titration of superFVa ex-vivo. In-vivo tail bleed analysis of FVIII-deficient mice showed a dose dependent reduction of bleeding by superFVa (mean blood loss was 25.9 µL/g at 10 U/kg; 9.7 µL/g at 40 U/kg and 2.5 µL/g at 200 U/kg of superFVa compared to 26.3 µL/g for saline). At the highest dose of superFVa (200 U/kg), bleed reduction was indistinguishable from the bleed reduction by rhFVIII (200 U/kg; 2.9 µL/g). Injection of 1 or 3 mg/kg rhFVIIa, reduced mean blood loss from 25.9 µL/g (saline control) to 16.8 (p=0.1) or 7.2 µL/g (p=0.003), respectively, but rhFVIIa’s effects did not reach the blood loss reduction achieved with rhFVIII (2.9 µL/g, p=0.03). However, combination of rhFVIIa (1 mg/kg) with 10 U/kg superFVa, a concentration that did not reduce bleeding by itself, significantly reduced bleeding from 16.7 to 10.2 µL/g (p=0.05). Combination of rhFVIIa (3 mg/kg) with superFVa (40 U/kg) decreased bleeding even further (1.6 µL/g; p=0.01), similar to what was observed with rhFVIII. Conclusion: The engineered superFVa variant showed synergistic procoagulant effects with rhFVIIa in vitro in hemophilic and normal plasma with inhibitors in thrombin generation and clot lysis assays. Notably, in vivo, superFVa reduced bleeding similar to rhFVIII in FVIII-deficient mice in a dose-dependent fashion, and it was able to enhance further bleed reduction when administered in combination with rhFVIIa. These results warrant further characterization of the potential therapeutic benefits of superFVa as a novel bypassing strategy either alone or in combination with rhFVIIa-based therapy in hemophilia patients with inhibitors. Disclosures von Drygalski: University of California, San Diego: University of California, San Diego Patents & Royalties. Gale:University of California, San Diego: University of California, San Diego Patents & Royalties. Griffin:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties. Mosnier:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties.

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Zhu, Chen, and Xin-Yuan Liu. "Cluster Preface: Radicals – by Young Chinese Organic Chemists." Synlett 32, no. 04 (2021): 354–55. http://dx.doi.org/10.1055/s-0040-1706715.

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(left) received his B.S. degree from Xiamen University in 2003 under the supervision of Prof. Pei-Qiang Huang, and his Ph.D. degree from the Shanghai Institute of Organic Chemistry in 2008 under the supervision of Prof. Guo-Qiang Lin. After postdoctoral research at Gakushuin University, Japan with Prof. Takahiko Akiyama, he moved to the University of Texas Southwestern Medical Center, working as a postdoctoral fellow with Prof. John R. Falck and Prof. Chuo Chen. He was appointed as a professor at Soochow University, China in December 2013. He is currently the Head of the Organic Chemistry Department at Soochow University. His current research interests include radical-mediated transformations, in particular radical rearrangements, and their applications in the construction of natural products and biologically active compounds. Xin-Yuan Liu (right) obtained his B.S. degree from Anhui Normal University (AHNU) in 2001. He continued his research studies at both the Shanghai Institute of Organic Chemistry (SIOC), CAS and AHNU under the joint supervision of Prof. Dr. Shizheng Zhu and Prof. Dr. Shaowu Wang, obtaining his master’s degree in 2004. After a one-year stint in Prof. Gang Zhao’s laboratory at SIOC, he joined Prof. Dr. Chi-Ming Che’s group at The University of Hong Kong (HKU) and earned his Ph.D. degree in 2010. He subsequently undertook postdoctoral studies in Prof. Che’s group at HKU and in Prof. Carlos F. Barbas III’s group at The Scripps Research Institute. At the end of 2012, he began his independent academic career at the Southern University of Science and Technology (SUSTech) and was promoted to a tenured Full Professor of SUSTech in 2018. His research interests are directed towards the design of novel chiral anionic ligands to solve radical-involved asymmetric reactions.

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Takagi, M., T. Kumagai, I. Lee, Y. Ono, and M. Maeno. "Light and Electron Microscope Immunohistochemical and Biochemical Studies of Vitronectin in Developing Rat Bone." Microscopy and Microanalysis 3, S2 (1997): 195–96. http://dx.doi.org/10.1017/s1431927600007868.

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Recently, Seiffert using light microscope (LM) immunohistochemical methods, has localized vitronectin (Vn) in the mineralized bone matrix of mature mouse long bone after demineralization with 10 % nitric acid, indicating that Vn is a specific component of bone tissue. This raises the possibility that Vn is involved in regulation of bone metabolism. The present study extends previous studies to the electron microscope (EM) level and utilizes biochemical methods to determine the distribution and nature of Vn in early bone formation of developing rat mandible with rabbit antimurine Vn IgG (antiVn).Developing jaws of fetuses were collected at embryonic day 15-18 from pregnant Wistar rats. After al-dehyde fixation, specimens with and without osmium post-fixation were dehydrated, and embedded in paraffin, Spurr's resin, or LR gold resin for morphological and immunohistochemical observations. Sections cut from paraffin- or LR gold resin-embedded specimens were immunostained with antiVn, which was kindly provided by Dr. D. Seiffert, The Scripps Research Institute, La Jolla, California.

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Frable, Benjamin, Charlotte Seid, Greg Rouse, and Philip Hastings. "Integration and Curation of At-Risk Collections into the Scripps Institution of Oceanography Collections." Biodiversity Information Science and Standards 2 (June 13, 2018): e26259. http://dx.doi.org/10.3897/biss.2.26259.

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The Scripps Institution of Oceanography (SIO) at the University of California, San Diego maintains one of the largest combined oceanographic collections in the world comprising four collections: Geological (sediment cores and dredged rocks), Pelagic Invertebrates, Benthic Invertebrates and Marine Vertebrates. After surviving threats of dissolution, the SIO Collections are now securely funded and have been able to make other collections available to the scientific community. Over the last few years, both the Marine Vertebrate (SIO-MVC) and Benthic Invertebrate (SIO-BIC) Collections have received National Science Foundation (NSF) and institutional funding to integrate important at-risk collections from University of California, Los Angeles (UCLA), the Monterey Bay Aquarium Research Institute (MBARI) and the University of Victoria. The UCLA Ichthyological Collection, around 9000 lots, was at risk of disposal due to hazardous material concerns and lack of institutional support. The collection, accumulated primarily under Boyd Walker (1949-1980) and later Don Buth (1980-), contains material from extensive surveys of the near-shore fishes of Southern California, Baja California and the Tropical Eastern Pacific including remote oceanic islands such as the Revillagigedos, Clipperton and the Galapagos. The UCLA collection also contains over 150 secondary types and over 100 species new to the SIO-MVC. Due to lack of support, the collection records were never digitized and the collection was minimally curated and its holdings were poorly known. For over two years, the collection manager and student employees have physically re-curated and integrated this material into the SIO-MVC. These data are now available online via iDigBio and VertNet and have already been used in numerous studies. The SIO-BIC, holding 45,000 lots, is accepting ownership of two deep-sea animal collections from Verena Tunnicliffe at the University of Victoria and Robert Vrijenhoek at MBARI. These collections include 10,900+ lots, largely from hydrothermal vents across the Pacific. Collected over 35 years from remote deep-sea sites that are difficult and expensive to access, these collections represent a major resource for systematics, genetics, and ecology. With Dr. Vrijenhoek now retired and Dr. Tunnicliffe nearing retirement, their collections were at risk of being lost. This material will be made discoverable online through the SIO-BIC database and iDigBio, and will be available for loan and examination. In the last year, the collection manager and five undergraduate employees have integrated some 3,000 lots. With support from the institution and the NSF, the SIO collections are solidifying their roles as central repositories for deep-sea and Eastern Pacific fauna.

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Nicolaou, K. C. "Professor K. C. Nicolaou*Department of Chemistry, The Scripps Research Institute and the University of California, San Diego, 10550 North Torrey Pines Road, La Jolla, California 92037 USA." Journal of the Chemical Society, Perkin Transactions 1, no. 5 (February 6, 2002): vii. http://dx.doi.org/10.1039/b200756h.

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Sun, Jian, and Subhash C. Sinha. "Stereoselective Total Synthesis of Epothilones by the Metathesis Approach Involving C9−C10 Bond Formation We are thankful to Professor Richard A. Lerner and Samuel J. Danishefsky for helpful discussions. This research was funded by the Scripps Research Institute and the Skaggs Institute for Chemical Biology." Angewandte Chemie 114, no. 8 (2002): 1439. http://dx.doi.org/10.1002/1521-3757(20020415)114:8<1439::aid-ange1439>3.0.co;2-1.

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Koh, Cho Yeow, Jasmine Nguyen, Sayaka Shibata, et al. "Structure-based drug design against Trypanosoma brucei methionyl-tRNA synthetase." Acta Crystallographica Section A Foundations and Advances 70, a1 (2014): C708. http://dx.doi.org/10.1107/s2053273314092912.

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Infection by the protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, commonly known as sleeping sickness. The disease is fatal without treatment; yet, current therapeutic options for the disease are inadequate due to toxicity, difficulty in administration and emerging resistance. Therefore, methionyl-tRNA synthetase of T. brucei (TbMetRS) is targeted for the development of new antitrypanosomal drugs. We have recently completed a high-throughput screening campaign against TbMetRS using a 364,131 compounds library in The Scripps Research Institute Molecular Screening Center. Here we outline our strategy to integrate the power of crystal structures with high-throughput screening in a drug discovery project. We applied the rapid crystal soaking procedure to obtain structures of TbMetRS in complex with inhibitors reported earlier[1] to approximately 70 high-throughput screening hits. This resulted in more than 20 crystal structures of TbMetRS·hit complexes. These hits cover a large diversity of chemical structures with IC50 values between 200 nM and 10 µM. Based on the solved structures and existing knowledge drawn from other in-house inhibitors, the IC50 value of the most promising hit has been improved. Further development of the compounds into potent TbMetRS inhibitors with desirable pharmacokinetic properties is on-going and will continue to benefit from information derived from crystal structures.

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Aoki, Nobuyuki, Shigeyuki Ishidoya, Yasunori Tohjima, et al. "Intercomparison of O2 ∕ N2 ratio scales among AIST, NIES, TU, and SIO based on a round-robin exercise using gravimetric standard mixtures." Atmospheric Measurement Techniques 14, no. 9 (2021): 6181–93. http://dx.doi.org/10.5194/amt-14-6181-2021.

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Abstract. A study was conducted to compare the δ(O2/N2) scales used by four laboratories engaged in atmospheric δ(O2/N2) measurements. These laboratories are the Research Institute for Environmental Management Technology, Advanced Industrial Science and Technology (EMRI/AIST); the National Institute for Environmental Studies (NIES); Tohoku University (TU); and Scripps Institution of Oceanography (SIO). Therefore, five high-precision standard mixtures for the O2 molar fraction gravimetrically prepared by the National Metrology Institute of Japan, AIST (NMIJ/AIST) with a standard uncertainty of less than 5 per meg (0.001 ‰) were used as round-robin standard mixtures. EMRI/AIST, NIES, TU, and SIO reported the analyzed values of the standard mixtures on their own δ(O2/N2) scales, and the values were compared with the δ(O2/N2) values gravimetrically determined by NMIJ/AIST (the NMIJ/AIST scale). The δ(O2/N2) temporal drift in the five standard mixtures during the intercomparison experiment from May 2017 to March 2020 was corrected based on the δ(O2/N2) values analyzed before and after the laboratory measurements by EMRI/AIST. The scales are compared based on offsets in zero and span. The relative span offsets of EMRI/AIST, TU, NIES, and SIO scales against the NMIJ/AIST scale were -0.11%±0.10%, -0.10%±0.13%, 3.39 %±0.13 %, and 0.93 %±0.10 %, respectively. The largest offset corresponded to a 0.30 Pg yr−1 decrease and increase in global estimates for land biospheric and oceanic CO2 uptakes based on trends in atmospheric CO2 and δ(O2/N2). The deviations in the measured δ(O2/N2) values on the laboratory scales from the NMIJ/AIST scale are 65.8±2.2, 425.7±3.1, 404.5±3.0, and 596.4±2.4 per meg for EMRI/AIST, TU, NIES, and SIO, respectively. The difference between atmospheric δ(O2/N2) values observed at Hateruma Island (HAT; 24.05∘ N, 123.81∘ E), Japan, by EMRI/AIST and NIES were reduced from -329.3±6.9 to -6.6±6.8 per meg by converting their scales to the NMIJ/AIST scale.

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Goswami, J. N., and J. D. Macdougall. "Devendra Lal. 14 February 1929—1 December 2012." Biographical Memoirs of Fellows of the Royal Society 70 (March 3, 2021): 263–81. http://dx.doi.org/10.1098/rsbm.2020.0047.

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Devendra Lal was an Indian nuclear physicist who began his career studying particle physics while a student at the Tata Institute of Fundamental Research (TIFR) in Bombay, using tracks in nuclear emulsions to study cosmic ray particles and their interactions. He soon moved on to the search for radionuclides produced in the atmosphere by cosmic ray bombardment, independently (with colleagues) discovering radioisotopes of Be, P and Si and using them as geophysical tracers for atmospheric, meteorological and oceanographic processes. His career revolved principally around multiple aspects of cosmic rays, employing theory and experiment to examine their flux, chemical composition and energy spectrum, both at present and in the past through (for example) studies of particle tracks in the minerals of meteorites and lunar samples. He played a major role in developing approaches for the use of terrestrial cosmic-ray-produced isotopes as dating tools and tracers for a wide range of Earth processes, from biological cycles in the ocean to landscape evolution and ice ablation in the Antarctic. At various stages of his career Lal was professor at TIFR and led the geophysics group there, was professor and director of the Physical Research Laboratory in Ahmedabad, India, and was professor at the Scripps Institution of Oceanography, University of California San Diego. He was elected fellow of numerous scientific organizations and academies internationally, and was the recipient of many scientific awards and prizes.

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Witczak, Zbigniew J. "C-Glycoside Synthesis. By Maarten H. D. Postema, (Scripps Research Institute, La Jolla, California), CRC Press Inc. Boca Raton. 1995, 379pp. $ 99.50 in USA/Outside U.S. $119.00. ISBN 0-8413-9150-4." Journal of Carbohydrate Chemistry 15, no. 1 (1996): 123–24. http://dx.doi.org/10.1080/07328309608005432.

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29

Farid, Marjan. "Pearls for Secondary Intraocular Lens Implantation." US Ophthalmic Review 10, no. 01 (2017): 13. http://dx.doi.org/10.17925/usor.2017.10.01.13.

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Marjan Farid is Director of the Cornea, Cataract, and Refractive Surgery Faculty and Vice-chair of the Ophthalmic Faculty at the Gavin Herbert Eye Institute (GHEI) at the University of California, Irvine (UCI), California, US. Dr Farid’s clinical practice is divided between patient care, teaching, and research. She enjoys teaching ophthalmology to medical students, ophthalmology residents, and cornea fellows. She serves on the Residency Education Committee and is the Director of the cornea fellowship program at the GHEI. Her research interests focus on corneal surgery, specifically in the use of the femtosecond laser for corneal transplantation. She performs all forms of corneal transplantation—femtosecond enabled and lamellar keratoplasty (DSEK and DALK). Dr Farid is also the founder of the severe ocular surface disease center at UCI. She performs limbal stem cell transplants, as well as artificial corneal transplantation for the treatment of patients with severe ocular surface disorders. She serves as an associate medical director for the Sight Life Eye Bank. Her work has been published in numerous peer-reviewed journals, she has authored six textbook chapters, and travels to multiple national meetings to present her research work. She serves as an Editorial Board member of Ophthalmology, the leading journal in her field. Dr Farid graduated summa cum laude from UCLA with a degree in biology. She earned her medical degree at UC-San Diego in 2002 and completed a transitional year internship at Scripps-Mercy Hospital in San Diego. She completed her residency training in ophthalmology at UCI. She subsequently completed her fellowship training in the area of cornea/external disease and refractive surgery under the mentorship of Dr Roger Steinert at UCI.

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Webb, David J. "David Edgar Cartwright. 21 October 1926 — 2 December 2015." Biographical Memoirs of Fellows of the Royal Society 63 (January 2017): 99–115. http://dx.doi.org/10.1098/rsbm.2017.0001.

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David Cartwright was one of the world's leading authorities on the tides. However, when reflecting on his life, Cartwright made the point that his early scientific career was not a success. Indeed in 1953, at the age of 27, he had virtually despaired of any creative scientific future. At the time he was being pressurized to stop his work on the statistics of ship motions but his prospects rapidly changed when he was invited to apply for a post at the new National Institute of Oceanography (NIO) being set up by George Deacon. At NIO he soon made important contributions to the study of ocean waves, especially the calculation of directional spectrum and wave climate. His earlier involvement with ship motions also culminated in a successful joint study with Louis Rydill on the response of ships to the spectrum of waves. Following this, his use of computer methods for time-series analysis led to an invitation to the Scripps Institution of Oceanography where, with Walter Munk, he developed the response method of analysing tides making use of the very long tidal records collected from Hawaii and Newlyn. He was also made aware of the significant lack of good tidal data from the deep ocean. Returning to the UK, he continued these interests, studying the deep-ocean tides of the Atlantic and leading an international collaboration that measured deep-ocean tides. He also investigated the effect of tides on storm surges around the UK. He became assistant director in charge of the Institute of Oceanographic Sciences (IOS) Bidston laboratory, where he continued these activities and started research on estimating the tides using data from the Seasat radar altimeter. After retirement he successfully extended this work with Richard Ray at the Goddard Space Flight Center. Using Geosat altimeter data they generated accurate global maps of the tides in a set of papers that Cartwright considered to be his best work. He wrote a successful book titled ‘ Tides: a scientific history ’, and later published further work with Ray on the internal tides of the ocean.

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Prisinzano, Thomas E. "Classics in Total Synthesis II By K. C. Nicolau and S. A. Synder (Scripps Research Institute). Wiley-VCH, Weinheim. 2003. xix + 639 pp. 71/2× 11 in. $64.95. (soft). ISBN 3-527-30684-6." Journal of Natural Products 69, no. 2 (2006): 308. http://dx.doi.org/10.1021/np0582729.

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Pan, Guohui, Zhengren Xu, Zhikai Guo, et al. "Discovery of the leinamycin family of natural products by mining actinobacterial genomes." Proceedings of the National Academy of Sciences 114, no. 52 (2017): E11131—E11140. http://dx.doi.org/10.1073/pnas.1716245115.

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Nature’s ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF–SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF–SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature’s rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature’s biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.

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Barchi, Joseph J. "Carbohydrate-Based Drug Discovery, Volumes 1 and 2 Edited by Chi-Huey Wong (Scripps Research Institute). Wiley-VCH, New York. 2003. xxxii + 459 (1) pp; xxiv + 486 (2) pp. 7 × 10.5 in. $295.00. ISBN 3-527-30632-3." Journal of Natural Products 67, no. 11 (2004): 1956–57. http://dx.doi.org/10.1021/np030750x.

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34

Saha, Rinku, Shraddha Thakkar, Ahmed Al-Dwairi, Kuppan Gokulan, Frank Simmen, and Kottayil Varughese. "Malic enzyme is a target for drug design to combat obesity and cancer." Acta Crystallographica Section A Foundations and Advances 70, a1 (2014): C846. http://dx.doi.org/10.1107/s2053273314091530.

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The cytosolic malic enzyme (ME1) plays an important role in insulin-induced lipogenesis and has profound effects on colon cancer progression. ME1 generates pyruvate, NADPH and carbon dioxide from malate, a Krebs cycle intermediate. NADPH has an important role in de novo synthesis of long-chain fatty acids whereas pyruvate is cycled back into mitochondria. The pyruvate cycle has been hypothesized to be a necessary component of glucose-stimulated insulin secretion. Increased insulin signaling in liver and adipose tissues leads to higher accumulation of fat mass increasing the risk for obesity. NADPH and fatty acids also support cancer cell proliferation and migration. Thus ME1 may be a suitable drug target to counter obesity and prevent cancer progression. In the current work, computer-aided drug design techniques were used to identify possible ME1 inhibitors with therapeutic value. The software package SYBYL was used for defining the binding pocket and virtual screening was performed to mine through large databases (ZINC-UCSF) containing drug-like molecules in order to identify molecules that could form hydrogen bonds to the enzyme and fit into the active site. The molecules so obtained were then used for docking using the software packages SURFLEX DOCK (SYBYL) and AutoDock Vina (Scripps Research Institute). Lead molecules having minimum binding energy score were identified and two in vitro assays were carried out on the top hit molecules. We tested a total of 11 compounds for activity using an enzyme assay and 4 of these compounds were found to diminish NADPH production significantly. Additionally we performed a cell proliferation assay with colorectal cancer cell line (HCT-116) using the above 4 compounds and three of these compounds exhibited strong activity against cancer cell growth. Supported in part by NIH grant CA136493.

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35

Whittaker, James W. "Annual Review of Biophysics and Biomolecular Structure, Volume 33 Edited by Douglas C. Rees (California Institute of Technology), Michael P. Sheetz (Columbia University), and James R. Williamson (The Scripps Research Institute). Annual Reviews: Palo Alto, CA. 2004. xiv + 520 pp. $84.00 (print and online for individuals). ISBN 0-8243-1833-1." Journal of the American Chemical Society 127, no. 3 (2005): 1061–62. http://dx.doi.org/10.1021/ja040969d.

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36

Ahlbäck, Tore. "Editorial." Scripta Instituti Donneriani Aboensis 25 (January 1, 2013): 5. http://dx.doi.org/10.30674/scripta.67429.

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Editorial note of Scripta Instituti Donneriani Aboensis vol. 25, Digital Religion, based on papers read at the conference arranged by the Donner Institute for Research in Religious and Cultural History, Åbo Akademi University, Åbo/Turku, Finland, on 13–15 June 2012.

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Mosnier, Laurent O., and John H. Griffin. "Non-Canonical Cleavage of Protease Activated Receptor 1 (PAR1) by Activated Protein C Provides Novel Insights Into the Repertoire of Cytoprotective and Proinflammatory PAR1 Signaling." Blood 118, no. 21 (2011): 534. http://dx.doi.org/10.1182/blood.v118.21.534.534.

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Abstract 534 Activated protein C (APC) exerts direct cytoprotective activities on cells that are required for APC's ability to reduce mortality in murine sepsis models and that likely have potential contributions to mortality reduction in patients with severe sepsis. Although multiple receptors have been implicated to promote APC direct cytoprotective activities on various cell types, the endothelial protein C receptor (EPCR) and PAR1 play pivotal roles in our current understanding of the molecular mechanisms for APC's direct effects on cells. According to the current generally accepted model, binding of APC to EPCR on the endothelial cell membrane facilitates activation of PAR1 and induction of signaling that ultimately results in cytoprotective effects. However, this model raises the dilemma of how thrombin and APC can often have seemingly opposing effects when activating PAR1. To gain insights into mechanisms for the contrasting effects of APC vs. thrombin signaling, PAR1 activation by APC was studied in greater detail. We hypothesized that APC might cleave PAR1 not only at Arg41 but also at Arg46 with distinctly different consequences than caused by Arg41 cleavage and that this alternative cleavage could distinguish APC's from thrombin's effects. Previously we found that, in the presence of EDTA, APC cleaved a synthetic PAR1 N-terminal peptide (TR33-66) at Arg41. Now we have found that, in buffers containing CaCl2, APC cleaved the PAR1 TR33-66 peptide at Arg41 and also at an additional site distal from Arg41. Proteolysis of the TR33-66 peptide with APC resulted in fragments corresponding to TR33-41 and TR42-66 similar to thrombin. But in contrast to thrombin, a third fragment was generated by APC and the TR42-66 fragment disappeared over time with the concomitant accumulation of a novel peptide. Furthermore, incubation of thrombin-cleaved TR33-66 with APC resulted in additional proteolysis of TR42-66 and generation of the same novel fragment, indicating the possibility of a second APC cleavage site in PAR1 that was distinct and distal from Arg41. Isolation of the novel proteolytic fragments and their MALDI-TOF analysis identified Arg46 as the second APC cleavage site in the TR33-66 peptide. When cells containing wild-type EPCR were transfected with SEAP-PAR1 wild type and mutant constructs, both thrombin and APC cleaved wt-PAR1. As anticipated, efficient cleavage by thrombin was observed for R46Q-PAR1 but not R41Q-PAR1 or R41Q/R46Q-PAR1. In contrast, APC readily cleaved both R41Q-PAR1 and R46Q-PAR1 whereas cleavage of R41Q/R46Q-PAR1 by APC was negligible. APC mediated cleavage of R41Q-PAR1 and R46Q-PAR1 required the presence of functional EPCR and was not supported by the APC-binding-defective E86A-EPCR mutant. These results indicate that on cells Arg46 in PAR1 can serve as a second cleavage site for APC. Since the new PAR1 N-terminus after proteolysis acts as a tethered ligand for receptor activation, cleavage at Arg41 vs. Arg46 could potentially create structurally distinct agonists, which might help explain the divergent patterns for PAR1-mediated cytoprotective APC signaling vs. proinflammatory IIa signaling. In studies to see if the APC-induced new PAR1 N-terminus starting at Asn47 could promote signaling, we found that a synthetic peptide with the PAR1 47–66 N-terminal sequence (NPND-peptide) increased Akt phosphorylation at Ser473 in endothelial cells over 30 min whereas neither a control scrambled sequence (47-66)-peptide nor a TRAP peptide had a similar remarkable effect on Akt phosphorylation. Moreover, the NPND-peptide, but neither the scrambled sequence-related peptide nor a TRAP peptide, inhibited staurosporine-induced endothelial cell apoptosis. Thus, it appears that the new N-terminus generated by APC's cleavage at Arg46 in PAR1 generates a novel tethered ligand that can induce cytoprotective APC-like but not thrombin-like signaling characteristics. In summary, APC is capable of a unique, functionally significant cleavage of PAR1 at Arg46 that can initiate distinctive signaling compared to canonical cleavage of PAR1 at Arg41. This implies activated PAR1 is a GPCR with multiple active conformations capable of multiple, agonist selective activity profiles which may help explain the divergent patterns for cytoprotective APC signaling vs. proinflammatory thrombin signaling. Disclosures: Mosnier: Scripps Research institute: Employment, Patents & Royalties. Griffin:ZZBiotech LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Scripps Research Institute: Employment, Patents & Royalties.

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38

I Puerto, Fernando, Jorge E Zavala, Arsenio Rosado-Franco, and Luis Jorge Gamboa-Albornoz. "Estudio serológico del virus de la Enfermedad de Borna en pacientes esquizofrénicos de Yucatán, México." REVISTA BIOMÉDICA 15, no. 3 (2004): 141–47. http://dx.doi.org/10.32776/revbiomed.v15i3.384.

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Antecedentes. El Virus de la Enfermedad de Borna (VEB) es un virus envuelto, con una cadena de RNA simple de polaridad negativa. VEB causa enfermedad a nivel del Sistema Nervioso Central en muchos animales vertebrados, que frecuentemente se manifiesta como anormalidades en la conducta. La infección silvestre con el VEB ocurre de manera natural. De hecho fue detectada primero en caballos y en ovejas en algunas regiones de Europa Central. Los resultados serológicos obtenidos de diferentes laboratorios en los últimos 15 años y recientemente con la biología molecular, muestran que el VEB puede infectar a los seres humanos y que también puede estar asociado a ciertos trastornos psiquiátricos. Reportamos el primer estudio de seroprevalencia del VEB en humanos de Latinoamérica. Metodología. Muestras de suero fueron obtenidas de 70 pacientes con diagnóstico de esquizofrenia y otras 70 muestras de suero se tomaron de personas sanas que participaron de manera voluntaria al estudio y que fueron pareados por edad, sexo y nivel socioeconómico. Las muestras de ambos grupos fueron procesadas para analizar por Western-blot en nuestro laboratorio y en The Scripps Research Institute en San Diego, CA USA. Como antígeno se utilizó a la fosfoproteína (P) obtenida de la expresión con GSTP. Resultados. El grupo de pacientes esquizofrénicos, fueron 47 hombres y 23 mujeres con un promedio de edad de 40 años (rango de 17 a 73 años). Todos ellos nacieron en la Península de Yucatán. Para su clasificación el diagnóstico se basó en el ICD-10. El estudio mostró una prevalencia de anticuerpos en los sueros contra la proteína GST-P de 21.43% (15/70), mientras que no se encontraron anticuerpos en el suero de las personas sanas. No se encontró relación entre el género, la edad y tipo de esquizofrenia y la presencia de anticuerpos contra VEB. Conclusiones. Hasta donde sabemos, éste es el primer estudio en Latinoamérica que se lleva a cabo para detectar anticuerpos contra el VEB en seres humanos. Nuestros resultados son semejantes a lo reportado en la literatura y apoyan la posible asociación entre la presencia de anticuerpos contra el VEB y los trastornos psiquiátricos. Sin embargo, se necesita continuar con más estudios para conocer si es realmente un problema de salud y cual podría ser su magnitud.

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Wu, Emma, Priyanka Samanta, Ye Li, Le Shen, Fatemeh Khalili, and Christopher Weber. "P144 IN SILICO IDENTIFICATION OF PUTATITVE CLAUDIN CHANNEL BLOCKERS." Inflammatory Bowel Diseases 26, Supplement_1 (2020): S30. http://dx.doi.org/10.1093/ibd/zaa010.073.

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Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea in IBD. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that molecules that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative drugs that bind in the claudin-15 pore. AutoDock Vina (Scripps Research Institute) was initially used to assess rigid docking using small molecule ligand databases. The ligands were analyzed based on binding affinity to the pore and visualized using VMD (University of Illinois at Urbana-Champaign) for their potential blockage of the channel. Overall, a total of eight candidate ligands from the databases were identified: three from the UICentre database of 10000 ligands, one chemically similar structure identified in another online database (Chemspider), and four which are modifications on the chemical structure generated using ChemDraw. The analysis revealed that the eight ligands were docked in two predominant positions. In the first position, the ligands with more rings docked in an almost linear fashion and interacted with both D55 and D64 pore residues. In the second position of binding, the ligands were more flexible and could hence fold to interact only with D55 residues, thus biding predominantly in the center of the pores. To further evaluate these ligands, we will now turn to 1) flexible claudin-15 docking studies, 2) molecular dynamic simulations and, 3) in vitro measurements using monolayers induced to express claudin -15 and claudin-15 mutants. We also developed a claudin-2 homology model on which we will perform docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Finally, other databases will be analyzed for potential ligand blockers of claudin-2 and -15.

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40

Bragato, P. L., D. Pesaresi, A. Saraò, P. Di Bartolomeo, and G. Durì. "OGS improvements in the year 2011 in running the Northeastern Italy Seismic Network." Advances in Geosciences 34 (April 30, 2013): 5–8. http://dx.doi.org/10.5194/adgeo-34-5-2013.

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Abstract. The Centro di Ricerche Sismologiche (CRS, Seismological Research Center) of the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale - OGS (Italian National Institute for Oceanography and Experimental Geophysics) in Udine (Italy) after the strong earthquake of magnitude Mw = 6.4 occurred in 1976 in the Italian Friuli-Venezia Giulia region, started to operate the Northeastern Italy Seismic Network: it currently consists of 12 very sensitive broad band and 21 simpler short period seismic stations, all telemetered to and acquired in real time at the OGS-CRS data centre in Udine. Real time data exchange agreements in place with other Italian, Slovenian, Austrian and Swiss seismological institutes lead to a total number of 93 seismic stations acquired in real time, which makes the OGS the reference institute for seismic monitoring of Northeastern Italy, as shown in Fig. 1 (Bragato et al., 2011; Saraò et al., 2010). Since 2002 OGS-CRS is using the Antelope software suite as the main tool for collecting, analyzing, archiving and exchanging seismic data, initially in the framework of the EU Interreg IIIA project "Trans-national seismological networks in the South-Eastern Alps" (Bragato et al., 2010; Pesaresi et al., 2008). SeisComP is also used as a real time data exchange server tool. In order to improve the seismological monitoring of the Northeastern Italy area, at OGS-CRS we tuned existing programs and created ad hoc ones like: a customized web server named PickServer to manually relocate earthquakes, a script for automatic moment tensor determination, scripts for web publishing of earthquake parametric data, waveforms, state of health parameters and shaking maps, noise characterization by means of automatic spectra analysis, and last but not least scripts for email/SMS/fax alerting. A new OGS-CRS real time seismological website (http://rts.crs.inogs.it/) has also been operative since several years.

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Krueger, Robert J. "Book Review of Molecules that Changed the World Molecules that Changed the World . Edited by K. C. Nicolau and T. Montanon (Scripps Research Institute and the University of Crete, respectively). Wiley-VCH , Weinheim . 2008 . xx + 336 pp. 23 × 30 cm. $55.00. ISBN 978-3-527-30983-2 ." Journal of Natural Products 73, no. 5 (2010): 1023–24. http://dx.doi.org/10.1021/np100167s.

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42

Saito, Emi, Yumiko Matsubara, Hidenori Suzuki, Yasuo Ikeda, and Mitsuru Murata. "Megakaryocytes and Functional Platelets Obtained from Human Subcutaneous Adipocytes in an In Vitro Differentiation System." Blood 110, no. 11 (2007): 3702. http://dx.doi.org/10.1182/blood.v110.11.3702.3702.

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Abstract Because of the difficulty in obtaining the sufficient amounts of hematopoietic stem cells from bone marrow, peripheral blood, and cord blood cells, studies of an in vitro experimental system that allows the production of abundant number of megakaryocytes (MKs) and platelets are currently the focus of research. Here, we present a novel system where human subcutaneous adipocytes were successfully differentiated into MK lineages in an in vitro liquid culture system. We also show that subcutaneous preadipocytes could be successfully transfected with vectors, to obtain modified MKs. Primary human subcutaneous preadipocytes (Cambrex Bio Science Walkersvile, Inc. Walkersville, MD, USA) were cultured in conditioned media to differentiate into mature adipocytes. Cells were cultured in serum-free media containing thrombopoietin for differentiation into MK lineages. The MKs or platelets were counted by flow cytometric analysis on day 14 using the relative value of CD41(+)/propidium iodide(+) cells or platelet size CD41(+) cells, respectively, versus 107 subcutaneous preadipocytes on day 0. The MK and platelet cell count was approximately 9600/ 107 and 2200/ 107, respectively. Morphological analysis with electron microscopy demonstrated that MKs, which had typical organelles such as granules, demarcation membrane, and nuclei, and platelets, which had typical contents such as granules, mitochondria, and open canalicular system, were successfully obtained from subcutaneous preadipocytes. We then attempted to transfect subcutaneous preadipocytes with vectors to obtain transformed MKs. Two glycoprotein (GP) Ib alpha polymorphisms, 145Thr/Met and 1–4 repeats of variable number tandem repeat of 13 amino-acid sequences, were used as the marker of gene transfer, which were detected by PCR-restricited fragment length polymorphism (RFLP) and Western blot analysis, respectively. Subcutaneous preadipocytes with the 145Thr/Thr and 1 repeat sequences were transfected with the expression vector carrying GPIb alpha with the 145Met and 4 repeats sequences. PCR-RFLP analysis with gel electrophoresis was performed on each RNA sample from the expression vector-transfected and non-transfected cells. Non-transfected cell sample had bands corresponding to the 145Thr sequence position, while the expression vector-transfected cell sample had bands corresponding to both the 145Thr and Met sequences. Western blot analysis with an anti-GPIb alpha monoclonal antibody, LJ-Ib alpha1 (a generous gift from Dr. ZM Ruggeri, The Scripps Research Institute, La Jolla, CA, USA), showed bands of the expected size corresponding to 1R and 1R/4R. In summary, we established an in vitro culture system to produce MKs and platelets from subcutaneous adipocytes. We were also able to obtain transfected MKs from subcutaneous preadipocytes.

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Griffin, John H., and Laurent O. Mosnier. "Activated Protein C Cellular Pathways Regulating Thrombosis." Blood 118, no. 21 (2011): SCI—44—SCI—44. http://dx.doi.org/10.1182/blood.v118.21.sci-44.sci-44.

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Abstract SCI-44 Plasma protein C is known for its mild deficiency linked to venous thrombosis risk and severe deficiency linked to neonatal purpura fulminans. Activated protein C (APC) exerts both anticoagulant activity via proteolytic inactivation of factors Va and VIIIa and cellular cytoprotective actions via direct initiation of cell signaling. Based on studies of engineered APC mutants and the use of genetically modified mice, APC’s cell signaling actions are thought to drive murine APC’s mortality reduction in sepsis models, neuroprotective actions in brain injury models, and nephroprotective effects in kidney injury models. These actions in vivo are generally suggested to involve multiple receptors (PAR1, endothelial protein C receptor [EPCR], PAR3, and CD11b), while in vitro studies implicate these receptors and potentially also other receptors (apoER2, β1 and β3 integrins, S1P1, and the angiopoietin/Tie-2 axis) for APC’s cellular effects. Crosstalk among these receptors may permit a timely integration of APC-induced signaling, which ultimately determines APC’s effects on a specific cell and organ. Central to many in vivo and in vitro published studies is the implication that APC provides beneficial effects via EPCR-dependent PAR1-dependent cell signaling. This central role for PAR1 poses the dilemma of how thrombin and APC can often seem to have opposing effects when activating PAR1. Microdomain-specific PAR1 signaling by APC versus thrombin may help explain some observations. Binding of protein C or APC to EPCR on endothelial cells appears to determine whether these proteins and PAR1 are or are not colocalized in microdomains with caveolin-1. APC’s activation of Rac1 via PAR1 requires EPCR and caveolin-1 whereas thrombin’s activation of RhoA via PAR1 is independent of EPCR and caveolin-1. We hypothesized that APC might cleave PAR1 not only at Arg41 but also at Arg46 with distinct consequences and that this could distinguish APC’s from thrombin’s signaling. We found that APC cleaved the PAR1 N-terminal synthetic TR33-66 peptide at Arg41 and also at another site distal from Arg41. Isolation of the novel proteolytic fragments and their MALDI-TOF analysis identified Arg46 as that cleavage site. When cells containing EPCR were transfected with secretable alkaline phosphatase (SEAP)-PAR1 wild type and mutant constructs, both thrombin and APC cleaved wt-PAR1 but not R41Q/R46Q-PAR1. As expected, thrombin also did not cleave R41A-PAR1 or R41Q-PAR1. But APC very efficiently cleaved both the R41A-PAR1 and the R41Q-PAR1 mutants. We tested a synthetic PAR1 analog peptide (Asn47-residue 66) to see if it could promote signaling. This PAR1 (47–66)-peptide increased Akt phosphorylation at Ser473 in endothelial cells over 30 minutes whereas neither a control scrambled sequence (47–66)-peptide nor a TRAP peptide had a similar effect. The PAR1 (47–66)-peptide, but the control scrambled sequence-peptide or TRAP, inhibited staurosporine-induced endothelial cell apoptosis. Thus, it appears that the new N-terminus generated by APC’s cleavage at Arg46 in PAR1 generates a novel tethered ligand, which could induce selective APC-like protective signaling. Hence, APC is capable of a unique, functionally significant cleavage of PAR1. Further in vitro and in vivo studies are needed to address a number of obvious questions. In summary, explanations for APC’s beneficial cellular cytoprotective effects may be found in its ability to signal via multiple receptors selectively located in different cell membrane microdomains and potentially also in its ability to activate PARs by cleavages at unique sites, which initiate unique signaling events on different cells in different organs. Disclosures: Griffin: ZZBiotech LLC: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Scripps Research Institute: Employment, Patents & Royalties. Mosnier:Scripps Research institute: Employment, Patents & Royalties.

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44

Smith, Milton R. "Review of C−H Activation. Topics in Current Chemistry, 292 Review of C−H Activation. Topics in Current Chemistry, 292 . Edited by Jin-Quan, Yu (Scripps Research Institute, La Jolla, CA) and Zhangjie, Shi (Peking University, Beijing, China). Springer-Verlag : Berlin, Heidelberg . 2010 . xx + 384 pp. $309. ISBN 978-3-642-12355-9 ." Journal of the American Chemical Society 133, no. 10 (2011): 3684. http://dx.doi.org/10.1021/ja200038d.

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Hudson, Derek. "Handbook of Combinatorial Chemistry. Vols. 1 and 2 Edited by K. C. Nicolaou (Scripps Research Institute and University of California, San Diego), R. Hanko (Bayer AG, Leverkusen), and W. Hartwig (Bayer AG, Wuppertal). Wiley-VCH Publishers, Weinheim. xxxi + 609 pp (Vol. 1), xxxi + 503 pp (Vol. 2). 17 × 24 cm. $345.00. ISBN 3-527-30509-2." Journal of Natural Products 65, no. 11 (2002): 1746–47. http://dx.doi.org/10.1021/np020735c.

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Kirkpatrick, Andy. "Research into language education at The Research Centre for Language Education and Acquisition in Multilingual Societies (RCLEAMS) at the Hong Kong Institute of Education, China." Language Teaching 44, no. 3 (2011): 394–98. http://dx.doi.org/10.1017/s0261444811000139.

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The Research Centre for Language Education and Acquisition in Multilingual Societies (RCLEAMS) is one of four Institute-level Research Centres at the Hong Kong Institute of Education (HKIEd). The principal aim of RCLEAMS is to study multilingual acquisition, language contact and the respective roles of different languages of education in contexts where the languages are not cognate (and where the scripts are often different), in order to be able to better understand the processes and issues involved and to inform governments and language policy-makers. Our particular focus is on Asian languages, including, of course, Chinese, and English. Further details about RCLEAMS, including our specific objectives and international partners, can be found at the website (www.ied.edu.hk/rcleams/). While RCLEAMS itself is relatively small, with only four full-time researchers, we conduct collaborative research with colleagues from the Institute itself, other universities in Hong Kong and with a number of international partners. There are also some thirty doctoral students in the field of language education who work closely with the Centre. We invite anyone who might be interested in working collaboratively with us to get in touch. This report will summarise current and recently completed research projects.

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Purnomo, SF Luthfie Arguby. "Ludic writing: Challenges in gamifying English creative writing class for technopreneurial purposes." Journal on English as a Foreign Language 7, no. 1 (2017): 59. http://dx.doi.org/10.23971/jefl.v7i1.503.

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This paper, first of three research parts, attempts to describe the challenges English Letters at IAIN (Institut Agama Islam Negeri/State Islamic Institute) Surakarta faced in implementing gamification for technopreneurial purposes in regard to the transformation of a creative writing class into a ludic writing class, a gamification infused writing class. The challenges revealed are story-game script adaptation, integration portion, and monetization. Specific problems occur on each challenge. Story-game script adaptation exposes three problems namely (1) conditional branching system (2) visualization (3) copyrighted material issues (4) and writing mechanics adaptation. Integration portion challenge displays a problem on the insufficient alloted time for gamifying the creative writing class. Monetization challenge indicates three problems namely (1) the inexistence of monetization team, (2) the inexistence of institutional regulation for monetization management by study programs, (3) responses to gaming trends. Responding to these problems, solutions specifically designed based on the nature of the problems are implemented.

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Sharif, Ahlam Ammar, and Andrew Karvonen. "Supporting, tinkering, adjusting and resisting: a typology of user translations of the built environment." Open House International 46, no. 2 (2021): 266–80. http://dx.doi.org/10.1108/ohi-10-2020-0151.

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PurposeArchitectural theorists have a long tradition of acknowledging the centrality of building users to architectural production. This article contributes to the discourse on architecture, actor–network theory (ANT), and users by proposing a typology of user translations ranging from supporting to tinkering to adjusting to resisting.Design/methodology/approachThe research utilises an ANT-inspired ethnography of sustainable lighting scripts at the Masdar Institute of Science and Technology (MIST). It comprises semi-structured interviews with MIST designers and students, and site visits and participant observation to understand how the users interpret the scripts and how they interact and change them on a daily basis.FindingsThere is a shared understanding that users do not simply receive architectural designs but interpret and change them to suit their preferences. The findings reveal the multiple ways that users interpret and respond to the assumptions of designers and in the process, recast the relations between themselves and their material surroundings.Originality/valueThe research contributes to acknowledging the centrality of users to architectural design processes and the interpretation of design scripts, addressing the limitation in current literature in demonstrating the diversity of ways that users react to such scripts. The research suggests that user actions have significant implications on long-term building performance. It accordingly points to the need for devising multiple means of user involvement in the design process and allowing greater flexibility in design scripts to improve the alignment with user preferences.

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Chan, Anthony K. N., Christopher D. Delaney, Lu Yang, et al. "Tudor Domain-Focused CRISPR Dropout Screen Identifies SGF29 As a Novel Essential Gene in MLL-Rearranged Leukemias." Blood 134, Supplement_1 (2019): 530. http://dx.doi.org/10.1182/blood-2019-131467.

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Leukemic patients with MLL gene rearrangements (MLL-r) suffer from unfavorable prognosis and lack of effective targeted therapy. Recent studies suggest that MLL-r leukemias are frequently associated with epigenetic dysregulations; therefore, targeting epigenetic machineries may provide therapeutic opportunities to improve outcomes for MLL-r leukemias. Tudor domains are chromatin reader modules that recognize the methylated-lysine/arginine on histones. Given the crucial roles of histone methylations in controlling gene expression, we hypothesized that certain Tudor domain-containing genes may play essential roles in MLL-r leukemias. To identify a Tudor domain-containing gene(s) that is crucial for MLL-r leukemic cells, we custom-built a CRISPR library of 1,000 sgRNAs that targets the exon regions of all known Tudor domains (total 56 Tudor domains in 33 genes) with an average density of 17.7 sgRNAs per Tudor domain (Fig. 1A & B). We delivered this sgRNA library by lentiviral transduction into mouse MLL-AF9 leukemic cells constitutively expressing Streptococcus pyogenesCas9 (SpCas9). We then compared the frequencies of each integrated sgRNA sequence before versus after 12 days of culture using high-throughput sequencing (NextSeq, Illumina), and identified Sgf29 (also known as Ccdc101) as a novel essential gene for MLL-r leukemia. Using SpCas9-mediated gene depletion (individual sgRNA co-expressed with a TagRFP reporter) and high-throughput flow cytometric growth competition assay (Attune NxT, ThermoFisher), we validated that SGF29 is essential in both mouse (MLL-AF9) and human (MV4-11 and MOLM-13) MLL-r leukemic cells. We also observed a stronger dependency to SGF29 in MLL-r leukemic cells compared to other cell types including T-cell lymphoma (Hut78), colon cancer (SW620), breast cancer (MDA-MB-231), lung cancer (H661) and glioblastoma (U251) using the growth competition assay. This suggests that targeting SGF29 may represent a novel therapeutic opportunity for MLL-r leukemias. Mechanistically, we found that CRISPR depletion of Sgf29 in MLL-AF9 cells induced morphological differentiation by Wright-Giemsa staining, and resulted in up-regulation of Cd11b (a myeloid-differentiation marker) and down-regulation of c-Kit (a hematopoietic progenitor and leukemic stem cell marker) by flow cytometry. To identify functionally important regions of Sgf29, we performed a saturation CRISPR-Cas9 gene body scan (also known as CRISPR-tiling screen) that targets all available "NGG" protospacer adjacent motifs (PAM) along the Sgf29 exons (total 147 sgRNAs; average targeting density of 6.0 bp per sgRNA) in MLL-AF9SpCas9+cells (Fig. 1A & C). After high-throughput sequencing of the integrated sgRNA sequences, we mapped the data onto a three-dimensional (3D) crystal structure of SGF29 (PDB: 3ME9) and found that the CRISPR-scan hotpots (i.e.the essential regions) are centered around the H3K4me3-recognition pocket of SGF29. Using RNA-seq and gene set enrichment analysis (GSEA), we observed that the proto-oncogene Myc and Myc-regulated gene sets were significantly down-regulated in the Sgf29 depleted condition. Importantly, ectopic expression of Myc cDNA significantly rescued the lethality induced by Sgf29 depletion. Our current analyses suggest that SGF29 may serve as an upstream regulator of MYC to support the continuous proliferation of the leukemic cells. Based on our 3D CRISPR-scan analysis, we reasoned that development of small molecules binding to the "CRISPR-hot" region may disrupt the normal function of SGF29 (Fig. 1C). Therefore, we performed a virtual screen by docking 1.7 million diverse compounds into this H3K4me3-recognizing pocket of SGF29 using AutoDock Vina (The Scripps Research Institute). By combining the CRISPR-tiling screen, 3D structural analysis, and in silico compound docking, we prioritized a list of candidate binders of SGF29 Tudor domain for in vitro binding and cell survival assays. These may pave the way to develop the first SGF29 inhibitor with the ability to suppress MLL-r leukemias. Taken all together, our data suggest the epigenetic reader protein, SGF29, is a novel therapeutic candidate for MLL-r leukemias. We anticipate that the Tudor domain-focused CRISPR dropout screening and CRISPR-tiling strategies can also be applied to identify therapeutically relevant Tudor domain-containing genes in other hematopoietic malignancies. Disclosures Armstrong: Janssen: Research Funding; OxStem Oncology: Consultancy, Equity Ownership; Accent Therapeutics: Consultancy, Equity Ownership; Syros Pharmaceuticals: Consultancy, Equity Ownership; Imago Biosciences, Inc.: Consultancy, Equity Ownership; Epizyme, Inc.: Consultancy, Equity Ownership; AstraZeneca: Research Funding; Novartis: Research Funding; Mana Therapeutics: Consultancy, Equity Ownership; Cyteir Therapeutics: Consultancy, Equity Ownership; C4 Therapeutics: Consultancy, Equity Ownership.

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Rycraft, Ann. "The Arrival of Humanistic Script in York?" Studies in Church History. Subsidia 12 (1999): 171–81. http://dx.doi.org/10.1017/s0143045900002507.

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Amongst the very fragmentary collection concerning elections of deans of York, now in the Borthwick Institute of Historical Research at the University of York, is a file of the surviving papers for the election, in 1503, of Christopher Bainbridge, ‘capellanum et consiliarium’ to Henry VII. In it there are two examples of humanistic script - an autograph subscription to a letter written for the prebendary of Botevant, John Colet, and a letter written by Peter Carmelian, prebendary of Ampleforth. The occurrence of this script is rare, possibly unique, in the archbishops’ archives.

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Journal articles on the topic 'Scripps Research Institute'

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