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SCIENTIFIC READING AND WRITING ASSIGNMENT YOUR NAME ________________________________________________________________ COURSE_____________________________________________________________________ Exercise 1.1: Find a primary scientific research article Title: _________________________________________________________________________ ______________________________________________________________________________ Citation: The scientific research paper is located: Journal name __________________________________________________________________ Year _________________________________________________________________________ Issue # (if applicable) ___________________________________________________________ Volume # (if applicable) _________________________________________________________ Page # s_______________________________________________________________________ Exercise 1.2: Citation 1. Identify the first author(s) (it is authors if there is a reference to "equal contributing authors") The first author (s)___________________________________________________________ ___________________________________________________________________________ 2. Identify affiliation (2h3r3 they work) for the first author (s) 3. The first author (s) affiliation _________________________________________________________ ________________________________________________________________________ Provide the full properly formatted CSE citation: Exercise 1.3: Abstract 1. Is the abstract organized in the traditional way with four major parts? Yes_____ No_____ 2. Does the abstract depart from tradition? If so, describe how it is different. If not, what are the four major parts? In your own words provide one descriptive sentence which is specific to your article for each part of the abstract. Exercise 1.4: Introduction 1. Why did the author (s) conduct the research? 2. What was the hypothesis, prediction, or objective of this study? 3. Was there enough background information given for a scientist in the field to identify and understand the question (s) or problem (s) that will be addressed by the research? Yes______ No____________ Explain your answer thoroughly (What did the authors describe that you needed to know to understand the questions- what was not described by the authors?) Exercise 1.4: Results and Conclusions 1. Write a paragraph describing the researcher’s key results. Be specific- give numbers and facts. Don’t simply say “the found a bigger of this than this”. How much bigger (ie 25% increase etc)- was it significant? 2. Choose one of the experimental methods used to support a key finding of the paper. Do some research on the method. Describe how the method is used in general. Briefly describe how it is performed.. What can it be used to tell the investigator? How was in used in this paper to test the hypothesis? Exercise 1.5: Discussion 1. What where the researchers main conclusions? Which findings were used to support specific conclusion(s) and why do such findings support this conclusion (rather than some other conclusion) Specifically link three results with the conclusion they support. 2.Do the results and conclusions support or differ from the original hypothesis? Explain your answer. 3. What does the author suggest is the major contribution of this study (why is it important to the field/society)? 4. What questions remain for further research? Exercise 1-6: Related literature Find two other papers closely related to the topic of the one you chose. Provide the correct complete citation for each paper. Describe the search strategy you used to find these papers (Include databases and key words used) Describe how the findings of this paper relate to those in your paper. Did their result confirm, contrast, or extend the findings in your original paper? How? 6 Cell Biology: Dr. Carroll Sum 21 The Journal of Clinical Investigation R E S E A R C H A R T I C L E 8 2 7jci.org Volume 130 Number 2 February 2020 Introduction In just over four decades since its global emergence, the AIDS epi- demic has taken millions of lives. While there have been exceptional advances in antiretroviral therapies, there remains a need for pre- ventive treatments and interventions to eliminate HIV-1 infection (1). In recent years, multiple mAbs with potent neutralization capac- ity have been isolated from HIV-1–infected persons (2, 3). A few of these broadly neutralizing HIV-1 mAbs (bNAbs) have demonstrated efficacy in preventing infection after a single dose of intravenous recombinant protein in nonhuman primates (NHPs) (4). Such obser- vations have generated enthusiasm in the field and progressed HIV- 1 bNAbs into the clinic for studies of prevention (ClinicalTrials.gov NCT02256631, NCT02568215, NCT02716675) as well as for HIV treatment toward cure strategies (5–9). Recently, clinical trials have explored the capability of these antibodies to lower viral loads or prevent rebound after analytical treatment interruption (ATI) (8, 9). Most notably, a study by Mendoza et al. demonstrated that a combi- nation of 2 bNAbs, 3BNC117 and 10-1074, prevented viral rebound for a median of 21 weeks in a subset of individuals compared with 2.3 weeks in historical controls (6). The widespread use of passive delivery of recombinant antibodies is affected due to infusion time, formulation issues, product temperature stability, redosing requirements, and sub- stantial manufacturing costs (10). Viral vector delivery with adeno- associated virus (AAV) has been previously evaluated as a delivery platform for HIV-1 bNAbs, with high-level and long-term expres- sion of the transgene antibody (11–13). However, AAV delivery can be limited in populations by preexisting neutralizing antibodies to the vector, safety concerns of permanent gene marking of the patient, temperature stability, and manufacturing cost as well as vector seroconversion potentially preventing readministration, ultimately resulting in reduced antibody levels in many subjects (14). Recent clinical results of recombinant AAV-1–delivered PG9 demonstrated limited detection of circulating PG9 in healthy males who were delivered a range of vector doses (4 × 1012 to 1.2 × 1014 vector genomes) (15). In this study, we explored the use of synthetic DNA-encoded mAbs (dmAbs) as a possible alterna- tive, serology-independent approach to passive transfer and AAV delivery. Upon injection and electroporation of optimized plasmid DNA with transgenes encoding antibody, locally transfected cells become the in vivo biofactory for antibody production. We have previously demonstrated that this dmAb technology was able to Interventions to prevent HIV-1 infection and alternative tools in HIV cure therapy remain pressing goals. Recently, numerous broadly neutralizing HIV-1 monoclonal antibodies (bNAbs) have been developed that possess the characteristics necessary for potential prophylactic or therapeutic approaches. However, formulation complexities, especially for multiantibody deliveries, long infusion times, and production issues could limit the use of these bNAbs when deployed, globally affecting their potential application. Here, we describe an approach utilizing synthetic DNA-encoded monoclonal antibodies (dmAbs) for direct in vivo production of prespecified neutralizing activity. We designed 16 different bNAbs as dmAb cassettes and studied their activity in small and large animals. Sera from animals administered dmAbs neutralized multiple HIV-1 isolates with activity similar to that of their parental recombinant mAbs. Delivery of multiple dmAbs to a single animal led to increased neutralization breadth. Two dmAbs, PGDM1400 and PGT121, were advanced into nonhuman primates for study. High peak- circulating levels (between 6 and 34 μg/ml) of these dmAbs were measured, and the sera of all animals displayed broad neutralizing activity. The dmAb approach provides an important local delivery platform for the in vivo generation of HIV-1 bNAbs and for other infectious disease antibodies. In vivo delivery of synthetic DNA–encoded antibodies induces broad HIV-1–neutralizing activity Megan C. Wise,1 Ziyang Xu,2,3 Edgar Tello-Ruiz,2 Charles Beck,4 Aspen Trautz,2 Ami Patel,2 Sarah T.C. Elliott,2 Neethu Chokkalingam,2 Sophie Kim,2 Melissa G. Kerkau,4 Kar Muthumani,2 Jingjing Jiang,1 Paul D. Fisher,1 Stephany J. Ramos,1 Trevor R.F. Smith,1 Janess Mendoza,1 Kate E. Broderick,1 David C. Montefiori,5 Guido Ferrari,4 Daniel W. Kulp,2 Laurent M. Humeau,1 and David B. Weiner2 1Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA. 2Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA. 3Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 4Duke Human Vaccine Institute and 5Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA. Authorship note: MCW and ZX contributed equally to this work. Conflict of interest: MCW, JJ, PF, SJR, TRFS, JM, KEB, and LH are employees of Inovio Pharmaceuticals and, as such, receive salary and benefits, including ownership of stock and stock options. KM receives grants and consulting fees from Inovio Phar- maceuticals related to DNA vaccine development. DBW has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees and board series. Remuneration received by DBW includes direct payments, stock, or stock options, and, in the interest of disclosure, he notes potential conflicts associ- ated with his work with Inovio Pharmaceuticals and possibly others. MCW and DBW have a pending US patent, 62750213. Copyright: © 2020, American Society for Clinical Investigation. Submitted: August 19, 2019; Accepted: October 24, 2019; Published: January 6, 2020. Reference information: J Clin Invest. 2020;130(2):827–837. https://doi.org/10.1172/JCI132779. https://www.jci.org https://www.jci.org https://www.jci.org/130/2 https://doi.org/10.1172/JCI132779 The Journal of Clinical Investigation R E S E A R C H A R T I C L E 8 2 8 jci.org Volume 130 Number 2 February 2020 Figure 1. In vivo expression of dmAb-encoded HIV-1 bNAbs in mice. (A) Peak dmAb expression levels (d14) of bNAbs in the sera of transiently immunodepleted mice. Groups of mice (n = 5) were administered dmAb constructs expressing 1 of 16 different bNAbs. (B) Binding curves for 4 dmAbs against HIV-1 trimer BG505_MD39. Serum dmAb levels were normalized for expression (colored lines, n = 5 mice) and compared with the similar purified recombinant protein (black lines) over various concentrations. (C) Individual mouse IC50 (n = 5) for 4 dmAbs across the 12 viruses of the global panels (blue circles) versus values reported in the literature (red squares). Literature values gathered from Los Alamos CATNAP. (D) Mean (n = 5) IC50 pseudotype neutralization of d14 mouse sera against the 12 viruses of the global panel and MLV control. Value of 45 corresponds to no neutralization at a 1:45 dilution, the lowest dilution of the mouse serum tested. All other values are in μg/ml. Horizontal bars indicate mean; error bars represent SEM. Expression levels are representative of 2 experimental replicates; binding and neutralization testing were performed once. https://www.jci.org https://www.jci.org https://www.jci.org/130/2 The Journal of Clinical Investigation R E S E A R C H A R T I C L E 8 2 9jci.org Volume 130 Number 2 February 2020 Next, we proceeded to assess in vivo expression in transient-