Some mechanical and metaphysical characteristics of form deciphered

Thesis (M.Arch)--Massachusetts Institute of Technology, Dept. of Architecture, 1985.MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH.Bibliography: leaves 40-41.by Benjamin Travis Wood.M.Arc

Process development and scale-up for gene circuit engineered CAR-NK cell manufacturing

Allogeneic Natural Killer (NK) cell therapy has shown promise in recent years for treating cancer in patients without inducing graft versus host disease and with potential for off-the-shelf administration. Senti Bio is using gene circuits to introduce logic-gating and regulated expression of payloads into next-generation CAR-NK cell therapies to broaden the therapeutic indications and improved efficacy in liquid and solid tumors. Key process development objectives for gene circuits include the ability to efficiently and stably transduce multi-gene constructs into primary NK cells while retaining cell expandability and anti-cancer function. Here, we describe a scalable GMP-ready manufacturing process for generating clinically relevant numbers of CAR-NK cells, and we demonstrate its potential applicability to our product pipeline. To achieve a batch size target of \u3e10^11 NK cells, we aimed to develop a process to start with ~25*10^6 isolated NK cells, achieve \u3e40% CAR+ transduction, and obtain \u3e5,600-fold expansion over 21 days. Enrichment of adult apheresis material from 12 healthy donors via CD3 depletion and CD56 selection yielded an average of ~3*10^8 NK cells, which were cryopreserved for later use. Upon thaw, NK cells were activated using proprietary irradiated gene-modified feeder cells and expanded in a closed system 1L G-Rex chamber. Seven days later, NK cells were transduced with retroviral vectors using closed system procedures, resulting in up to 80% CAR+ population. Gene circuits were tested across multiple retroviral vector delivery systems, and successful constructs were developed into producer cell lines (HEK293) using various single cell cloning techniques with the goal of generating stable, high titer vector producer clones. Primary NK cell transduction efficiency was optimized by testing a range of MOI, comparing different vector addition and spinoculation vessels, and the effect of GMP-compatible transduction enhancers. Transduced NK cells were expanded further in multiple closed system G-Rex culture vessels for a total process time (initial NK thaw to CAR-NK harvest) of approximately 21 days. Different expansion methods were assessed including different irradiated modified cell lines and feeder-free NK expansion technologies achieving ~10,000-fold expansion in the 1L vessels. At cell harvest, the cell suspension was volume-reduced, harvested and formulated into cryopreservation medium using an automated cell processing system, yielding ~4*10^9 cells per liter of culture. Formulated cells were filled in vials and stored in liquid nitrogen vapor phase. Functional assessment was performed via both in vitro and in vivo studies, demonstrating significant CAR-specific cancer cell killing compared to non-transduced NK cells. We also evaluated multiple donors for transduction efficiency, growth characteristics, cancer cell killing specificity, scalability, immunomodulatory function, single cell transcriptomics and distribution and kinetics in vivo to determine desirable attributes for manufacturing. This CAR-NK manufacturing process is expected to be suitable for translation to GMP clinical manufacturing in support of Senti Bio’s internal allogeneic CAR-NK cell pipeline

POLARIS: A 30-meter probabilistic soil series map of the contiguous United States

A newcomplete map of soil series probabilities has been produced for the contiguous United States at a 30mspatial resolution. This innovative database, named POLARIS, is constructed using available high-resolution geospatial environmental data and a state-of-the-art machine learning algorithm (DSMART-HPC) to remap the Soil Survey Geographic (SSURGO) database. This 9 billion grid cell database is possible using available high performance computing resources. POLARIS provides a spatially continuous, internally consistent, quantitative prediction of soil series. It offers potential solutions to the primary weaknesses in SSURGO: 1) unmapped areas are gap-filled using survey data from the surrounding regions, 2) the artificial discontinuities at political boundaries are removed, and 3) the use of high resolution environmental covariate data leads to a spatial disaggregation of the coarse polygons. The geospatial environmental covariates that have the largest role in assembling POLARIS over the contiguous United States (CONUS) are fine-scale (30 m) elevation data and coarse-scale (~2 km) estimates of the geographic distribution of uranium, thorium, and potassium. A preliminary validation of POLARIS using the NRCS National Soil Information System (NASIS) database shows variable performance over CONUS. In general, the best performance is obtained at grid cells where DSMART-HPC is most able to reduce the chance of misclassification. The important role of environmental covariates in limiting prediction uncertainty suggests including additional covariates is pivotal to improving POLARIS\u27 accuracy. This database has the potential to improve the modeling of biogeochemical, water, and energy cycles in environmental models; enhance availability of data for precision agriculture; and assist hydrologic monitoring and forecasting to ensure food and water security

Developing a Prototype Ground Station for the Processing, Exploitation, and Dissemination of pLEO Sensor Data

The Air Force’s Space and Missile Systems Center (SMC) recently executed a quick-turnaround (16 month) effort through the Defense Innovation Unit to develop a prototype ground architecture demonstrating low-latency processing, exploitation, and dissemination of data collected by notional multi-phenomenology sensors hosted on small satellites in a proliferated LEO constellation. This effort, led by the Southwest Research Institute and supported by teammates, Amazon Web Services, SpaceX, and SciTec, Inc., involved the modeling and simulation of a variety of different OPIR, EO/IR, and SAR data streams; transporting these data via space and ground networks; processing the data in the AWS cloud environment; and then disseminating resulting products to tactical users. In this paper, we present an overview of the data transport and mission data processing, performance results from the application of our various Mission Data Processing Chains, a summary of our findings on the latencies associated with both data transport and data processing, and lessons learned including insight into ground-based vs. on-board processing

The Inadequate Treatment of Pain: Collateral Damage from the War on Drugs

Jason Nickerson and Amir Attaran examine the vast inequities in medical pain relief around the world and argue that the global control of licit narcotics be shifted from the International Narcotic Control Board to WHO

Characterizing the Habitable Zones of Exoplanetary Systems with a Large Ultraviolet/Visible/Near-IR Space Observatory

Understanding the surface and atmospheric conditions of Earth-size, rocky planets in the habitable zones (HZs) of low-mass stars is currently one of the greatest astronomical endeavors. Knowledge of the planetary effective surface temperature alone is insufficient to accurately interpret biosignature gases when they are observed in the coming decades. The UV stellar spectrum drives and regulates the upper atmospheric heating and chemistry on Earth-like planets, is critical to the definition and interpretation of biosignature gases, and may even produce false-positives in our search for biologic activity. This white paper briefly describes the scientific motivation for panchromatic observations of exoplanetary systems as a whole (star and planet), argues that a future NASA UV/Vis/near-IR space observatory is well-suited to carry out this work, and describes technology development goals that can be achieved in the next decade to support the development of a UV/Vis/near-IR flagship mission in the 2020s.Comment: Submitted in response to NASA call for white papers: "Large Astrophysics Missions to Be Studied by NASA Prior to the 2020 Decadal Survey

Can Observation Skills of Citizen Scientists Be Estimated Using Species Accumulation Curves?

Volunteers are increasingly being recruited into citizen science projects to collect observations for scientific studies. An additional goal of these projects is to engage and educate these volunteers. Thus, there are few barriers to participation resulting in volunteer observers with varying ability to complete the project’s tasks. To improve the quality of a citizen science project’s outcomes it would be useful to account for inter-observer variation, and to assess the rarely tested presumption that participating in a citizen science projects results in volunteers becoming better observers. Here we present a method for indexing observer variability based on the data routinely submitted by observers participating in the citizen science project eBird, a broad-scale monitoring project in which observers collect and submit lists of the bird species observed while birding. Our method for indexing observer variability uses species accumulation curves, lines that describe how the total number of species reported increase with increasing time spent in collecting observations. We find that differences in species accumulation curves among observers equates to higher rates of species accumulation, particularly for harder-to-identify species, and reveals increased species accumulation rates with continued participation. We suggest that these properties of our analysis provide a measure of observer skill, and that the potential to derive post-hoc data-derived measurements of participant ability should be more widely explored by analysts of data from citizen science projects. We see the potential for inferential results from analyses of citizen science data to be improved by accounting for observer skill

Conducting a Large Public Health Data Collection Project in Uganda: Methods, Tools, and Lessons Learned

We report on the implementation experience of carrying out data collection and other activities for a public health evaluation study on whether U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) investment improved utilization of health services and health system strengthening in Uganda. The retrospective study period focused on the PEPFAR scale-up, from mid-2005 through mid-2011, a period of expansion of PEPFAR programing and health services. We visited 315 health care facilities in Uganda in 2011 and 2012 to collect routine health management information system data forms, as well as to conduct interviews with health system leaders. An earlier phase of this research project collected data from all 112 health district headquarters, reported elsewhere. This article describes the lessons learned from collecting data from health care facilities, project management, useful technologies, and mistakes. We used several new technologies to facilitate data collection, including portable document scanners, smartphones, and web-based data collection, along with older but reliable technologies such as car batteries for power, folding tables to create space, and letters of introduction from appropriate authorities to create entrée. Research in limited-resource settings requires an approach that values the skills and talents of local people, institutions and government agencies, and a tolerance for the unexpected. The development of personal relationships was key to the success of the project. We observed that capacity building activities were repaid many fold, especially in data management and technology