A Framework for Computing Discrete-Time Systems and Functions using DNA

University of Minnesota Ph.D. dissertation. July 2017. Major: Electrical/Computer Engineering. Advisors: Keshab Parhi, Marc Riedel. 1 computer file (PDF); xvii, 216 pages.Due to the recent advances in the field of synthetic biology, molecular computing has emerged as a non-conventional computing technology. A broad range of computational processes has been considered for molecular implementation. In this dissertation, we investigate the development of molecular systems for performing the following computations: signal processing, Markov chains, polynomials, and mathematical functions. First, we present a \textit{fully asynchronous} framework to design molecular signal processing algorithms. The framework maps each delay unit to two molecular types, i.e., first-type and second-type, and provides a 4-phase scheme to synchronize data flow for any multi-input/multi-output signal processing system. In the first phase, the input signal and values stored in all delay elements are consumed for computations. Results of computations are stored in the first-type molecules corresponding to the delay units and output variables. During the second phase, the values of the first-type molecules are transferred to the second-type molecules for the output variable. In the third phase, the concentrations of the first-type molecules are transferred to the second-type molecules associated with each delay element. Finally, in the fourth phase, the output molecules are collected. The method is illustrated by synthesizing a simple finite-impulse response (FIR) filter, an infinite-impulse response (IIR) filter, and an 8-point real-valued fast Fourier transform (FFT). The simulation results show that the proposed framework provides faster molecular signal processing systems compared to prior frameworks. We then present an overview of how continuous-time, discrete-time and digital signal processing systems can be implemented using molecular reactions. We also present molecular sensing systems where molecular reactions are used to implement analog-to-digital converters (ADCs) and digital-to-analog converters (DACs). These converters can be used to design mixed-signal processing molecular systems. A complete example of the addition of two molecules using digital implementation is described where the concentrations of two molecules are converted to digital by two 3-bit ADCs, and the 4-bit output of the digital adder is converted to analog by a 4-bit DAC. Furthermore, we describe implementation of other forms of molecular computation. We propose an approach to implement any first-order Markov chain using molecular reactions in general and DNA in particular. The Markov chain consists of two parts: a set of states and state transition probabilities. Each state is modeled by a unique molecular type, referred to as a data molecule. Each state transition is modeled by a unique molecular type, referred to as a control molecule, and a unique molecular reaction. Each reaction consumes data molecules of one state and produces data molecules of another state. The concentrations of control molecules are initialized according to the probabilities of corresponding state transitions in the chain. The steady-state probability of the Markov chain is computed by the equilibrium concentration of data molecules. We demonstrate our method for the Gambler’s Ruin problem as an instance of the Markov chain process. We analyze the method according to both the stochastic chemical kinetics and the mass-action kinetics model. Additionally, we propose a novel {\em unipolar molecular encoding} approach to compute a certain class of polynomials. In this molecular encoding, each variable is represented using two molecular types: a \mbox{type-0} and a \mbox{type-1}. The value is the ratio of the concentration of type-1 molecules to the sum of the concentrations of \mbox{type-0} and \mbox{type-1} molecules. With the new encoding, CRNs can compute any set of polynomial functions subject only to the limitation that these polynomials can be expressed as linear combinations of Bernstein basis polynomials with positive coefficients less than or equal to 1. The proposed encoding naturally exploits the expansion of a power-form polynomial into a Bernstein polynomial. We present molecular encoders for converting any input in a standard representation to the fractional representation, as well as decoders for converting the computed output from the fractional to a standard representation. Lastly, we expand the unipolar molecular encoding for bipolar molecular encoding and propose simple molecular circuits that can compute multiplication and scaled addition. Using these circuits, we design molecular circuits to compute more complex mathematical functions such as $e^{-x}$, $\sin (x)$, and sigmoid$(x)$. According to this approach, we implement a molecular perceptron as a simple artificial neural network

AGNI: In-Situ, Iso-Latency Stochastic-to-Binary Number Conversion for In-DRAM Deep Learning

Recent years have seen a rapid increase in research activity in the field of DRAM-based Processing-In-Memory (PIM) accelerators, where the analog computing capability of DRAM is employed by minimally changing the inherent structure of DRAM peripherals to accelerate various data-centric applications. Several DRAM-based PIM accelerators for Convolutional Neural Networks (CNNs) have also been reported. Among these, the accelerators leveraging in-DRAM stochastic arithmetic have shown manifold improvements in processing latency and throughput, due to the ability of stochastic arithmetic to convert multiplications into simple bit-wise logical AND operations. However,the use of in-DRAM stochastic arithmetic for CNN acceleration requires frequent stochastic to binary number conversions. For that, prior works employ full adder-based or serial counter based in-DRAM circuits. These circuits consume large area and incur long latency. Their in-DRAM implementations also require heavy modifications in DRAM peripherals, which significantly diminishes the benefits of using stochastic arithmetic in these accelerators. To address these shortcomings, this paper presents a new substrate for in-DRAM stochastic-to-binary number conversion called AGNI. AGNI makes minor modifications in DRAM peripherals using pass transistors, capacitors, encoders, and charge pumps, and re-purposes the sense amplifiers as voltage comparators, to enable in-situ binary conversion of input statistic operands of different sizes with iso latency.Comment: (Preprint) To Appear at ISQED 202

Bioactive Terpenoids and Flavonoids from Daucus littoralis Smith subsp. hyrcanicus Rech.f, an Endemic Species of Iran

BACKGROUND: Daucus littoralis Smith subsp. hyrcanicus Rech.f. (Apiaceae) is an endemic species in northern parts of Iran where it is commonly named Caspian carrot. The fruits have been used as condiment. METHODS: In a series of in vitro assays, antioxidant (DPPH and FRAP assays), cytotoxic and antimicrobial activities of different extracts of roots and fruits were evaluated for the first time. The separation and purification of the compounds were carried out on the most potent extracts using various chromatographic methods and identified by spectroscopic data ((1)H and (13)C NMR). RESULTS: The results showed that among the extracts only fruit methanol extract (FME) has significant antioxidant activity (IC(50) = 145.93 μg.ml(-1) in DPPH assay and 358 ± 0.02 mmol FeII/g dry extract in FRAP assay). The radical scavenging activity of FME at 400 μg.ml(-1) was comparable with α-tocopherol (40 μg.ml(-1)) and with BHA (100 μg.ml(-1)) (p > 0.05). FME did not show any toxicity against cancerous and normal cell lines. Fruit ethyl acetate extract (FEE) had cytotoxic activity against breast carcinoma and hepatocellular carcinoma cells (IC(50) 168.4 and 185 μg.ml(-1), respectively), while it did not possess antioxidant activity in comparison with α-tocopherol and BHA as standard compounds. Ethyl acetate and methanol extract of fruits showed antimicrobial activity against Staphylococcus aureus (MIC: 3.75 mg.ml(-1)) and Candida albicans (MIC: 15.6 and 7.8 mg.ml(-1), respectively). Four terpenoids were isolated form FEE including: β-sitosterol (1), stigmasterol (2), caryophyllene oxide (3), β-amyrin (4). Also, three flavonoids namely quercetin 3-O-β-glucoside (5), quercetin 3-O-β-galactoside (6) and luteolin (7) were isolated from FME. CONCLUSION: This study showed that FEE and FME of D. littoralis Smith subsp. hyrcanicus Rech.f. had the highest biological activities which may be correlated with in vitro cytotoxic, antimicrobial and antioxidant activities of terpenoids and flavonoids components of the extracts

Lessons from the development process of the Afghanistan integrated package of essential health services

In 2017, in the middle of the armed conflict with the Taliban, the Ministry of Public Health decided that the Afghan health system needed a well-defined priority package of health services taking into account the increasing burden of non-communicable diseases and injuries and benefiting from the latest evidence published by DCP3. This leads to a 2-year process involving data analysis, modelling and national consultations, which produce this Integrated Package of Essential health Services (IPEHS). The IPEHS was finalised just before the takeover by the Taliban and could not be implemented. The Afghanistan experience has highlighted the need to address not only the content of a more comprehensive benefit package, but also its implementation and financing. The IPEHS could be used as a basis to help professionals and the new authorities to define their priorities

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Global injury morbidity and mortality from 1990 to 2017 : results from the Global Burden of Disease Study 2017

Correction:Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.Peer reviewe

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-Adjusted life-years for 29 cancer groups, 1990 to 2017 : A systematic analysis for the global burden of disease study

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-Adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572000 deaths and 15.2 million DALYs), and stomach cancer (542000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601000 deaths and 17.4 million DALYs), TBL cancer (596000 deaths and 12.6 million DALYs), and colorectal cancer (414000 deaths and 8.3 million DALYs). Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. © 2019 American Medical Association. All rights reserved.Peer reviewe