Uncovering potential interventions for pancreatic cancer patients via mathematical modeling

Pancreatic Ductal Adenocarcinoma (PDAC) is widely known for its poor prognosis because it is often diagnosed when the cancer is in a later stage. We built a model to analyze the microenvironment of pancreatic cancer in order to better understand the interplay between pancreatic cancer, stellate cells, and their signaling cytokines. Specifically, we have used our model to study the impact of inducing four common mutations: KRAS, TP53, SMAD4, and CDKN2A. After implementing the various mutation combinations, we used our stochastic simulator to derive aggressiveness scores based on simulated attractor probabilities and long-term trajectory approximations. These aggression scores were then corroborated with clinical data. Moreover, we found sets of control targets that are effective among common mutations. These control sets contain nodes within both the pancreatic cancer cell and the pancreatic stellate cell, including PIP3, RAF, PIK3 and BAX in pancreatic cancer cell as well as ERK and PIK3 pancreatic stellate cell. Many of these nodes were found to be differentially expressed among pancreatic cancer patients in the TCGA database. Furthermore, literature suggests that many of these nodes can be targeted by drugs currently in circulation. The results herein help provide a proof of concept in the path towards personalized medicine through a means of mathematical systems biology. All data and code used for running simulations, statistical analysis, and plotting is available on a GitHub repository at https://github.com/drplaugher/PCC_Mutations .

PIRATARIA FLUVIAL NA SERRA DO ESPIGÃO: DIVISÓRIA DOS RIOS URUGUAI E IGUAÇU-AMÉRICA DO SUL

Stream capture is a drainage rearrangement where a flux transference occurs and a contribution area from a drainage basin is incorporated to another. It is about expanding a river system over another one, caused by erosive advantage earned by conditioning factors such as lithostructure, pluviometric regime, topographic gradient, and base level. However, in the southern region of Brazil, a rare dynamic of stream piracy was verified between the drainage basins of the Uruguay and Iguazu (Paraná) rivers. Stream captures were observed along the Serra of Espigão, part of the drainage divide between the two basins. Still, it was not possible to identify which basin was advancing over the other. This paper investigated the occurrence of stream captures, identifying which factors are responsible for this atypical stream dynamic. Mapping the stream captures by remote sensing and further validation with fieldwork, it was verified that there is stream piracy for both sides of the drainage divide. Still, it is not clear which basin is behaving more aggressively. A longitudinal profile analysis of the channels involved in the stream captures showed a local control in the drainage network. This control sets a local base level to the Iguazu river tributaries. It indicates the lithostructural limit between two different geological units: the Serra Geral group basalts and the Botucatu formation sandstones. Depending on the geographic location of this base level, channels that drain to the Iguazu (Paraná) river become more aggressive or less aggressive than the ones that drain to the Uruguai basin, and so they capture or lose area for the other basin. Therefore, it is impossible to identify a river basin that exclusively pirates the other, prevailing, in this case, a mutual competition between the Uruguai and Iguazu (Paraná) rivers basins. This fact highlights the significance of local base levels to promote stream capture processes.

Control sets for bilinear and affine systems

For homogeneous bilinear control systems, the control sets are characterized using a Lie algebra rank condition for the induced systems on projective space. This is based on a classical Diophantine approximation result. For affine control systems, the control sets around the equilibria for constant controls are characterized with particular attention to the question when the control sets are unbounded.

Information Security Assurance and the Role of Security Configuration Management: Substantive and Symbolic Perspectives

This paper explores whether IT and audit professionals have different perceptions of the substantive and symbolic perspectives of information security assurance and the role of security configuration management (SCM) using a mixture of qualitative and quantitative approaches. Importance performance analysis (IPA) is utilized to identify differences in perceived importance and perceived controllability from both substantive and symbolic perspectives between these two professional groups. Our results suggest that SCM plays a vital role in maintaining consistency between the IT and audit professionals by enhancing their confidence in controlling and managing information security control sets. IPA also helps determine an information security program's strengths and weaknesses and supports remedial strategic actions more efficiently. Implications for both research and practice are discussed.

Geometry of Multiprimary Display Colors II: Metameric Control Sets and Gamut Tiling Color Control Functions

<div>For multiprimary displays that have four or more primaries, a color may be reproduced using multiple alternative control vectors. We provide a complete characterization of the Metameric Control Set (MCS), i.e., the set of control vectors that reproduce a given color on the display. Specifically, we show that MCS is a convex polytope whose vertices are control vectors obtained from (parallelepiped) tilings of the gamut, i.e., the range of colors that the display can produce. The mathematical framework that we develop: (a) characterizes gamut tilings in terms of fundamental building blocks called facet spans, (b) establishes that the vertices of the MCS are fully characterized by the tilings of the gamut, and (c) introduces a methodology for the efficient enumeration of gamut tilings. The framework reveals the fundamental inter-relations between the geometry of the MCS and the geometry of the gamut developed in a companion Part I paper, and provides insight into alternative strategies for color control. Our characterization of tilings and the strategy for their enumeration also advance knowledge in geometry, providing new approaches and computational results for the enumeration of tilings for a broad class of zonotopes in R³.</div>

Geometry of Multiprimary Display Colors II: Metameric Control Sets and Gamut Tiling Color Control Functions

<div>For multiprimary displays that have four or more primaries, a color may be reproduced using multiple alternative control vectors. We provide a complete characterization of the Metameric Control Set (MCS), i.e., the set of control vectors that reproduce a given color on the display. Specifically, we show that MCS is a convex polytope whose vertices are control vectors obtained from (parallelepiped) tilings of the gamut, i.e., the range of colors that the display can produce. The mathematical framework that we develop: (a) characterizes gamut tilings in terms of fundamental building blocks called facet spans, (b) establishes that the vertices of the MCS are fully characterized by the tilings of the gamut, and (c) introduces a methodology for the efficient enumeration of gamut tilings. The framework reveals the fundamental inter-relations between the geometry of the MCS and the geometry of the gamut developed in a companion Part I paper, and provides insight into alternative strategies for color control. Our characterization of tilings and the strategy for their enumeration also advance knowledge in geometry, providing new approaches and computational results for the enumeration of tilings for a broad class of zonotopes in R³.</div>

Systems Biology Guided Gene Enrichment Approaches Improve Prediction of Chronic Post-surgical Pain After Spine Fusion

ObjectivesIncorporation of genetic factors in psychosocial/perioperative models for predicting chronic postsurgical pain (CPSP) is key for personalization of analgesia. However, single variant associations with CPSP have small effect sizes, making polygenic risk assessment important. Unfortunately, pediatric CPSP studies are not sufficiently powered for unbiased genome wide association (GWAS). We previously leveraged systems biology to identify candidate genes associated with CPSP. The goal of this study was to use systems biology prioritized gene enrichment to generate polygenic risk scores (PRS) for improved prediction of CPSP in a prospectively enrolled clinical cohort.MethodsIn a prospectively recruited cohort of 171 adolescents (14.5 ± 1.8 years, 75.4% female) undergoing spine fusion, we collected data about anesthesia/surgical factors, childhood anxiety sensitivity (CASI), acute pain/opioid use, pain outcomes 6–12 months post-surgery and blood (for DNA extraction/genotyping). We previously prioritized candidate genes using computational approaches based on similarity for functional annotations with a literature-derived “training set.” In this study, we tested ranked deciles of 1336 prioritized genes for increased representation of variants associated with CPSP, compared to 10,000 randomly selected control sets. Penalized regression (LASSO) was used to select final variants from enriched variant sets for calculation of PRS. PRS incorporated regression models were compared with previously published non-genetic models for predictive accuracy.ResultsIncidence of CPSP in the prospective cohort was 40.4%. 33,104 case and 252,590 control variants were included for association analyses. The smallest gene set enriched for CPSP had 80/1010 variants associated with CPSP (p &lt; 0.05), significantly higher than in 10,000 randomly selected control sets (p = 0.0004). LASSO selected 20 variants for calculating weighted PRS. Model adjusted for covariates including PRS had AUROC of 0.96 (95% CI: 0.92–0.99) for CPSP prediction, compared to 0.70 (95% CI: 0.59–0.82) for non-genetic model (p &lt; 0.001). Odds ratios and positive regression coefficients for the final model were internally validated using bootstrapping: PRS [OR 1.98 (95% CI: 1.21–3.22); β 0.68 (95% CI: 0.19–0.74)] and CASI [OR 1.33 (95% CI: 1.03–1.72); β 0.29 (0.03–0.38)].DiscussionSystems biology guided PRS improved predictive accuracy of CPSP risk in a pediatric cohort. They have potential to serve as biomarkers to guide risk stratification and tailored prevention. Findings highlight systems biology approaches for deriving PRS for phenotypes in cohorts less amenable to large scale GWAS.

Comprehensive mapping of local and diaspora scientists: a database and analysis of 63951 Greek scientists

ABSTRACTResearch policy and planning for a given country may benefit from reliable data on both its scientific workforce as well as the diaspora of scientists for countries with substantial brain drain. Here we use a systematic approach using Scopus to generate a comprehensive country-level database of all scientists in Greece. Moreover, we expand that database to include also Greek diaspora scientists. The database that we have compiled includes 63951 scientists who have published at least 5 papers indexed in Scopus. Of those, 35116 have an affiliation in Greece. We validate the sensitivity and specificity of the database against different control sets of scientists. We also analyze the scientific disciplines of these scientists according to the Science Metrix classification (174 subfield disciplines) and provide detailed data on each of the 63951 scientists using multiple citation indicators and a composite thereof. These analyses demonstrate differential concentrations in specific subfields for the local versus the diaspora cohorts, as well as an advantage of the diaspora cohort in terms of citation indicators especially among top-impact researchers. The approach that we have taken can be applied to map also the scientific workforce of other countries and nations for evaluation, planning and policy purposes.

Blockchain as an Enabler for Zero-Trust Architectures

From the lessons that can be learned so far in this book, the author justifies why a new strategy is required to refocus our perception and utilization of computerized capabilities in the future. Chapter 8 focuses on the advancement of the cyber security discipline by determining trust-less control-sets – a fourth dimension if you will, comprising blockchain technology. Blockchain has been implemented in fungible forms, such as public bitcoin and Ethereum, and in a non-fungible manner like private keyless signature infrastructure. It is the latter that is of particular interest, where proven implementations have the potential to demonstrably act as a verifiable trust anchor, embellishing cyber security controls in a number of critical areas to ensure (1) preservation of data integrity, (2) digital finger printing of IoT assets to prove the source of data is trustworthy, (3) validation of identity and access management mechanisms, and (4) software provenance in the supply chain for not only traditional code-bases but also AI algorithms.