Predicting Enzyme Targets for Optimization of Metabolic Networks under Uncertainty

Recently, ensemble modeling was applied to metabolic networks for the sake of predicting the effects of genetic manipulations on the observed phenotype of the system. The ensemble of models is generated from experimental wild-type flux data and screened using phenotypic data from gene overexpression and knockout experiments, leaving predictive models. The need for data from multiple genetic perturbation experiments is an inherent limitation to this approach. In this investigation, ensemble modeling is used alongside elementary mode analysis to attempt to predict those enzymatic perturbations that are most likely to result in an increase in a target yield and a target flux when only the wild-type flux distribution is known. Elementary mode analysis indicates the maximum theoretical yield and its associated steady-state flux distribution(s), and the minimal cut set knockouts are determined that eliminate all but the highest-yield elementary modes. These knockouts and other perturbations are simulated using all of the ensemble models, and the distributions of predicted fluxes and yields over the models are compared to elucidate which reactions and metabolites most likely limit the target yield and flux. Additionally, a systematic method is developed to simultaneously identify multiple reactions that are responsible for bottlenecks after the minimal cut set knockouts are performed. These methods are applied to a metabolic network that models 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) production in E. coli. Results show that pyruvate accumulation due to glucose uptake and erythrose-4-phosphate (E4P) shortages resulting from the slow reaction rate of transketolase (tkt) limit DAHP production. These results are consistent with published data, indicating that a detailed understanding of metabolic networks can be obtained with minimal experimental data. Additionally, the systematic method identifies four enzymes (Tkt, Tal, Pps, and AroG) that, when overexpressed experimentally, increase yield to nearly the maximum theoretical limit. Systematic analysis of a toy network also correctly identifies the post-MCS overexpression that results in the largest increases in yield and absolute fluxes. These results indicates that wild-type steady-state flux data can be used to accurately identify enzyme perturbation targets for increasing yield and target flux values

Shock Synthesis of Organic Molecules by Meteoroids in the Atmosphere of Titan

Thermochemical modeling and shock-tube experiments show that shocks applied to N$_2$/CH$_4$ gas mixtures can synthesize organic molecules. Sufficiently large, hypersonic meteoroids entering the atmosphere of Saturn's moon Titan should therefore drive organic chemistry. To do so meteoroids must be sufficiently large compared to the atmospheric mean free path at a given altitude to generate shocks, and deposit enough energy per path length to produce temperatures high enough to excite and dissociate the relevant molecules. The Cassini spacecraft imaged multiple meteoroid impacts on Saturn's rings, allowing for the first time an empirical estimate to be made of the flux and size-frequency distributions of meteoroids in the millimeter-to-meter size range. We combine these results with an atmospheric entry model and thermochemical and experimental shock production efficiencies for N$_2$/CH$_4$ atmospheres and calculate the shock production rates for HCN, C$_2$H$_2$, and C$_2$H$_4$ as well as the resulting H$_2$ generation. We find that meteoroids may be producing these molecules at as much as $\sim$1% the production rate of photochemistry driven by UV photons, and may be depositing more energy than magnetospheric ions and 90-100 nm UV photons. Moreover, these meteoroids produce these organic molecules hundreds of kilometers lower in Titan's atmosphere than the relevant UV photons and magnetospheric ions penetrate, with peak production occurring between 200 and 500 km altitudes, i.e., at the observed haze layer. Meteoroid-driven shock generation of molecules may therefore be crucial to understanding Titan's atmospheric chemistry.Comment: 12 pages, 6 figure

Incidence Patterns and Outcomes for Hodgkin Lymphoma Patients in the United States

Hodgkin lymphoma (HL) demonstrates heterogenous histologic findings, clinical presentation, and outcomes. Using the United States Surveillance, Epidemiology, and End Results (SEER) data we examined relationships between patient characteristics, clinical features at diagnosis, and survival in HL patients. From 2000 to 2007, 16,710 cases were recorded in 17 SEER registries. Blacks and Asians had low incidence (black/white incidence rate ratio (IRR) 0.86, P < .01; Asian/white IRR 0.43, P < .01). The bimodal pattern of incidence was less prominent for black males. Asians and Blacks presented at a mean age of 38 years compared to 42 years for Whites (P < .001). Race was a predictor for survival with HR of 1.19 (95% CI 1.11–1.28) for Blacks. Age was the most important predictor of survival (HR for patients ≥45 years 5.08, 95% CI 4.86–5.31). These current patterns for presentation and outcomes of HL help to delineate key populations in order to explore risk factors for HL and strategies to improve treatment outcomes

Final Cultural Resources Report of the Salt Creek Midstream, LLC Proposed Olifant Eight Inch Pipeline Project on University Lands in Ward County, Texas

Enercon Services, Inc. (ENERCON), in support of Salt Creek Midstream, LLC, conducted an intensive archeological survey for the proposed Olifant Eight Inch Pipeline Project located near Pyote in Ward County, Texas. The proposed project consists of the construction of an approximately 800 foot (244 m) long eight inch steel pipeline on University Lands, extending from a tie-in at an existing well pad, trending generally south-southeast to a tie-in on the existing Quito Draw pipeline. The Olifant Eight Inch Pipeline Project area is mapped on the United States Geological Survey (USGS) Soda Lake NE, Texas (1967, photorevised 1981) 7.5 Minute Quadrangle map. The construction corridor consists of a 50 foot (15 m) wide permanent pipeline right-of-way (ROW) and a 50 foot (15 m) wide temporary workspace corridor. The cultural resources survey corridor and the area of potential effect (APE) was 100 feet (30 m) wide for the entire 800 foot (244 m) length of the proposed Olifant Eight Inch Pipeline Project, totaling 1.84 acres (.74 hectares). The proposed project is entirely on University Lands, a political subdivision of the State of Texas. The archeological survey was completed under Texas Antiquities Permit No. 9012. The cultural resources field investigation on University Lands was conducted on February 26, 2019 by ENERCON archeologist Gary Edington, who meets the U.S. Secretary of the Interior’s Professional Qualification Standards for archeology as set forth in 36 CFR 61, and consisted of an intensive pedestrian survey utilizing transects spaced no greater than 15 m apart, with shovel tests in areas which had the potential for buried cultural resources. The field investigation was conducted in accordance with the Texas Historical Commission (THC) Archeological Survey Standards for Texas. The entire project was supervised by Michael Margolis, an ENERCON archeologist who meets the U.S. Secretary of the Interior’s Professional Qualification Standards for archeology as set forth in 36 CFR 61. The cultural resources survey did not result in finding any historic or prehistoric artifacts, features, cultural lenses, or sites over 50 years of age on University Lands. Therefore, it is recommended that the project will have no effect on any historic property that may qualify for inclusion in the National Register of Historic Places (NRHP) on University Lands. No further cultural resources investigations are recommended prior to construction of the proposed Olifant Eight Inch Pipeline Project on University Lands. If cultural material, including sites, features, or artifacts that are 50 years old or older are encountered within the ROW during construction of this project, work in the area must cease and the THC must be immediately be notified

Timing information at HL-LHC: Complete determination of masses of Dark Matter and Long lived particle

A long standing problem in kinematics at the hadron colliders is to determine the mass of invisible particles. This issue is particularly important for the signals of dark matter, which becomes one of the prominent targets of future collider experiments. In this paper, we show that the additional information from the precise timing measurement, which will be available at the planned high-liminosity run of the LHC (HL-LHC), will shade new light on the kinematics study. As a concrete example, we focus on the signal of the pair produced long-lived particles ($LLP_{1,2}$), respectively leaving displaced vertex with visible ($V_{1,2}$) and invisible ($I_{1,2}$) final state, $pp \to LLP_1+LLP_2 \to (V_1+I_1)+(V_2+I_2)$. We explicitly show that this system is completely solvable with timing information.Comment: 14 pages, 5 figure

Timing information at HL-LHC: complete determination of masses of dark matter and long lived particle

A long-standing kinematic challenge in data analysis at hadron colliders is the determination of the masses of invisible particles. This issue is particularly relevant in searches for evidence of dark matter production, which remains one of the prominent targets of future collider experiments. In this paper, we show that the additional information from the precision timing measurements, provided by planned detector upgrades during the high- luminosity run of the LHC (HL-LHC), allows for previously unrealizable measurements of invisible particle kinematics. As a concrete example, we focus on the signal of pair produced long-lived particles (LLP1,2), each decaying with a displaced vertex to visible (V1,2) and invisible (I1,2) final state particles, pp → LLP1 + LLP2 → (V1 + I1) + (V2 + I2). We explicitly show that the complete kinematics of the invisible particles in such events can be determined with the addition of timing information, and evaluate the precision with which the masses of new long-lived and invisible particles can be determined

Clinical, Molecular, and Environmental Risk Factors for Hodgkin Lymphoma

Epidemiological studies suggest unique occurrence patterns of Hodgkin lymphoma (HL) worldwide. In most Western countries there is a clear bimodal age distribution with an early peak in young adults followed by a second peak in older adults, particularly among males. In the Middle East and Asia, HL is more common in early childhood. There also are marked racial differences in the presentations of HL and HL subtypes, and particular single nucleotide polymorphisms (SNPs) have been identified as etiological factors suggesting that gene-gene and gene-environment interactions are involved. Personal health choices such as exercise and smoking may modify an individual's chances of developing HL. Numerous studies highlight the impact that exposure to Epstein-Barr virus and other environmental factors have on HL risk. Understanding the relative importance of each of these findings and their links to HL development and survival will help clinical researchers expand curative therapies and create preventative strategies for HL

Posttransplant Thrombopoiesis Predicts Survival in Patients Undergoing Autologous Hematopoietic Progenitor Cell Transplantation

AbstractThe frequency and clinical significance of secondary thrombocytopenia following initial engraftment in autologous hematopoietic progenitor cell transplantation (HPCT) is unknown. An institutional review board approved retrospective study of thrombopoiesis was performed in 359 patients transplanted with autologous blood (97%) or marrow (3%) who achieved platelet engraftment to >50,000/μL. Idiopathic secondary posttransplant thrombocytopenia (ISPT) was defined as >50% decline in blood platelets to <100,000/μL in the absence of relapse or sepsis. ISPT occurred at a median of day +35 posttransplant in 17% of patients. Patients with ISPT had similar initial platelet engraftment (median 17 days) versus non-ISPT patients (18 days; P = NS) and recovered platelet counts (median 123,00 K/μL) by day 110 posttransplant. Four factors were independently associated with post-transplant death in a multivariate model: disease status at transplant; the number of prior chemotherapy regimens, failure to achieve a platelet count of >150,000/μL posttransplant, and the occurrence of ISPT. A prognostic score was developed based upon the occurrence of ISPT and posttransplant platelet counts of <150,000/μL. Survival of patients with both factors (n = 25) was poor (15% alive at 5 years); patients with 1 factor (n = 145) had 49% 5-year survival; patients with 0 factors (n = 189) had 72% 5-year survival. Patients who failed to achieve a platelet count of >150,000/μL received significantly fewer CD34+ cells/kg (P < .001), whereas patients with ISPT received fewer CD34+CD38− cells/kg (P = .0006). The kinetics of posttransplant thrombopoiesis is an independent prognostic factor for long-term survival following autologous HPC. ISPT and lower initial posttransplant platelet counts reflect poor engraftment with long-term and short-term repopulating CD34+ hematopoietic stem cells, respectively, and are associated with an increased risk of death from disease relapse

Development of the Lymphoma Enterprise Architecture Database: A caBIG(tm) Silver level compliant System

Lymphomas are the fifth most common cancer in United States with numerous histological subtypes. Integrating existing clinical information on lymphoma patients provides a platform for understanding biological variability in presentation and treatment response and aids development of novel therapies. We developed a cancer Biomedical Informatics Grid™ (caBIG™) Silver level compliant lymphoma database, called the Lymphoma Enterprise Architecture Data-system™ (LEAD™), which integrates the pathology, pharmacy, laboratory, cancer registry, clinical trials, and clinical data from institutional databases. We utilized the Cancer Common Ontological Representation Environment Software Development Kit (caCORE SDK) provided by National Cancer Institute’s Center for Bioinformatics to establish the LEAD™ platform for data management. The caCORE SDK generated system utilizes an n-tier architecture with open Application Programming Interfaces, controlled vocabularies, and registered metadata to achieve semantic integration across multiple cancer databases. We demonstrated that the data elements and structures within LEAD™ could be used to manage clinical research data from phase 1 clinical trials, cohort studies, and registry data from the Surveillance Epidemiology and End Results database. This work provides a clear example of how semantic technologies from caBIG™ can be applied to support a wide range of clinical and research tasks, and integrate data from disparate systems into a single architecture. This illustrates the central importance of caBIG™ to the management of clinical and biological data

Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States.

BACKGROUND: Median age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is \u3e 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting. METHODS: The Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010-2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan-Meier methods were used to evaluate overall survival. CLL- and infection-related mortality were assessed using cumulative incidence functions (CIF) and cause-specific hazards. Logistic regression was used to develop a classification model. RESULTS: A total of 455 E-CLL patients were enrolled; 259 were enrolled in LOT1 and 196 in LOT ≥ 2. E-CLL patients were more likely to receive rituximab monotherapy (19.3 vs. 8.6%; p \u3c 0.0001) and chemotherapy-alone regimens (p \u3c 0.0001) than younger patients. Overall and complete responses were lower in E-CLL patients than younger patients when given similar regimens. With a median follow-up of 3 years, CLL-related deaths were higher in E-CLL patients than younger patients in LOT1 (12.6 vs. 5.1% p = 0.0005) and LOT ≥ 2 (31.3 vs. 21.5%; p = 0.0277). Infection-related deaths were also higher in E-CLL patients than younger patients in LOT1 (7.4 vs. 2.7%; p = 0.0033) and in LOT ≥ 2 (16.2 vs. 11.2%; p = 0.0786). A prognostic score for E-CLL patients was developed: time from diagnosis to treatment \u3c 3 months, enrollment therapy other than bendamustine/rituximab, and anemia, identified patients at higher risk of inferior survival. Furthermore, higher-risk patients experienced an increased risk of CLL- or infection-related death (30.6 vs 10.3%; p = 0.0006). CONCLUSION: CLL- and infection-related mortality are higher in CLL patients aged ≥ 75 years than younger patients, underscoring the urgent need for alternative treatment strategies for these understudied patients. TRIAL REGISTRATION: The Connect CLL registry was registered at clinicaltrials.gov: NCT01081015 on March 4, 2010