Synthesising executable gene regulatory networks in haematopoiesis from single-cell gene expression data

A fundamental challenge in biology is to understand the complex gene regulatory networks which control tissue development in the mammalian embryo, and maintain homoeostasis in the adult. The cell fate decisions underlying these processes are ultimately made at the level of individual cells. Recent experimental advances in biology allow researchers to obtain gene expression profiles at single-cell resolution over thousands of cells at once. These single-cell measurements provide snapshots of the states of the cells that make up a tissue, instead of the population-level averages provided by conventional high-throughput experiments. The aim of this PhD was to investigate the possibility of using this new high resolution data to reconstruct mechanistic computational models of gene regulatory networks. In this thesis I introduce the idea of viewing single-cell gene expression profiles as states of an asynchronous Boolean network, and frame model inference as the problem of reconstructing a Boolean network from its state space. I then give a scalable algorithm to solve this synthesis problem. In order to achieve scalability, this algorithm works in a modular way, treating different aspects of a graph data structure separately before encoding the search for logical rules as Boolean satisfiability problems to be dispatched to a SAT solver. Together with experimental collaborators, I applied this method to understanding the process of early blood development in the embryo, which is poorly understood due to the small number of cells present at this stage. The emergence of blood from Flk1+ mesoderm was studied by single cell expression analysis of 3934 cells at four sequential developmental time points. A mechanistic model recapitulating blood development was reconstructed from this data set, which was consistent with known biology and the bifurcation of blood and endothelium. Several model predictions were validated experimentally, demonstrating that HoxB4 and Sox17 directly regulate the haematopoietic factor Erg, and that Sox7 blocks primitive erythroid development. A general-purpose graphical tool was then developed based on this algorithm, which can be used by biological researchers as new single-cell data sets become available. This tool can deploy computations to the cloud in order to scale up larger high-throughput data sets. The results in this thesis demonstrate that single-cell analysis of a developing organ coupled with computational approaches can reveal the gene regulatory networks that underpin organogenesis. Rapid technological advances in our ability to perform single-cell profiling suggest that my tool will be applicable to other organ systems and may inform the development of improved cellular programming strategies.Microsoft Research PhD Scholarshi

Large-scale unit commitment under uncertainty: an updated literature survey

The Unit Commitment problem in energy management aims at finding the optimal production schedule of a set of generation units, while meeting various system-wide constraints. It has always been a large-scale, non-convex, difficult problem, especially in view of the fact that, due to operational requirements, it has to be solved in an unreasonably small time for its size. Recently, growing renewable energy shares have strongly increased the level of uncertainty in the system, making the (ideal) Unit Commitment model a large-scale, non-convex and uncertain (stochastic, robust, chance-constrained) program. We provide a survey of the literature on methods for the Uncertain Unit Commitment problem, in all its variants. We start with a review of the main contributions on solution methods for the deterministic versions of the problem, focussing on those based on mathematical programming techniques that are more relevant for the uncertain versions of the problem. We then present and categorize the approaches to the latter, while providing entry points to the relevant literature on optimization under uncertainty. This is an updated version of the paper "Large-scale Unit Commitment under uncertainty: a literature survey" that appeared in 4OR 13(2), 115--171 (2015); this version has over 170 more citations, most of which appeared in the last three years, proving how fast the literature on uncertain Unit Commitment evolves, and therefore the interest in this subject

The effect of contact angles and capillary dimensions on the burst frequency of super hydrophilic and hydrophilic centrifugal microfluidic platforms, a CFD study.

This paper employs the volume of fluid (VOF) method to numerically investigate the effect of the width, height, and contact angles on burst frequencies of super hydrophilic and hydrophilic capillary valves in centrifugal microfluidic systems. Existing experimental results in the literature have been used to validate the implementation of the numerical method. The performance of capillary valves in the rectangular and the circular microfluidic structures on super hydrophilic centrifugal microfluidic platforms is studied. The numerical results are also compared with the existing theoretical models and the differences are discussed. Our experimental and computed results show a minimum burst frequency occurring at square capillaries and this result is useful for designing and developing more sophisticated networks of capillary valves. It also predicts that in super hydrophilic microfluidics, the fluid leaks consistently from the capillary valve at low pressures which can disrupt the biomedical procedures in centrifugal microfluidic platforms

Effect of local papaverine on arteriovenous fistula maturation in patients with end-stage renal disease

BACKGROUND: Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and accelerating fistula maturation is valuable. The aim of this study was to evaluate the effects of papaverine injection on AVF maturation and success rate. METHOD: This study was a randomized clinical trial that involved 110 patients with ESRD that were referred for AVF construction. Patients were allocated in papaverine group and control group with block randomization according to age and sex. In the case group, papaverine (0.1 or 0.2 cc) was injected locally within the subadventitia of artery and vein after proximal and distal control during AVF construction and in the control group, AVF construction was done routinely without papaverine injection. RESULTS: Maturation time in case and control groups was 37.94 +/- 11.49 and 44.23 +/- 9.57 days, respectively (p=0.004). Hematoma was not seen in the case group but occurred in one patient in the control group. One patient of the case group developed venous hypertension. Four functional fistulas, 1 (1.8) in the case group and 3 (5.5) in the control group, failed to mature (p=0.618). Maturation rate did not differ between the two groups statistically (p=0.101). CONCLUSION: Local papaverine injection increased vessel diameter and blood flow, increasing shearing stress in both arterial and venous segment of recently created AVF. In this way, papaverine probably can decrease AVF maturation time without an increase in complications

Incidence and predictive factors of perioperative cardiac events in patients undergoing noncardiac major vascular surgery in imam reza university hospital from december 2010 to December 2013

Background: Cardiovascular morbidity and mortality represent a special concern in a patient with known or unknown cardiovascular disease undergoing high-risk noncardiac surgeries such as major vascular surgery. Methods: Over a period of 36 months, from 2010 to 2013, we enrolled 65 patients in the Vascular Surgery Department of Imam Reza University Hospital. To assess the patients before major vascular surgery, we performed electrocardiography and echocardiography; and depending on these modality findings, some of the patients were candidated for the exercise test, thallium scan, and coronary angiography. During surgery, the patients had cardiac monitoring; and after surgery, they underwent cardiac monitoring, echocardiography, and cardiac troponin tests. Results: In the entire study population, the prevalence rate of perioperative ischemia was 18.5, myocardial infarctions 4.6, and arrhythmias 6.4 and hypotension 9.2 in the operating room. The prevalence of death owing to cardiac events during surgery was 4.6 in the whole study population. Additionally, 27.7 of the patients had no perioperative cardiac events. In the comparison of the risk factors, hypertension (72.2 vs 57.4; P = 0.021), diabetes (50 vs 19.1; P = 0.017), smoking (62 vs 40; P = 0.05), and previous ischemic heart diseases (58.5 vs 31.5; P = 0.042) were more common in the patients with cardiac events. Conclusions: Perioperative cardiac assessments and cardiac risk factor modifications may be considered in major vascular surgery. Close cardiac monitoring during and after surgery plays a significant role in decreasing cardiac events. © 2020, Iranian Heart Association. All rights reserved

Semiparametric MEWMA for Phase II profile monitoring

A control chart is one of the statistical process techniques that is used to monitor different processes. Some processes are characterized by functions or profiles, and a profile is a functional relationship between the dependent and independent variable(s) used to monitor the quality of the process. Several research studies were conducted on linear profiling where only fixed effects are considered. However, in this research, we focus on random effects as they represent the differences between profiles and thus are more proper for interpretation. Two approaches are proposed in this study for Phase II profile monitoring; the first approach is the nonparametric via residuals and the second is the semiparametric approach, where this technique combines the parametric estimates with a portion of the nonparametric estimates to the residuals. Usually, parametric estimations lead to biased estimates when the model is misspecified, whereas nonparametric estimates may give high variances, and thus semiparametric estimates are preferred. New nonparametric and semiparametric multivariate exponential weighted moving average (MEWMA) control charts are introduced and their performances compared to the parametric approach for different samples and shift sizes, and the correlation between and within profiles was considered. The average run length (ARL) and average time to signal (ATS) criteria are used for choosing the best approach. Simulation studies and real datasets were utilized for comparing the performance of the proposed MEWMA charts.The authors would like to thank the reviewers for the time and efforts. Abdel-Salam Gomaa acknowledges funding support from Graduate Grant, Qatar University (QUST-2-CAS-2020-15).Scopu

Node-based Lagrangian relaxations for multicommodity capacitated fixed-charge network design

Classical Lagrangian relaxations for the multicommodity capacitated fixed-charge network design problem are the so-called flow and knapsack relaxations, where the resulting Lagrangian subproblems decompose by commodities and by arcs, respectively. We introduce node-based Lagrangian relaxations, where the resulting Lagrangian subproblem decomposes by nodes. We show that the Lagrangian dual bounds of these relaxations improve upon the linear programming relaxation bound, known to be equal to the Lagrangian dual bounds for the flow and knapsack relaxations. We also develop a Lagrangian matheuristic to compute upper bounds. The computational results on a set of benchmark instances show that the Lagrangian matheuristic is competitive with the state-of-the-art heuristics from the literature