Browsing by Author "Coarfa, Cristian"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming
    (Wiley, 2021) Tao, Ling; Moreno-Smith, Myrthala; Ibarra-García-Padilla, Rodrigo; Milazzo, Giorgio; Drolet, Nathan A.; Hernandez, Blanca E.; Oh, Young S.; Patel, Ivanshi; Kim, Jean J.; Zorman, Barry; Patel, Tajhal; Kamal, Abu Hena Mostafa; Zhao, Yanling; Hicks, John; Vasudevan, Sanjeev A.; Putluri, Nagireddy; Coarfa, Cristian; Sumazin, Pavel; Perini, Giovanni; Parchem, Ronald J.; Uribe, Rosa A.; Barbieri, Eveline
    Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain-of-function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti-tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.
  • Thumbnail Image
    Item
    Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection
    (Public Library of Science, 2020) Rajan, Anubama; Robertson, Matthew J.; Carter, Hannah E.; Poole, Nina M.; Clark, Justin R.; Green, Sabrina I.; Criss, Zachary K.; Zhao, Boyang; Karandikar, Umesh; Xing, Yikun; Margalef-Català, Mar; Jain, Nikhil; Wilson, Reid L.; Bai, Fan; Hyser, Joseph M.; Petrosino, Joseph; Shroyer, Noah F.; Blutt, Sarah E.; Coarfa, Cristian; Song, Xuezheng; Prasad, BV Venkataram; Amieva, Manuel R.; Grande-Allen, Jane; Estes, Mary K.; Okhuysen, Pablo C.; Maresso, Anthony W.; Bioengineering
    Enteroaggregative Escherichia coli (EAEC) is a significant cause of acute and chronic diarrhea, foodborne outbreaks, infections of the immunocompromised, and growth stunting in children in developing nations. There is no vaccine and resistance to antibiotics is rising. Unlike related E. coli pathotypes that are often associated with acute bouts of infection, EAEC is associated with persistent diarrhea and subclinical long-term colonization. Several secreted virulence factors have been associated with EAEC pathogenesis and linked to disease in humans, less certain are the molecular drivers of adherence to the intestinal mucosa. We previously established human intestinal enteroids (HIEs) as a model system to study host-EAEC interactions and aggregative adherence fimbriae A (AafA) as a major driver of EAEC adherence to HIEs. Here, we report a large-scale assessment of the host response to EAEC adherence from all four segments of the intestine across at least three donor lines for five E. coli pathotypes. The data demonstrate that the host response in the duodenum is driven largely by the infecting pathotype, whereas the response in the colon diverges in a patient-specific manner. Major pathways altered in gene expression in each of the four enteroid segments differed dramatically, with responses observed for inflammation, apoptosis and an overwhelming response to different mucin genes. In particular, EAEC both associated with large mucus droplets and specific mucins at the epithelial surface, binding that was ameliorated when mucins were removed, a process dependent on AafA. Pan-screening for glycans for binding to purified AafA identified the human ligand as heparan sulfate proteoglycans (HSPGs). Removal of HSPG abrogated EAEC association with HIEs. These results may mean that the human intestine responds remarkably different to distinct pathobionts that is dependent on the both the individual and intestinal segment in question, and uncover a major role for surface heparan sulfate proteoglycans as tropism-driving factor in adherence and/or colonization.
  • Thumbnail Image
    Item
    Performance analysis of TLS Web servers
    (2003) Coarfa, Cristian; Druschel, Peter
    TLS is the protocol of choice for securing today's e-commerce and online transactions, but adding TLS to a web server imposes a significant overhead relative to an insecure web server on the same platform. We perform a comprehensive study of the performance costs of TLS. Our methodology is to profile TLS web servers with trace-driven workloads, replace individual components inside TLS with no-ops and measure the observed increase in server throughput. We estimate the relative costs of each TLS processing stage, identifying the areas for which future optimizations would be worthwhile. Our results show that while the RSA operations represent the largest performance cost in TLS web servers, they do not solely account for TLS overhead. RSA accelerators are effective for e-commerce site workloads since they experience low TLS session reuse. Accelerators appear to be less effective for sites at which all requests are handled by a TLS server, because they have a higher session reuse rate. In this case investing in a faster CPU might provide a greater boost in performance. Our experiments show that having a second CPU is at least as useful as an RSA accelerator. As CPUs become more powerful, the relative cost of the cryptographic components of TLS is decreasing; faster CPUs will eventually bridge the performance gap between TLS-secured and insecure web servers. Our results suggest that long-term research efforts should consequently focus on designing more efficient web servers.
  • Thumbnail Image
    Item
    Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse
    (Public Library of Science, 2017) Wangler, Michael F.; Chao, Yu-Hsin; Bayat, Vafa; Giagtzoglou, Nikolaos; Shinde, Abhijit Babaji; Putluri, Nagireddy; Coarfa, Cristian; Donti, Taraka; Graham, Brett H.; Faust, Joseph E.; McNew, James A.; Moser, Ann; Sardiello, Marco; Baes, Myriam; Bellen, Hugo J.
    Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants. These mutants are short-lived with defects in locomotion and activity. Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. In addition, mutant flies are starvation sensitive and are very sensitive to glucose deprivation exhibiting dramatic shortening of lifespan and hyperactivity on low-sugar food. We use bioinformatic transcriptional profiling to examine gene co-regulation between peroxisomal genes and other metabolic pathways and we observe that the expression of peroxisomal and carbohydrate pathway genes in flies and mouse are tightly correlated. Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. Moreover mice lacking peroxisomes exhibit defective carbohydrate metabolism at the same key steps in carbohydrate breakdown. Our data indicate an unexpected link between these two metabolic processes and suggest metabolism of carbohydrates could be a new therapeutic target for patients with PBD.
  • Thumbnail Image
    Item
    Portable high performance and scalability of partitioned global address space languages
    (2007) Coarfa, Cristian; Mellor-Crummey, John
    Large scale parallel simulations are fundamental tools for engineers and scientists. Consequently, it is critical to develop both programming models and tools that enhance development time productivity, enable harnessing of massively-parallel systems, and to guide the diagnosis of poorly scaling programs. This thesis addresses this challenge in two ways. First, we show that Co-array Fortran (CAF), a shared-memory parallel programming model, can be used to write scientific codes that exhibit high performance on modern parallel systems. Second, we describe a novel technique for analyzing parallel program performance and identifying scalability bottlenecks, and apply it across multiple programming models. Although the message passing parallel programming model provides both portability and high performance, it is cumbersome to program. CAF eases this burden by providing a partitioned global address space, but has before now only been implemented on shared-memory machines. To significantly broaden CAF's appeal, we show that CAF programs can deliver high-performance on commodity cluster platforms. We designed and implemented cafc, the first multiplatform CAF compiler, which transforms CAF programs into Fortran 90 plus communication primitives. Our studies show that CAF applications matched or exceeded the performance of the corresponding message passing programs. For good node performance, cafc employs an automatic transformation called procedure splitting, for high performance on clusters, we vectorize and aggregate communication at the source level. We extend CAF with hints enabling overlap of communication with computation. Overall, our experiments show that CAF versions of NAS benchmarks match the performance of their MPI counterparts on multiple platforms. The increasing scale of parallel systems makes it critical to pinpoint and fix scalability bottlenecks in parallel programs. To automatize this process, we present a novel analysis technique that uses parallel scaling expectations to compute scalability scores for calling contexts, and then guides an analyst to hot spots using an interactive viewer. Our technique is general and may thus be applied to several programming models; in particular, we used it to analyze CAF and MPI codes, among others. Applying our analysis to CAF programs highlighted the need for language-level collective operations which we both propose and evaluate.