Bourns College of Engineering

AbstractBabesiosis, caused by protozoan parasites of the genus Babesia, is an emerging tick-borne disease of significance for both human and animal health. Babesia parasites infect erythrocytes of vertebrate hosts where they develop and multiply rapidly to cause the pathological symptoms associated with the disease. The identification of new Babesia species underscores the ongoing risk of zoonotic pathogens capable of infecting humans, a concern amplified by anthropogenic activities and environmental changes. One such pathogen, Babesia MO1, previously implicated in severe cases of human babesiosis in the United States, was initially considered a subspecies of B. divergens, the predominant agent of human babesiosis in Europe. Here we report comparative multiomics analyses of B. divergens and B. MO1 that offer insight into their biology and evolution. Our analysis shows that despite their highly similar genomic sequences, substantial genetic and genomic divergence occurred throughout their evolution resulting in major differences in gene functions, expression and regulation, replication rates and susceptibility to antiparasitic drugs. Furthermore, both pathogens have evolved distinct classes of multigene families, crucial for their pathogenicity and adaptation to specific mammalian hosts. Leveraging genomic information for B. MO1, B. divergens, and other members of the Babesiidae family within Apicomplexa provides valuable insights into the evolution, diversity, and virulence of these parasites. This knowledge serves as a critical tool in preemptively addressing the emergence and rapid transmission of more virulent strains.

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis^1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4⁺ T cells³ and agonism of the pregnane X receptor⁴. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.

High fat diets (HFDs) have been linked to several diseases including obesity, diabetes, fatty liver, inflammatory bowel disease (IBD) and colon cancer. In this study, we examined the impact on intestinal gene expression of three isocaloric HFDs that differed only in their fatty acid composition-coconut oil (saturated fats), conventional soybean oil (polyunsaturated fats) and a genetically modified soybean oil (monounsaturated fats). Four functionally distinct segments of the mouse intestinal tract were analyzed using RNA-seq-duodenum, jejunum, terminal ileum and proximal colon. We found considerable dysregulation of genes in multiple tissues with the different diets, including those encoding nuclear receptors and genes involved in xenobiotic and drug metabolism, epithelial barrier function, IBD and colon cancer as well as genes associated with the microbiome and COVID-19. Network analysis shows that genes involved in metabolism tend to be upregulated by the HFDs while genes related to the immune system are downregulated; neurotransmitter signaling was also dysregulated by the HFDs. Genomic sequencing also revealed a microbiome altered by the HFDs. This study highlights the potential impact of different HFDs on gut health with implications for the organism as a whole and will serve as a reference for gene expression along the length of the intestines.

Human untargeted metabolomics studies annotate only ~10% of molecular features. We introduce reference-data-driven analysis to match metabolomics tandem mass spectrometry (MS/MS) data against metadata-annotated source data as a pseudo-MS/MS reference library. Applying this approach to food source data, we show that it increases MS/MS spectral usage 5.1-fold over conventional structural MS/MS library matches and allows empirical assessment of dietary patterns from untargeted data.

Hybrid fuzzing that combines fuzzing and concolic execution has become an advanced technique for software vulnerability detection. Based on the observation that fuzzing and concolic execution are complementary in nature, state-of-the-art hybrid fuzzing systems deploy 'optimal concolic testing' and 'demand launch' strategies. Although these ideas sound intriguing, we point out several fundamental limitations in them, due to unrealistic or oversimplified assumptions. Further, we propose a novel 'discriminative dispatch' strategy and design a probabilistic hybrid fuzzing system to better utilize the capability of concolic execution. Specifically, we design a Monte Carlo-based probabilistic path prioritization model to quantify each path's difficulty, and then prioritize them for concolic execution. Our model assigns the most difficult paths to concolic execution. We implement a prototype named DigFuzz and evaluate our system with two representative datasets and real-world programs. Results show that the concolic execution in DigFuzz outperforms than those in state-of-the-art hybrid fuzzing systems in every major aspect. In particular, the concolic execution in DigFuzz contributes to discovering more vulnerabilities (12 versus 5) and producing more code coverage (18.9 versus 3.8 percent) on the CQE dataset than the concolic execution in Driller.

Modern NoSQL database systems use log-structured merge (LSM) storage architectures to support high write throughput. LSM architectures aggregate writes in a mutable MemTable (stored in memory), which is regularly flushed to disk, creating a new immutable file called an SSTable. Some of the SSTables are chosen to be periodically merged—replaced with a single SSTable containing their union. A mergepolicy (a.k.a. compaction policy) specifies when to do merges and which SSTables to combine. A bounded depth merge policy is one that guarantees that the number of SSTables never exceeds a given parameter k, typically in the range 3–10. Bounded depth policies are useful in applications where low read latency is crucial, but they and their underlying combinatorics are not yet well understood. This paper compares several bounded depth policies, including representative policies from industrial NoSQL databases and two new ones based on recent theoretical modeling, as well as the standard Tiered policy and Leveled policy. The results validate the proposed theoretical model and show that, compared to the existing policies, the newly proposed policies can have substantially lower write amplification with comparable read amplification.

Access to web-based platforms has enabled scientists to perform research remotely. A critical aspect of mass spectrometry data analysis is the inspection, analysis, and visualization of the raw data to validate data quality and confirm statistical observations. We developed the GNPS Dashboard, a web-based data visualization tool, to facilitate synchronous collaborative inspection, visualization, and analysis of private and public mass spectrometry data remotely.