Computational Biology Commons^™

Early Onset Alzheimer’S Disease Markers In Mouse Hippocampus Unveiled By Single-Cell Transcriptomic Analysis Following Cranial Radiotherapy, Tuba Aksoy

Dissertations and Theses (Open Access)

Cranial radiation therapy plays an integral role in the treatment of brain tumors but can lead to progressive cognitive deficits in survivors by mechanisms that are poorly understood. To develop preventive or mitigative strategies, it is crucial to better understand the underlying pathogenesis of radiation-induced cognitive impairments. The study investigated single-cell transcriptomics and DNA methylation changes as potential drivers of persistent cellular dysfunction after radiation exposure, specifically concentrating on the CA1-3 regions of the hippocampus and the prefrontal cortex due to their role in cognitive functions. Thirteen-week-old mice underwent whole-brain radiation at clinically relevant doses. Following whole-brain radiation, an assessment …

Utilizing The In4mer Crispr/Cas12a Multiplex Knockout Platform To Investigate Synthetic Lethality In The Human Genome, Xingdi Ma

Dissertations and Theses (Open Access)

The emergence of high-throughput sequencing technologies and the development of targeted cancer therapies have significantly advanced our understanding of cancer genomics and prolonged patient survival. Despite these advances, durable response remains difficult to achieve in the clinic. The concept of synthetic lethality has gained traction as a promising opportunity to discover novel cancer-specific vulnerabilities and therapeutic targets. Unfortunately, initial technologies for combinatorial genetic perturbation in mammalian cells suffer from inefficiency and are challenging to scale. In this dissertation, I report: 1) paralog selection method to select candidate synthetic lethal paralogs; 2) our Cas12a multiplex platform “IN4MER” that provides superior sensitivity …

Genomic Data Science Approaches For Understanding Human Diseases, Snehal Shah

All Dissertations

The intricate interplay of genetic predisposition, environmental influences, and lifestyle acts as the multifactorial landscape of diseases. Understanding this complexity presents a significant challenge. Molecular insights into disease mechanisms, particularly the interactions of DNA, RNA, and proteins with environmental and lifestyle factors, have revolutionized disease diagnosis, prognosis, and treatment. High-throughput technologies, such as next-generation sequencing, generate large amounts of molecular data, holding a wealth of knowledge. These datasets unveil the roles of genes and their interactions with various factors through analysis, shedding light on previously unknown molecular mechanisms underlying disease pathogenesis. Furthermore, they facilitate the discovery of biomarkers crucial for …

Computational Drug Repositioning And 3d Skin-Like Tissues Identify Anti-Fibrotic Targets For Systemic Sclerosis (Ssc), Dillon Popovich

Dartmouth College Ph.D Dissertations

Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by dermal and internal organ fibrosis, including heart, lungs, and gastrointestinal tract, and autoantibody formation. Although disease etiology is currently unknown, like other autoimmune diseases, SSc likely develops due to environmental factor exposure in genetically susceptible individuals. Fibrotic diseases are notoriously difficult to treat. Coupled with the autoimmune aspect, SSc is difficult to study scientifically due to the lack of complex disease models that can recapitulate the immune-fibrotic axis of the disease. Due to this, there are only two FDA approved medical treatments for SSc approved for symptomatic treatment of SSc …

Motif-Vi Loop Acts As A Nucleotide Valve In The West Nile Virus Ns3 Helicase, Priti Roy, Zachary Walter, Lauren Berish, Holly Ramage, Martin Mccullagh

Department of Microbiology and Immunology Faculty Papers

The Orthoflavivirus NS3 helicase (NS3h) is crucial in virus replication, representing a potential drug target for pathogenesis. NS3h utilizes nucleotide triphosphate (ATP) for hydrolysis energy to translocate on single-stranded nucleic acids, which is an important step in the unwinding of double-stranded nucleic acids. Intermediate states along the ATP hydrolysis cycle and conformational changes between these states, represent important yet difficult-to-identify targets for potential inhibitors. Extensive molecular dynamics simulations of West Nile virus NS3h+ssRNA in the apo, ATP, ADP+Pi and ADP bound states were used to model the conformational ensembles along this cycle. Energetic and structural clustering analyses depict a clear …

Identifying And Training Deep Learning Neural Networks On Biomedical-Related Datasets, Alan E. Woessner, Usman Anjum, Hadi Salman, Jacob Lear, Jeffrey T. Turner, Ross Campbell, Laura Beaudry, Justin Zhan, Lawrence E. Cornett, Susan Gauch, Kyle P. Quinn

Computer Science and Computer Engineering Faculty Publications and Presentations

This manuscript describes the development of a resources module that is part of a learning platform named 'NIGMS Sandbox for Cloud-based Learning' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox at the beginning of this Supplement. This module delivers learning materials on implementing deep learning algorithms for biomedical image data in an interactive format that uses appropriate cloud resources for data access and analyses. Biomedical-related datasets are widely used in both research and clinical settings, but the ability for professionally trained clinicians and researchers to interpret datasets becomes difficult as the size and …

Computational Analysis Of O6-Methylated Guanine And Thioguanine Complexes, Kirsten Stinson, Michael Bowman

Lux et Fides: A Journal for Undergraduate Christian Scholars

DNA methylation occurring on the O⁶ position of guanine has been linked to the formation of cancer. DNA complexes with O⁶-methylated guanine have been studied experimentally, yet questions remain concerning the carcinogenic properties of O⁶-methylguanine. This present research explored the interaction between O⁶-methylguanine and its potential nucleobase pairs of cytosine and adenine in hopes of elucidating the mutagenic characteristics of O⁶-methylguanine. A variety of computational methods including Density Functional Theory (DFT), Symmetry Adapted Perturbation Theory (SAPT), Noncovalent Interaction (NCI) analysis, and Natural Bond Orbital (NBO) analysis were employed to comprehensively probe …

Evolution And Adaptation To Temperature In Thermotogota, Anne Amelia Farrell

Dartmouth College Ph.D Dissertations

Life thrives across incredibly diverse environmental conditions, yet most organisms are restricted to growing within a narrow range around their optimum growth temperature (OGT). The evolutionary events leading to changes in OGT are poorly understood, and it is uncertain if specific genes are required to thrive at a particular temperature. The bacterial phylum Thermotogota is an excellent model for the evolution of OGT. It comprises mesophilic, thermophilic, and hyperthermophilic members that collectively grow between 20°C and 90°C.

In this work, I analyze the history of OGT in the Thermotogota phylum and show how horizontal gene transfer contributes to the evolution …

Big Life-Science: Study Of Omics From Microscopic To Mesoscopic Scales, Jiarui Wu

Bulletin of Chinese Academy of Sciences (Chinese Version)

The human genome project at the turn of the century opened a new era of life science research and formed various omics characterized by holistic high-throughput research. The initial omics research was mainly carried out at the molecular level, such as genomics, transcriptomics, proteomics, etc., showing a new paradigm of data-driven research. With the development of research technologies, the omics research has risen to the mesoscopic level, the representative is the “Human Cell Atlas” project launched in 2017. At present, researchers have been able to carry out omics research at the level of tissues, organs, and even individuals, and resulted …

Promoting Ecosystem Based Marine Management Through A Marine Ecological Classification And Zoning System, Wenhai Lu, Xiao Li, Meng Cui

Bulletin of Chinese Academy of Sciences (Chinese Version)

Ecosystem based ocean management is an important means of building marine ecological civilization. The current marine ecological classification and zoning in China comprehensively sorts out the types and natural geographical characteristics of marine ecosystems, divided the Chinese seas and adjacent waters into several levels of ecological spatial units according to different scales, effectively characterizes the geographical distribution features of marine biological communities and their habitats, and provides effective support for ecosystem based marine management. This study analyzed the practical significance of marine ecological classification and zoning. Based on a review of the development of marine ecological classification and zoning, this …

Optimizing Immunotherapies For Improved Cancer Treatment, Anne Talkington, Anthony Kearsley

Biology and Medicine Through Mathematics Conference

No abstract provided.

Omani Camels From A Cultural And Genomics Perspective, Al Muatasim Al Zadjali

Electronic Theses and Dissertations

The Dromedarian camel, Camelus dromedarius, is native to the Arabian Peninsula, including the Sultanate of Oman. These camels are used for food, milk, as well as show and racing competitions. Despite their economic and cultural importance research on camels in Oman is limited. The goal of this study was to examine their genomic variation, relationship with camels in other parts of the Arabian Peninsula, and to determine if selective breeding has led to the establishment of distinct breeds in Oman. Information was compiled from multiple sources to produce a comprehensive review on the breeding, management, economic and cultural use, …

The Trnaval Half: A Strong Endogenous Toll-Like Receptor 7 Ligand With A 5′-Terminal Universal Sequence Signature, Kamlesh Ganesh Pawar, Takuya Kawamura, Yohei Kirino

Computational Medicine Center Faculty Papers

Toll-like receptors (TLRs) are crucial components of the innate immune system. Endosomal TLR7 recognizes single-stranded RNAs, yet its endogenous ssRNA ligands are not fully understood. We previously showed that extracellular (ex-) 5'-half molecules of tRNA^HisGUG (the 5'-tRNA^HisGUG half) in extracellular vesicles (EVs) of human macrophages activate TLR7 when delivered into endosomes of recipient macrophages. Here, we fully explored immunostimulatory ex-5'-tRNA half molecules and identified the 5'-tRNA^ValCAC/AAC half, the most abundant tRNA-derived RNA in macrophage EVs, as another 5'-tRNA half molecule with strong TLR7 activation capacity. Levels of the ex-5'-tRNA^ValCAC/AAC half were highly up-regulated in macrophage EVs …

Integrated Transcriptomics And Histopathology Approach Identifies A Subset Of Rejected Donor Livers With Potential Suitability For Transplantation, Ankita Srivastava, Alexandra Manchel, John Waters, Manju Ambelil, Benjamin K. Barnhart, Jan B. Hoek, Ashesh P. Shah, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Liver transplantation is an effective treatment for liver failure. There is a large unmet demand, even as not all donated livers are transplanted. The clinical selection criteria for donor livers based on histopathological evaluation and liver function tests are variable. We integrated transcriptomics and histopathology to characterize donor liver biopsies obtained at the time of organ recovery. We performed RNA sequencing as well as manual and artificial intelligence-based histopathology (10 accepted and 21 rejected for transplantation).

RESULTS: We identified two transcriptomically distinct rejected subsets (termed rejected-1 and rejected-2), where rejected-2 exhibited a near-complete transcriptomic overlap with the accepted livers, …

Transcriptomic Profiling Of Engineered Human Gene Integration In The Mouse Genome Following In Vitro Gene Editing, Ethan Potts, Made Harumi Padmaswari, Christopher Nelson

Biomedical Engineering Undergraduate Honors Theses

Gene replacement is a promising method of therapy for genetic diseases. However, safety and efficacy are areas that need more research. This experiment aims to use RNA sequencing and bioinformatic techniques to provide answers to these questions and provide direction to future studies to develop a gene replacement therapeutic. C2C12 mouse myoblast cells were transfected with a vector containing a CRISPR-Cas9 system and the Human Factor IX (hF9) gene in order to hijack target genes and integrate the hF9 gene. The two target genes, myoglobin (Mb) and creatine kinase (Ckm), were chosen for their high rate of expression and low …

Exploring Genomic Convergence For Adaptations To Freezing Environments In Polar Fish, Ethan Talley

Biological Sciences Undergraduate Honors Theses

Convergent evolution provides valuable insights into how natural selection shapes species traits. Genomic analysis of lineages that display convergent traits has the potential to identify candidate genes for environmental adaptations across the scope of entire genomes. One remarkable example of convergent evolution is the independent development of antifreeze proteins (AFPs) in phylogenetically distant polar fish lineages. While AFPs themselves are relatively well studied, the full genomic context of adaptation to freezing conditions in these fish lineages remains largely unexplored. Leveraging the whole genome sequences previously assembled in our lab, along with other high-quality genomes available in GenBank, I examined the …

Mismatch Repair Deficient Neoantigen And Associated Circulating T-Cell Receptor Repertoires In Lynch Syndrome, Ana Bolivar

Dissertations and Theses (Open Access)

Lynch Syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome. It constitutes the perfect model to understand DNA mismatch repair deficient (MMRd) carcinogenesis, which underlies 15% of early-stage CRC. LS patients develop MMRd tumors with high loads of shared neoantigens (neoAgs), which are recognized by the immune system. Previous research has concentrated on discovering neoAgs and their potential as targets for vaccines in LS patients. However, these studies have primarily identified shared neoAgs from cancers, lacking detailed information on targetable neoAgs present in precancerous lesions. Understanding this landscape of pre-cancer derived neoAgs is crucial for intercepting cancer development …

Uncovering Capillary Endothelial Cells Response During Lung Injury-Repair, Celine Shuet Lin Kong

Dissertations and Theses (Open Access)

Once thought to be a homogenous population, capillary endothelial cells (ECs) have embodied organotypic specialization and heterogenous properties, both during homeostasis and tissue injury. In the lung, capillary ECs consist of two distinct populations, CAP1 and CAP2s; how each population responds to diverse tissue injury is incompletely understood. In this thesis, I report the induction and function of a truncated isoform of Ntrk2, Ntrk2^-tk (lacking the tyrosine kinase domain) in multiple injury models. Using a combinatorial approach of single-cell multiome, mouse genetics and viral infection models, I found that Ntrk2^-tk is broadly induced in CAP1s after the initial …

Epigenetic Modification As A Therapeutic Target In Brafv600e-Mutated Metastatic Colorectal Cancer, Hey Min Lee

Dissertations and Theses (Open Access)

Patients with BRAF^V600E-mutated metastatic colorectal cancer (mCRC) experience a worse prognosis and demonstrate only a 5% response rate to BRAF inhibitor treatment. In this study, adaptive resistance, and a potential combination of standard therapies in BRAF^V600E CRC were unveiled. Intriguingly, a robust association of BRAF^V600E mutation and DNA hypermethylation suggests this is a unique subgroup harboring aberrant epigenetic phenotype. Firstly, DNA methyltransferase (DNMT) inhibitor treatment induced profound DNA hypomethylation in vivo, but minimal change in gene expression due to adaptive elevation of the repressive histone methylation, H3K27me3, leading to compensatory suppression of key tumor suppressor genes, …

The In4mer Crispr/Cas12a Multiplex Knockout Platform And Its Applications, Nazanin Esmaeili Anvar

Dissertations and Theses (Open Access)

Discovering synthetic lethal interactions between genes holds the key to uncovering cancer vulnerabilities, enabling the development of more effective drugs for patients. However, identifying these vulnerabilities in the complex genome of human, which comprises thousands of genes, poses a significant challenge. One alternative approach to investigate these interactions involves exploring enriched sources of synthetic lethal interactions, such as paralog pairs. In recent years, a couple of studies have conducted dual-gene knockout experiments on paralog pairs using different approaches to identify synthetic lethal interactions. In this study, we conducted a meta-analysis of CRISPR genetic interaction screens. We identified a candidate set …