Glioblastoma (GBM) is the most common aggressive primary malignant brain tumorin adults with a median age of onset of 65 years of age. Although advanced age is often associated with worse GBM patient survival, the predominant source(s) of maladaptive aging
effects remains to be established. Here we studied intra-tumoral and...
Kaposi’ sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). PEL cell lines require expression of the cellular FLICE inhibitory protein (cFLIP) for survival, although KSHV encodes a viral homolog of this protein (vFLIP). Cellular and viral FLIP proteins have several functions, including, most importantly, the inhibition of pro-apoptotic caspase 8...
Cancer is a complex and heterogeneous disease characterized by aberrant gene regulation. Gene regulation is fundamentally orchestrated by the 3D genome organization which involves chromatin looping, compartmentalization, and the formation of topologically associating domains (TADs). Structural variations (SVs), such as genomic rearrangements, deletions, inversions, and duplications, are commonly observed in...
Transcription plays a pivotal role in the transfer of genetic information within living organisms. It serves as the initial step in gene expression, allowing cells to convert the instructions encoded in their DNA into functional molecules. Eukaryotic transcription initiation is a complex and dynamic process that requires joint efforts from...
This dissertation focuses on quantifying protein folding stability determinants and presenting initial experiments that can guide the development of a novel assay that identifies cell-penetrating miniproteins. First, despite over a century of scholarship on protein folding stability, applying this knowledge to design proteins computationally remains limited. Usually, protein designers generate...
This dissertation focuses on quantifying protein folding stability determinants and presenting initial experiments that can guide the development of a novel assay that identifies cell-penetrating miniproteins. First, despite over a century of scholarship on protein folding stability, applying this knowledge to design proteins computationally remains limited. Usually, protein designers generate...
The negative early and late health consequences from exposure to artificial sources of radiation are particularly apparent in victims of radiological emergencies who were diagnosed with cancer, radiation pneumonitis, among other conditions. The renaissance of nuclear energy, increased use of ionizing radiation in the medical field, and nuclear threats from...
Stimulation of the cGAS-STING (cycle GMP-AMP synthase-Stimulator of Interferon Genes) pathway increases T cell activation and tracking into the tumor and reverses the immunosuppressive phenotype of myeloid cells. Direct targeting of the STING receptor using synthetic cyclic dinucleotide (CDN) ligands represents an attractive immunotherapeutic strategy for the treatment of lymphocyte-depleted...
Pediatric high-grade gliomas (pHGGs) are aggressive pediatric CNS tumors and an important subset are characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). Substitution of Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described and characterized in a large cohort...
Involuntary motor activities such as spasms arise from hyperreflexia in about 70% of individuals with spinal cord injuries (SCI). Despite this prevalence and the negative impact on health and safety, it is unclear what determines the severity of the spasms that develop. This study investigated the impact of injury severity...
The reprogramming of somatic cells to a spontaneously contracting cardiomyocyte-like state using defined transcription factors has proven successful in mouse fibroblasts. However, this process has been less successful in human cells, thus limiting the potential clinical applicability of this technology in regenerative medicine. We hypothesized that this issue is due...
Tumor-initiating cells with reprogramming plasticity are thought to be essential for cancer development and metastatic regeneration in many cancers; however, the molecular mechanisms are not fully understood. We have previously identified that CD44, a breast tumor-initiating cell marker, drives mammosphere self-renewal and multicellular aggregation of circulating tumor cell (CTC) clusters,...
One of the fundamental questions in developmental biology is how a single cell gives rise to a complex organism. More specifically, how a totipotent egg divides into cells that become increasingly restricted in their potential. Development is a process of increasingly restricted cellular potential, and here I home in on...
ABSTRACTFor several decades, dams have played an essential role in human development. In many low-and middle-income countries (LMICs), the construction of dams remains an integral part of industrialization and modernization. However, dam construction and associated infrastructure have significantly contributed to socioecological destruction and population displacement. For example, the construction of...
A central theme in biological anthropology is investigating how the human body responds to interactions with the surrounding environment. The microbiome—the collection of microorganisms (and their genes) that live in and on the human body— represents one such pathway that mediates the environment’s influence on human biology, physiology, and health....
Nuclear receptors (NRs) are an important family of transcription factors that often regulate genes in response to ligands and by way of direct interactions with coactivator proteins. Many NR-coactivator pairs have been identified that cooperate to regulate transcription but fully understanding how NRs recruit specific coactivators involves learning which of...
Meiosis is a specialized form of cell division that occurs to generate sperm and eggs with unique sets of paternal or maternal DNA; this process shuffles genetic information to promote the amazing variation that we observe in living organisms. In order to carry out two rounds of DNA separation with...
Pattern formation of biological structures involves the arrangement of different types of cells in an ordered spatial configuration. Patterning is thought to involve the spatial organization of molecular pre-patterns that precede and drive subsequent cell differentiation and coinciding morphogenesis. These molecular prepatterns are often, although not exclusively, organized through Turing...
The worldwide community of patients affected by Basal Cell Carcinoma of the skin (BCC) is larger than that of any other cancer. While BCC is rarely lethal, currently available treatment strategies often leave patients with disfiguring scars on their faces, heads, and necks. Moreover, the high recurrence rates of BCC...
The NLRP3 inflammasome is a multi-protein complex that drives sterile and pathogen-dependent inflammation. Activation of the NLRP3 inflammasome occurs in two steps: priming and activation. Priming occurs in response to an inflammatory stimulus, such as LPS. LPS-primed macrophages are subsequently activated by a second stimuli, most of which require K+...