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School of Medicine (4) Institute for Clinical and Translational Science (1) UC Museum of Paleontology (1) UCLA School of Public Affairs (1)

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Critical Planning (1) PaleoBios (1)

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## Scholarly Works (21 results)

Let $X$ be a topological space and $k$ a field of characteristic $p$. Let $A^\cdot$ be a bounded below complex of sheaves of differential graded commutative $\F_p$-algebras. We show that there exist Steenrod operations canonically defined on the sheaf hypercohomology groups, $\mathbf{H}^\cdot(X, A^\cdot)$. These Steenrod operations satisfy most of their usual properties, including the Cartan formula and the Adem relations. Suppose further that $A^\cdot$ is equipped with a filtration $F^\cdot$, which is finite in each degree, and compatible with the product on $A^\cdot$. The filtration on $F^\cdot A^\cdot$ induces a spectral sequence that converges to $\mathbf{H}^\cdot(X, A^\cdot)$, and we prove that the constructed Steenrod operations also have a compatible action on the $E_1$ and $E_\infty$ pages of this spectral sequence. When $X$ is a smooth projective variety over $k$, we obtain Steenrod operations on the algebraic De Rham cohomology groups, $H^\cdot_\text{DR}(X/k)$, as well as the Hodge cohomology groups. The Steenrod operations on $H^\cdot_\text{DR}(X/k)$ have a compatible action on the first and infinite pages of the Hodge to De Rham spectral sequence, as well as the spectral sequence from Katz and Oda related to the Gauss-Manin connection.

The notion of phase transitions as a characterization of a change in physical properties

pervades modern physics. Such abrupt and fundamental changes in the behavior of physical systems are evident in condensed matter system and also occur in nuclear and subatomic settings. While this concept is less prevalent in the field of biology, recent advances have pointed to its relevance in a number of settings. Recent studies have modeled both the cell cycle and cancer as phase transition in physical systems. In this dissertation we construct simplified models for two biological systems. As described by those models, both systems exhibit phase transitions.

The first model is inspired by the shape transition in the nuclei of neutrophils during differentiation. During differentiation the nucleus transitions from spherical to a shape often described as “beads on a string.” As a simplified model of this system, we investigate the spherical-to-wrinkled transition in an elastic core bounded to a fluid shell system. We find that this model exhibits a first-order phase transition, and the shape that minimizes the energy of the system scales as (µr 3 /κ).

The second system studied is motivated by the dynamics of globular proteins. These proteins may undergoes conformational changes with large displacements relative to their size. Transitions between conformational states are not possible if the dynamics are governed strictly by linear elasticity. We construct a model consisting of an predominantly elastic region near the energetic minimum of the system and a non-linear softening of the system at a critical displacement. We find that this simple model displays very rich dynamics include a sharp dynamical phase transition and driving-force-dependent symmetry breaking.

Chromosomal abnormalities are frequent events in human cancer and are especially prevalent in hematological malignancies. Here, through the characterization of chromosomal abnormalities del(20q) and t(8;21) we reveal unexpected non-canonical functions of the mammalian Hippo kinase in hematologic cancer.

Somatic heterozygous deletions on chromosome 20q are detected in several hematopoietic malignancies, including myelodysplastic syndrome (MDS), classical myeloproliferative neoplasm (MPN), MDS/MPN overlap disorders, and acute leukemias. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have remained elusive. Through assessment of patient gene expression we have identified STK4 (encoding Hippo kinase MST1) as a 20q gene that is downregulated below haploinsufficient amounts in MDS and MPN. Functional modeling of hematopoietic-specific gene inactivation in mice revealed Hippo kinase loss to cause phenotypes that closely resemble those observed in patients harboring del(20q), and to cooperate with JAK2-V617F mutation in promoting adverse MPN disease progression to myelofibrosis. Mechanistic studies revealed that myelofibrotic transformation in mice was associated with cooperative effects of JAK2-V617F and Hippo kinase inactivation on IRAK1-dependent innate immune-associated proinflammatory cytokine production, including IL-1β and IL-6. In summary, we find Hippo kinase MST1 (STK4) as having a central role in the biology of del(20q)-associated hematologic malignancies.

Through biochemical and functional studies based on the characterization of t(8;21) in acute myeloid leukemia, we also define a novel Hippo-RASSF2 signaling pathway that regulates basal Rac GTPase activity in hematological cancer and can be exploited for therapy in patients. This non-canonical signaling mechanism is independent of Hippo kinase activity, and is instead mediated by a SARAH domain-dependent interaction. Using proximity-based biotin labeling, we associate RASSF2 with Rho GTPase-related complexes and identify a direct interaction with the critical Rac guanine nucleotide exchange factor (GEF), DOCK2. RASSF2 promotes DOCK2 GEF activity in vitro; and RASSF2 knockdown is sufficient to functionally abolish GTP-bound Rac and promote growth-arrest in leukemia cells. Importantly, RASSF2 expression is broadly correlated with leukemia cell sensitivity to small-molecule inhibition of DOCK2 GEF activity, revealing novel mechanistic insight and providing a functional biomarker for sensitivity to perturbation of this pathway in hematological cancer.

*Archaeohippus mourningi*,

*Scaphohippus sumani*, and

*Parahippus brevidens*.

*Scaphohippus intermontanus*is considered a junior subjective synonym of

*S. sumani*.

*Parahippus brevidens*is identified from an upper molar that closely resembles the morphology of the holotype as well as referred specimens of

*Pa. brevidens*from the Mascall Formation in Oregon and the Temblor Formation in California. The presence of

*Pa. brevidens*in the Cajon Valley Formation represents a geographic range extension for the taxon of over 400 km. Interesting ecological implications emerge for the Cajon Valley Formation when compared to the nearby Barstow Formation, including the presence of chalicotheres and apparent lack of

*Hypohippus affinis*and

*Megahippus mckennai*.

- 1 supplemental ZIP