Scientific

These lectures will review and develop methods in algebraic geometry (in particular, derived algebraic geometry) to describe topological and holomorphic sectors of quantum field theories. A recurring theme will be the interaction of local and extended operators, and of QFT's in different dimensions. The main examples will come from twists of supersymmetric gauge theories, and will connect to a large body of recent and ongoing work on 3d Coulomb branches, 3d mirror symmetry (and geometric Langlands), logarithmic VOA's and non-semisimple TQFT's, and categorified cluster algebras.

The basic plan for the lectures is:

• Lecture 1 (2d warmup): categories of boundary conditions, interfaces, and Koszul duality
• Lectures 2 and 3 (3d): twists of 3d N=2 and N=4 gauge theories; vertex algebras, chiral categories, and braided tensor categories; d mirror symmetry; quantum groups at roots of unity and derived non-semisimple 3d TQFT's (compared and contrasted with Chern-Simons theory)
• Lecture 4 (4d): line and surface operators in 4d N=2 gauge theory, the coherent Satake category, and relations to Schur indices and 4d N=2 vertex algebras

1. Lecture 1
2. Lecture 2
3. Lecture 3
4. Lecture 4

Throughout my lectures I will explain the geometry of elliptic fibration which can gave rise to understanding the spectra and anomalies in lower-dimensional theories from the Calabi-Yau compactifications of F-theory. I will first explain what elliptic fibration is and explain Kodaira types, which gives rise an ADE classification. Utilizing Weierstrass model of elliptic fibrations, I will discuss Tate’s algorithm and Mordell-Weil group. By considering codimension one and two singularities and studying the geometry of crepant resolutions, we can define G-models that are geometrically-engineered models from F-theory. I will discuss the dictionary between the gauge theory and the elliptic fibrations and how to incorporate this to learn about topological invariants of the compactified Calabi-Yau that is one of the ingredient to understand spectra in the compactified theories. I will explain the more refined connection to understand the Coulomb branch of the 5d N=1 theories and 6d (1,0) theories and their anomalies from this perspective.

1. Lecture 1
2. Lecture 2
3. Lecture 3
4. Lecture 4

Throughout my lectures I will explain the geometry of elliptic fibration which can give rise to understanding the spectra and anomalies in lower-dimensional theories from the Calabi-Yau compactifications of F-theory. I will first explain what elliptic fibration is and explain Kodaira types, which gives rise an ADE classification. Utilizing Weierstrass model of elliptic fibrations, I will discuss Tate’s algorithm and Mordell-Weil group. By considering codimension one and two singularities and studying the geometry of crepant resolutions, we can define G-models that are geometrically-engineered models from F-theory. I will discuss the dictionary between the gauge theory and the elliptic fibrations and how to incorporate this to learn about topological invariants of the compactified Calabi-Yau that is one of the ingredient to understand spectra in the compactified theories. I will explain the more refined connection to understand the Coulomb branch of the 5d N=1 theories and 6d (1,0) theories and their anomalies from this perspective.

1. Lecture 1
2. Lecture 2
3. Lecture 3
4. Lecture 4

The plasma membrane contains a wide array of glycans and glycolipids, many of which are capped by sialic acids (also called neuraminic acid). As a result, sialic acids are front-line mediators of interactions between the extracellular surface and the external environment. Examples include host-pathogen interactions (e.g. influenza) and the recognition of host cells by leukocytes (white blood cells). Thus, the composition of sialosides in the membrane can influence receptor-receptor interactions critical to immunity and cellular function. Our group is investigating the influence of sialic acid on the function of adhesion and immune receptors through the development of tools that alter catabolism of membrane sialosides. The human neuraminidases (NEU) are a family of four isoenzymes (NEU1, NEU2, NEU3, and NEU4) which have a range of substrate preferences as well as cellular and tissue localization. Our group has developed a panel of selective inhibitors, many with nanomolar potency, are being used to investigate how degradation of sialosides influences the function of cellular receptors. We use fluorescence microscopy to measure the size of receptor clusters and lateral mobility of receptors. These biophysical methods provide critical insight into the influence of NEU activity on membrane receptor organization. We have examined the role of NEU enzymes on the function and organization of leukocyte adhesion receptors. We find that specific NEU enzymes can modulate integrin adhesion and affect leukocyte transmigration. In related work, we have examined the influence of synthetic glycoconjugates and inhibitors of NEU on the organization of the CD22 receptor of B cells. We propose that understanding the specific roles of NEU isoenzymes will identify new therapeutic strategies for autoimmunity, inflammation, and cancer.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily impacting motor neurons. Mutations in superoxide dismutase 1 (SOD1) are the second most common cause of familial ALS. Several of these mutations lead to misfolding or toxic gain of function in the SOD1 protein. Recently, we reported that misfolded SOD1 interacts with TNF receptor-associated factor 6 (TRAF6) in the SOD1-G93A rat model of ALS. Further, we showed in cultured cells that several mutant SOD1 proteins, but not wild type SOD1 protein, interact with TRAF6 via the MATH domain. Here, we sought to uncover the structural details of this interaction through molecular dynamics (MD) simulations of a dimeric model system, coarse grained using the AWSEM force field. We used direct MD simulations to identify buried residues, and predict binding poses by clustering frames from the trajectories. Metadynamics simulations were also used to deduce preferred binding regions on the protein surfaces from the potential of the mean force in orientation space. Well-folded SOD1 was found to bind TRAF6 via co-option of its native homodimer interface. However, if loops IV and VII of SOD1 were disordered, as typically occurs in the absence of stabilizing Zn2+ ion binding, these disordered loops now participated in novel interactions with TRAF6. On TRAF6, multiple interaction hot-spots were distributed around the equatorial region of the MATH domain beta barrel. Expression of TRAF6 variants with mutations in this region in cultured cells demonstrated that TRAF6 residue T475 facilitates interaction with different SOD1 mutants. These findings contribute to our understanding of the disease mechanism and uncover potential targets for the development of therapeutics.