Explore the vast range of titles available.

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING . The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206 + myeloid cells and reduced effector CD8 + T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape. STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

Development and commercial introduction of high throughput RNA sequencing technologies has enabled a deeper look into the complex mechanisms present at sub-cellular level in diseases such as cancer and Alzheimer's disease. Bulk RNA sequencing measures the total or average content of the gene expressions per sample and allows for population level studies. These studies enable comparisons of genes and gene pathways that can predict prognosis outcome of patients or help biologists identify genes to target using immuno-therapies. More recently, spatial RNA sequencing technologies, measure tens of thousands of gene types over a grid of locations on the sample. Spatial RNA sequencing preserves location information of the measurements, hence it can be used to study the highly complex tumor micro-environment. This spatial information is crucial in understanding how immune system shuts down in and around the cancer cells, the interactions between malignant and healthy cells, and tumor metastasis. Spatial RNA sequencing, similar to other high dimensional data, requires a careful selection of important variables, in this case genes, for downstream analysis. Selecting a subset of the genes measured increases the biological signal and reduces the noise present in the data, both of which are crucial steps for any successful downstream analysis.In this dissertation, I present a new statistical model and computational framework to select biologically informative genes for further analysis. I demonstrate the strength of this model and the computational framework through extensive simulations and applications on real datasets. In the rest of this dissertation, I present statistical analyses of bulk RNA sequencing data from Head and Neck Squamous Cancers from three different experiments.

The nature of dark matter, the origin of cosmological baryon asymmetry, and a theory of quantum gravity are big questions in physics beyond the Standard Model of known elementary particles. In this work, topics related to all of these important questions are presented. First, we introduce an effective theory for soft and collinear limits of gravitational scatterings. It is a well-known fact that amplitudes including gravitons are extremely laborious to calculate. Our effective theory can substantially simplify calculations of scattering amplitudes including gravitons. Our step by step procedure gives all operators at the leading and next-to-leading powers for any full theory that couples to gravitons. In addition, the soft graviton theorem and decoupling of collinear gravitons at the leading power are manifest from the outset thanks to the effective symmetries of the theory.At the next-to-leading power, certain simple structures of amplitudes, which are completely obscure in Feynman diagrams of the full theory, are also revealed. We will also discuss how ambiguity in the choice of light-cone coordinates introduces fundamental redundancies in the Effective Theory. Physical predictions should be independent of these redundancies, and the constraints from this requirement further reduces calculations needed for a scattering process. Second, thermal freeze-out of weakly interacting massive particles (WIMPs) can provide a unified origin of dark matter and baryon abundances in our universe. We show that this unification can exhibit a rich collider phenomenology. The collider signatures we point out can be tested at the future experiments at the LHC, even if the WIMPs do not couple to Standard Model particles. In particular, the simplest such implementation can already offer a very clean signal of a TeV-scale resonance that decays to diphotons with a cross section that can easily be within the reach of the near-future LHC runs in the region of parameter space that leads to a successful abundance of cosmological baryons.Other characteristic signatures include the production of multi-bottom and/or multi-top quarks, promptly or displaced. An even more exotic possibility is the production of two separate sets of isolated emerging jets connected by a charged track, which may require new dedicated studies.Finally, di-nucleon decay can also provide a powerful probe of the mechanism.

We present how to construct a Soft Collinear Effective Theory (SCET) for gravity at the leading and next-to-leading powers from the ground up. The soft graviton theorem and decoupling of collinear gravitons at the leading power are manifest from the outset in the effective symmetries of the theory. At the next-to-leading power, certain simple structures of amplitudes, which are completely obscure in Feynman diagrams of the full theory, are also revealed, which greatly simplifies calculations. The effective lagrangian is highly constrained by effectively multiple copies of diffeomorphism invariance that are inevitably present in gravity SCET due to mode separation, an essential ingredient of any SCET. Further explorations of effective theories of gravity with mode separation may shed light on lagrangian-level understandings of some of the surprising properties of gravitational scattering amplitudes. A gravity SCET with an appropriate inclusion of Glauber modes may serve as a powerful tool for studying gravitational scattering in the Regge limit.

Two topics in soft collinear effective theory (SCET) for gravitational interactions are explored. First, the collinear Wilson lines---necessary building blocks for maintaining multiple copies of diffeomorphism invariance in gravity SCET---are extended to all orders in the SCET expansion parameter \\(\\), where it has only been known to \\(O()\\) in the literature. Second, implications of reparametrization invariance (RPI) for the structure of gravity SCET lagrangians are studied. The utility of RPI is illustrated by an explicit example in which \\(O(^2)\\) hard interactions of a collinear graviton are completely predicted by RPI from its \\(O()\\) hard interactions. It is also pointed out that the multiple diffeomorphism invariances and RPI together require certain relations among \\(O()\\) terms, thereby reducing the number of \\(O()\\) terms that need to be fixed by matching onto the full theory in the first place.

A robust mechanism was recently proposed in which thermal freeze-out of WIMPs can provide a unified origin of dark matter and baryon abundances in our universe. We point out that this WIMP-triggered baryogenesis mechanism can exhibit a rich collider phenomenology and be tested at the current and near-future experiments at LHC, even in the case where the WIMPs are completely devoid of SM gauge and higgs portal interactions, as may be motivated by the persistent null results of WIMP dark matter searches. We catalogue a rich array of LHC signatures robustly present in such a scenario. In particular, the simplest such implementation can already offer a very clean signal of a TeV-scale resonance that decays to diphotons with a cross section that can easily be within the reach of the current and near-future LHC runs in the region of parameter space that leads to a successful baryogenesis. Other characteristic signatures include the production of multi-bottom and/or multi-top quarks, promptly or displaced. An even more exotic possibility is the production of two separate sets of isolated emerging jets connected by a charged track, which may require new dedicated studies. Finally, di-nucleon decay can also provide a powerful probe of the mechanism.

Aberrant immune activation within the gut mucosa and gut dysbiosis have been implicated in the pathogenesis of Crohn’s disease (CD). However, the specific immune responses triggered by dysbiotic microbiota, as well as the bacteria responsible for this activation, remain incompletely understood. Here, using the human microbiota-associated (HMA) mouse system, we demonstrated that colonization with dysbiotic gut microbiota from CD patients specifically induces the accumulation of mononuclear phagocytes, which may drive an interleukin-1 (IL-1)-driven inflammatory signature. Moreover, we identified pathobiont strains with a potent IL-1β-inducing capacity, termed ‘IL-1β-inducing pathobionts’ (IBIP). Isolated IBIP strains exhibit genetic and functional similarities to adherent-invasive Escherichia coli but harbor unique virulence-associated genes. Colonization with the IBIP E. coli strain exacerbated experimental colitis in an IL-1 signal-dependent manner. Notably, the colonization of IBIP E. coli can be detected by measuring the levels of specific immunoglobulin A (IgA) in their stool samples. Moreover, the level of IBIP-reactive IgA in stool may serve as a predictive biomarker for treatment response to anti-TNF therapies in treatment-naïve pediatric CD patients. Altogether, IBIP colonization could help identify CD patients with inflammatory dysbiosis who are likely to be refractory to anti-TNF therapies.