Dynamical properties of a two-dimensional electron gas in a magnetic field within the composite fermion model

We investigate the response of a two-dimensional electron gas, in the fractional quantum Hall regime, to the sudden appearance of a localised charged probe using the Chern-Simons theory of composite fermions. The dynamic structure factor of the electron gas is found to have a major influence on the spectral function of the probe. In particular, there is an orthogonality catastrophe when the filling factor is an even-denominator filling fraction due to the compressibility of the state, but there is no catastrophe at odd-denominator filling factors because these states have a gap to excitations. The catastrophe is found to be more severe for composite fermions in zero effective magnetic field than it is for electrons in zero real magnetic field. Oscillations in the spectral function, arising when the composite fermions are at integer filling, have a period equal to the composite fermion cyclotron energy. We propose a tunneling experiment which directly measures the spectral function from which one could determine the composite fermion effective mass.Comment: 15 pages of REVTEX. Uses multicol package. Twoside option is default. There are 29 figures in GIF format to save spac

Orthogonality catastrophe in a composite fermion liquid

We discuss the emergence of an orthogonality catastrophe in the response of a composite fermion liquid as the filling factor \nu approaches 1/2m, where m=1,2,3.... A tunneling experiment is proposed in which dramatic changes in the I-V characteristic should be observable as \nu is varied. Explicit I-V characteristics calculated within the so-called Modified Random Phase Approximation, are provided for \nu=1/3 -> \nu=1/2.Comment: Latex two-column 6 pages including 5 figure

Optical properties of a two-dimensional electron gas at even-denominator filling fractions

The optical properties of an electron gas in a magnetic field at filling fractions \nu = {1\over 2m} (m=1,2,3...) are investigated using the composite fermion picture. The response of the system to the presence of valence-band holes is calculated. The shapes of the emission spectra are found to differ qualitatively from the well-known electron-hole results at zero magnetic field. In particular, the asymmetry of the emission lineshape is found to be sensitive to the hole-composite fermion plane separation.Comment: 17 pages, LaTeX, 7 figures. This revised version is to appear in Physical Review

Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei

As part of the Seattle Structural Genomics Center for Infectious Disease, we seek to enhance structural genomics with ligand-bound structure data which can serve as a blueprint for structure-based drug design. We have adapted fragment-based screening methods to our structural genomics pipeline to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms. In this study, we report fragment screening methods and structure determination results for 2C-methyl-D-erythritol-2,4-cyclo-diphosphate (MECP) synthase from Burkholderia pseudomallei, the gram-negative bacterium which causes melioidosis. Screening by nuclear magnetic resonance spectroscopy as well as crystal soaking followed by X-ray diffraction led to the identification of several small molecules which bind this enzyme in a critical metabolic pathway. A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site. These ligand-bound structures now serve to guide medicinal chemists and structural biologists in rational design of novel inhibitors for this enzyme

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy