In complex systems, crucial parameters are often subject to unpredictable changes in time. Climate, biological evolution and networks provide numerous examples for such non-stationarities. In many cases, improved statistical models are urgently called for. In a general setting, we study systems of correlated quantities to which we refer as amplitudes. We are interested in the case of non-stationarity, i.e., seemingly random covariances. We present a general method to derive the distribution of the covariances from the distribution of the amplitudes. To ensure analytical tractability, we construct a properly deformed Wishart ensemble of random matrices. We apply our method to financial returns where the wealth of data allows us to carry out statistically significant tests. The ensemble that we find is characterized by an algebraic distribution which improves the understanding of large events.
We identify and analyze statistical regularities and irregularities in the recent order flow of different NASDAQ stocks, focusing on the positions where orders are placed in the orderbook. This includes limit orders being placed outside of the spread, inside the spread and (effective) market orders. We find that limit order placement inside the spread is strongly determined by the dynamics of the spread size. Most orders, however, arrive outside of the spread. While for some stocks order placement on or next to the quotes is dominating, deeper price levels are more important for other stocks. As market orders are usually adjusted to the quote volume, the impact of market orders depends on the orderbook structure, which we find to be quite diverse among the analyzed stocks as a result of the way limit order placement takes place.
Hepatitis B virus (HBV) reactivation in immunosuppressed patients can cause considerable morbidity and mortality. The aim of our study was to evaluate factors associated with acute liver failure (ALF) in HBV reactivation. Clinical, laboratory, and virological data of 87 patients with HBV reactivation were analyzed retrospectively. Teno torque virus (TTV) plasma loads were measured as a measure of immune competence. HBV genomes isolated from 47 patients were analyzed by next-generation sequencing. A functional analysis of identified HBsAg mutants was performed. In patients with ALF the diagnosis was significantly later confirmed than in the non-ALF group. Patients diagnosed during immunosuppression had a milder clinical course compared to later diagnosed patients (p = 0.018, OR = 4.17). TTV viral loads did not differ significantly between the two groups. The HBV genomes isolated from ALF patients had higher viral complexity. A mutation in C-region of HBsAg (L216*), was associated with reduced HBsAg production and secretion. Patients diagnosed with HBV reactivation during immunosuppression had a milder clinical course compared to patients diagnosed during immune reconstitution. ALF was associated with higher viral complexity. An HBsAg mutation (L216*) was found to be more frequent in ALF patients and was associated with reduced HBsAg production and secretion.
Background and aimsThere is growing interest in T cell-based immune therapies for a functional cure of chronic HBV infection including check-point inhibition, T cell-targeted vaccines or TCR-grafted effector cells. All these approaches depend on recognition of HLA class I-presented viral peptides. The HBV core region 18-27 is an immunodominant target of CD8+ T cells and represents the prime target for T cell-based therapies. Here, a high-resolution analysis of the core18-27 specific CD8+ T cell and the selected escape pathways was performed.MethodsHLA class I typing and viral sequence analyses were performed for 464 patients with chronic HBV infection. HBV-specific CD8+ T-cell responses against the prototype and epitope variants were characterized by flow cytometry.ResultsConsistent with promiscuous presentation of the core18-27 epitope, antigen-specific T cells were detected in patients carrying HLA-A*02:01, HLA-B*35:01, HLA-B*35:03 or HLA-B*51:01. Sequence analysis confirmed reproducible selection pressure on the core18-27 epitope in the context of these alleles. Interestingly, the selected immune escape pathways depend on the presenting HLA-class I-molecule. Although cross-reactive T cells were observed, some epitope variants achieved functional escape by impaired TCR-interaction or disturbed antigen processing. Of note, selection of epitope variants was exclusively observed in HBeAg negative HBV infection and here, detection of variants associated with significantly greater magnitude of the CD8 T cell response compared to absence of variants.ConclusionThe core18-27 epitope is highly variable and under heavy selection pressure in the context of different HLA class I-molecules. Some epitope variants showed evidence for impaired antigen processing and reduced presentation. Viruses carrying such escape substitutions will be less susceptible to CD8+ T cell responses and should be considered for T cell-based therapy strategies.
We identify and analyze statistical regularities and irregularities in the recent order flow of different NASDAQ stocks, focusing on the positions where orders are placed in the orderbook. This includes limit orders being placed outside of the spread, inside the spread and (effective) market orders. We find that limit order placement inside the spread is strongly determined by the dynamics of the spread size. Most orders, however, arrive outside of the spread. While for some stocks order placement on or next to the quotes is dominating, deeper price levels are more important for other stocks. As market orders are usually adjusted to the quote volume, the impact of market orders depends on the orderbook structure, which we find to be quite diverse among the analyzed stocks as a result of the way limit order placement takes place.
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