Long-Term Dependence Characteristics of European Stock Indices

In this paper we show the degrees of persistence of the time series if eight European stock market indices are measured, after their lack of ergodicity and stationarity has been established. The proper identification of the nature of the persistence of financial time series forms a crucial step in deciding whether econometric modeling of such series might provide meaningful results. Testing for ergodicity and stationarity must be the first step in deciding whether the assumptions of numerous time series models are met. Our results indicate that ergodicity and stationarity are very difficult to establish in daily observations of these market indexes and thus various time-series models cannot be successfully identified. However, the measured degrees of persistence point to the existence of certain dependencies, most likely of a nonlinear nature, which, perhaps can be used in the identification of proper empirical econometric models of such dynamic time paths of the European stock market indexes. The paper computes and analyzes the long- term dependence of the equity index data as measured by global Hurst exponents, which are computed from wavelet multi-resolution analysis. For example, the FTSE turns out to be an ultra-efficient market with abnormally fast mean-reversion, faster than theoretically postulated by a Geometric Brownian Motion. Various methodologies appear to produce non-unique empirical measurement results and it is very difficult to obtain definite conclusions regarding the presence or absence of long term dependence phenomena like persistence or anti-persistence based on the global or homogeneous Hurst exponent. More powerful methods, such as the computation of the multifractal spectra of financial time series may be required. However, the visualization of the wavelet resonance coefficients and their power spectrograms in the form of localized scalograms and average scalegrams, forcefully assist with the detection and measurement of several nonlinear types of market price diffusion.Long-Term Dependence, European Stock Indices

Towards a grapho-phonologically parsed corpus of medieval Scots:Database design and technical solutions

This paper presents a newly constructed corpus of sound-to-spelling mappings in medieval Scots, which stems from the work of the From Inglis to Scots (FITS) project. We have developed a systematic approach to the relationships between individual spellings and proposed sound values, and recorded these mutual links in a relational database. In this paper, we introduce the theoretical underpinnings of sound-to-spelling and spelling-to-sound mappings, and show how a Scots root morpheme undergoes grapho-phonological parsing, the analytical procedure that is employed to break down spelling sequences into sound units. We explain the data collection and annotation for the FITS Corpus (Alcorn et al., forthcoming), drawing attention to the extensive meta-data which accompany each analysed unit of spelling and sound. The database records grammatical and lexical information about the root, the positional arrangement of segments within the root, labels for the nuclei, vowels and consonants, the morphological context, and extra-linguistic detail of the text a given root was taken from (date, place and text type). With this wealth of information, the FITS corpus is capable of answering complex queries about the sound and spelling systems of medieval Scots. We also suggest how our methodology can be transferred to other non-standardised spelling systems

Kinase-Impaired BTK Mutations Are Susceptible to Clinical-Stage BTK and IKZF1/3 Degrader NX-2127

INTRODUCTION: Bruton’s tyrosine kinase (BTK) is a nonreceptor kinase in the B cell receptor (BCR) signaling cascade critical for B cell survival. As such, chronic lymphocytic leukemia (CLL) and other B cell cancers are sensitive to inhibition of BTK. Covalent and noncovalent inhibitors of BTK have revolutionized the treatment of these cancers. Therefore, understanding mechanisms by which acquired mutation in BTK confer drug resistance and developing new therapies to overcome resistance are critically important. RATIONALE: We recently discovered BTK mutations that confer resistance across covalent and noncovalent BTK inhibitors. In this study, we found that a group of these mutants impair BTK kinase activity despite still enabling downstream BCR signaling. We therefore set out to understand the nonenzymatic functions of BTK and explored targeted protein degradation to overcome the oncogenic scaffold function of mutant BTK. This effort included evaluation of BTK degradation in patients with CLL treated in a phase 1 clinical trial of NX-2127, a first-in-class BTK degrader (NCT04830137). RESULTS: BTK enzymatic activity assays revealed that drug resistance mutations in BTK fall into two distinct groups: kinase proficient and kinase impaired. Immunoprecipitation mass spectrometry of kinase-impaired BTK L528W (Leu528→Trp) revealed a scaffold function of BTK with downstream signaling and survival dependent on surrogate kinases that bind to kinase-impaired BTK proteoforms. To target the nonenzymatic functions of BTK, we developed NX-2127, a heterobifunctional molecule that engages the ubiquitin-proteasome system to simultaneously bind both BTK and the cereblon E3 ubiquitin ligase complex, inducing polyubiquitination and proteasome-dependent degradation of IKZF1/3 and all recurrent drug-resistant forms of mutant BTK. The activity of NX-2127 on BTK degradation was further demonstrated in patients with CLL treated in a phase 1 clinical trial of NX-2127, where \u3e80% BTK degradation was achieved and clinical responses were also seen in 79% of evaluable patients, independent of mutant BTK genotypes. CONCLUSION: We identified that BTK inhibitor resistance mutations fall into two distinct functional categories. Kinase-impaired BTK mutants disable BTK kinase activity while promoting physical interactions with other kinases to sustain downstream BCR signaling. This scaffold function of BTK was disrupted by NX-2127, a potent BTK degrader, which showed promising responses for patients with relapsed and refractory CLL, independently of mutant BTK functional category

Measuring the Neutrino Cross Section Using 8 years of Upgoing Muon Neutrinos Observed with IceCube

The IceCube Neutrino Observatory detects neutrinos at energies orders of magnitude higher than those available to current accelerators. Above 40 TeV, neutrinos traveling through the Earth will be absorbed as they interact via charged current interactions with nuclei, creating a deficit of Earth-crossing neutrinos detected at IceCube. The previous published results showed the cross section to be consistent with Standard Model predictions for 1 year of IceCube data. We present a new analysis that uses 8 years of IceCube data to fit the ν$_{μ}$ absorption in the Earth, with statistics an order of magnitude better than previous analyses, and with an improved treatment of systematic uncertainties. It will measure the cross section in three energy bins that span the range 1 TeV to 100 PeV. We will present Monte Carlo studies that demonstrate its sensitivity

Multi-messenger searches via IceCube’s high-energy neutrinos and gravitational-wave detections of LIGO/Virgo

We summarize initial results for high-energy neutrino counterpart searches coinciding with gravitational-wave events in LIGO/Virgo\u27s GWTC-2 catalog using IceCube\u27s neutrino triggers. We did not find any statistically significant high-energy neutrino counterpart and derived upper limits on the time-integrated neutrino emission on Earth as well as the isotropic equivalent energy emitted in high-energy neutrinos for each event

Non-standard neutrino interactions in IceCube

Non-standard neutrino interactions (NSI) may arise in various types of new physics. Their existence would change the potential that atmospheric neutrinos encounter when traversing Earth matter and hence alter their oscillation behavior. This imprint on coherent neutrino forward scattering can be probed using high-statistics neutrino experiments such as IceCube and its low-energy extension, DeepCore. Both provide extensive data samples that include all neutrino flavors, with oscillation baselines between tens of kilometers and the diameter of the Earth. DeepCore event energies reach from a few GeV up to the order of 100 GeV - which marks the lower threshold for higher energy IceCube atmospheric samples, ranging up to 10 TeV. In DeepCore data, the large sample size and energy range allow us to consider not only flavor-violating and flavor-nonuniversal NSI in the μ−τ sector, but also those involving electron flavor. The effective parameterization used in our analyses is independent of the underlying model and the new physics mass scale. In this way, competitive limits on several NSI parameters have been set in the past. The 8 years of data available now result in significantly improved sensitivities. This improvement stems not only from the increase in statistics but also from substantial improvement in the treatment of systematic uncertainties, background rejection and event reconstruction

IceCube Search for Earth-traversing ultra-high energy Neutrinos

The search for ultra-high energy neutrinos is more than half a century old. While the hunt for these neutrinos has led to major leaps in neutrino physics, including the detection of astrophysical neutrinos, neutrinos at the EeV energy scale remain undetected. Proposed strategies for the future have mostly been focused on direct detection of the first neutrino interaction, or the decay shower of the resulting charged particle. Here we present an analysis that uses, for the first time, an indirect detection strategy for EeV neutrinos. We focus on tau neutrinos that have traversed Earth, and show that they reach the IceCube detector, unabsorbed, at energies greater than 100 TeV for most trajectories. This opens up the search for ultra-high energy neutrinos to the entire sky. We use ten years of IceCube data to perform an analysis that looks for secondary neutrinos in the northern sky, and highlight the promise such a strategy can have in the next generation of experiments when combined with direct detection techniques