Transient localized wave patterns and their application to migraine

Transient dynamics is pervasive in the human brain and poses challenging problems both in mathematical tractability and clinical observability. We investigate statistical properties of transient cortical wave patterns with characteristic forms (shape, size, duration) in a canonical reaction-diffusion model with mean field inhibition. The patterns are formed by a ghost near a saddle-node bifurcation in which a stable traveling wave (node) collides with its critical nucleation mass (saddle). Similar patterns have been observed with fMRI in migraine. Our results support the controversial idea that waves of cortical spreading depression (SD) have a causal relationship with the headache phase in migraine and therefore occur not only in migraine with aura (MA) but also in migraine without aura (MO), i.e., in the two major migraine subforms. We suggest a congruence between the prevalence of MO and MA with the statistical properties of the traveling waves' forms, according to which (i) activation of nociceptive mechanisms relevant for headache is dependent upon a sufficiently large instantaneous affected cortical area anti-correlated to both SD duration and total affected cortical area such that headache would be less severe in MA than in MO (ii) the incidence of MA is reflected in the distance to the saddle-node bifurcation, and (iii) the contested notion of MO attacks with silent aura is resolved. We briefly discuss model-based control and means by which neuromodulation techniques may affect pathways of pain formation.Comment: 14 pages, 11 figure

Propagation failure of excitation waves on trees and random networks

Excitation waves are studied on trees and random networks of coupled active elements. Undamped propagation of such waves is observed in those networks. It represents an excursion from the resting state and a relaxation back to it for each node. However, the degrees of the nodes influence drastically the dynamics. Excitation propagates more slowly through nodes with larger degrees and beyond some critical degree waves lose their stability and disappear. For regular trees with a fixed branching ratio, the critical degree is determined with an approximate analytical theory which also holds locally for the early stage of excitation spreading in random networks.Comment: 7 pages, 7 figures, submitted to ep

Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in Hepatocellular carcinoma

BACKGROUND AIMS: Hepatocellular carcinoma (HCC) is the most common primary liver tumor with an increasing incidence worldwide. HCC is a heterogeneous malignancy and develops usually in a chronically injured liver. The nuclear factor kappa B (NF-κB) signaling network consists of a canonical and a non-canonical branch. An activation of canonical NF-κB in HCC is documented. However, a functional and clinically relevant role of non-canonical NF-κB and its downstream effectors is not established. APPROACH RESULTS: Four human HCC cohorts (total n=1,462) and four mouse HCC models were assessed for expression and localization of NF-κB signaling components and activating ligands. In vitro, NF-κB signaling, proliferation and cell death were measured, proving a pro-proliferative role of RELB activated via NIK. In vivo, Lymphotoxin beta (LTβ) was identified as predominant inducer of RELB activation. Importantly, hepatocyte-specific RELB knockout in a murine HCC model led to a lower incidence compared to controls and lower maximal tumor diameters. In silico, RELB activity and RELB directed transcriptomics were validated on the TCGA HCC cohort using inferred protein activity and Gene Set Enrichment Analysis (GSEA). In RELB-active HCC, pathways mediating proliferation were significantly activated. In contrast to RELA, nuclear enrichment of non-canonical RELB expression identified patients with a poor prognosis in an etiology-independent manner. Moreover, RELB activation was associated with malignant features metastasis and recurrence. CONCLUSIONS: This study demonstrates a prognostically relevant, etiology-independent and cross-species consistent activation of a LTβ/LTβR/RELB axis in hepatocarcinogenesis. These observations may harbor broad implications for HCC, including possible clinical exploitation

Experimental demonstration of attosecond pump–probe spectroscopy with an X-ray free-electron laser

Pump–probe experiments with subfemtosecond resolution are the key to understanding electronic dynamics in quantum systems. Here we demonstrate the generation and control of subfemtosecond pulse pairs from a two-colour X-ray free-electron laser. By measuring the delay between the two pulses with an angular streaking diagnostic, we characterize the group velocity of the X-ray free-electron laser and show control of the pulse delay down to 270 as. We confirm the application of this technique to a pump–probe measurement in core-ionized para-aminophenol. These results reveal the ability to perform pump–probe experiments with subfemtosecond resolution and atomic site specificity