Effective Field Theory of Random Quantum Circuits.

Quantum circuits have been widely used as a platform to simulate generic quantum many-body systems. In particular, random quantum circuits provide a means to probe universal features of many-body quantum chaos and ergodicity. Some such features have already been experimentally demonstrated in noisy intermediate-scale quantum (NISQ) devices. On the theory side, properties of random quantum circuits have been studied on a case-by-case basis and for certain specific systems, and a hallmark of quantum chaos-universal Wigner-Dyson level statistics-has been derived. This work develops an effective field theory for a large class of random quantum circuits. The theory has the form of a replica sigma model and is similar to the low-energy approach to diffusion in disordered systems. The method is used to explicitly derive the universal random matrix behavior of a large family of random circuits. In particular, we rederive the Wigner-Dyson spectral statistics of the brickwork circuit model by Chan, De Luca, and Chalker [Phys. Rev. X 8, 041019 (2018)] and show within the same calculation that its various permutations and higher-dimensional generalizations preserve the universal level statistics. Finally, we use the replica sigma model framework to rederive the Weingarten calculus, which is a method of evaluating integrals of polynomials of matrix elements with respect to the Haar measure over compact groups and has many applications in the study of quantum circuits. The effective field theory derived here provides both a method to quantitatively characterize the quantum dynamics of random Floquet systems (e.g., calculating operator and entanglement spreading) and a path to understanding the general fundamental mechanism behind quantum chaos and thermalization in these systems.

Brain tumour cells interconnect to a functional and resistant network.

Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.

Many-Body Level Statistics of Single-Particle Quantum Chaos.

We consider a noninteracting many-fermion system populating levels of a unitary random matrix ensemble (equivalent to the q=2 complex Sachdev-Ye-Kitaev model)-a generic model of single-particle quantum chaos. We study the corresponding many-particle level statistics by calculating the spectral form factor analytically using algebraic methods of random matrix theory, and match it with an exact numerical simulation. Despite the integrability of the theory, the many-body spectral rigidity is found to have a surprisingly rich landscape. In particular, we find a residual repulsion of distant many-body levels stemming from single-particle chaos, together with islands of level attraction. These results are encoded in an exponential ramp in the spectral form factor, which we show to be a universal feature of nonergodic many-fermion systems embedded in a chaotic medium.

Dephasing Catastrophe in 4-ε Dimensions: A Possible Instability of the Ergodic (Many-Body-Delocalized) Phase.

In two dimensions, dephasing by a bath cuts off Anderson localization that would otherwise occur at any energy density for fermions with disorder. For an isolated system with short-range interactions, the system can be its own bath, exhibiting diffusive (non-Markovian) thermal density fluctuations. We recast the dephasing of weak localization due to a diffusive bath as a self-interacting polymer loop. We investigate the critical behavior of the loop in d=4-ε dimensions, and find a nontrivial fixed point corresponding to a temperature T^{*}∼ε>0 where the dephasing time diverges. Assuming that this fixed point survives to ε=2, we associate it with a possible instability of the ergodic phase. Our approach may open a new line of attack against the problem of the ergodic to many-body-localized phase transition in d>1 spatial dimensions.

Critical Percolation without Fine-Tuning on the Surface of a Topological Superconductor.

We present numerical evidence that most two-dimensional surface states of a bulk topological superconductor (TSC) sit at an integer quantum Hall plateau transition. We study TSC surface states in class CI with quenched disorder. Low-energy (finite-energy) surface states were expected to be critically delocalized (Anderson localized). We confirm the low-energy picture, but find instead that finite-energy states are also delocalized, with universal statistics that are independent of the TSC winding number, and consistent with the spin quantum Hall plateau transition (percolation).

Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy.

Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infantile seizures are caused by mutations in the gene SCN2A encoding the voltage-gated Na(+) channel Na(V)1.2. We identified two novel SCN2A mutations causing benign familial neonatal-infantile seizures and analysed the functional consequences of these mutations in a neonatal and an adult splice variant of the human Na(+) channel Na(V)1.2 expressed heterologously in tsA201 cells together with beta1 and beta2 subunits. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na(+) current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced for the adult form for the other, suggesting that a differential developmental splicing does not provide a general explanation for seizure remission. We therefore analysed the developmental expression of Na(V)1.2 and of another voltage-gated Na(+) channel, Na(V)1.6, using immunohistochemistry and real-time reverse transcription-polymerase chain reaction in mouse brain slices. We found that Na(V)1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by Na(V)1.6 during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant Na(V)1.2 channels.

Identification and Characterization of Cancer Cells That Initiate Metastases to the Brain and Other Organs.

Specific biological properties of those circulating cancer cells that are the origin of brain metastases (BM) are not well understood. Here, single circulating breast cancer cells were fate-tracked during all steps of the brain metastatic cascade in mice after intracardial injection over weeks. A novel in vivo two-photon microscopy methodology was developed that allowed to determine the specific cellular and molecular features of breast cancer cells that homed in the brain, extravasated, and successfully established a brain macrometastasis. Those BM-initiating breast cancer cells (BMIC) were mainly originating from a slow-cycling subpopulation that included only 16% to 20% of all circulating cancer cells. BMICs showed enrichment of various markers of cellular stemness. As a proof of principle for the principal usefulness of this approach, expression profiling of BMICs versus non-BMICs was performed, which revealed upregulation of NDRG1 in the slow-cycling BMIC subpopulation in one BM model. Here, BM development was completely suppressed when NDRG1 expression was downregulated. In accordance, in primary human breast cancer, NDRG1 expression was heterogeneous, and high NDRG1 expression was associated with shorter metastasis-free survival. In conclusion, our data identify temporary slow-cycling breast cancer cells as the dominant source of brain and other metastases and demonstrates that this can lead to better understanding of BMIC-relevant pathways, including potential new approaches to prevent BM in patients. IMPLICATIONS: Cancer cells responsible for successful brain metastasis outgrowth are slow cycling and harbor stemness features. The molecular characteristics of these metastasis-initiating cells can be studied using intravital microscopy technology.

Impact of Blood-Brain Barrier Integrity on Tumor Growth and Therapy Response in Brain Metastases.

PURPOSE: The role of blood-brain barrier (BBB) integrity for brain tumor biology and therapy is a matter of debate. EXPERIMENTAL DESIGN: We developed a new experimental approach using in vivo two-photon imaging of mouse brain metastases originating from a melanoma cell line to investigate the growth kinetics of individual tumor cells in response to systemic delivery of two PI3K/mTOR inhibitors over time, and to study the impact of microregional vascular permeability. The two drugs are closely related but differ regarding a minor chemical modification that greatly increases brain penetration of one drug. RESULTS: Both inhibitors demonstrated a comparable inhibition of downstream targets and melanoma growth in vitro In vivo, increased BBB permeability to sodium fluorescein was associated with accelerated growth of individual brain metastases. Melanoma metastases with permeable microvessels responded similarly to equivalent doses of both inhibitors. In contrast, metastases with an intact BBB showed an exclusive response to the brain-penetrating inhibitor. The latter was true for macro- and micrometastases, and even single dormant melanoma cells. Nuclear morphology changes and single-cell regression patterns implied that both inhibitors, if extravasated, target not only perivascular melanoma cells but also those distant to blood vessels. CONCLUSIONS: Our study provides the first direct evidence that nonpermeable brain micro- and macrometastases can effectively be targeted by a drug designed to cross the BBB. Small-molecule inhibitors with these optimized properties are promising agents in preventing or treating brain metastases in patients. Clin Cancer Res; 22(24); 6078-87. ©2016 AACRSee related commentary by Steeg et al., p. 5953.

Bevacizumab Prevents Brain Metastases Formation in Lung Adenocarcinoma.

Patients with nonsquamous non-small cell lung cancer (nsNSCLC; largely lung adenocarcinoma) are at high risk of developing brain metastases. Preclinical data suggested that anti-VEGF-A therapy may prevent the formation of nsNSCLC brain metastases. Whether non-brain metastases are also prevented, and whether bevacizumab shows a brain metastases-preventive activity in cancer patients is unknown. Data of one nsNSCLC (stage IIIB/IV, AVAiL) and two breast cancer bevacizumab trials (HER2 negative, AVADO; HER2 positive, AVEREL) were retrospectively analyzed regarding the frequency of the brain versus other organs being the site of first relapse. For animal studies, the outgrowth of PC14-PE6 lung adenocarcinoma cells to brain macrometastases in mice was measured by intravital imaging: under control IgG (25 mg/kg) treatment, or varying doses of bevacizumab (25 mg/kg, 2.5 mg/kg, 0.25 mg/kg). Brain metastases as site of first relapse were significantly less frequent in the bevacizumab arm of the AVAiL trial (HR = 0.36, P < 0.001). In AVADO and AVEREL, no significant difference was seen. In mice, bevacizumab treatment led to secondary regressions of non-brain macrometastases, but did not reduce their total incidence, and did not improve survival. In a brain-seeking nsNSCLC metastasis model, treatment with bevacizumab inhibited brain metastases formation, which resulted in improved overall survival. In summary, bevacizumab has the potential to prevent brain metastases in nsNSCLC, but no preventive activity could be detected outside the brain. These data indicate that anti-VEGF-A agents might be particularly relevant for those stage III nsNSCLC patients who are at high risk to develop future brain metastases. Mol Cancer Ther; 15(4); 702-10. ©2016 AACR.