Power-law entanglement spectrum in many-body localized phases

The entanglement spectrum of the reduced density matrix contains information beyond the von Neumann entropy and provides unique insights into exotic orders or critical behavior of quantum systems. Here, we show that strongly disordered systems in the many-body localized phase have power-law entanglement spectra, arising from the presence of extensively many local integrals of motion. The power-law entanglement spectrum distinguishes many-body localized systems from ergodic systems, as well as from ground states of gapped integrable models or free systems in the vicinity of scale-invariant critical points. We confirm our results using large-scale exact diagonalization. In addition, we develop a matrix-product state algorithm which allows us to access the eigenstates of large systems close to the localization transition, and discuss general implications of our results for variational studies of highly excited eigenstates in many-body localized systems

Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells

Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34(+) hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells.The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah(-/-) mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV.Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah(-/-) mice by 5-100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia.Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis.Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called liver chimeric mice with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens

CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus

Chronic hepatitis B virus (HBV) infection is prevalent, deadly, and seldom cured due to the persistence of viral episomal DNA (cccDNA) in infected cells. Newly developed genome engineering tools may offer the ability to directly cleave viral DNA, thereby promoting viral clearance. Here, we show that the CRISPR/Cas9 system can specifically target and cleave conserved regions in the HBV genome, resulting in robust suppression of viral gene expression and replication. Upon sustained expression of Cas9 and appropriately chosen guide RNAs, we demonstrate cleavage of cccDNA by Cas9 and a dramatic reduction in both cccDNA and other parameters of viral gene expression and replication. Thus, we show that directly targeting viral episomal DNA is a novel therapeutic approach to control the virus and possibly cure patients.United States. National Institutes of Health (DK085713)National Cancer Institute (U.S.) (P30-CA14051)National Institute of Environmental Health Sciences (P30-ES002109)United States. National Institutes of Health (1K08DK101754

Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder with many patients experiencing poor seizure control with existing anti-epileptic drugs. Thus, novel insights into the mechanisms of epileptogenesis and identification of new drug targets can be transformative. Changes in ion channel function have been shown to play a role in generating the aberrant neuronal activity observed in TLE. Previous work demonstrates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are mislocalized within CA1 pyramidal cells in a rodent model of TLE. The subcellular distribution of HCN channels is regulated by an auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), and disruption of this interaction correlates with channel mislocalization. However, the molecular mechanisms responsible for HCN channel dysregulation in TLE are unclear. Here we investigated whether changes in TRIP8b phosphorylation are sufficient to alter HCN channel function. We identified a phosphorylation site at residue Ser237 of TRIP8b that enhances binding to HCN channels and influences channel gating by altering the affinity of TRIP8b for the HCN cytoplasmic domain. Using a phosphospecific antibody, we demonstrate that TRIP8b phosphorylated at Ser237 is enriched in CA1 distal dendrites and that phosphorylation is reduced in the kainic acid model of TLE. Overall, our findings indicate that the TRIP8b-HCN interaction can be modulated by changes in phosphorylation and suggest that loss of TRIP8b phosphorylation may affect HCN channel properties during epileptogenesis. These results highlight the potential of drugs targeting posttranslational modifications to restore TRIP8b phosphorylation to reduce excitability in TLE

Profit-oriented resource allocation using online scheduling in flexible heterogeneous networks

In this paper, we discuss a generalized measurement-based adaptive scheduling framework for dynamic resource allocation in flexible heterogeneous networks, in order to ensure efficient service level performance under inherently variable traffic conditions. We formulate our generalized optimization model based on the notion of a “profit center” with an arbitrary number of service classes, nonlinear revenue and cost functions and general performance constraints. Subsequently, and under the assumption of a linear pricing model and average queue delay requirements, we develop a fast, low complexity algorithm for online dynamic resource allocation, and examine its properties. Finally, the proposed scheme is validated through an extensive simulation study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47990/1/11235_2006_Article_6525.pd

GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics

Mosaic variants in genes GNAQ or GNA11 lead to a spectrum of vascular and pigmentary diseases including Sturge-Weber syndrome, in which progressive postnatal neurological deterioration led us to seek biologically targeted therapeutics. Using two cellular models, we find that disease-causing GNAQ/11 variants hyperactivate constitutive and G-protein coupled receptor ligand–induced intracellular calcium signaling in endothelial cells. We go on to show that the aberrant ligand-activated intracellular calcium signal is fueled by extracellular calcium influx through calcium-release-activated channels. Treatment with targeted small interfering RNAs designed to silence the variant allele preferentially corrects both the constitutive and ligand-activated calcium signaling, whereas treatment with a calcium-release-activated channel inhibitor rescues the ligand-activated signal. This work identifies hyperactivated calcium signaling as the primary biological abnormality in GNAQ/11 mosaicism and paves the way for clinical trials with genetic or small molecule therapies

Add-on topiramate in the treatment of refractory partial-onset epilepsy: Clinical experience of outpatient epilepsy clinics from 11 general hospitals

SummaryAn open, prospective, observational study was performed to assess efficacy and adverse-event profile of topiramate as add-on therapy in epilepsy. Outpatient neurology clinics from 11 general hospitals in Greece participated in the study. In total, 211 patients with treatment resistant partial-onset seizures who met the inclusion criteria, were studied. After baseline evaluation, topiramate was given at a target dose of 200mg/day over a 1-month titration period. In the subsequent maintenance period, the topiramate dose could be varied according to the clinical results. Patients were followed for in total 6 months, with monthly visits and regular physical, neurological and laboratory examinations. Seizure frequencies decreased to 35–40% of baseline values following 3 months of treatment and remained relatively constant thereafter. The average monthly seizure frequency over the 6-month study period was 4.61, compared to 9.21 at baseline. The number of responders (patients with at least 50% reduction in seizure frequency) followed a similar pattern, i.e., increase during the first 3 months levelling off at a final 80–85% response rate. Of those completing the study, 30% had been seizure-free for at least 3 months and 12% for 5 months. Topiramate was well tolerated, no deviations in laboratory values were found. Adverse events appeared to occur less frequently, and antiepileptic effects were more pronounced in this prospective open-label study than in earlier reports from randomised controlled trials. The nature of the patient population and the application of individualised dose optimisation are proposed as contributing factors to explain the favourable results of this study