General Control Nonderepressible 2 (GCN2) Kinase Protects Oligodendrocytes and White Matter during Branched-Chain Amino Acid Deficiency in Mice

Branched-chain amino acid (BCAA) catabolism is regulated by branched-chain α-keto acid dehydrogenase, an enzyme complex that is inhibited when phosphorylated by its kinase (BDK). Loss of BDK function in mice and humans causes BCAA deficiency and epilepsy with autistic features. In response to amino acid deficiency, phosphorylation of eukaryotic initiation factor 2α (eIF2∼P) by general control nonderepressible 2 (GCN2) activates the amino acid stress response. We hypothesized that GCN2 functions to protect the brain during chronic BCAA deficiency. To test this idea, we generated mice lacking both Gcn2 and Bdk (GBDK) and examined the development of progeny. GBDK mice appeared normal at birth, but they soon stopped growing, developed severe ataxia, tremor, and anorexia, and died by postnatal day 15. BCAA levels in brain were diminished in both Bdk−/− and GBDK pups. Brains from Bdk−/− pups exhibited robust eIF2∼P and amino acid stress response induction, whereas these responses were absent in GBDK mouse brains. Instead, myelin deficiency and diminished expression of myelin basic protein were noted in GBDK brains. Genetic markers of oligodendrocytes and astrocytes were also reduced in GBDK brains in association with apoptotic cell death in white matter regions of the brain. GBDK brains further demonstrated reduced Sod2 and Cat mRNA and increased Tnfα mRNA expression. The data are consistent with the idea that loss of GCN2 during BCAA deficiency compromises glial cell defenses to oxidative and inflammatory stress. We conclude that GCN2 protects the brain from developing a lethal leukodystrophy in response to amino acid deficiencies

Current Fluctuations of the One Dimensional Symmetric Simple Exclusion Process with Step Initial Condition

For the symmetric simple exclusion process on an infinite line, we calculate exactly the fluctuations of the integrated current $Q_t$ during time $t$ through the origin when, in the initial condition, the sites are occupied with density $\rho_a$ on the negative axis and with density $\rho_b$ on the positive axis. All the cumulants of $Q_t$ grow like $\sqrt{t}$. In the range where $Q_t \sim \sqrt{t}$, the decay $\exp [-Q_t^3/t]$ of the distribution of $Q_t$ is non-Gaussian. Our results are obtained using the Bethe ansatz and several identities recently derived by Tracy and Widom for exclusion processes on the infinite line.Comment: 2 figure

Aperiodicity-Induced Second-Order Phase Transition in the 8-State Potts Model

We investigate the critical behavior of the two-dimensional 8-state Potts model with an aperiodic distribution of the exchange interactions between nearest-neighbor rows. The model is studied numerically through intensive Monte Carlo simulations using the Swendsen-Wang cluster algorithm. The transition point is located through duality relations, and the critical behavior is investigated using FSS techniques at criticality. For strong enough fluctuations of the aperiodic sequence under consideration, a second order phase transition is found. The exponents $\beta/\nu$ and $\gamma /\nu$ are obtained at the new fixed point.Comment: LaTeX file with Revtex, 4 pages, 5 eps figures, to appear in Phys. Rev. Let

Evidence for geometry-dependent universal fluctuations of the Kardar-Parisi-Zhang interfaces in liquid-crystal turbulence

We provide a comprehensive report on scale-invariant fluctuations of growing interfaces in liquid-crystal turbulence, for which we recently found evidence that they belong to the Kardar-Parisi-Zhang (KPZ) universality class for 1+1 dimensions [Phys. Rev. Lett. 104, 230601 (2010); Sci. Rep. 1, 34 (2011)]. Here we investigate both circular and flat interfaces and report their statistics in detail. First we demonstrate that their fluctuations show not only the KPZ scaling exponents but beyond: they asymptotically share even the precise forms of the distribution function and the spatial correlation function in common with solvable models of the KPZ class, demonstrating also an intimate relation to random matrix theory. We then determine other statistical properties for which no exact theoretical predictions were made, in particular the temporal correlation function and the persistence probabilities. Experimental results on finite-time effects and extreme-value statistics are also presented. Throughout the paper, emphasis is put on how the universal statistical properties depend on the global geometry of the interfaces, i.e., whether the interfaces are circular or flat. We thereby corroborate the powerful yet geometry-dependent universality of the KPZ class, which governs growing interfaces driven out of equilibrium.Comment: 31 pages, 21 figures, 1 table; references updated (v2,v3); Fig.19 updated & minor changes in text (v3); final version (v4); J. Stat. Phys. Online First (2012

Crossover between aperiodic and homogeneous semi-infinite critical behaviors in multilayered two-dimensional Ising models

We investigate the surface critical behavior of two-dimensional multilayered aperiodic Ising models in the extreme anisotropic limit. The system under consideration is obtained by piling up two types of layers with respectively $p$ and $q$ spin rows coupled via nearest neighbor interactions $\lambda r$ and $\lambda$, where the succession of layers follows an aperiodic sequence. Far away from the critical regime, the correlation length $\xi_\perp$ is smaller than the first layer width and the system exhibits the usual behavior of an ordinary surface transition. In the other limit, in the neighborhood of the critical point, $\xi_\perp$ diverges and the fluctuations are sensitive to the non-periodic structure of the system so that the critical behavior is governed by a new fixed point. We determine the critical exponent associated to the surface magnetization at the aperiodic critical point and show that the expected crossover between the two regimes is well described by a scaling function. From numerical calculations, the parallel correlation length $\xi_\parallel$ is then found to behave with an anisotropy exponent $z$ which depends on the aperiodic modulation and the layer widths.Comment: LaTeX file, 9 pages, 8 eps figures, to appear in Phys. Rev.

Alpha band prefrontal asymmetry does not underlie pain approach-avoidance: Results from two EEG studies

Pain research is often focused on escape from pain or approach of relief, yet individuals with chronic pain make complex choices to face their pain to satiate other drives (approach-avoidance conflicts). An abundance of research has indicated that prefrontal alpha band asymmetry (PFA) underlies approach-avoidance in general, but there is limited information about whether PFA underlies pain approach-avoidance conflicts. Electroencephalogram activity was recorded while 70 participants with chronic pain (n=33) and without chronic pain (n=37) approached/avoided stimuli containing simultaneous pain (low-high) and monetary reward (low-high). Findings from both studies revealed that approach-avoidance for pain stimuli is not accompanied by prefrontal asymmetry, irrespective of the presence of chronic pain

Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib

Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit. (C) 2019 Published by Elsevier Ltd

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program