Tighter Relations Between Sensitivity and Other Complexity Measures

Sensitivity conjecture is a longstanding and fundamental open problem in the area of complexity measures of Boolean functions and decision tree complexity. The conjecture postulates that the maximum sensitivity of a Boolean function is polynomially related to other major complexity measures. Despite much attention to the problem and major advances in analysis of Boolean functions in the past decade, the problem remains wide open with no positive result toward the conjecture since the work of Kenyon and Kutin from 2004. In this work, we present new upper bounds for various complexity measures in terms of sensitivity improving the bounds provided by Kenyon and Kutin. Specifically, we show that deg(f)^{1-o(1)}=O(2^{s(f)}) and C(f) < 2^{s(f)-1} s(f); these in turn imply various corollaries regarding the relation between sensitivity and other complexity measures, such as block sensitivity, via known results. The gap between sensitivity and other complexity measures remains exponential but these results are the first improvement for this difficult problem that has been achieved in a decade.Comment: This is the merged form of arXiv submission 1306.4466 with another work. Appeared in ICALP 2014, 14 page

Current concepts in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a disease entity first described in the 1990s, but showing an increasing incidence that is characterized clinically by esophageal dysfunction and histologically by a striking eosinophil infiltration. This article discusses new aspects of the pathogenesis, symptoms, diagnosis, and treatment of EoE. EoE affects both children and adults and is frequently associated with atopic disease and IgE sensitization. Barrier dysfunction and T‑helper 2 inflammation are considered to be pathogenetically important factors. Recently, a proton pump inhibitor (PPI)-sensitive EoE subtype as well as an EoE-like disorder have been described. Research in recent years has contributed to a better understanding of the disease spectrum and pathogenesis of EoE, including genetic dispositions, thereby laying the foundation for innovative treatment approaches

The Release Kinetics of Eosinophil Peroxidase and Mitochondrial DNA Is Different in Association with Eosinophil Extracellular Trap Formation.

Eosinophils are a subset of granulocytes characterized by a high abundance of specific granules in their cytoplasm. To act as effector cells, eosinophils degranulate and form eosinophil extracellular traps (EETs), which contain double-stranded DNA (dsDNA) co-localized with granule proteins. The exact molecular mechanism of EET formation remains unknown. Although the term "EET release" has been used in scientific reports, it is unclear whether EETs are pre-formed in eosinophils and subsequently released. Moreover, although eosinophil degranulation has been extensively studied, a precise time-course of granule protein release has not been reported until now. In this study, we investigated the time-dependent release of eosinophil peroxidase (EPX) and mitochondrial DNA (mtDNA) following activation of both human and mouse eosinophils. Unexpectedly, maximal degranulation was already observed within 1 min with no further change upon complement factor 5 (C5a) stimulation of interleukin-5 (IL-5) or granulocyte/macrophage colony-stimulating factor (GM-CSF)-primed eosinophils. In contrast, bulk mtDNA release in the same eosinophil populations occurred much slower and reached maximal levels between 30 and 60 min. Although no single-cell analyses have been performed, these data suggest that the molecular pathways leading to degranulation and mtDNA release are at least partially different. Moreover, based on these data, it is likely that the association between the mtDNA scaffold and granule proteins in the process of EET formation occurs in the extracellular space

Comparison of different biopsy forceps models for tissue sampling in eosinophilic esophagitis.

Background and aims: Eosinophilic esophagitis (EoE) is a mixed inflammatory and fibrostenotic disease. Unlike superficial inflammatory changes, subepithelial fibrosis is not routinely sampled in esophageal biopsies. This study aimed to evaluate the efficacy and safety of deep esophageal sampling with four different types of biopsy forceps. Patients and methods: In this cross-sectional study, esophageal biopsies were taken in 30 adult patients by one expert endoscopist. Biopsies sampled from distal esophagus using a static jaw forceps (Olympus, FB-11K-1) were compared with proximal biopsies sampled with static jaw (Olympus, FB-45Q-1), alligator jaw (Olympus, FB-210K), and large-capacity forceps (Boston Scientific, Radial Jaw 4). One pathologist calculated the surface area of epithelial and subepithelial layers in hematoxylin and eosin (H&amp;E)-stained biopsies. Results: Subepithelial tissue was acquired in 97 % (static jaw FB-11K-1), 93 % (static jaw FB-45Q-1), 80 % (alligator jaw), and 55 % (large-capacity) of samples. Median (interquartile [IQR]) ratios of surface area of epithelial to subepithelial tissue were: static jaw FB-45Q-1, 1.07 (0.65 - 4.465); static jaw FB-11K-1, 1.184 (0.608 - 2.545); alligator jaw, 2.353 (1.312 - 4.465); and large-capacity, 2.71 (1.611 - 4.858). The static jaw models obtained a larger surface area of subepithelial tissue compared with the alligator jaw (P &lt; 0.001 and P = 0.037, for FB-11K-1 and FB-45Q-1, respectively) and the large-capacity forceps (P &lt; 0.001, for both static jaw models). No esophageal perforations occurred. Conclusions: The static jaw forceps models allowed sampling of subepithelial tissue in &gt; 90 % of biopsies and appear to be superior to alligator or large-capacity forceps in sampling larger amounts of subepithelial tissue

Is bicarbonate in Photosystem II the equivalent of the glutamate ligand to the iron atom in bacterial reaction centers?

Photosystem II of oxygen-evolving organisms exhibits a bicarbonate-reversible formate effect on electron transfer between the primary and secondary acceptor quinones, QA and QB. This effect is absent in the otherwise similar electron acceptor complex of purple bacteria, e.g. Rhodobacter sphaeroides. This distinction has led to the suggestion that the iron atom of the acceptor quinone complex in PS II might lack the fifth and sixth ligands provided in the bacterial reaction center (RC) by a glutamate residue at position 234 of the M-subunit in Rb. sphaeroides,RCs (M232 in Rps. viridis). By site-directed mutagenesis we have altered GluM234 in RCs from Rb. sphaeroides, replacing it with valine, glutamine and glycine to form mutants M234EV, M234EQ and M234EG, respectively. These mutants grew competently under phototrophic conditions and were tested for the formate-bicarbonate effect. In chromatophores there were no detectable differences between wild type (Wt) and mutant M234EV with respect to cytochrome b-561 reduction following a flash, and no effect of bicarbonate depletion (by incubation with formate). In isolated RCs, several electron transfer activities were essentially unchanged in Wt and M234EV, M234EQ and M234EG mutants, and no formate-bicarbonate effect was observed on: (a) the fast or slow phases of recovery of the oxidized primary donor (P+) in the absence of exogenous donor, i.e., the recombination of P+QA− or P+QB−, respectively; (b) the kinetics of electron transfer from QA− to QB; or (c) the flash dependent oscillations of semiquinone formation in the presence of donor to P+ (QB turnover). The absence of a formate-bicarbonate effect in these mutants suggests that GluM234 is not responsible for the absence of the formate-bicarbonate effect in Wt bacterial RCs, or at least that other factors must be taken into account. The mutant RCs were also examined for the fast primary electron transfer along the active (A-)branch of the pigment chain, leading to reduction of QA. The kinetics were resolved to reveal the reduction of the monomer bacteriochlorophyll (τ = 3.5 ps), followed by reduction of the bacteriopheophytin (τ = 0.9 ps). Both steps were essentially unaltered from the wild type. However, the rate of reduction of QA was slowed by a factor of 2 (τ = 410 ± 30 and 47 ± 30 ps for M234EQ and M234EV, respectively, compared to 220 ps in the wild type). EPR studies of the isolated RCs showed a characteristic g = 1.82 signal for the QA semiquinone coupled to the iron atom, which was indistinguishable from the wild type. It is concluded that GluM234 is not essential to the normal functioning of the acceptor quinone complex in bacterial RCs and that the role of bicarbonate in PS II is distinct from the role of this residue in bacterial RCs

A Solvable Regime of Disorder and Interactions in Ballistic Nanostructures, Part I: Consequences for Coulomb Blockade

We provide a framework for analyzing the problem of interacting electrons in a ballistic quantum dot with chaotic boundary conditions within an energy $E_T$ (the Thouless energy) of the Fermi energy. Within this window we show that the interactions can be characterized by Landau Fermi liquid parameters. When $g$, the dimensionless conductance of the dot, is large, we find that the disordered interacting problem can be solved in a saddle-point approximation which becomes exact as $g\to\infty$ (as in a large-N theory). The infinite $g$ theory shows a transition to a strong-coupling phase characterized by the same order parameter as in the Pomeranchuk transition in clean systems (a spontaneous interaction-induced Fermi surface distortion), but smeared and pinned by disorder. At finite $g$, the two phases and critical point evolve into three regimes in the $u_m-1/g$ plane -- weak- and strong-coupling regimes separated by crossover lines from a quantum-critical regime controlled by the quantum critical point. In the strong-coupling and quantum-critical regions, the quasiparticle acquires a width of the same order as the level spacing $\Delta$ within a few $\Delta$'s of the Fermi energy due to coupling to collective excitations. In the strong coupling regime if $m$ is odd, the dot will (if isolated) cross over from the orthogonal to unitary ensemble for an exponentially small external flux, or will (if strongly coupled to leads) break time-reversal symmetry spontaneously.Comment: 33 pages, 14 figures. Very minor changes. We have clarified that we are treating charge-channel instabilities in spinful systems, leaving spin-channel instabilities for future work. No substantive results are change

Modeling the Subsurface Structure of Sunspots

While sunspots are easily observed at the solar surface, determining their subsurface structure is not trivial. There are two main hypotheses for the subsurface structure of sunspots: the monolithic model and the cluster model. Local helioseismology is the only means by which we can investigate subphotospheric structure. However, as current linear inversion techniques do not yet allow helioseismology to probe the internal structure with sufficient confidence to distinguish between the monolith and cluster models, the development of physically realistic sunspot models are a priority for helioseismologists. This is because they are not only important indicators of the variety of physical effects that may influence helioseismic inferences in active regions, but they also enable detailed assessments of the validity of helioseismic interpretations through numerical forward modeling. In this paper, we provide a critical review of the existing sunspot models and an overview of numerical methods employed to model wave propagation through model sunspots. We then carry out an helioseismic analysis of the sunspot in Active Region 9787 and address the serious inconsistencies uncovered by \citeauthor{gizonetal2009}~(\citeyear{gizonetal2009,gizonetal2009a}). We find that this sunspot is most probably associated with a shallow, positive wave-speed perturbation (unlike the traditional two-layer model) and that travel-time measurements are consistent with a horizontal outflow in the surrounding moat.Comment: 73 pages, 19 figures, accepted by Solar Physic

Solving loop equations by Hitchin systems via holography in large-N QCD_4

For (planar) closed self-avoiding loops we construct a "holographic" map from the loop equations of large-N QCD_4 to an effective action defined over infinite rank Hitchin bundles. The effective action is constructed densely embedding Hitchin systems into the functional integral of a partially quenched or twisted Eguchi-Kawai model, by means of the resolution of identity into the gauge orbits of the microcanonical ensemble and by changing variables from the moduli fields of Hitchin systems to the moduli of the corresponding holomorphic de Rham local systems. The key point is that the contour integral that occurs in the loop equations for the de Rham local systems can be reduced to the computation of a residue in a certain regularization. The outcome is that, for self-avoiding loops, the original loop equations are implied by the critical equation of an effective action computed in terms of the localisation determinant and of the Jacobian of the change of variables to the de Rham local systems. We check, at lowest order in powers of the moduli fields, that the localisation determinant reproduces exactly the first coefficient of the beta function.Comment: 65 pages, late

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders