N=1 Sigma Models in AdS_4

We study sigma models in AdS_4 with global N=1 supersymmetry and find that they differ significantly from their flat-space cousins -- the target space is constrained to be a Kahler manifold with an exact Kahler form, the superpotential transforms under Kahler transformations, the space of supersymmetric vacua is generically a set of isolated points even when the superpotential vanishes, and the R-symmetry is classically broken by the cosmological constant. Remarkably, the exactness of the Kahler class is also required for the sigma model to arise as a decoupling limit of N=1 supergravity, and ensures the vanishing of gravitational anomalies. As simple applications of these results, we argue that fields with AdS_4 scale masses are ubiquitous in, for example, type IIB N=1 AdS_4 vacua stabilized near large volume; we also show that the Affleck-Dine-Seiberg runaway of N_f < N_c SQCD is regulated by considering the theory in AdS_4.Comment: 32 pages; v2: minor changes and references added; v3: discussion in sect. 5 extended, version published in JHE

Nonabelian 2D Gauge Theories for Determinantal Calabi-Yau Varieties

The two-dimensional supersymmetric gauged linear sigma model (GLSM) with abelian gauge groups and matter fields has provided many insights into string theory on Calabi--Yau manifolds of a certain type: complete intersections in toric varieties. In this paper, we consider two GLSM constructions with nonabelian gauge groups and charged matter whose infrared CFTs correspond to string propagation on determinantal Calabi-Yau varieties, furnishing another broad class of Calabi-Yau geometries in addition to complete intersections. We show that these two models -- which we refer to as the PAX and the PAXY model -- are dual descriptions of the same low-energy physics. Using GLSM techniques, we determine the quantum K\"ahler moduli space of these varieties and find no disagreement with existing results in the literature.Comment: v3: 46 pages, 1 figure. Corrected phase structure of general linear determinantal varieties. Typos correcte

Two-Sphere Partition Functions and Gromov-Witten Invariants

Many N=(2,2) two-dimensional nonlinear sigma models with Calabi-Yau target spaces admit ultraviolet descriptions as N=(2,2) gauge theories (gauged linear sigma models). We conjecture that the two-sphere partition function of such ultraviolet gauge theories -- recently computed via localization by Benini et al. and Doroud et al. -- yields the exact K\"ahler potential on the quantum K\"ahler moduli space for Calabi-Yau threefold target spaces. In particular, this allows one to compute the genus zero Gromov-Witten invariants for any such Calabi-Yau threefold without the use of mirror symmetry. More generally, when the infrared superconformal fixed point is used to compactify string theory, this provides a direct method to compute the spacetime K\"ahler potential of certain moduli (e.g., vector multiplet moduli in type IIA), exactly in {\alpha}'. We compute these quantities for the quintic and for R{\o}dland's Pfaffian Calabi-Yau threefold and find agreement with existing results in the literature. We then apply our methods to a codimension four determinantal Calabi-Yau threefold in P^7, recently given a nonabelian gauge theory description by the present authors, for which no mirror Calabi-Yau is currently known. We derive predictions for its Gromov-Witten invariants and verify that our predictions satisfy nontrivial geometric checks.Comment: 25 pages + 2 appendices; v2 corrects a divisor in K\"ahler moduli space and includes a new calculation that confirms a geometric prediction; v3 contains minor update of Gromov-Witten invariant extraction procedur

The intrinsic stiffness of human trabecular meshwork cells increases with senescence.

Dysfunction of the human trabecular meshwork (HTM) plays a central role in the age-associated disease glaucoma, a leading cause of irreversible blindness. The etiology remains poorly understood but cellular senescence, increased stiffness of the tissue, and the expression of Wnt antagonists such as secreted frizzled related protein-1 (SFRP1) have been implicated. However, it is not known if senescence is causally linked to either stiffness or SFRP1 expression. In this study, we utilized in vitro HTM senescence to determine the effect on cellular stiffening and SFRP1 expression. Stiffness of cultured cells was measured using atomic force microscopy and the morphology of the cytoskeleton was determined using immunofluorescent analysis. SFRP1 expression was measured using qPCR and immunofluorescent analysis. Senescent cell stiffness increased 1.88±0.14 or 2.57±0.14 fold in the presence or absence of serum, respectively. This was accompanied by increased vimentin expression, stress fiber formation, and SFRP1 expression. In aggregate, these data demonstrate that senescence may be a causal factor in HTM stiffening and elevated SFRP1 expression, and contribute towards disease progression. These findings provide insight into the etiology of glaucoma and, more broadly, suggest a causal link between senescence and altered tissue biomechanics in aging-associated diseases

The Timing of Reward-Seeking Action Tracks Visually-Cued Theta Oscillations in Primary Visual Cortex

An emerging body of work challenges the view that primary visual cortex (V1) represents the visual world faithfully. Theta oscillations in the local field potential (LFP) of V1 have been found to convey temporal expectations and, specifically, to express the delay between a visual stimulus and the reward that it portends. We extend this work by showing how these oscillatory states in male, wild-type rats can even relate to the timing of a visually cued reward-seeking behavior. In particular, we show that, with training, high precision and accuracy in behavioral timing tracks the power of these oscillations and the time of action execution covaries with their duration. These LFP oscillations are also intimately related to spiking responses at the single-unit level, which themselves carry predictive timing information. Together, these observations extend our understanding of the role of cortical oscillations in timing generally and the role of V1 in the timing of visually cued behaviors specifically.Fil: Levy, Joshua M.. University Johns Hopkins; Estados UnidosFil: Zold, Camila Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Namboodiri, Vijay Mohan K.. University of North Carolina; Estados UnidosFil: Hussain Shuler, Marshall G. University Johns Hopkins; Estados Unido

Antibody-associated inflammation in and outside the joint in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by pain, chronic inflammation and joint destruction. Epidemiological investigations in large populationbased cohorts have identified both genetic (such as HLA-DRB1 Shared epitope, SE) and environmental (such as smoking) risk factors for the development of RA. One of the hallmarks of the disease is the presence of antibodies against a large array of citrullinated proteins (anti citrullinated protein antibodies, ACPA), which are present years before the onset of clinical symptoms. These findings suggest that RA-associated autoimmunity might be initiated somewhere else than the joints, possibly at the mucosal surfaces of the lungs. In the current thesis we aimed to investigate immunological events in the lungs contributing to ACPA generation and to identify novel targets for these antibodies. Presence of ACPA associates with parenchymal lung abnormalities (as detected by high resolution computed tomography, HRCT) in early-untreated RA. Recognition of more than one citrullinated target by ACPA and specifically recognition of citrullinated fibrinogen peptides increases the odds of detecting HRCT lung abnormalities. Beside HRCT abnormalities, significantly decreased microbial richness and diversity is present in the bronchoalveolar lavage of early-untreated RA patients as compared to healthy volunteers. Interestingly, a similar microbiota dysbiosis is also detected in the presence of overt lung inflammation in the bronchoalveolar lavage of patients with lung sarcoidosis, suggesting that similar inflammatory mechanisms might be active in both lung sarcoidosis and RA. To further explore the possibility that changes in the lungs contribute to generation of autoimmunity in RA, we investigated the presence of citrullinated targets in the mucosal biopsies of early-untreated RA. We identified several novel citrullinated targets, with two citrullinated vimentin peptides detected in a majority of the biopsies. Interestingly these two peptides were also identified in the inflamed synovial tissues of RA patients showing that shared immunological targets are present in the lungs and joints in RA patients. Antibodies against these novel targets were detectable in RA patients suggesting that they could act as immunological targets during disease development. Using a similar approach, we further screened for antibody-reactivity against novel citrullinated targets identified in the synovial fluid of RA patients. Several citrullinated fibrinogen peptides specifically reacted with the antibodies in RA serum, with varying proportion of reactivity for each of these peptides. Interestingly, these antibodies differ from the classical ACPA being associated with the PTPN22 risk allele but not with the HLA-DRB1 SE. As such RA patients carrying the PTPN22 risk allele displayed higher proportion of B cells reacting with citrullinated fibrinogen loaded B cell antigen tetramers than those lacking the risk allele. In conclusion, we provide evidence for a pathogenic link between early events in the lungs and autoimmunity in RA and identify several novel immunological targets for this autoimmunity. Our studies contribute to the understanding of the longitudinal development of RA, opening the possibility for future targeting of early pathogenic events in order to delay and/or prevent the disease

Effect of Geometric Complexity on Intuitive Model Selection

Occam’s razor is the principle stating that, all else being equal, simpler explanations for a set of observations are to be preferred to more complex ones. This idea can be made precise in the context of statistical inference, where the same quantitative notion of complexity of a statistical model emerges naturally from different approaches based on Bayesian model selection and information theory. The broad applicability of this mathematical formulation suggests a normative model of decision-making under uncertainty: complex explanations should be penalized according to this common measure of complexity. However, little is known about if and how humans intuitively quantify the relative complexity of competing interpretations of noisy data. Here we measure the sensitivity of naive human subjects to statistical model complexity. Our data show that human subjects bias their decisions in favor of simple explanations based not only on the dimensionality of the alternatives (number of model parameters), but also on finer-grained aspects of their geometry. In particular, as predicted by the theory, models intuitively judged as more complex are not only those with more parameters, but also those with larger volume and prominent curvature or boundaries. Our results imply that principled notions of statistical model complexity have direct quantitative relevance to human decision-making

How Occam’s Razor Guides Human Inference

Occam’s razor is the principle stating that, all else being equal, simpler explanations for a set of observations are preferred over more complex ones. This idea is central to multiple formal theories of statistical model selection and is posited to play a role in human perception and decision-making, but a general, quantitative account of the specific nature and impact of complexity on human decision-making is still missing. Here we use preregistered experiments to show that, when faced with uncertain evidence, human subjects bias their decisions in favor of simpler explanations in a way that can be quantified precisely using the framework of Bayesian model selection. Specifically, these biases, which were also exhibited by artificial neural networks trained to optimize performance on comparable tasks, reflect an aversion to complex explanations (statistical models of data) that depends on specific geometrical features of those models, namely their dimensionality, boundaries, volume, and curvature. Moreover, the simplicity bias persists for human, but not artificial, subjects even for tasks for which the bias is maladaptive and can lower overall performance. Taken together, our results imply that principled notions of statistical model complexity have direct, quantitative relevance to human and machine decision-making and establish a new understanding of the computational foundations, and behavioral benefits, of our predilection for inferring simplicity in the latent properties of our complex world

Comparison of the Efficacy of Caudal, Interlaminar, and Transforaminal Epidural Injections in Managing Lumbar Disc Herniation: Is One Method Superior to the Other?

Background: Epidural injections are performed utilizing 3 approaches in the lumbar spine: caudal, interlaminar, and transforaminal. The literature on the efficacy of epidural injections has been sporadic. There are few high-quality randomized trials performed under fluoroscopy in managing disc herniation that have a long-term follow-up and appropriate outcome parameters. There is also a lack of literature comparing the efficacy of these 3 approaches. Methods: This manuscript analyzes data from 3 randomized controlled trials that assessed a total of 360 patients with lumbar disc herniation. There were 120 patients per trial either receiving local anesthetic alone (60 patients) or local anesthetic with steroids (60 patients). Results: Analysis showed similar efficacy for caudal, interlaminar, and transforaminal approaches in managing chronic pain and disability from disc herniation. The analysis of caudal epidural injections showed the potential superiority of steroids compared with local anesthetic alone a 2-year follow-up, based on the average relief per procedure. In the interlaminar group, results were somewhat superior for pain relief in the steroid group at 6 months and functional status at 12 months. Interlaminar epidurals provided improvement in a significantly higher proportion of patients. The proportion of patients nonresponsive to initial injections was also lower in the group for local anesthetic with steroid in the interlaminar trial. Conclusions: The results of this assessment show significant improvement in patients suffering from chronic lumbar disc herniation with 3 lumbar epidural approaches with local anesthetic alone, or using steroids with long-term follow-up of up to 2 years, in a contemporary interventional pain management setting

Phylogenetic identification of bacterial MazF toxin protein motifs among probiotic strains and foodborne pathogens and potential implications of engineered probiotic intervention in food

BACKGROUND: Toxin-antitoxin (TA) systems are commonly found in bacteria and Archaea, and it is the most common mechanism involved in bacterial programmed cell death or apoptosis. Recently, MazF, the toxin component of the toxin-antitoxin module, has been categorized as an endoribonuclease, or it may have a function similar to that of a RNA interference enzyme. RESULTS: In this paper, with comparative data and phylogenetic analyses, we are able to identify several potential MazF-conserved motifs in limited subsets of foodborne pathogens and probiotic strains and further provide a molecular basis for the development of engineered/synthetic probiotic strains for the mitigation of foodborne illnesses. Our findings also show that some probiotic strains, as fit as many bacterial foodborne pathogens, can be genetically categorized into three major groups based on phylogenetic analysis of MazF. In each group, potential functional motifs are conserved in phylogenetically distant species, including foodborne pathogens and probiotic strains. CONCLUSION: These data provide important knowledge for the identification and computational prediction of functional motifs related to programmed cell death. Potential implications of these findings include the use of engineered probiotic interventions in food or use of a natural probiotic cocktail with specificity for controlling targeted foodborne pathogens