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The principle of maximum ignorance posits that the coarse-grained description of a system is maximally agnostic about its underlying microscopic structure. We briefly review this principle for random matrix theory and for the eigenstate thermalization hypothesis. We then apply this principle in holography to construct ensembles of random mixed states. This leads to an ensemble of microstates which models our microscopic ignorance, and which on average reproduces the effective semiclassical physics of a given bulk state. We call this ensemble the state-averaging ansatz. The output of our model is a prediction for semiclassical contributions to variances and higher statistical moments over the ensemble of microstates. The statistical moments provide coarse-grained — yet gravitationally non-perturbative — information about the microstructure of the individual states of the ensemble. We show that these contributions exactly match the on-shell action of known wormhole configurations of the gravitational path integral. These results strengthen the view that wormholes simply parametrize the ignorance of the microstructure of a fundamental state, given a fixed semiclassical bulk description. [ABSTRACT FROM AUTHOR]

Driven quantum systems exhibit a large variety of interesting and sometimes exotic phenomena. Of particular interest are driven conformal field theories (CFTs) which describe quantum many-body systems at criticality. In this paper, we develop both a spacetime and a quantum information geometry perspective on driven 2d CFTs. We show that for a large class of driving protocols the theories admit an alternative but equivalent formulation in terms of a CFT defined on a spacetime with a time-dependent metric. We prove this equivalence both in the operator formulation as well as in the path integral description of the theory. A complementary quantum information geometric perspective for driven 2d CFTs employs the so-called Bogoliubov-Kubo-Mori (BKM) metric, which is the counterpart of the Fisher metric of classical information theory, and which is obtained from a perturbative expansion of relative entropy. We compute the BKM metric for the universal sector of Virasoro excitations of a thermal state, which captures a large class of driving protocols, and find it to be a useful tool to classify and characterize different types of driving. For Möbius driving by the SL(2, ℝ) subgroup, the BKM metric becomes the hyperbolic metric on the disk. We show how the non-trivial dynamics of Floquet driven CFTs is encoded in the BKM geometry via Möbius transformations. This allows us to identify ergodic and non-ergodic regimes in the driving. We also explain how holographic driven CFTs are dual to driven BTZ black holes with evolving horizons. The deformation of the black hole horizon towards and away from the asymptotic boundary provides a holographic understanding of heating and cooling in Floquet CFTs. [ABSTRACT FROM AUTHOR]

We study various aspects of the Carroll limit in which the speed of light is sent to zero. A large part of this paper is devoted to the quantization of Carroll field theories. We show that these exhibit infinite degeneracies in the spectrum and may suffer from non-normalizable ground states. As a consequence, partition functions of Carroll systems are ill-defined and do not lead to sensible thermodynamics. These seemingly pathological properties might actually be a virtue in the context of flat space holography. Better defined is the Carroll regime, in which we consider the leading order term in an expansion around vanishing speed of light without taking the strict Carroll limit. Such an expansion may lead to sensible notions of Carroll thermodynamics. An interesting example is a gas of massless particles with an imaginary chemical potential conjugate to the momentum. In the Carroll regime we show that the partition function of such a gas leads to an equation of state with w = −1. As a separate story, we study aspects of Carroll gravity and couplings to Carrollian energy-momentum tensors. We discuss many examples of solutions to Carroll gravity, including wormholes, Maxwell fields, solutions with a cosmological constant, and discuss the structure of geodesics in a Carroll geometry. The coupling of matter to Carroll gravity also allows us to derive energy-momentum tensors for hypothetical Carroll fluids from expanding relativistic fluids as well as directly from hydrostatic partition functions. [ABSTRACT FROM AUTHOR]

The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional regulator of SREBP activation. Constitutive or inducible global ablation of Spring in mice is not tolerated, and we therefore develop liver-specific Spring knockout mice (LKO). Transcriptomics and proteomics analysis reveal attenuated SREBP signaling in livers and hepatocytes of LKO mice. Total plasma cholesterol is reduced in male and female LKO mice in both the low-density lipoprotein and high-density lipoprotein fractions, while triglycerides are unaffected. Loss of Spring decreases hepatic cholesterol and triglyceride content due to diminished biosynthesis, which coincides with reduced very-low-density lipoprotein secretion. Accordingly, LKO mice are protected from fructose diet-induced hepatosteatosis. In humans, we find common genetic SPRING variants that associate with circulating high-density lipoprotein cholesterol and ApoA1 levels. This study positions SPRING as a core component of hepatic SREBP signaling and systemic lipid metabolism in mice and humans. Hendrix et al show that absence of hepatic Spring dramatically lowers levels of lipids in the liver and plasma in mice, and protects from development of diet-induced steatosis. In line, genetic variation in SPRING is associated with lipid levels in humans. [ABSTRACT FROM AUTHOR]

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We construct worldsheet traversable wormholes by considering the effects of a double-trace deformation, δ L ∼ h ∂ ϕ L ∂ ϕ R , coupling the endpoints of an open string in AdS space. The operator deforming the theory is irrelevant and makes the boundaries bend inward toward the IR. This effect, reminiscent of two-dimensional dilaton gravities, renders the teleportation protocol more efficient and facilitates the transfer of information between the members of the dual Bell pair. We compare our results with those obtained with the standard double-trace deformation, δ L ∼ h ϕ L ϕ R , introduced by Gao, Jafferis and Wall. [ABSTRACT FROM AUTHOR]

Objective: To investigate the incidences of prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) using different methods to define PTI, to compare the incidence of PTI among different PSMA PET tracers, and to evaluate the clinical consequences of PTI. Methods: PSMA PET/CT scans in consecutive patients with primary prostate cancer were analyzed for the presence of PTI using a structured visual (SV) analysis reporting any elevated thyroidal uptake; a semi-quantitative (SQ) analysis using a SUVmax thyroid/bloodpool (t/b) ratio ≥ 2.0 as cutoff; and an analysis of PTI incidence in the clinical reports (RV analysis). Results: A total of 502 patients were included. The incidence of PTIs was 22% in the SV analysis, 7% in the SQ analysis, and 2% in the RV analysis. PTI incidences differed significantly from 29 to 64% (SQ, resp. SV analysis) for [18F]PSMA-1007, 7 to 23% for [68Ga]PSMA-11, 2 to 8% for [18F]DCFPyL, and to 0% for [18F]PSMA-JK-7. The majority of PTI in the SV and SQ analyses consisted of diffuse (72–83%) and/or only slightly elevated thyroidal uptake (70%). Inter-observer agreement in the SV analysis was substantial (kappa = 0.76–0.78). During follow-up (median 16.8 months), there were no thyroid-related adverse events except in three patients. Conclusions: The incidence of PTI varies greatly among different PSMA PET tracers and is strongly dependent on the analysis method applied. PTI may safely be restricted to focal thyroidal uptake with a SUVmax t/b ratio ≥ 2.0. The clinical pursuit of a PTI must be weighed up to the expected outcome of the underlying disease. Key Points: • Thyroid incidentalomas (PTIs) are recognized in PSMA PET/CT. • Incidence of PTI varies greatly among PET tracers and analysis methods. • Incidence of thyroid-related adverse events in PTI cases is low. [ABSTRACT FROM AUTHOR]

We construct operators in holographic two-dimensional conformal field theory, which act locally in the code subspace as arbitrary bulk spacelike vector fields. Key to the construction is an interplay between parallel transport in the bulk spacetime and in kinematic space. We outline challenges, which arise when the same construction is extended to timelike vector fields. We also sketch several applications, including boundary formulations of the bulk Riemann tensor, dreibein, and spin connection, as well as an application to holographic complexity. [ABSTRACT FROM AUTHOR]

The spectral form factor is a powerful probe of quantum chaos that diagnoses the statistics of energy levels, but is blind to other features of a theory such as matrix elements of operators or OPE coefficients in conformal field theories. In this paper, we introduce generalized spectral form factors: new probes of quantum chaos sensitive to the dynamical data of a theory. These quantities can be studied using random matrix theory and an effective theory of quantum chaos. We focus our attention on a particular combination of heavy-heavy-heavy OPE coefficients that generalizes the genus-2 partition function of two-dimensional CFTs, for which we define a form factor. Assuming that random matrix theory applies to chaotic CFTs, we probe heavy-heavy-heavy OPE coefficients and find statistical correlations that agree with the OPE Randomness Hypothesis: these coefficients have a random tensor component. The EFT of quantum chaos predicts that the genus-2 form factor displays a ramp and a plateau. Our results suggest that this is a common property of generalized spectral form factors. [ABSTRACT FROM AUTHOR]

The Eigenstate Thermalization Hypothesis makes a prediction for the statistical distribution of matrix elements of simple operators in energy eigenstates of chaotic quantum systems. As a leading approximation, off-diagonal matrix elements are described by Gaussian random variables but higher-point correlation functions enforce non-Gaussian corrections which are further exponentially suppressed in the entropy. In this paper, we investigate non- Gaussian corrections to the statistical distribution of heavy-heavy-heavy OPE coefficients in chaotic two-dimensional conformal field theories. Using the Virasoro crossing kernels, we provide asymptotic formulas involving arbitrary numbers of OPE coefficients from modular invariance on genus-g surfaces. We find that the non-Gaussianities are further exponentially suppressed in the entropy, much like the ETH. We discuss the implication of these results for products of CFT partition functions in gravity and Euclidean wormholes. Our results suggest that there are new connected wormhole geometries that dominate over the genus-two wormhole. [ABSTRACT FROM AUTHOR]

We present new asymptotic formulas for the distribution of OPE coefficients in conformal field theories. These formulas involve products of four or more coefficients and include light-light-heavy as well as heavy-heavy-heavy contributions. They are derived from crossing symmetry of the six and higher point functions on the plane and should be interpreted as non-Gaussianities in the statistical distribution of the OPE coefficients. We begin with a formula for arbitrary operator exchanges (not necessarily primary) valid in any dimension. This is the first asymptotic formula constraining heavy-heavy-heavy OPE coefficients in d > 2. For two-dimensional CFTs, we present refined asymptotic formulas stemming from exchanges of quasi-primaries as well as Virasoro primaries. [ABSTRACT FROM AUTHOR]

Purpose: A prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) is an unexpected, PSMA-avid thyroid lesion, newly detected during the investigation of an unrelated condition using PSMA PET/CT. The aim of this study is to examine the incidence and clinical significance of PTI and the associated management strategies since the implementation of the PSMA PET/CT scan. Methods: This study involves a retrospective cohort study of 61 PTI cases depicted on PSMA PET/CT scans performed between January 2016 and July 2021, almost exclusively for (re)staging prostate cancer. The medical records of the included cases were retrospectively reviewed and data of the PSMA PET/CT scans, primary malignancy, thyroid diagnostics, treatment, and follow-up were collected. Results: PTI was reported in 1.1% of the patients who underwent oncologic PSMA PET/CT scans included in this study. Two PTI cases had a histologically proven thyroid cancer: one a benign thyroid lesion and one a metastasis of a renal cell carcinoma. In none of the cases in whom any form of further thyroid workup was withheld, the PTI became clinically relevant during follow-up (median 1.8 years (1.1–3.3)). Six patients (10%) died due to their primary cancer. Conclusion: The incidence of thyroid incidentalomas on PSMA PET/CT was low (1.1%) in this large, two-center experience. Less than half of the PTI cases were analyzed and the risk of malignancy, despite being low, was not negligible. The clinical outcome was good using a standard diagnostic workup for PTI, while the prognosis of the patient was determined by the primary malignancy. The consideration to analyze and treat PTI cases should be part of the shared decision-making in cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery. Methods: In the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11–50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder. Results: Median ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A ΔMTV or ΔTLG of at least − 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a ΔTLG of − 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median − 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen. Conclusions: Primary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials. Trial registration: https://www.clinicaltrials.gov/, NCT03003637, December 28, 2016. [ABSTRACT FROM AUTHOR]

We study the parallel transport of modular Hamiltonians encoding entanglement properties of a state. In the case of 2d CFT, we consider a change of state through action with a suitable diffeomorphism on the circle: one that diagonalizes the adjoint action of the modular Hamiltonian. These vector fields exhibit kinks at the interval boundary, thus together with their central extension they differ from usual elements of the Virasoro algebra. The Berry curvature associated to state-changing parallel transport is the Kirillov-Kostant symplectic form on an associated coadjoint orbit, one which differs appreciably from known Virasoro orbits. We find that the boundary parallel transport process computes a bulk symplectic form for a Euclidean geometry obtained from the backreaction of a cosmic brane, with Dirichlet boundary conditions at the location of the brane. We propose that this gives a reasonable definition for the symplectic form on an entanglement wedge. [ABSTRACT FROM AUTHOR]

Objective: The objective was to assess swallowing, mouth opening and speech function during the first year after radiation-based treatment (RT(+)) after introduction of a dedicated preventive rehabilitation program for stage III–IV oropharyngeal carcinoma (OPC). Methods: Swallowing, mouth opening and speech function were collected before and at six- and twelve-month follow-up after RT(+) for OPC as part of ongoing prospective assessments by speech-language pathologists. Results: Objective and patient-perceived function deteriorated until 6 months and improved until 12 months after treatment, but did not return to baseline levels with 25%, 20% and 58% of the patients with objective dysphagia, trismus and speech problems, respectively. Feeding tube dependency and pneumonia prevalence was low. Conclusion: Despite successful implementation, a substantial proportion of patients still experience functional limitations after RT(+) for OPC, suggesting room for improvement of the current rehabilitation program. Pretreatment sarcopenia seems associated with worse functional outcomes and might be a relevant new target for rehabilitation strategies. [ABSTRACT FROM AUTHOR]

We discuss some general aspects of commutators of local operators in Lorentzian CFTs, which can be obtained from a suitable analytic continuation of the Euclidean operator product expansion (OPE). Commutators only make sense as distributions, and care has to be taken to extract the right distribution from the OPE. We provide explicit computations in two and four-dimensional CFTs, focusing mainly on commutators of components of the stress-tensor. We rederive several familiar results, such as the canonical commutation relations of free field theory, the local form of the Poincaré algebra, and the Virasoro algebra of two-dimensional CFT. We then consider commutators of light-ray operators built from the stress-tensor. Using simplifying features of the light sheet limit in four-dimensional CFT we provide a direct computation of the BMS algebra formed by a specific set of light-ray operators in theories with no light scalar conformal primaries. In four-dimensional CFT we define a new infinite set of light-ray operators constructed from the stress-tensor, which all have well-defined matrix elements. These are a direct generalization of the two-dimensional Virasoro light-ray operators that are obtained from a conformal embedding of Minkowski space in the Lorentzian cylinder. They obey Hermiticity conditions similar to their two-dimensional analogues, and also share the property that a semi-infinite subset annihilates the vacuum. [ABSTRACT FROM AUTHOR]

We propose that finite cutoff regions of holographic spacetimes represent quantum circuits that map between boundary states at different times and Wilsonian cutoffs, and that the complexity of those quantum circuits is given by the gravitational action. The optimal circuit minimizes the gravitational action. This is a generalization of both the "complexity equals volume" conjecture to unoptimized circuits, and path integral optimization to finite cutoffs. Using tools from holographic T T ¯ , we find that surfaces of constant scalar curvature play a special role in optimizing quantum circuits. We also find an interesting connection of our proposal to kinematic space, and discuss possible circuit representations and gate counting interpretations of the gravitational action. [ABSTRACT FROM AUTHOR]

Reciprocity between cells and their surrounding extracellular matrix is one of the main drivers for cellular function and, in turn, matrix maintenance and remodelling. Unravelling how cells respond to their environment is key in understanding mechanisms of health and disease. In all these examples, matrix anisotropy is an important element, since it can alter the cell shape and fate. In this work, the objective is to develop and exploit easy-to-produce platforms that can be used to study the cellular response to natural proteins assembled into diverse topographical cues. We demonstrate a robust and simple approach to form collagen substrates with different topographies by evaporating droplets of a collagen solution. Upon evaporation of the collagen solution, a stain of collagen is left behind, composed of three regions with a distinct pattern: an isotropic region, a concentric ring pattern, and a radially oriented region. The formation and size of these regions can be controlled by the evaporation rate of the droplet and initial collagen concentration. The patterns form topographical cues inducing a pattern-specific cell (tenocyte) morphology, density, and proliferation. Rapid and cost-effective production of different self-agglomerated collagen topographies and their interfaces enables further study of the cell shape-phenotype relationship in vitro. Substrate topography and in analogy tissue architecture remains a cue that can and will be used to steer and understand cell function in vitro, which in turn can be applied in vivo, e.g. in optimizing tissue engineering applications. [ABSTRACT FROM AUTHOR]

Natural evolution tackles optimization by producing many genetic variants and exposing these variants to selective pressure, resulting in the survival of the fittest. We use high throughput screening of large libraries of materials with differing surface topographies to probe the interactions of implantable device coatings with cells and tissues. However, the vast size of possible parameter design space precludes a brute force approach to screening all topographical possibilities. Here, we took inspiration from Nature to optimize materials surface topographies using evolutionary algorithms. We show that successive cycles of material design, production, fitness assessment, selection, and mutation results in optimization of biomaterials designs. Starting from a small selection of topographically designed surfaces that upregulate expression of an osteogenic marker, we used genetic crossover and random mutagenesis to generate new generations of topographies. [ABSTRACT FROM AUTHOR]

We argue for an exponential bound characterizing the chaotic properties of modular Hamiltonian flow of QFT subsystems. In holographic theories, maximal modular chaos is reflected in the local Poincare symmetry about a Ryu-Takayanagi surface. Generators of null deformations of the bulk extremal surface map to modular scrambling modes — positive CFT operators saturating the bound — and their algebra probes the bulk Riemann curvature, clarifying the modular Berry curvature proposal of arXiv:1903.04493. [ABSTRACT FROM AUTHOR]

Purpose: The CONDOR study showed that docetaxel/cisplatin/5-fluorouracil (TPF) followed by conventional radiotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 (cis100 + RT; n = 27)) versus accelerated radiotherapy with cisplatin weekly 40 mg/m2 (cis40 + ART; n = 29) in locally advanced head and neck cancer (LAHNC) patients was not feasible. Here, we report the analysis of health-related quality of life (HRQOL) of the patients entered in this study.Methods: HRQOL was assessed at baseline, after two TPF, before start of chemoradiotherapy, and 1, 4, 8, 12, and 24 months after completion of chemoradiotherapy using the EORTC-QLQ-C30 and QLQ-H&N35 in 62 patients.Results: Compliance with the QOL questionnaires was 94% (59/62) at baseline and 61% (30/49) at 12 months, respectively. HRQOL decreased after TPF and further decreased during chemoradiohteray in both arms equally. Pain and swallowing dysfunction improved significantly during TPF but deteriorated below baseline levels during chemoradiotherapy, cis40 + ART > cis100 + RT (p < 0.05). HRQOL and symptoms restored to baseline within 12 months in both arms and remained at that level until 24 months.Conclusions: After TPF, cis40 + ART had a larger negative impact on symptoms than cis100 + RT, probably due to the ART. HRQOL and symptoms restored to baseline levels within 12 months after end of treatment in both arms, which is an important perspective for patients during the phase of most serious acute side effects of treatment.Trial Registration: NCT00774319. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that a loss of chromosome 9 open reading frame 72 ( C9ORF72) expression, formation of dipeptide-repeat proteins, and generation of RNA foci contribute to disease pathogenesis in amyotrophic lateral sclerosis and frontotemporal dementia. Although the levels of C9ORF72 transcripts and dipeptide-repeat proteins have already been examined thoroughly, much remains unknown about the role of RNA foci in C9ORF72-linked diseases. As such, we performed a comprehensive RNA foci study in an extensive pathological cohort of C9ORF72 expansion carriers ( n = 63). We evaluated two brain regions using a newly developed computer-automated pipeline allowing recognition of cell nuclei and RNA foci (sense and antisense) supplemented by manual counting. In the frontal cortex, the percentage of cells with sense or antisense RNA foci was 26 or 12%, respectively. In the cerebellum, 23% of granule cells contained sense RNA foci and 1% antisense RNA foci. Interestingly, the highest percentage of cells with RNA foci was observed in cerebellar Purkinje cells (~70%). In general, more cells contained sense RNA foci than antisense RNA foci; however, when antisense RNA foci were present, they were usually more abundant. We also observed that an increase in the percentage of cells with antisense RNA foci was associated with a delayed age at onset in the frontal cortex ( r = 0.43, p = 0.003), whereas no other associations with clinico-pathological features were seen. Importantly, our large-scale study is the first to provide conclusive evidence that RNA foci are not the determining factor of the clinico-pathological variability observed in C9ORF72 expansion carriers and it emphasizes that the distribution of RNA foci does not follow the pattern of neurodegeneration, stressing the complex interplay between different aspects of C9ORF72-related diseases. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) survivors are at increased risk of second malignancies, but few studies have assessed colorectal cancer (CRC) risk after HL treatment. We assessed long-term, subsite-specific CRC risk associated with specific radiation fields and chemotherapy regimens.Methods: In a Dutch cohort of 3121 5-year HL survivors treated between 1965 and 1995, subsite-specific CRC incidence was compared with general population rates. Treatment effects were quantified by Cox regression analyses.Results: After a median follow-up of 22.9 years, 55 patients developed CRC. The standardized incidence ratios (SIR) was 2.4-fold increased (95% confidence interval (95%CI) 1.8-3.2), leading to 5.7 excess cases per 10 000 patient-years. Risk was still increased 30 years after HL treatment (SIR: 2.8; 95%CI: 1.6-4.6). The highest (SIR: 6.5, 95%CI: 3.3-11.3) was seen for transverse colon cancer (15.0 (95%CI: 4.3-40.8) after inverted-Y irradiation). A prescribed cumulative procarbazine dose >4.2 g m-2 was associated with a 3.3-fold higher CRC risk (95%CI: 1.8-6.1) compared to treatment without procarbazine. Patients receiving >4.2 g m-2 procarbazine and infradiaphragmatic radiotherapy had a hazard ratio of 6.8 (95%CI: 3.0-15.6) compared with patients receiving neither treatment, which is significantly higher than an additive joint effect (Padditivity=0.004).Conclusions: Colorectal cancer surveillance should be considered for HL survivors who received Infradiaphragmatic radiotherapy and a high cumulative procarbazine dose. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a three-dimensional (3D) structure composed of proteinaceous fibres that provide physical and biological cues to direct cell behaviour. Here, we build a library of hybrid collagen-polymer fibrous scaffolds with nanoscale dimensions and screen them for their ability to grow chondrocytes for cartilage repair. Poly(lactic acid) and poly (lactic-co-glycolic acid) at two different monomer ratios (85:15 and 50:50) were incrementally blended with collagen. Physical properties (wettability and stiffness) of the scaffolds were characterized and related to biological performance (proliferation, ECM production, and gene expression) and structure-function relationships were developed. We found that soft scaffolds with an intermediate wettability composed of the highly biodegradable PLGA50:50 and collagen, in two ratios (40:60 and 60:40), were optimal for chondrogenic differentiation of ATDC5 cells as determined by increased ECM production and enhanced cartilage specific gene expression. Long-term cultures indicated a stable phenotype with minimal de-differentiation or hypertrophy. The combinatorial methodology applied herein is a promising approach for the design and development of scaffolds for regenerative medicine. [ABSTRACT FROM AUTHOR]

We discuss the thermodynamics of recently constructed three-dimensional higher spin black holes in SL(N,R) × SL(N,R) Chern-Simons theory with generalized asymptotically-anti-de Sitter boundary conditions. From a holographic perspective, these bulk theories are dual to two-dimensional CFTs withWN symmetry algebras, and the black hole solutions are dual to thermal states with higher spin chemical potentials and charges turned on. Because the notion of horizon area is not gauge-invariant in the higher spin theory, the traditional approaches to the computation of black hole entropy must be reconsidered. One possibility, explored in the recent literature, involves demanding the existence of a partition function in the CFT, and consistency with the first law of thermodynamics. This approach is not free from ambiguities, however, and in particular different definitions of energy result in different expressions for the entropy. In the present work we show that there are natural definitions of the thermodynamically conjugate variables that follow from careful examination of the variational principle, and moreover agree with those obtained via canonical methods. Building on this intuition, we derive general expressions for the higher spin black hole entropy and free energy which are written entirely in terms of the Chern-Simons connections, and are valid for both static and rotating solutions. We compare our results to other proposals in the literature, and provide a new and efficient way to determine the generalization of the Cardy formula to a situation with higher spin charges. [ABSTRACT FROM AUTHOR]

Potato (Solanum tuberosum L.) originates from the Andes and evolved short-day-dependent tuber formation as a vegetative propagation strategy. Here we describe the identification of a central regulator underlying a major-effect quantitative trait locus for plant maturity and initiation of tuber development. We show that this gene belongs to the family of DOF (DNA-binding with one finger) transcription factors and regulates tuberization and plant life cycle length, by acting as a mediator between the circadian clock and the StSP6A mobile tuberization signal. We also show that natural allelic variants evade post-translational light regulation, allowing cultivation outside the geographical centre of origin of potato. Potato is a member of the Solanaceae family and is one of the world's most important food crops. This annual plant originates from the Andean regions of South America. Potato develops tubers from underground stems called stolons. Its equatorial origin makes potato essentially short-day dependent for tuberization and potato will not make tubers in the long-day conditions of spring and summer in the northern latitudes. When introduced in temperate zones, wild material will form tubers in the course of the autumnal shortening of day-length. Thus, one of the first selected traits in potato leading to a European potato type is likely to have been long-day acclimation for tuberization. Potato breeders can exploit the naturally occurring variation in tuberization onset and life cycle length, allowing varietal breeding for different latitudes, harvest times and markets. [ABSTRACT FROM AUTHOR]

Aims: FDG-PET can be used to identify vulnerable plaques in atherosclerotic disease. Clinical FDG-PET camera systems are restricted in terms of resolution for the visualization of detailed inflammation patterns in smaller vascular structures. The aim of the study is to evaluate the possible added value of a high-resolution microPET system in excised carotid plaques using FDG.Methods and Results: In this study, 17 patients with planned carotid endarterectomy were included. Excised plaques were incubated in FDG and subsequently imaged with microPET. Macrophage presence in plaques was evaluated semi-quantitatively by immunohistochemistry. Plaque calcification was assessed additionally with CT and correlated to FDG uptake. Finally, FDG uptake and macrophage infiltration were compared with patient symptomatology. Heterogeneous distributions and variable intensities of FDG uptake were found within the plaques. A positive correlation between the distribution of macrophages and the FDG uptake (r = 0.68, P < .01) was found. A negative correlation was found between areas of calcifications and FDG uptake (r = -0.84, P < .001). Ratio FDG(max) values as well as degree of CD68 accumulation were significantly higher in CVA patients compared with TIA or amaurosis fugax patients (P < .05) and CVA patients compared with asymptomatic patients (P < .05).Conclusion: This ex vivo study demonstrates that excised carotid plaques can be visualized in detail using FDG microPET. Enhancement of clinical PET/CT resolution for similar imaging results in patients is needed. [ABSTRACT FROM AUTHOR]

A cytogenetic map has been developed for diploid potato (Solanum tuberosum), in which the arms of the 12 potato bivalents can be identified in pachytene complements using multicolor fluorescence in situ hybridization (FISH) with a set of 60 genetically anchored bacterial artificial chromosome (BAC) clones from the RHPOTKEY BAC library. This diagnostic set of selected BACs (five per chromosome) hybridizes to euchromatic regions and corresponds to well-defined loci in the ultradense genetic map, and with these probes a new detailed and reliable pachytene karyotype could be established. Chromosome size has been estimated both from microscopic length measurements and from 4′,6-diamidino-2-phenylindole fluorescence-based DNA content measurements. In both approaches, chromosome 1 is the largest (100–115 Mb) and chromosome 11 the smallest (49–53 Mb). Detailed measurements of mega-base-pair to micrometer ratios have been obtained for chromosome 5, with average values of 1.07 Mb/μm for euchromatin and 3.67 Mb/μm for heterochromatin. In addition, our FISH results helped to solve two discrepancies in the potato genetic map related to chromosomes 8 and 12. Finally, we discuss the significance of the potato cytogenetic map for extended FISH studies in potato and related Solanaceae, which will be especially beneficial for the potato genome-sequencing project. [ABSTRACT FROM AUTHOR]

In Asembagus (East Java, Indonesia), surface water is contaminated with effluent from the hyperacid Ijen Crater Lake. In a previous study, we reported that food crops irrigated with this water had increased concentrations of various elements. Here, we present a total diet study for adults and 6-year-old children to determine if the mean daily intake of a broad range of elements is safe and adequate. For children, the intake of B, Mg, Mn and V is high with Hazard Quotients (HQ) of 1.1 (B), 1.4 (Mn) and 1.4 (V), respectively (no TDI is available for Mg). For Mn, the daily intake is high due to the consumption of locally produced rice. Drinking water is the main source of B, Mg and V. For adults, the intake of Mg, Mn and V is also high but HQ values are ≤0.7. For both children and adults, the intake of Ca, Zn and particularly Fe is below the RNI (Fe intake is 90% below the RNI for women). It is concluded the mean intake of elements is unbalanced and Fe deficiency is probably the most serious health problem. Toxic effects cannot be fully excluded since deficiency of essential elements such as Ca, Fe and Zn can increase the absorption and retention of various elements. [ABSTRACT FROM AUTHOR]

Two screening methods were developed for rapid analysis of a great number of urine and blood samples within the framework of an exposure check of the population after a firework explosion. A total of 56 elements was measured including major elements. Sample preparation consisted of simple dilution. Extensive quality controls were applied including element addition and the use of certified reference materials. Relevant results at levels similar to those found in the literature were obtained for Co, Ni, Cu, Zn, Sr, Cd, Sn, Sb, Ba, Tl, and Pb in urine and for the same elements except Ni, Sn, Sb, and Ba in blood. However, quadrupole ICP-MS has limitations, mainly related to spectral interferences, for the analysis of urine and blood, and these cause higher detection limits. The general aspects discussed in the paper give it wider applicability than just for analysis of blood and urine-it can for example be used in environmental analysis. [ABSTRACT FROM AUTHOR]

We consider ?9=1 supersymmetric U(N) field theories in four dimensions with adjoint chiral matter and a multi-trace tree-level superpotential. We show that the computation of the effective action as a function of the glueball superfield localizes to computing matrix integrals. Unlike the single-trace case, holomorphy and symmetries do not forbid non-planar contributions. Nevertheless, only a special subset of the planar diagrams contributes to the exact result. In addition, the computation of the superpotential localizes to doing matrix integrals. In view of the results of Dijkgraaf and Vafa for single-trace theories, one might have naively expected that these matrix integrals are related to the free energy of a multi-trace matrix model. We explain why this naive identification does not work. Rather, an auxiliary single-trace matrix model with additional singlet fields can be used to exactly compute the field theory superpotential. Along the way we also describe a general technique for computing the large-N limits of multi-trace Matrix models and raise the challenge of finding the field theories whose effective actions they may compute. Since our models can be treated as ?9=1 deformations of pure ?9=2 gauge theory, we show that the effective superpotential that we compute also follows from the ?9=2 Seiberg-Witten solution. Finally, we observe an interesting connection between multi-trace local theories and non-local field theory. [ABSTRACT FROM AUTHOR]

A generalized Wakimoto realization of can be associated with each parabolic subalgebra of a simple Lie algebra according to an earlier proposal by Feigin and Frenkel. In this paper the proposal is made explicit by developing the construction of Wakimoto realizations from a simple but unconventional viewpoint. An explicit formula is derived for the Wakimoto current first at the Poisson bracket level by Hamiltonian symmetry reduction of the WZNW model. The quantization is then performed by normal ordering the classical formula and determining the required quantum correction for it to generate by means of commutators. The affine-Sugawara stress-energy tensor is verified to have the expected quadratic form in the constituents, which are symplectic bosons belonging to and a current belonging to . The quantization requires a choice of special polynomial coordinates on the big cell of the flag manifold . The effect of this choice is investigated in detail by constructing quantum coordinate transformations. Finally, the explicit form of the screening charges for each generalized Wakimoto realization is determined, and some applications are briefly discussed. [ABSTRACT FROM AUTHOR]

Learning rules by which cell shape impacts cell function would enable control of cell physiology and fate in medical applications, particularly, on the interface of cells and material of the implants. We defined the phenotypic response of human bone marrow-derived mesenchymal stem cells (hMSCs) to 2176 randomly generated surface topographies by probing basic functions such as migration, proliferation, protein synthesis, apoptosis, and differentiation using quantitative image analysis. Clustering the surfaces into 28 archetypical cell shapes, we found a very strict correlation between cell shape and physiological response and selected seven cell shapes to describe the molecular mechanism leading to phenotypic diversity. Transcriptomics analysis revealed a tight link between cell shape, molecular signatures, and phenotype. For instance, proliferation is strongly reduced in cells with limited spreading, resulting in down-regulation of genes involved in the G2/M cycle and subsequent quiescence, whereas cells with large filopodia are related to activation of early response genes and inhibition of the osteogenic process. In this paper we were aiming to identify a universal set of genes that regulate the material-induced phenotypical response of human mesenchymal stem cells. This will allow designing implants that can actively regulate cellular, molecular signalling through cell shape. Here we are proposing an approach to tackle this question. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy. Anti-androgen therapy inhibits prostate cancer (PC) progression, and is thought to act directly on cancer cells. Here the authors show that androgen receptor is expressed on normal and PC-associated macrophages, and its stimulation alters macrophage secretome to promote migration of cultured PC cell lines. [ABSTRACT FROM AUTHOR]