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An amendment to this paper has been published and can be accessed via a link at the top of the paper.We hypothesized that, in discrimination between benign and malignant parotid gland tumors, high diagnostic accuracy could be obtained with a small amount of imbalanced data when anomaly detection (AD) was combined with deep leaning (DL) model and the L2-constrained softmax loss. The purpose of this study was to evaluate whether the proposed method was more accurate than other commonly used DL or AD methods. Magnetic resonance (MR) images of 245 parotid tumors (22.5% malignant) were retrospectively collected. We evaluated the diagnostic accuracy of the proposed method (VGG16-based DL and AD) and that of classification models using conventional DL and AD methods. A radiologist also evaluated the MR images. ROC and precision-recall (PR) analyses were performed, and the area under the curve (AUC) was calculated. In terms of diagnostic performance, the VGG16-based model with the L2-constrained softmax loss and AD (local outlier factor) outperformed conventional DL and AD methods and a radiologist (ROC-AUC = 0.86 and PR-ROC = 0.77). The proposed method could discriminate between benign and malignant parotid tumors in MR images even when only a small amount of data with imbalanced distribution is available.Matter under different equilibrium conditions of pressure and temperature exhibits different states such as solid, liquid, gas, and plasma. Exotic states of matter, such as Bose-Einstein condensates, superfluidity, chiral magnets, superconductivity, and liquid crystalline blue phases are observed in thermodynamic equilibrium. Rather than being a result of an aggregation of matter, their emergence is due to a change of a topological state of the system. These topological states can persist out of thermodynamics equilibrium. Here we investigate topological states of matter in a system with injection and dissipation of energy by means of oscillatory forcing. In an experiment involving a liquid crystal cell under the influence of a low-frequency oscillatory electric field, we observe a transition from a non-vortex state to a state in which vortices persist, topological transition. Depending on the period and the type of the forcing, the vortices self-organise, forming square lattices, glassy states, and disordered vortex structures. The bifurcation diagram is characterised experimentally. A continuous topological transition is observed for the sawtooth and square forcings. The scenario changes dramatically for sinusoidal forcing where the topological transition is discontinuous, which is accompanied by serial transitions between square and glassy vortex lattices. Based on a stochastic amplitude equation, we recognise the origin of the transition as the balance between stochastic creation and deterministic annihilation of vortices. Numerical simulations show topological transitions and the emergence of square vortex lattice. Our results show that the matter maintained out of equilibrium by means of the temporal modulation of parameters can exhibit exotic states.Compartmental transmission models have become an invaluable tool to study the dynamics of infectious diseases. selleckchem The Susceptible-Infectious-Recovered (SIR) model is known to have an exact semi-analytical solution. In the current study, the approach of Harko et al. (Appl. Math. Comput. 236184-194, 2014) is generalised to obtain an approximate semi-analytical solution of the Susceptible-Exposed-Infectious-Recovered (SEIR) model. The SEIR model curves have nearly the same shapes as the SIR ones, but with a stretch factor applied to them across time that is related to the ratio of the incubation to infectious periods. This finding implies an approximate characteristic timescale, scaled by this stretch factor, that is universal to all SEIR models, which only depends on the basic reproduction number and initial fraction of the population that is infectious.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an "exhaustion-resistant" phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed.The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3% increase, p value  less then  6e-08 and 22.9% increase, p value  less then  5e-05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.Recently, flood risk assessments have been extended to national and continental scales. Most of these assessments assume homogeneous scenarios, i.e. the regional risk estimate is obtained by summing up the local estimates, whereas each local damage value has the same probability of exceedance. This homogeneity assumption ignores the spatial variability in the flood generation processes. Here, we develop a multi-site, extreme value statistical model for 379 catchments across Europe, generate synthetic flood time series which consider the spatial correlation between flood peaks in all catchments, and compute corresponding economic damages. We find that the homogeneity assumption overestimates the 200-year flood damage, a benchmark indicator for the insurance industry, by 139%, 188% and 246% for the United Kingdom (UK), Germany and Europe, respectively. Our study demonstrates the importance of considering the spatial dependence patterns, particularly of extremes, in large-scale risk assessments.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Automatic remote reflectance spectral imaging of large painted areas in high resolution, from distances of tens of meters, has made the imaging of entire architectural interior feasible. However, it has significantly increased the volume of data. Here we present a machine learning based method to automatically detect 'hidden' writings and map material variations. Clustering of reflectance spectra allowed materials at inaccessible heights to be properly identified by performing non-invasive analysis on regions in the same cluster at accessible heights using a range of complementary spectroscopic techniques. The world heritage site of the Mogao caves, along the ancient Silk Road, consists of 492 richly painted Buddhist cave temples dating from the fourth to fourteenth century. Cave 465 at the northern end of the site is unique in its Indo-Tibetan tantric Buddhist style, and like many other caves, the date of its construction is still under debate. This study demonstrates the powers of an interdisciplinary approach that combines material identification, palaeographic analysis of the revealed Sanskrit writings and archaeological evidence for the dating of the cave temple paintings, narrowing it down to the late twelfth century to thirteenth century.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The evidence supporting an initial mycophenolate mofetil (MMF) dose of 2 g daily in tacrolimus-treated renal transplant recipients is limited. In a non-contemporaneous single-centre cohort study we compared the incidence of leukopaenia, rejection and graft dysfunction in patients initiated on MMF 1.5 g and 2 g daily. Baseline characteristics and tacrolimus trough levels were similar by MMF group. MMF doses became equivalent between groups by 12-months post-transplant, driven by dose reductions in the 2 g group. Leukopaenia occurred in 42.4% of patients by 12-months post-transplant. MMF 2 g was associated with a 1.80-fold increased risk of leukopaenia compared to 1.5 g. Rejection occurred in 44.8% of patients by 12-months post-transplantation. MMF 2 g was associated with half the risk of rejection relative to MMF 1.5 g. Over the first 7-years post-transplantation there was no difference in renal function between groups. Additionally, the development of leukopaenia or rejection did not result in reduced renal function at 7-years post-transplant.