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We derive an extension of the sequential homotopy method that allows for the application of inexact solvers for the linear (double) saddle‐point systems arising in the local semismooth Newton method for the homotopy subproblems. For the class of problems that exhibit (after suitable partitioning of the variables) a zero in the off‐diagonal blocks of the Hessian of the Lagrangian, we propose and analyze an efficient, parallelizable, symmetric positive definite preconditioner based on a double Schur complement approach. For discretized optimal control problems with PDE constraints, this structure is often present with the canonical partitioning of the variables in states and controls. We conclude with numerical results for a badly conditioned and highly nonlinear benchmark optimization problem with elliptic partial differential equations and control bounds. The resulting method allows for the parallel solution of large 3D problems. [ABSTRACT FROM AUTHOR]

Background: The incidence of early-onset colorectal cancer (EOCRC), diagnosed before age 50, has been rising in many countries in the past few decades. This study aims to evaluate this trend in Aotearoa New Zealand and assess its impact on Māori. Methods: Crude incidence and age-standardized incidence of colorectal cancer (CRC) was analyzed from all new cases from the Aotearoa New Zealand national cancer registry for the period 2000–2020. Trends were estimated by sex, ethnicity, age group and location of cancer and projections made to 2040. Results: Between 2000 and 2020, there were a total of 56,761 cases of CRC diagnosed in Aotearoa New Zealand, 3,702 of these being EOCRC, with age-standardized incidence decreasing significantly (P = 8.2 × 10− 80) from 61.0 to 47.3 cases per 100,000. EOCRC incidence increased on average by 26% per decade (incidence rate ratio (IRR) 1.26, p = < 0.0001) at all sites (proximal colon, distal colon and rectum), while the incidence in those aged 50–79 years decreased on average by 18% per decade (IRR 0.82, p = < 0.0005), again across all sites. There was no significant average change in CRC incidence in those over 80 years. In Māori, there was no significant change in age-standardized incidence. There was however a significant increase in crude incidence rates (IRR 1.28, p = < 0.0005) driven by significant increases in EOCRC (IRR1.36, p = < 0.0005). By 2040, we predict the incidence of EOCRC will have risen from 8.00 to 14.9 per 100,000 (6.33 to 10.00 per 100,000 in Māori). However, due to the aging population an estimated 43.0% of all CRC cases will be diagnosed in those over 80 years of age (45.9% over 70 years of age in Māori). Conclusion: The age-standardized incidence of CRC from 2000 to 2020 decreased in Aotearoa New Zealand, but not for Māori. The incidence of EOCRC over the same period continues to rise, and at a faster rate in Māori. However, with the ageing of the population in Aotearoa New Zealand, and for Māori, CRC in the elderly will continue to dominate case numbers. [ABSTRACT FROM AUTHOR]

Learning skilled behaviors requires intensive practice over days, months, or years. Behavioral hallmarks of practice include exploratory variation and long-term improvements, both of which can be impacted by circadian processes. During weeks of vocal practice, the juvenile male zebra finch transforms highly variable and simple song into a stable and precise copy of an adult tutor's complex song. Song variability and performance in juvenile finches also exhibit circadian structure that could influence this long-term learning process. In fact, one influential study reported juvenile song regresses towards immature performance overnight, while another suggested a more complex pattern of overnight change. However, neither of these studies thoroughly examined how circadian patterns of variability may structure the production of more or less mature songs. Here we relate the circadian dynamics of song maturation to circadian patterns of song variation, leveraging a combination of data-driven approaches. In particular we analyze juvenile singing in learned feature space that supports both data-driven measures of song maturity and generative developmental models of song production. These models reveal that circadian fluctuations in variability lead to especially regressive morning variants even without overall overnight regression, and highlight the utility of data-driven generative models for untangling these contributions. Author summary: Children learn many critical behaviors like language in part by imitating adults. For young learners, effective practice is thought to require random variation that can produce unexpectedly successful–or unsuccessful–outcomes. This kind of practice lasts weeks or months, so it is also structured by the learner's circadian rhythm. In this paper we analyze the song of juvenile male zebra finches, which also learn to imitate adult vocalizations through extensive practice. We validate and deploy a novel combination of analysis tools to study this behavior, allowing us to relate vocal variation and performance using a succinct set of vocal features learned directly from song recordings. Specifically, we investigate how overnight changes in song variability affects performance quality. Although we do not find evidence that average song performance gets better or worse overnight–a subject of debate in the field–we show nonetheless that heightened morning variability reintroduces immature performance variations that were avoided the evening before. Thus, heightened morning variability may allow birds to avoid overcommitting to recently learned solutions. Our approach may be broadly useful to researchers interested in the connections between vocal variation and performance in this model of juvenile imitative learning. [ABSTRACT FROM AUTHOR]

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers. The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers. [ABSTRACT FROM AUTHOR]

Modelling of many real-world processes, such as drug delivery, wastewater treatment, and pharmaceutical production, requires accurate descriptions of the dynamics of hard particles confined in complicated domains. In particular, when modelling sedimentation processes or systems with driven flows, it is important to accurately capture volume exclusion effects. This work applies Dynamic Density Functional Theory to the evolution of a particle density under diffusion, external forces, particle–particle interaction, and volume exclusion. Using a spectral element framework, for the first time it is possible to include all of these effects in dynamic simulations on complex domains. Moreover, this allows one to apply complicated no-flux, and other non-local, non-linear, boundary conditions. The methodology is also extended to control problems, addressing questions of how to enhance production set-up in industrially-motivated processes. In this work the relevant models are introduced, numerical methods are discussed, and several example problems are solved to demonstrate the methods' versatility. It is shown that incorporating volume exclusion is crucial for simulation accuracy and we illustrate that the choice of boundary conditions significantly impacts the dynamics. [ABSTRACT FROM AUTHOR]

Background: Carriage of certain bacterial species may represent potential biomarkers of colorectal cancer (CRC). Prominent among these is Fusobacterium nucleatum. We explored the association of F. nucleatum DNA in stool samples with the presence of colonic neoplastic lesions in a cohort of primary care patients, and compared our findings with those from an unrelated cohort of colonoscopy patients followed clinically over time. Methods: Carriage rates of F. nucleatum in stool samples were assessed in 185 patients referred for a faecal immunochemical test (FIT) by their general practitioners (GPs). Comparisons were made with stool samples from 57 patients diagnosed with CRC and 57 age-matched healthy controls, and with tissue samples taken at colonoscopy from 150 patients with a decade of subsequent clinical follow-up. Findings: F. nucleatum DNA was found at a high rate (47.0%) in stool samples from primary care patients, and more often in stool samples from CRC patients (47.4%) than in healthy controls (7.0%), (P = 7.66E-7). No association was found between carriage of F. nucleatum and FIT positivity (P = 0.588). While evidence of stool-associated F. nucleatum DNA was significantly more likely to indicate a lesion in those primary care patients progressed to colonoscopy (P = 0.023), this finding did not extend to the progression of neoplastic lesions in the 150 patients with a decade of follow up. Conclusion: The finding of F. nucleatum DNA at similar rates in stool samples from patients diagnosed with CRC and in primary care patients with pre-cancerous lesions supports growing awareness that the presence of these bacteria may be a biomarker for increased risk of disease. However, molecular evidence of F. nucleatum did not predict progression of colonic lesions, which may lessen the utility of this bacterium as a biomarker for increased risk of disease. [ABSTRACT FROM AUTHOR]

Maternal tobacco smoking during pregnancy is a large driver of health inequalities and a higher prevalence of conduct problem (CP) has been observed in exposed offspring. Further, maternal tobacco use during pregnancy can also alter offspring DNA methylation. However, currently, limited molecular evidence has been found to support this observation. Thus we aim to examine the association between maternal tobacco use in pregnancy and offspring CP, to determine whether offspring CP is mediated by tobacco exposure-induced DNA methylation differences. Understanding the etiology of the association between maternal tobacco use and offspring CP will be crucial in the early identification and treatment of CP in children and adolescents. Here, a sub group of N = 96 individuals was sourced from the Christchurch Health and Development Study, a longitudinal birth cohort studied for over 40 years in New Zealand. Whole blood samples underwent bisulphite-based amplicon sequencing at 10 loci known to play a role in neurodevelopment, or which had associations with CP phenotypes. We identified significant (P < 0.05) differential DNA methylation at specific CpG sites in CYP1A1, ASH2L and MEF2C in individuals with CP who were exposed to tobacco in utero. We conclude that environmentally-induced DNA methylation differences could play a role in the observed link between maternal tobacco use during pregnancy and childhood/ adolescent CP. However, larger sample sizes are needed to produce an adequate amount of power to investigate this interaction further. [ABSTRACT FROM AUTHOR]

In this article, we derive a new, fast, and robust preconditioned iterative solution strategy for the all‐at‐once solution of optimal control problems with time‐dependent PDEs as constraints, including the heat equation and the non‐steady convection–diffusion equation. After applying an optimize‐then‐discretize approach, one is faced with continuous first‐order optimality conditions consisting of a coupled system of PDEs. As opposed to most work in preconditioning the resulting discretized systems, where a (first‐order accurate) backward Euler method is used for the discretization of the time derivative, we employ a (second‐order accurate) Crank–Nicolson method in time. We apply a carefully tailored invertible transformation for symmetrizing the matrix, and then derive an optimal preconditioner for the saddle‐point system obtained. The key components of this preconditioner are an accurate mass matrix approximation, a good approximation of the Schur complement, and an appropriate multigrid process to apply this latter approximation—these are constructed using our work in transforming the matrix system. We prove the optimality of the approximation of the Schur complement through bounds on the eigenvalues, and test our solver against a widely‐used preconditioner for the linear system arising from a backward Euler discretization. These demonstrate the effectiveness and robustness of our solver with respect to mesh‐sizes, regularization parameter, and diffusion coefficient. [ABSTRACT FROM AUTHOR]

The development of nanoplatforms prepared to perform both multimodal imaging and combined therapies in a single entity is a fast-growing field. These systems are able to improve diagnostic accuracy and therapy success. Multicomponent Nanoparticles (MCNPs), composed of iron oxide and gold, offer new opportunities for Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) diagnosis, as well as combined therapies based on Magnetic Hyperthermia (MH) and Photothermal Therapy (PT). In this work, we describe a new seed-assisted method for the synthesis of Au@Fe Nanoparticles (NPs) with a flower-like structure. For biomedical purposes, Au@Fe NPs were functionalized with a PEGylated ligand, leading to high colloidal stability. Moreover, the as-obtained Au@Fe-PEG NPs exhibited excellent features as both MRI and CT Contrast Agents (CAs), with high r2 relaxivity (60.5 mM−1⋅s−1) and X-ray attenuation properties (8.8 HU mM−1⋅HU). In addition, these nanoflowers presented considerable energy-to-heat conversion under both Alternating Magnetic Fields (AMFs) (∆T ≈ 2.5 °C) and Near-Infrared (NIR) light (∆T ≈ 17 °C). Finally, Au@Fe-PEG NPs exhibited very low cytotoxicity, confirming their potential for theranostics applications. [ABSTRACT FROM AUTHOR]

The vibrational spectrum of ammonia has received an enormous amount of attention due to its potential prevalence in hot exo-planet atmospheres and persistent challenges in assigning and modeling highly excited and often highly perturbed states. Effective Hamiltonian models face challenges due to strong coupling between the large amplitude inversion and the other small amplitude vibrations. To date, only the ground and ν2 positions could be modeled to experimental accuracy using effective Hamiltonians. Several previous attempts to analyze the 2ν2 and 4 energy levels failed to model both the microwave and infrared transitions to experimental accuracy. In this work, we performed extensive experimental measurements and data analysis for the 2ν2 and ν4 inversion-rotation and vibrational transitions. We measured 159 new transition frequencies with microwave precision and assigned 1680 new ones from existing Fourier transform spectra recorded in Synchrotron SOLEIL. The newly assigned data significantly expand the range of assigned quantum numbers; combined with all the previously published high-resolution data, the 2ν2 and ν4 states are reproduced to experimental accuracy using a global model described here. Achieving experimental accuracy required inclusion of a number of terms in the effective Hamiltonian that were neglected in previous work. These terms have also been neglected in the analysis of states higher than 2ν2 and ν4 suggesting that the inversion-rotation-vibration spectrum of ammonia may be far more tractable to effective Hamiltonians than previously believed. [ABSTRACT FROM AUTHOR]

The strongest epidemiological clue that the environment at the population level has a significant impact on the risk of developing multiple sclerosis is the well established, and in many instances, increasing latitudinal gradient of prevalence, incidence and mortality globally, with prevalence increasing by up to 10-fold between the equator and 60° north and south. The drivers of this gradient are thought to be environmental with latitude seen as a proxy for ultraviolet radiation and thus vitamin D production; however, other factors may also play a role. Several important questions remain unanswered, particularly when in the life course is the gradient established, does lifetime migration mitigate or exacerbate previously reported latitude gradients at location of diagnosis, and do factors such as sex or multiple sclerosis disease phenotype influence the timing or significance of the gradient? Utilizing lifetime residence calendars collected as part of the New Zealand National Multiple Sclerosis Prevalence Study, we constructed lifetime latitudinal gradients for multiple sclerosis from birth to prevalence day in 2006 taking into account migration internally and externally and then analysed by sex and multiple sclerosis clinical course phenotype. Of 2917 individuals living in New Zealand on prevalence day, 7 March 2006, with multiple sclerosis, 2127 completed the life course questionnaire and of these, 1587 were born in New Zealand. All cohorts and sub-cohorts were representative of the overall multiple sclerosis population in New Zealand on prevalence day. We found that the prevalence gradient was present at birth and was, in fact, stronger than at census day, and the slope of the gradient persisted until the age of 12 before gradually declining. We found that internal and external migration into New Zealand had little, if any, effect on the gradient except to decrease the significance of the gradient somewhat. Finally, we found as we had reported previously, that the lifetime prevalence gradients were largely driven by females with relapse onset multiple sclerosis. These findings confirm for the first time the importance of early life environmental exposures in the risk of multiple sclerosis indicating strongly that exposures as early as in utero and at birth drive the latitudinal gradient. Consequently, prevention studies should be focused on high-risk individuals and populations from the earliest possible time points especially, when appropriate, on females. [ABSTRACT FROM AUTHOR]

Counterfactual theories propose that people's capacity for causal judgment depends on their ability to consider alternative possibilities: The lightning strike caused the forest fire because had it not struck, the forest fire would not have ensued. To accommodate a variety of psychological effects on causal judgment, a range of recent accounts have proposed that people probabilistically sample counterfactual alternatives from which they compute a graded measure of causal strength. While such models successfully describe the influence of the statistical normality (i.e., the base rate) of the candidate and alternate causes on causal judgments, we show that they make further untested predictions about how normality influences people's confidence in their causal judgments. In a large (N = 3,020) sample of participants in a causal judgment task, we found that normality indeed influences people's confidence in their causal judgments and that these influences were predicted by a counterfactual sampling model in which people are more confident in a causal relationship when the effect of the cause is less variable among imagined counterfactual possibilities. Public Significance Statement: People are thought to identify an event as a cause of an effect when altering it would make a difference to the effect. Despite stable patterns in causal judgments across scenarios, however, people often disagree about the causes of particular effects. Here, we asked how people determine their confidence in such judgments, and we found evidence that people are more confident in their judgments when the difference made by the cause to the effect is robust to changes in background factors. [ABSTRACT FROM AUTHOR]

How might an interdisciplinary approach involving experimental archaeology improve our knowledge of glassmaking in medieval Iberia? Our current limited understanding lacks an appreciation of how surviving remains were created through the actual practice of glassmaking—herein lies the biggest single gap in knowledge. Archaeological experiments show that while the infima glassmaking recipe offers a credible guide to basic glassmaking technology, it is best interpreted as a set of learned instructions rooted in, though not describing, workshop practice. Awareness of the sensory qualities of glass, the conducting of experiments, and observation of glass production practice, all combined within a theoretical framework that embraces embodied knowledge and phenomenological aspects of space and time, suggest the potential existence of an encoded "text" of past glassmaking practice within archaeological workshop remains. The authors advocate further experimental archaeology on a more ambitious scale, exploring the sensory and performative aspects of glassmaking practice, to better learn to read the distinctive handwriting of this "text" in medieval Iberian archaeology. [ABSTRACT FROM AUTHOR]

The collective behavior of geometrically frustrated magnetization in connected networks of ferromagnetic nanowires, known as artificial spin ice, leads to complex magnetotransport behavior in those structures. Here, we present temperature- and current-dependent magnetotransport studies on a connected square artificial spin-ice system and correlate our observations to micromagnetic simulations. We find that the field at which the lattice magnetization collectively switches increases as the temperature is lowered. Our experimental findings highlight the importance of the global and local temperatures for the onset of a collective magnetization reversal in the connected system. These studies may also provide useful insights into novel storage concepts and applications in neuromorphic computing. [ABSTRACT FROM AUTHOR]

When simulating a mechanism from science or engineering, or an industrial process, one is frequently required to construct a mathematical model, and then resolve this model numerically. If accurate numerical solutions are necessary or desirable, this can involve solving large‐scale systems of equations. One major class of solution methods is that of preconditioned iterative methods, involving preconditioners which are computationally cheap to apply while also capturing information contained in the linear system. In this article, we give a short survey of the field of preconditioning. We introduce a range of preconditioners for partial differential equations, followed by optimization problems, before discussing preconditioners constructed with less standard objectives in mind. [ABSTRACT FROM AUTHOR]

We propose a saddle‐point preconditioner for an optimization problem constrained by the time‐dependent Stokes equations, discretized using the backward Euler method in time. The key ingredients are an inner iteration for the (1, 1)‐block, accelerated by a known preconditioner for the heat control problem, and an approximation of the Schur complement involving a commutator argument applied to a block matrix. Numerical results demonstrate the efficacy and robustness of this approach. [ABSTRACT FROM AUTHOR]

There are currently many tools available for capturing and defining the context of one's environment. Digital phenotyping, the use of technology and sensors to capture moment-to-moment behavior, has shown potential in quantifying the lived experience of mental illness and in the identification of individualized targets related to recovery. Environmental data suggests that greenspace may have a restorative capacity on mental health. In this paper, we explore the relationship of greenspace derived from geolocation with self-reported symptomatology from individuals with schizophrenia as well as healthy controls. Individuals with schizophrenia had less exposure to greenspace than controls, but their exposure demonstrated a dosage effect: high greenspace environments were associated with lower symptoms for anxiety (Cohen's d = -0.70), depression (d = -0.97), and psychosis (d = -0.94), whereas effect sizes for healthy controls were all negligible or small (d < 0.38). The notion that greenspace may have a more pronounced effect on individuals with mental illness presents both potential areas for recovery as well as implications for health care policy, especially in cities with a broad range of greenspace environments. [ABSTRACT FROM AUTHOR]

Monkeys and humans implement causal inference to simultaneously localize auditory and visual stimuli. J Neurophysiol 124: 715-727, 2020. First published July 29, 2020; doi:10.1152/jn.00046.2020.--The environment is sampled by multiple senses, which are woven together to produce a unified perceptual state. However, optimally unifying such signals requires assigning particular signals to the same or different underlying objects or events. Many prior studies (especially in animals) have assumed fusion of cross-modal information, whereas recent work in humans has begun to probe the appropriateness of this assumption. Here we present results from a novel behavioral task in which both monkeys (Macaca mulatta) and humans localized visual and auditory stimuli and reported their perceived sources through saccadic eye movements. When the locations of visual and auditory stimuli were widely separated, subjects made two saccades, while when the two stimuli were presented at the same location they made only a single saccade. Intermediate levels of separation produced mixed response patterns: a single saccade to an intermediate position on some trials or separate saccades to both locations on others. The distribution of responses was well described by a hierarchical causal inference model that accurately predicted both the explicit "same vs. different" source judgments as well as biases in localization of the source(s) under each of these conditions. The results from this task are broadly consistent with prior work in humans across a wide variety of analogous tasks, extending the study of multisensory causal inference to nonhuman primates and to a natural behavioral task with both a categorical assay of the number of perceived sources and a continuous report of the perceived position of the stimuli. [ABSTRACT FROM AUTHOR]

In this paper, we present numerical methods suitable for solving convex quadratic fractional differential equation (FDE) constrained optimization problems, with box constraints on the state and/or control variables. We develop an alternating direction method of multipliers (ADMM) framework, which uses preconditioned Krylov subspace solvers for the resulting subproblems. The latter allows us to tackle a range of partial differential equation (PDE) optimization problems with box constraints, posed on space-time domains, that were previously out of the reach of state-of-the-art preconditioners. In particular, by making use of the powerful generalized locally Toeplitz (GLT) sequences theory, we show that any existing GLT structure present in the problem matrices is preserved by ADMM, and we propose some preconditioning methodologies that could be used within the solver, to demonstrate the generality of the approach. Focusing on convex quadratic programs with time-dependent 2-dimensional FDE constraints, we derive multilevel circulant preconditioners, which may be embedded within Krylov subspace methods, for solving the ADMM subproblems. Discretized versions of FDEs involve large dense linear systems. In order to overcome this difficulty, we design a recursive linear algebra, which is based on the fast Fourier transform (FFT). We manage to keep the storage requirements linear, with respect to the grid size $N$, while ensuring an order $N \log N$ computational complexity per iteration of the Krylov solver. We implement the proposed method and demonstrate its scalability, generality, and efficiency through a series of experiments over different setups of the FDE optimization problem. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests a role for the gut microbiome in the development and progression of many diseases and many studies have been carried out to analyse the microbiome using a variety of methods. In this study, we compare MinION sequencing with meta-transcriptomics and amplicon-based sequencing for microbiome analysis of colorectal tumour tissue samples. Methods: DNA and RNA were extracted from 11 colorectal tumour samples. 16S rRNA amplicon sequencing and MinION sequencing was carried out using genomic DNA, and RNA-Sequencing for meta-transcriptomic analysis. Non-human MinION and RNA-Sequencing reads, and 16S rRNA amplicon sequencing reads were taxonomically classified using a database built from available RefSeq bacterial and archaeal genomes and a k-mer based algorithm in Kraken2. Concordance between the three platforms at different taxonomic levels was tested on a per-sample basis using Spearman's rank correlation. Results: The average number of reads per sample using RNA-Sequencing was greater than 129 times that generated using MinION sequencing. However, the average read length of MinION sequences was more than 13 times that of RNA or 16S rRNA amplicon sequencing. Taxonomic assignment using 16S sequencing was less reliable beyond the genus level, and both RNA-Sequencing and MinION sequencing could detect greater numbers of phyla and genera in the same samples, compared to 16S sequencing. Bacterial species associated with colorectal cancer, Fusobacterium nucleatum, Parvimonas micra, Bacteroides fragilis and Porphyromonas gingivalis, were detectable using MinION, RNA-Sequencing and 16S rRNA amplicon sequencing data. Conclusions: Long-read sequences generated using MinION sequencing can compensate for low numbers of reads for bacterial classification. MinION sequencing can discriminate between bacterial strains and plasmids and shows potential as a cost-effective tool for rapid microbiome sequencing in a clinical setting. [ABSTRACT FROM AUTHOR]

Understanding how humans make competitive decisions in complex environments is a key goal of decision neuroscience. Typical experimental paradigms constrain behavioral complexity (e.g. choices in discrete-play games), and thus, the underlying neural mechanisms of dynamic social interactions remain incompletely understood. Here, we collected fMRI data while humans played a competitive real-time video game against both human and computer opponents, and then, we used Bayesian non-parametric methods to link behavior to neural mechanisms. Two key cognitive processes characterized behavior in our task: (i) the coupling of one's actions to another's actions (i.e. opponent sensitivity) and (ii) the advantageous timing of a given strategic action. We found that the dorsolateral prefrontal cortex displayed selective activation when the subject's actions were highly sensitive to the opponent's actions, whereas activation in the dorsomedial prefrontal cortex increased proportionally to the advantageous timing of actions to defeat one's opponent. Moreover, the temporoparietal junction tracked both of these behavioral quantities as well as opponent social identity, indicating a more general role in monitoring other social agents. These results suggest that brain regions that are frequently implicated in social cognition and value-based decision-making also contribute to the strategic tracking of the value of social actions in dynamic, multi-agent contexts. [ABSTRACT FROM AUTHOR]

In this paper, we propose and analyze a new matching-type Schur complement preconditioner for solving the discretized first-order necessary optimality conditions that characterize the optimal control of wave equations. Coupled with this is a recently developed second-order implicit finite difference scheme used for the full space-time discretization of the optimality system of PDEs. Eigenvalue bounds for the preconditioned system are derived, which provide insights into the convergence rates of the preconditioned Krylov subspace method applied. Numerical examples are presented to validate our theoretical analysis and demonstrate the effectiveness of the proposed preconditioner, in particular its robustness with respect to very small regularization parameters, and all mesh sizes in the spatial variables. [ABSTRACT FROM AUTHOR]

In this paper, we consider the fast numerical solution of an optimal control formulation of the Keller--Segel model for bacterial chemotaxis. Upon discretization, this problem requires the solution of huge-scale saddle point systems to guarantee accurate solutions. We consider the derivation of effective preconditioners for these matrix systems, which may be embedded within suitable iterative methods to accelerate their convergence. We also construct low-rank tensor-train techniques which enable us to present efficient and feasible algorithms for problems that are finely discretized in the space and time variables. Numerical results demonstrate that the number of preconditioned GMRES iterations depends mildly on the model parameters. Moreover, the low-rank solver makes the computing time and memory costs sublinear in the original problem size. [ABSTRACT FROM AUTHOR]

Natriuretic peptides (NP) have multiple actions benefitting cardiovascular and metabolic health. Although many of these are mediated by Guanylyl Cyclase (GC) receptors NPR1 and NPR2, their role and relative importance in vivo is unclear. The intracellular mediator of NPR1 and NPR2, cGMP, circulates in plasma and can be used to examine relationships between receptor activity and tissue responses targeted by NPs. Plasma cGMP was measured in 348 participants previously recruited in a multidisciplinary community study (CHALICE) at age 50 years at a single centre. Associations between bio-active NPs and bio-inactive aminoterminal products with cGMP, and of cGMP with tissue response, were analysed using linear regression. Mediation of associations by NPs was assessed by Causal Mediation Analysis (CMA). ANP's contribution to cGMP far exceed those of other NPs. Modelling across three components (demographics, NPs and cardiovascular function) shows that ANP and CNP are independent and positive predictors of cGMP. Counter intuitively, findings from CMA imply that in specific tissues, NPR1 responds more to BNP stimulation than ANP. Collectively these findings align with longer tissue half-life of BNP, and direct further therapeutic interventions towards extending tissue activity of ANP and CNP. [ABSTRACT FROM AUTHOR]

Binary fluorescence time series obtained from single-molecule imaging experiments can be used to infer protein binding kinetics, in particular, association and dissociation rate constants from waiting time statistics of fluorescence intensity changes. In many cases, rate constants inferred from fluorescence time series exhibit nonintuitive dependence on ligand concentration. Here, we examine several possible mechanistic and technical origins that may induce ligand dependence of rate constants. Using aggregated Markov models, we show under the condition of detailed balance that non-fluorescent bindings and missed events due to transient interactions, instead of conformation fluctuations, may underly the dependence of waiting times and thus apparent rate constants on ligand concentrations. In general, waiting times are rational functions of ligand concentration. The shape of concentration dependence is qualitatively affected by the number of binding sites in the single molecule and is quantitatively tuned by model parameters. We also show that ligand dependence can be caused by non-equilibrium conditions which result in violations of detailed balance and require an energy source. As to a different but significant mechanism, we examine the effect of ambient buffers that can substantially reduce the effective concentration of ligands that interact with the single molecules. To demonstrate the effects by these mechanisms, we applied our results to analyze the concentration dependence in a single-molecule experiment EGFR binding to fluorophore-labeled adaptor protein Grb2 by Morimatsu et al. [Proc. Natl. Acad. Sci. U.S.A. 104, 18013 (2007)]. [ABSTRACT FROM AUTHOR]

Complete and reliable knowledge of the ammonia spectrum is needed to enable the analysis and interpretation of astrophysical and planetary observations. Ammonia has been observed in the interstellar medium up to J=18 and more highly excited transitions are expected to appear in hot exoplanets and brown dwarfs. As a result, there is considerable interest in observing and assigning the high J (rovibrational) spectrum. In this work, numerous spectroscopic techniques were employed to study its high J transitions in the ground and ν2=1 states. Measurements were carried out using a frequency multiplied submillimeter spectrometer at Jet Propulsion Laboratory (JPL), a tunable far-infrared spectrometer at University of Toyama, and a high-resolution Bruker IFS 125 Fourier transform spectrometer (FTS) at Synchrotron SOLEIL. Highly excited ammonia was created with a radiofrequency discharge and a dc discharge, which allowed assignments of transitions with J up to 35. One hundred and seventy seven ground state and ν2=1 inversion transitions were observed with microwave accuracy in the 0.3-4.7 THz region. Of these, 125 were observed for the first time, including 26 ΔK=3 transitions. Over 2000 far-infrared transitions were assigned to the ground state and ν2=1 inversion bands as well as the ν2 fundamental band. Of these, 1912 were assigned using the FTS data for the first time, including 222 ΔK=3 transitions. The accuracy of these measurements has been estimated to be 0.0003-0.0006 cm-1. A reduced root mean square error of 0.9 was obtained for a global fit of the ground and ν2=1 states, which includes the lines assigned in this work and all previously available microwave, terahertz, far-infrared, and mid-infrared data. The new measurements and predictions reported here will support the analyses of astronomical observations by high-resolution spectroscopy telescopes such as Herschel, SOFIA, and ALMA. The comprehensive experimental rovibrational energy levels reported here will permit further refinement of the potential energy surface to improve ammonia ab initio calculations and facilitate assignment of new high-resolution spectra of hot ammonia. [ABSTRACT FROM AUTHOR]

Abstract The European Solvents Industry Group (ESIG) has established volatile organic compound emission inventories for solvents for individual countries or groups of countries within the European Union for 2008, 2009, 2013 and 2015. A top-down approach has been adopted starting with EU-wide solvents industry sales data as supplied by solvent manufacturers, to which atmospheric release factors were applied for each solvent use sector. ESIG total solvent emissions for the EU ranged from 2159 thousand tonnes year−1 in 2008 to 1981 thousand tonnes year−1 in 2015. Comparison with internationally-agreed solvent emissions suggests that official estimates of total solvent emissions across the EU are over 30% too high by comparison with ESIG estimates and showed too high a trend with time. Using official statistics on chemical exports and imports for each country, ESIG has been able to compile solvent emissions for each European country or groups of countries. The over-estimation by the internationally-agreed solvent emissions compared with the ESIG estimates for Europe as a whole was mirrored in the individual country estimates for 2008, 2009, 2013 and 2015. No simple, uniform relationship between national solvent emissions and per capita population for either total or domestic sector solvent emissions was found. Assumption of uniform solvents emission factors on a per-head of population basis, has led to the introduction of inaccuracies in internationally-agreed solvent emission inventories. More detailed work with Member States has shown that non-solvents are also being included in the official solvent VOC inventories-indeed these VOC inventories are for 'solvents and other product use'. Highlights • Solvent industry sales data have been used to generate top-down VOC emission inventories. • Industry estimates are over 30% lower than internationally-agreed solvent emissions. • No simple relationship is found between solvent VOC emissions and population. [ABSTRACT FROM AUTHOR]

Optimal transport problems pose many challenges when considering their numerical treatment. We investigate the solution of a PDE-constrained optimisation problem subject to a particular transport equation arising from the modelling of image metamorphosis. We present the nonlinear optimisation problem, and discuss the discretisation and treatment of the nonlinearity via a Gauss–Newton scheme. We then derive preconditioners that can be used to solve the linear systems at the heart of the (Gauss–)Newton method. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) and lithium are widely used in the treatment of bipolar disorder. However, the underlying mechanism of action of these drugs is not clearly understood. We used RNA-Seq analysis to examine the global profile of gene expression in a rat serotonergic cell line (RN46A) after exposure to these two mood stabilizer drugs. Numerous genes were differentially regulated in response to VPA (log2 fold change ≥ 1.0; i.e., odds ratio of ≥ 2, at false discovery rate <5%), but only two genes (Dynlrb2 and Cdyl2) showed significant differential regulation after exposure of the cells to lithium, with the same analysis criteria. Both of these genes were also regulated by VPA. Many of the differentially expressed genes had functions of potential relevance to mood disorders or their treatment, such as several serpin family genes (including neuroserpin), Nts (neurotensin), Maob (monoamine oxidase B), and Ap2b1, which is important for synaptic vesicle function. Pathway analysis revealed significant enrichment of Gene Ontology terms such as extracellular matrix remodeling, cell adhesion, and chemotaxis. This study in a cell line derived from the raphe nucleus has identified a range of genes and pathways that provide novel insights into potential therapeutic actions of the commonly used mood stabilizer drugs. [ABSTRACT FROM AUTHOR]

The gamma function was originally discovered by Euler to solve an interpolation problem for the factorials. However, its ubiquity cannot be due to its algebraic nature alone. This article presents the close connection between the volumes of various spaces and the values of the gamma function to better understand its frequent appearance in many mathematical formulas. This connection produces a surprising similarity between Viète’s formula for π and Knar’s formula. [ABSTRACT FROM AUTHOR]

We show that if a Turing instability occurs in a reaction–diffusion system with a nearly scalar diffusion matrix, then the parameters of the corresponding well-mixed system are necessarily such that the well-mixed system has at least two eigenvalues near zero. Conversely, if the corresponding well-mixed system is sufficiently close to a coalescence point of Hopf and saddle-node bifurcations (two eigenvalues are zero at such a point), and if the spatial domain is sufficiently large, then there exists a nearly scalar diffusion matrix such that a Turing instability occurs. These results imply that information on bifurcation loci from experiments in continuous-flow stirred tank reactor suffices to locate regions of parameter space where Turing instabilities are likely to occur; no knowledge of the reaction mechanism and rate constants is needed. In order to illustrate these results, we have analyzed a six-step model of the Belousov–Zhabotinskii reaction due to Showalter, Noyes, and Bar-Eli. In this model, the sixth step describes the reduction of the metal ion catalyst by the organic substrate. Depending on the rate constant of this step, we find that Turing instabilities can occur when the diffusion coefficient of either Ce4+ or of HOBr is very near, but slightly larger than that of Br-. [ABSTRACT FROM AUTHOR]

Steady spatial chemical patterns have been found in model reaction–diffusion systems but have not yet been observed in any laboratory experiments. The reasons for this are discussed and the need for open reactors is stressed. A model open reactor is investigated in order to guide the experimental search for steady patterns. Specifically, Turing bifurcations in this reactor are studied for a simple autocatalytic chemistry (the Gray–Scott model) in order to determine the effects of varying diffusion coefficients, chemical time scales, and residence time. A description of all the steady-state bifurcations from an initially homogeneous state is obtained. The Liapunov–Schmidt reduction is used to determine the stability of the bifurcating solutions and a steady-state continuation technique is used to follow stable and unstable branches of bifurcating solutions. [ABSTRACT FROM AUTHOR]

The striatum supports learning from immediate feedback by coding prediction errors (PEs), whereas the hippocampus (HC) plays a parallel role in learning from delayed feedback. Both regions show evidence of decline in human aging, but behavioral research suggests greater decline in HC versus striatal functions. The present study included male and female humans and used fMRI to examine younger and older adults' brain activation patterns during a learning task with choice feedback presented immediately or after a brief delay. Participants then completed a surprise memory task that tested their recognition of trial-unique feedback stimuli, followed by assessments of postlearning cue preference, outcome probability awareness, and willingness to pay. The study yielded three main findings. First, behavioral measures indicated similar rates of learning in younger and older adults across conditions, but postlearning measures indicated impairment in older adults' ability to subsequently apply learning to discriminate between cues. Second, PE signals in the striatum were greater for immediate versus delayed feedback in both age groups, but PE signals in the HC were greater for delayed versus immediate feedback only in younger adults. Third, unlike younger adults, older adults failed to exhibit enhanced episodic memory for outcome stimuli in the delayed-feedback condition. Together, these findings indicate that HC circuits supporting learning and memory decline more than striatal circuits in healthy aging, which suggests that declines in HC learning signals may be an important predictor of deficits in learning-dependent economic decisions among older adults. [ABSTRACT FROM AUTHOR]

This article explores the relationship between culture and cyberloafing. A survey measuring individuals’ propensity to engage in cyberloafing in the workplace was conducted with people from 17 countries representing a wide range of cultures. Tests were performed to explore relationships between participants’ propensity to cyberloaf and the cultural dimension ratings for their individual countries of origin. The results show that some types of cyberloafing activity relate significantly with culture. This has potential implications for multinational organizations. Employees from different cultures may have different workplace tendencies. [ABSTRACT FROM AUTHOR]

Neutrophil-derived myeloperoxidase (MPO) is recognized as a major source of oxidative stress at the airway surface of a cystic fibrosis (CF) lung where, despite limited evidence, the antioxidant glutathione is widely considered to be low. The aims of this study were to establish whether oxidative stress or glutathione status are associated with bronchiectasis and whether glutathione deficiency is inherently linked to CF or a consequence of oxidative stress. MPO was measured by ELISA in 577 bronchoalveolar lavage samples from 205 clinically-phenotyped infants and children with CF and 58 children without CF (ages 0.2–6.92 years). Reduced glutathione (GSH), oxidized glutathione species (GSSG; glutathione attached to proteins, GSSP; glutathione sulfonamide, GSA) and allantoin, an oxidation product of uric acid, were measured by mass spectrometry. The odds of having bronchiectasis were associated with MPO and GSSP. GSH was low in children with CF irrespective of oxidation. Oxidized glutathione species were significantly elevated in CF children with pulmonary infections compared to uninfected CF children. In non-CF children, infections had no effect on glutathione levels. An inadequate antioxidant response to neutrophil-mediated oxidative stress during infections exists in CF due to an inherent glutathione deficiency. Effective delivery of glutathione and inhibition of MPO may slow the development of bronchiectasis. [ABSTRACT FROM AUTHOR]

What we are currently thinking influences where we attend. The finding that active maintenance of visual items in working memory (WM) biases attention toward memory-matching objects-even when WM content is irrelevant for attentional goals-suggests a tight link between WM and attention. To test whether this link is reliable enough to infer specific WM content from measures of attentional bias, we applied multivariate pattern classification techniques to response times from an unrelated visual search task during a WM delay. Single-trial WM content was successfully decoded from incidental attentional bias within an individual, highlighting the specificity and reliability of the WM-attention link. Furthermore, classifiers trained on a group of individuals predicted WM content in another, completely independent individual-implying a shared cognitive mechanism of memory-driven attentional bias. The existence of such classifiers demonstrates that memory-based attentional bias is both a robust and generalizable probe of WM. [ABSTRACT FROM AUTHOR]

The two most commonly used hypergeometric functions are the confluent hypergeometric function and the Gauss hypergeometric function. We review the available techniques for accurate, fast, and reliable computation of these two hypergeometric functions in different parameter and variable regimes. The methods that we investigate include Taylor and asymptotic series computations, Gauss-Jacobi quadrature, numerical solution of differential equations, recurrence relations, and others. We discuss the results of numerical experiments used to determine the best methods, in practice, for each parameter and variable regime considered. We provide 'roadmaps' with our recommendation for which methods should be used in each situation. [ABSTRACT FROM AUTHOR]

Background: Enterotoxigenic Bacteroides fragilis (ETBF) is a toxin-producing bacteria thought to possibly promote colorectal carcinogenesis by modulating the mucosal immune response and inducing epithelial cell changes. Here, we aim to examine the association of colonic mucosal colonization with ETBF and the presence of a range of lesions on the colonic neoplastic spectrum. Methods: Mucosal tissue from up to four different colonic sites was obtained from a consecutive series of 150 patients referred for colonoscopy. The presence and relative abundance of the B. fragilis toxin gene (bft) in each tissue sample was determined using quantitative PCR, and associations with clinicopathological characteristics were analysed. Findings: We found a high concordance of ETBF between different colonic sites (86%). Univariate analysis showed statistically significant associations between ETBF positivity and the presence of low-grade dysplasia (LGD), tubular adenomas (TA), and serrated polyps (P-values of 0.007, 0.027, and 0.007, respectively). A higher relative abundance of ETBF was significantly associated with LGD and TA (P-values of < 0.0001 and 0.025, respectively). Increased ETBF positivity and abundance was also associated with left-sided biopsies, compared to those from the right side of the colon. Conclusion: Our results showing association of ETBF positivity and increased abundance with early-stage carcinogenic lesions underlines its importance in the development of colorectal cancer, and we suggest that detection of ETBF may be a potential marker of early colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Objectives Telomeres are nucleoprotein complexes that cap the ends of linear chromosomes. Telomeric DNA decreases with age and shows considerable heterogeneity in the wider population. There is interest in the application of telomere length measures as a biomarker of general health or 'biological age,' and the possibility of using mean telomere length to gauge individual disease risk, and to promote lifestyle changes to improve health. This study examined the effectiveness of telomere length as a biomarker for an individual's current overall health status by assessing several measures of general health including SF-36v2 score, current smoking status and a comprehensive obesity phenotype. Methods Participants were from the Canterbury Health, Ageing and Lifecourse (CHALICE) cohort, a New Zealand population based multidisciplinary study of aging. Telomere length measurements were obtained on DNA from peripheral blood samples at age 49-51 ( n = 351), using a quantitative polymerase chain reaction assay. Results No associations were found between telomere length measured at age 49-51 and any measures of current health status. The only significant association observed was between telomere length and gender, with females having longer telomere length than men. Conclusions Our results suggest that telomere length measurements are unlikely to provide information of much predictive significance for an individual's health status. [ABSTRACT FROM AUTHOR]

We propose a new preconditioner for the Ohta{Kawasaki equation, a nonlocal Cahn{ Hilliard equation that describes the evolution of diblock copolymer melts. We devise a computable approximation to the inverse of the Schur complement of the coupled second-order formulation via a matching strategy. The preconditioner achieves mesh independence: as the mesh is refined, the number of Krylov iterations required for its solution remains approximately constant. In addition, the preconditioner is robust with respect to the interfacial thickness parameter if a timestep criterion is satisfied. This enables the highly resolved finite element simulation of three-dimensional diblock copolymer melts with over 1 billion degrees of freedom. [ABSTRACT FROM AUTHOR]

Terahertz absorption spectroscopy was employed to measure the ground state pure rotational transitions of the water isotopologue HD 18 O . A total of 105 pure rotational transitions were observed in the 0.5–5.0 THz region with ∼ 100 kHz accuracy for the first time. The observed positions were fit to experimental accuracy using the Euler series expansion of the asymmetric-top Hamiltonian together with the literature Microwave, Far-IR and IR data in the ground state and ν 2 . The new measurements and predictions reported here support the analysis of astronomical observations by high-resolution spectroscopic telescopes such as SOFIA and ALMA where laboratory rest frequencies with uncertainties of 1 MHz or less are required for proper analysis of velocity resolved astrophysical data. [ABSTRACT FROM AUTHOR]

In this manuscript we consider the development of fast iterative solvers for Stokes control problems, an important class of PDE-constrained optimization problems. In particular we wish to develop effective preconditioners for the matrix systems arising from finite element discretizations of time-dependent variants of such problems. To do this we consider a suitable rearrangement of the matrix systems, and exploit the saddle point structure of many of the relevant sub-matrices involved – we may then use this to construct representations of these sub-matrices based on good approximations of their ( 1 , 1 ) -block and Schur complement. We test our recommended iterative methods on a distributed control problem with Dirichlet boundary conditions, and on a time-periodic problem. [ABSTRACT FROM AUTHOR]

Objectives. To use publicly available, crowdsourced data to understand geospatial trends in discarded needles. Methods. We completed multiple geospatial analyses of discarded needles reported through the Boston, Massachusetts, 311 service request system. Results. Between May 2015 and August 2017, 4763 discarded needles were reported. The highest concentration of needles were reported in census block groups in the South End and Roxbury neighborhoods. Cumulatively, 78.3% of the needles were reported within 1 kilometer of methadone clinics, safe needle deposit sites, homeless shelters, or hospitals. Conclusions. Publicly reported data can help identify hot spots of discarded needles and examine indicators of spatial association. In Boston, the number of discarded needles being reported is rising, with the highest density of needles found in 2 central neighborhoods with several outlying hot spots. Most needles were found near areas associated with social stress and substance use disorder. Public Health Implications. This analysis represents a novel way of leveraging publicly available information to target community responses to the opioid epidemic. Identifying hot spots of discarded needles may enable public health organizations to target future efforts to encourage safer needle disposal practices and reduce public injection drug use. [ABSTRACT FROM AUTHOR]

The purpose of this article was to review and compare the international guidelines and surveillance protocols for post-nephrectomy renal cell carcinoma ( RCC). PubMed database searches were conducted, according to the PRISMA statement for reporting systematic reviews, to identify current international surveillance guidelines and surveillance protocols for surgically treated and clinically localized RCC. A total of 17 articles were reviewed. These included three articles on urological guidelines, three on oncological guidelines and 11 on proposed strategies. Guidelines and strategies varied significantly in relation to follow-up, specifically with regard to the frequency and timing of radiological imaging. Although there is currently no consensus within the literature regarding surveillance protocols, various guidelines and strategies have been developed using both patient and tumour characteristics. [ABSTRACT FROM AUTHOR]

This study measures ethical intentions of students utilizing the Theory of Planned Behavior (TPB). The direct and moderating effects of religiosity, and also the direct and mediating effects of ethical ideologies (idealism and relativism) are considered in this study. An online survey was used to collect data from 300 college students. Utilizing SmartPLS, the results indicate that along with attitude, idealism and relativism have the strongest influence on ethical intentions. While there is evidence of partial mediation by idealism and relativism on the religiosity-intention relationship, there is no evidence of a moderating effect by religiosity on the attitude-intention relationship. [ABSTRACT FROM AUTHOR]

Fractional differential equations have recently received much attention within computational mathematics and applied science, and their numerical treatment is an important research area as such equations pose substantial challenges to existing algorithms. An optimization problem with constraints given by fractional differential equations is considered, which in its discretized form leads to a high-dimensional tensor equation. To reduce the computation time and storage, the solution is sought in the tensor-train format. We compare three types of solution strategies that employ sophisticated iterative techniques using either preconditioned Krylov solvers or tailored alternating schemes. The competitiveness of these approaches is presented using several examples with constant and variable coefficients. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a pivotal component adult tissues and of many tissue-specific stem cell niches. It provides structural support and regulates niche signaling during tissue maintenance and regeneration. In many tissues, ECM remodeling depends on the regulation of MMP (atrix etalloroteinase) activity by inhibitory TIMP (issue nhibitors of metalloproteinases) proteins. Here, we report that the only Drosophila timp gene is required for maintaining the normal organization and function of the germline stem cell niche in adult females. timp mutant ovaries show reduced levels of both Drosophila Collagen IV α chains. In addition, tissue stiffness and the cellular organization of the ovarian niche are affected in timp mutants. Finally, loss of timp impairs the ability of the germline stem cell niche to generate new cysts. Our results demonstrating a crucial role for timp in tissue organization and gamete production thus provide a link between the regulation of ECM metabolism and tissue homeostasis. [ABSTRACT FROM AUTHOR]