The quasipotential with respect to a given attractor of a system, evolving according to a stochastic differential equation (SDE) with a small noise, is a function that allows us to find the expected ...exit time from its basin of attraction and to estimate the equilibrium probability density in its neighborhood. This work is devoted to the study of the quasipotential of nongradient SDEs with isotropic diffusion. The goals are: (i) to understand the theoretical behavior of the quasipotential, and (ii) to develop tools for its numerical study.
This work is focused on 2D equations with asymptotically stable equilibria and limit cycles. In the theoretical part, we establish a number of properties of the quasipotential. For 2D linear equations, we derive an exact formula for the quasipotential. For 2D nonlinear equations, we establish how the quasipotential grows near the stable equilibria and the stable limit cycles. In the numerical part of this work we adjust the OUM for computing the quasipotential on a regular mesh. We show that the quasipotential satisfies a Hamilton–Jacobi–Bellman equation with an anisotropic and unbounded speed function. The unbounded speed function may lead to an additional consistency error in specific areas of the phase space. However, we conduct an error analysis and show that even if this error appears, it decays quadratically as we refine the mesh.
We apply the proposed numerical algorithm to a number of examples: linear systems, the Maier–Stein model, a system with stochastic resonance, and a system with two stable limit cycles. Whenever it is appropriate, we compute the Minimum Action Paths by shooting characteristics. The Minimum Action Paths found in this way are necessarily the global minimizers of the Freidlin–Wentzell action.
► Exact formula for quasipotential for 2D linear SDEs. ► Growth estimates near stable equilibrium points and limit cycles. ► Discussion of the Hamilton–Jacobi–Bellman equation for the quasipotential. ► Adjustment of the Ordered Upwind Method for the unbounded speed function. ► Quadratic decay of the additional consistency error with mesh refinement.
NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that is defined by the presence of BRD-NUT fusion oncogenes, which encode chimeric proteins that block differentiation and ...maintain tumor growth. BRD-NUT oncoproteins contain two bromodomains whose binding to acetylated histones is required for the blockade of differentiation in NMC, but the mechanisms by which BRD-NUT act remain uncertain. Here, we provide evidence that MYC is a key downstream target of BRD4-NUT. Expression profiling of NMCs shows that the set of genes whose expression is maintained by BRD4-NUT is highly enriched for MYC upregulated genes, and MYC and BRD4-NUT protein expression is strongly correlated in primary NMCs. More directly, we find that BRD4-NUT associates with the MYC promoter and is required to maintain MYC expression in NMC cell lines. Moreover, both siRNA knockdown of MYC and a dominant-negative form of MYC, omomyc, induce differentiation of NMC cells. Conversely, differentiation of NMC cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of MYC. Together, these findings suggest that MYC is a downstream target of BRD4-NUT that is required for maintenance of NMC cells in an undifferentiated, proliferative state. Our findings support a model in which dysregulation of MYC by BRD-NUT fusion proteins has a central role in the pathogenesis of NMC.
Variation in food resources can result in dramatic fluctuations in the body condition of animals dependent on those resources. Decreases in body mass can disrupt patterns of energy allocation and ...impose stress, thereby altering immune function. In this study, we investigated links between changes in body mass of captive cane toads (
), their circulating white blood cell populations, and their performance in immune assays. Captive toads that lost weight over a three-month period had increased levels of monocytes and heterophils and reduced levels of eosinophils. Basophil and lymphocyte levels were unrelated to changes in mass. Because individuals that lost mass had higher heterophil levels but stable lymphocyte levels, the ratio of these cell types was also higher, partially consistent with a stress response. Phagocytic ability of whole blood was higher in toads that lost mass, owing to increased circulating levels of phagocytic cells. Other measures of immune performance were unrelated to mass change. These results highlight the challenges faced by invasive species as they expand their range into novel environments which may impose substantial seasonal changes in food availability that were not present in the native range. Individuals facing energy restrictions may shift their immune function towards more economical and general avenues of combating pathogens. This article is part of the theme issue 'Amphibian immunity: stress, disease and ecoimmunology'.
The use of AI and robots in library and information science is garnering attention due to early applications and their potential to contribute to the digital transformation of the information ...professions. This paper assesses the challenges and opportunities for LIS education in these topics. To achieve this aim, this paper reviews the curriculum, through subject descriptions, of five ALIA accredited LIS courses in Australia and the ALIA foundation knowledge documentation. Content analysis is employed to identify and assess the framing of AI, robotics and related themes in the documentation. Findings indicate only one subject mentions AI to position subject content and none mention robotics. An analysis of the framing of related themes, such as digital technology, data, and information ethics, is discussed. Findings also indicate multiple areas for the inclusion of these topics within the five categories of the ALIA foundation knowledge, while allowing for differentiation among programmatic and institutional foci. This paper argues that a form of integration of these topics in LIS professional education will be necessary in order to meet future skills needs. This paper concludes with opportunities for LIS education in Australia.
The burnettramic acids are a new class of antibiotics from an Australian fungus Aspergillus burnettii. The rare bolaamphiphilic scaffold consists of β-d-mannose linked to a pyrrolizidinedione unit ...via a 26-carbon chain. The most abundant metabolite displayed potent in vitro antifungal activity. Comparative genomics identified the hybrid PKS-NRPS bua gene cluster, which was verified by heterologous pathway reconstitution in Aspergillus nidulans.
Vaccine hesitancy during the COVID-19 pandemic was exacerbated by an infodemic of conflating accurate and inaccurate information with divergent political messages, leading to varying adherence to ...health-related behaviors. In addition to the media, people received information about COVID-19 and the vaccine from their physicians and closest networks of family and friends.
This study explored individuals' decision-making processes in receiving the COVID-19 vaccine, focusing on the influence of specific media outlets, political orientation, personal networks, and the physician-patient relationship. We also evaluated the effect of other demographic data like age and employment status.
An internet survey was disseminated through the Western Michigan University Homer Stryker MD School of Medicine Facebook account. The survey included questions on media sources for COVID-19 information, political affiliation, presidential candidate choice, and multiple Likert-type agreement scale questions on conceptions of the vaccine. Each respondent was assigned a media source score, which represented the political leaning of their media consumption. This was calculated using a model based on data from the Pew Research Center that assigned an ideological profile to various news outlets.
The sample consisted of 1757 respondents, with 89.58% (1574/1757) of them choosing to take the COVID-19 vaccine. Those employed part-time and the unemployed were at 1.94 (95% CI 1.15-3.27) and 2.48 (95% CI 1.43-4.39) greater odds of choosing the vaccine than those employed full-time. For every 1-year increase in age, there was a 1.04 (95% CI 1.02-1.06) multiplicative increase in odds of choosing to receive the vaccine. For every 1-point increase in media source score toward more Liberal or Democrat, there was a 1.06 (95% CI 1.04-1.07) multiplicative increase in odds of choosing to take the COVID-19 vaccine. The Likert-type agreement scale showed statistically significant differences (P<.001) between respondents; those who chose the vaccine agreed more strongly on their belief in the safety and efficacy of vaccines, the influence of their personal beliefs, and the encouragement and positive experiences of family and friends. Most respondents rated their personal relationship with their physician to be good, but this factor did not correlate with differences in vaccine decision.
Although multiple factors are involved, the role of mass media in shaping attitudes toward vaccines cannot be ignored, especially its ability to spread misinformation and foster division. Surprisingly, the effect of one's personal physician may not weigh as heavily in one's decision-making process, potentially indicating the need for physicians to alter their communication style, including involvement in social media. In the era of information overload, effective communication is critical in ensuring the dissemination of accurate and reliable information to optimize the vaccination decision-making process.
The Affordable Care Act included a provision to gradually eliminate the Medicare prescription drug coverage gap between 2011 and 2020, which substantially lower medication costs in the gap. Using ...2007–2016 Medicare claims data, we estimate how filling the gap affects individuals' out‐of‐pocket spending and medication use, separately for branded and generic drugs. One important difficulty in estimating the policy impact is that around the same time, many blockbuster drugs commonly used by the Medicare population experienced patent expiration and began to see generic entry. Because generic entries affected different therapeutic classes at different times, we run difference‐in‐differences models by therapeutic category at the beneficiary‐month level to isolate the effect of the gap closure from that of generic entry. Overall, we find that filling the gap substantially reduced out‐of‐pocket spending and increased the use of branded drugs, which had larger discount rates during the analysis period. Beneficiaries reaching the gap, at older ages, or with comorbidities experienced larger reduction in out‐of‐pocket spending. We show that without accounting for generic entry, the effect of filling the coverage gap on medication use is underestimated for branded drugs and overestimated for generic drugs.
Dopaminergic (DA) neurons in the midbrain provide rich topographic innervation of the striatum and are central to learning and to generating actions. Despite the importance of this DA innervation, it ...remains unclear whether and how DA neurons are specialized on the basis of the location of their striatal target. Thus, we sought to compare the function of subpopulations of DA neurons that target distinct striatal subregions in the context of an instrumental reversal learning task. We identified key differences in the encoding of reward and choice in dopamine terminals in dorsal versus ventral striatum: DA terminals in ventral striatum responded more strongly to reward consumption and reward-predicting cues, whereas DA terminals in dorsomedial striatum responded more strongly to contralateral choices. In both cases the terminals encoded a reward prediction error. Our results suggest that the DA modulation of the striatum is spatially organized to support the specialized function of the targeted subregion.
Breast surgery is exceedingly common and may result in significant acute as well as chronic pain. Numerous options exist for the control of perioperative breast pain, including several newly ...described regional anesthesia techniques, but anesthesiologists have an insufficient understanding of the anatomy of the breast, the anatomic structures disrupted by the various breast surgeries, and the theoretical and experimental evidence supporting the use of the various analgesic options. In this article, we review the anatomy of the breast, common breast surgeries and their potential anatomic sources of pain, and analgesic techniques for managing perioperative pain. We performed a systematic review of the evidence for these analgesic techniques, including intercostal block, epidural administration, paravertebral block, brachial plexus block, and novel peripheral nerve blocks.
Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite ...being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics.
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