Identification of targetable epigenetic vulnerabilities in uveal melanoma.

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, which preferentially metastasizes to the liver in approximately half of all cases. Metastatic UM is notoriously resistant to therapy and is almost uniformly fatal. UM metastasis is most strongly associated with mutational inactivation of the BAP1 tumor suppressor gene. Given the role of BAP1 in epigenetic regulation as the ubiquitin hydrolase subunit of the polycomb repressive deubiquitinase (PR-DUB) complex, we conducted high-throughput drug screening using a well-characterized epigenetic compound library to identify new therapeutic vulnerabilities. We identified several promising new lead compounds, in particular the extra-terminal domain protein (BET) inhibitor mivebresib (ABBV-075). Mivebresib significantly improved survival rates in a metastatic uveal melanoma xenograft mouse model and entirely prevented detectable metastases to the bones, spinal cord, and brain. RNA sequencing revealed a notable overlap between the genes and pathways affected by HDAC and BET inhibition, including the reversal of gene signatures linked to high metastatic risk and upregulation of genes associated with a neuronal phenotype. Together, we found that UM cells are particularly vulnerable to class I HDAC and BET inhibition, and highlight the BET inhibitor mivebresib as a promising candidate for further clinical evaluation.

Threat Type Moderates Agency Assignment: A Partial Matching Effect.

This study examined the effects of agency assignment on response to messages advocating threat preparedness, highlighting interactions between agency assignment and threat type. Participants were randomly assigned to one of four conditions crossing human agency vs. threat agency with human ascribed threats vs. threats not ascribed to humans. Two messages were shown in random order in each condition with responses measured after each message. In line with extant research, results showed a significant main effect for agency assignment on behavioral intentions such that, relative to human agency, threat agency increased intentions to follow message recommendations for threat preparedness. The main effect of agency assignment was qualified by an agency assignment by threat type interaction, indicating a partial matching effect on behavioral intentions wherein threat agency led to greater behavioral intentions than human agency for threats not ascribed to humans - but not for threats ascribed to humans. Results, limitations, and implications of the study are discussed.

Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility.

Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural "switch" affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.

A metamodel-based flexible insulin therapy for type 1 diabetes patients subjected to aerobic physical activity.

Patients with type 1 diabetes are subject to exogenous insulin injections, whether manually or through (semi)automated insulin pumps. Basic knowledge of the patient's characteristics and flexible insulin therapy (FIT) parameters are then needed. Specifically, artificial pancreas-like closed-loop insulin delivery systems are some of the most promising devices for substituting for endogenous insulin secretion in type 1 diabetes patients. However, these devices require self-reported information such as carbohydrates or physical activity from the patient, introducing potential miscalculations and delays that can have life-threatening consequences. Here, we display a metamodel for glucose-insulin dynamics that is subject to carbohydrate ingestion and aerobic physical activity. This metamodel incorporates major existing knowledge-based models. We derive comprehensive and universal definitions of the underlying FIT parameters to form an insulin sensitivity factor (ISF). In addition, the relevance of physical activity modelling is assessed, and the FIT is updated to take physical exercise into account. Specifically, we cope with physical activity by using heart rate sensors (watches) with a fully automated closed insulin loop, aiming to maximize the time spent in the glycaemic range (75.5% in the range and 1.3% below the range for hypoglycaemia on a virtual patient simulator).These mathematical parameter definitions are interesting on their own, may be new tools for assessing mathematical models and can ultimately be used in closed-loop artificial pancreas algorithms or to extend distinguished FIT.

Physical Aggression and Coronary Artery Calcification: A North Texas Healthy Heart Study.

BACKGROUND: The purpose of this study was to determine the association between aspects of hostility and coronary artery calcification (CAC) scores. Specifically, analyses differentiated between subtypes of hostility and their relation to CAC. METHODS: A sample of 571 patients aged 45 or older with no history of cardiovascular disease completed assessments of demographic, psychosocial, and medical history, along with a radiological CAC determination. Logistic regression was used to determine the association between hostility and CAC. Hostility was measured using the Aggression Questionnaire, which measured total aggression and how aggression is manifested on four scales: Physical, Verbal, Anger, and Hostility Aggression. RESULTS: Regression analyses indicated that only the physical aggression parameter was related to CAC: a 5% increase in odds of CAC presence was indicated for every point increase in physical aggression. The association remained significant in adjusted analyses. Other factors associated with CAC in adjusted analyses included: age, gender, race/ethnicity, BMI, and dyslipidemia. CONCLUSIONS: Psychosocial factors, such as physical aggression, are emerging factors that need to be considered in cardiovascular risk stratification.

Structure-based identification of sensor species for anticipating critical transitions.

Ecological systems can undergo sudden, catastrophic changes known as critical transitions. Anticipating these critical transitions remains challenging in systems with many species because the associated early warning signals can be weakly present or even absent in some species, depending on the system dynamics. Therefore, our limited knowledge of ecological dynamics may suggest that it is hard to identify those species in the system that display early warning signals. Here, we show that, in mutualistic ecological systems, it is possible to identify species that early anticipate critical transitions by knowing only the system structure-that is, the network topology of plant-animal interactions. Specifically, we leverage the mathematical theory of structural observability of dynamical systems to identify a minimum set of "sensor species," whose measurement guarantees that we can infer changes in the abundance of all other species. Importantly, such a minimum set of sensor species can be identified by using the system structure only. We analyzed the performance of such minimum sets of sensor species for detecting early warnings using a large dataset of empirical plant-pollinator and seed-dispersal networks. We found that species that are more likely to be sensors tend to anticipate earlier critical transitions than other species. Our results underscore how knowing the structure of multispecies systems can improve our ability to anticipate critical transitions.

The Effects of Agency Assignment and Reference Point on Responses to COVID-19 Messages.

As the COVID-19 pandemic poses severe threats to human life around the globe, effective risk messages are needed to warn the public and encourage recommended actions for avoiding infection, especially as steps are taken to ease physical restrictions and restart economies. The present study examines the effects of agency assignment and reference point on perceptions of SARS-CoV-2 threat and assesses key message responses, including psychological reactance, source derogation, counterarguing, and behavioral intentions. Participants (N = 207) were randomly assigned to one of four conditions crossing agency assignment (SARS-CoV-2/human) and reference point (self/self-other). Results show, relative to human agency, SARS-CoV-2 agency assignment generated significantly more psychological reactance in the form of greater perceptions of freedom threat, anger, and negative cognitions, as well as more source derogation and counterarguing. No significant effects were found for reference point, and the interaction between agency assignment and reference point was not significant. The study findings, limitations, and implications are discussed.

From the hospital scale to nationwide: observability and identification of models for the COVID-19 epidemic waves.

Two mathematical models of the COVID-19 dynamics are considered as the health system in some country consists in a network of regional hospital centers. The first macroscopic model for the virus dynamics at the level of the general population of the country is derived from a standard SIR model. The second local model refers to a single node of the health system network, i.e. it models the flows of patients with a smaller granularity at the level of a regional hospital care center for COVID-19 infected patients. Daily (low cost) data are easily collected at this level, and are worked out for a fast evaluation of the local health status thanks to control systems methods. Precisely, the identifiability of the parameters of the hospital model is proven and thanks to the availability of clinical data, essential characteristics of the local health status are identified. Those parameters are meaningful not only to alert on some increase of the infection, but also to assess the efficiency of the therapy and health policy.

Hypoglycaemia-free artificial pancreas project.

Driving blood glycaemia from hyperglycaemia to euglycaemia as fast as possible while avoiding hypoglycaemia is a major problem for decades for type-1 diabetes and is solved in this study. A control algorithm is designed that guaranties hypoglycaemia avoidance for the first time both from the theory of positive systems point of view and from the most pragmatic clinical practice. The solution consists of a state feedback control law that computes the required hyperglycaemia correction bolus in real-time to safely steer glycaemia to the target. A rigorous proof is given that shows that the control-law respects the positivity of the control and of the glucose concentration error: as a result, no hypoglycaemic episode occurs. The so-called hypo-free strategy control is tested with all the UVA/Padova T1DM simulator patients (i.e. ten adults, ten adolescents, and ten children) during a fasting-night scenario and in a hybrid closed-loop scenario including three meals. The theoretical results are assessed by the simulations on a large cohort of virtual patients and encourage clinical trials.

A theoretical framework for controlling complex microbial communities.

Microbes form complex communities that perform critical roles for the integrity of their environment or the well-being of their hosts. Controlling these microbial communities can help us restore natural ecosystems and maintain healthy human microbiota. However, the lack of an efficient and systematic control framework has limited our ability to manipulate these microbial communities. Here we fill this gap by developing a control framework based on the new notion of structural accessibility. Our framework uses the ecological network of the community to identify minimum sets of its driver species, manipulation of which allows controlling the whole community. We numerically validate our control framework on large communities, and then we demonstrate its application for controlling the gut microbiota of gnotobiotic mice infected with Clostridium difficile and the core microbiota of the sea sponge Ircinia oros. Our results provide a systematic pipeline to efficiently drive complex microbial communities towards desired states.

Enhancement of BDNF Expression and Memory by HDAC Inhibition Requires BET Bromodomain Reader Proteins.

Histone deacetylase (HDAC) inhibitors may have therapeutic utility in multiple neurological and psychiatric disorders, but the underlying mechanisms remain unclear. Here, we identify BRD4, a BET bromodomain reader of acetyl-lysine histones, as an essential component involved in potentiated expression of brain-derived neurotrophic factor (BDNF) and memory following HDAC inhibition. In in vitro studies, we reveal that pharmacological inhibition of BRD4 reversed the increase in BDNF mRNA induced by the class I/IIb HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Knock-down of HDAC2 and HDAC3, but not other HDACs, increased BDNF mRNA expression, whereas knock-down of BRD4 blocked these effects. Using dCas9-BRD4, locus-specific targeting of BRD4 to the BDNF promoter increased BDNF mRNA. In additional studies, RGFP966, a pharmacological inhibitor of HDAC3, elevated BDNF expression and BRD4 binding to the BDNF promoter, effects that were abrogated by JQ1 (an inhibitor of BRD4). Examining known epigenetic targets of BRD4 and HDAC3, we show that H4K5ac and H4K8ac modifications and H4K5ac enrichment at the BDNF promoter were elevated following RGFP966 treatment. In electrophysiological studies, JQ1 reversed RGFP966-induced enhancement of LTP in hippocampal slice preparations. Last, in behavioral studies, RGFP966 increased subthreshold novel object recognition memory and cocaine place preference in male C57BL/6 mice, effects that were reversed by cotreatment with JQ1. Together, these data reveal that BRD4 plays a key role in HDAC3 inhibitor-induced potentiation of BDNF expression, neuroplasticity, and memory.SIGNIFICANCE STATEMENT Some histone deacetylase (HDAC) inhibitors are known to have neuroprotective and cognition-enhancing properties, but the underlying mechanisms have yet to be fully elucidated. In the current study, we reveal that BRD4, an epigenetic reader of histone acetylation marks, is necessary for enhancing brain-derived neurotrophic factor (BDNF) expression and improved memory following HDAC inhibition. Therefore, by identifying novel epigenetic regulators of BDNF expression, these data may lead to new therapeutic targets for the treatment of neuropsychiatric disorders.

Model Free iPID Control for Glycemia Regulation of Type-1 Diabetes.

OBJECTIVE: The objective is to design a fully automated glycemia controller of Type-1 Diabetes (T1D) in both fasting and postprandial phases on a large number of virtual patients. METHODS: A model-free intelligent proportional-integral-derivative (iPID) is used to infuse insulin. The feasibility of iPID is tested in silico on two simulators with and without measurement noise. The first simulator is derived from a long-term linear time-invariant model. The controller is also validated on the UVa/Padova metabolic simulator on 10 adults under 25 runs/subject for noise robustness test. RESULTS: It was shown that without measurement noise, iPID mimicked the normal pancreatic secretion with a relatively fast reaction to meals as compared to a standard PID. With the UVa/Padova simulator, the robustness against CGM noise was tested. A higher percentage of time in target was obtained with iPID as compared to standard PID with reduced time spent in hyperglycemia. CONCLUSION: Two different T1D simulators tests showed that iPID detects meals and reacts faster to meal perturbations as compared to a classic PID. The intelligent part turns the controller to be more aggressive immediately after meals without neglecting safety. Further research is suggested to improve the computation of the intelligent part of iPID for such systems under actuator constraints. Any improvement can impact the overall performance of the model-free controller. SIGNIFICANCE: The simple structure iPID is a step for PID-like controllers since it combines the classic PID nice properties with new adaptive features.

Protein-free formation of bone-like apatite: New insights into the key role of carbonation.

The nanometer-sized plate-like morphology of bone mineral is necessary for proper bone mechanics and physiology. However, mechanisms regulating the morphology of these mineral nanocrystals remain unclear. The dominant hypothesis attributes the size and shape regulation to organic-mineral interactions. Here, we present data supporting the hypothesis that physicochemical effects of carbonate integration within the apatite lattice control the morphology, size, and mechanics of bioapatite mineral crystals. Carbonated apatites synthesized in the absence of organic molecules presented plate-like morphologies and nanoscale crystallite dimensions. Experimentally-determined crystallite size, lattice spacing, solubility and atomic order were modified by carbonate concentration. Molecular dynamics (MD) simulations and density functional theory (DFT) calculations predicted changes in surface energy and elastic moduli with carbonate concentration. Combining these results with a scaling law predicted the experimentally observed scaling of size and energetics with carbonate concentration. The experiments and models describe a clear mechanism by which crystal dimensions are controlled by carbonate substitution. Furthermore, the results demonstrate that carbonate substitution is sufficient to drive the formation of bone-like crystallites. This new understanding points to pathways for biomimetic synthesis of novel, nanostructured biomaterials.

A Long-Term Model of the Glucose-Insulin Dynamics of Type 1 Diabetes.

A new glucose-insulin model is introduced which fits with the clinical data from in- and outpatients for two days. Its stability property is consistent with the glycemia behavior for type 1 diabetes. This is in contrast to traditional glucose-insulin models. Prior models fit with clinical data for a few hours only or display some nonnatural equilibria. The parameters of this new model are identifiable from standard clinical data as continuous glucose monitoring, insulin injection, and carbohydrate estimate. Moreover, it is shown that the parameters from the model allow the computation of the standard tools used in functional insulin therapy as the basal rate of insulin and the insulin sensitivity factor. This is a major outcome as they are required in therapeutic education of type 1 diabetic patients.

Activatory and inhibitory Fcγ receptors augment rituximab-mediated internalization of CD20 independent of signaling via the cytoplasmic domain.

Type I anti-CD20 mAb such as rituximab and ofatumumab engage with the inhibitory FcγR, FcγRIIb on the surface of B cells, resulting in immunoreceptor tyrosine-based inhibitory motif (ITIM) phosphorylation. Internalization of the CD20·mAb·FcγRIIb complex follows, the rate of which correlates with FcγRIIb expression. In contrast, although type II anti-CD20 mAb such as tositumomab and obinutuzumab also interact with and activate FcγRIIb, this interaction fails to augment the rate of CD20·mAb internalization, raising the question of whether ITIM phosphorylation plays any role in this process. We have assessed the molecular requirements for the internalization process and demonstrate that in contrast to internalization of IgG immune complexes, FcγRIIb-augmented internalization of rituximab-ligated CD20 occurs independently of the FcγRIIb ITIM, indicating that signaling downstream of FcγRIIb is not required. In transfected cells, activatory FcγRI, FcγRIIa, and FcγRIIIa augmented internalization of rituximab-ligated CD20 in a similar manner. However, FcγRIIa mediated a slower rate of internalization than cells expressing equivalent levels of the highly homologous FcγRIIb. The difference was maintained in cells expressing FcγRIIa and FcγRIIb lacking cytoplasmic domains and in which the transmembrane domains had been exchanged. This difference may be due to increased degradation of FcγRIIa, which traffics to lysosomes independently of rituximab. We conclude that the cytoplasmic domain of FcγR is not required for promoting internalization of rituximab-ligated CD20. Instead, we propose that FcγR provides a structural role in augmenting endocytosis that differs from that employed during the endocytosis of immune complexes.

Vested interest, disaster preparedness, and strategic campaign message design.

In recent years, the United States has recognized an increasing need for individual-level disaster preparedness, with federal, state, and local government agencies finding only limited success in instituting campaign-based disaster preparedness programs. Extant research indicates Americans generally remain poorly informed and badly unprepared for imminent disasters. Vested interest theory (Crano, 1997) is presented as a framework for designing and testing the effectiveness of television-based disaster preparedness campaign messages. High- and low-vested versions of an extant control message are compared to assess message efficacy as indicated by behavioral intentions, message acceptance, and preparedness related attitudes. Results indicate television-based video public service announcements manipulated with subtle message variations can be effective at influencing critical preparedness-related attitudes. The high-vested condition performed significantly better than the low-vested and control conditions for both behavioral intentions and perceptions of self-efficacy, two vitally important outcome variables associated with disaster preparedness.

Mathematical Modeling of HIV Dynamics After Antiretroviral Therapy Initiation: A Review.

This review shows the potential ground-breaking impact that mathematical tools may have in the analysis and the understanding of the HIV dynamics. In the first part, early diagnosis of immunological failure is inferred from the estimation of certain parameters of a mathematical model of the HIV infection dynamics. This method is supported by clinical research results from an original clinical trial: data just after 1 month following therapy initiation are used to carry out the model identification. The diagnosis is shown to be consistent with results from monitoring of the patients after 6 months. In the second part of this review, prospective research results are given for the design of individual anti-HIV treatments optimizing the recovery of the immune system and minimizing side effects. In this respect, two methods are discussed. The first one combines HIV population dynamics with pharmacokinetics and pharmacodynamics models to generate drug treatments using impulsive control systems. The second one is based on optimal control theory and uses a recently published differential equation to model the side effects produced by highly active antiretroviral therapy therapies. The main advantage of these revisited methods is that the drug treatment is computed directly in amounts of drugs, which is easier to interpret by physicians and patients.