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This paper provides a general analysis of signaling under double-crossing preferences with a continuum of types. There are natural economic environments where the indifference curves of two types cross twice, such that the celebrated single-crossing property fails to hold. Equilibrium exhibits a threshold type below which types choose actions that are fully revealing and above which they pool in a pairwise fashion, with a gap separating the actions chosen by these two sets of types. The resulting signaling action is quasi-concave in type. We also provide an algorithm to establish equilibrium existence by construction.

Most combination therapies are developed based on targets of existing drugs, which only represent a small portion of the human proteome. We introduce a network controllability-based method, OptiCon, for de novo identification of synergistic regulators as candidates for combination therapy. These regulators jointly exert maximal control over deregulated genes but minimal control over unperturbed genes in a disease. Using data from three cancer types, we show that 68% of predicted regulators are either known drug targets or have a critical role in cancer development. Predicted regulators are depleted for known proteins associated with side effects. Predicted synergy is supported by disease-specific and clinically relevant synthetic lethal interactions and experimental validation. A significant portion of genes regulated by synergistic regulators participate in dense interactions between co-regulated subnetworks and contribute to therapy resistance. OptiCon represents a general framework for systemic and de novo identification of synergistic regulators underlying a cellular state transition. Synergistic interactions may arise between regulators in complex molecular networks. Here, the authors develop OptiCon, a computational method for de novo identification of synergistic key regulators and investigate their potential roles as candidate targets for combination therapy.

Background Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities. It is expressed in various cell types in the brain and is involved in the pathogenesis of inflammatory and neurodegenerative diseases. Alzheimer’s disease (AD) is a progressive neuroinflammatory and neurodegenerative disease. However, the pathological significance of sEH and underlying molecular mechanism in AD remain unclear. Methods To examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient ( sEH −/− ) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic ( APP/PS1 Tg) and APP/PS1 Tg/ sEH −/− mice. Western blotting analysis and immunohistochemistry assay were performed to evaluate the protein expression. Locomotion, nesting building ability, Y-maze, and Morris water maze tests were conducted to study mouse behavior. The levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10 and the activities of NF-κB and nuclear factor of activated T cells (NFAT) were measured by commercial assay kits. The quantitative protein level profiling in the brain lysate was analyzed using LC-MS/MS approaches. Results We demonstrated that the level of sEH was increased in the brain and predominantly appeared in hippocampal astrocytes of APP/PS1 Tg mice. Genetic ablation of sEH in APP/PS1 Tg mice delayed the progression of AD as evidenced by the alleviation in behavior outcomes and Aβ plaque deposition. In addition, loss of the function of sEH in APP/PS1 Tg mice increased astrogliosis and the production of astrocyte-derived anti-inflammatory cytokines including IL-1β, IL-4, and IL-10, as well as the activity of NF-kB and NFAT. Moreover, analysis of gene ontology in the AD brain revealed that important signaling pathways and processes related to AD pathogenesis such as translational regulation, oxidative stress, cytoskeleton reorganization, and small GTPase signal transduction were altered in APP/PS1 Tg/ sEH −/− mice compared with APP/PS1 Tg mice. Conclusion Our results suggest that sEH is a crucial regulator in the progression of AD and might be a potential therapeutic target for the treatment of AD.

Background/Aims: Olanzapine, an atypical antipsychotic drug, has therapeutic effects for schizophrenia. However, clinical reports indicate that patients taking atypical antipsychotic drugs are at high risk of metabolic syndrome with unclear mechanisms. We investigated the effect of olanzapine on atherosclerosis and the mechanisms in apolipoprotein E-null (apoE -/- ) mice. Methods: ApoE -/- mice were used as in vivo models. Western blot analysis was used to evaluate protein expression. Conventional assay kits were applied to assess the levels of cholesterol, triglycerides, free cholesterol, cholesteryl ester, fatty acids, glycerol, and cytokines. Results: Daily treatment with olanzapine (3 mg/kg body weight) for four weeks increased mean arterial blood pressure and the whitening of brown adipose tissue in mice. In addition, olanzapine impaired aortic cholesterol homeostasis and exacerbated hyperlipidemia and aortic inflammation, which accelerated atherosclerosis in mice. Moreover, lipid accumulation in liver, particularly total cholesterol, free cholesterol, fatty acids, and glycerol, was increased with olanzapine treatment in apoE -/- mice by upregulating the expression of de novo lipid synthesis-related proteins and downregulating that of cholesterol clearance- or very low-density lipoprotein secretion-related proteins. Conclusion: Olanzapine may exacerbate atherosclerosis by deregulating hepatic lipid metabolism and worsening hyperlipidemia and aortic inflammation.

Background Radiation dose evaluation is important to cone-beam computed tomography (CBCT) for routine orthodontic treatment planning, especially for a significant proportion of children in orthodontic patients. This study evaluated the patient radiation dose and estimated the radiation cancer risk on dental CBCT according to the calculations by the Monte Carlo simulation method. Methods The dental CBCT scanner evaluated in this project was the i- CAT® (Imaging Sciences International Inc., PA, U.S.A.) device. Organ doses and effective doses were calculated by using personal computer-based Monte Carlo simulation (PCXMC 2.0 Rotation) software. The cancer risk resulting from the exposure to ionizing radiation was estimated by using the BEIR VII (Biologic Effects of Ionizing Radiation VII) report model, and the risk of exposure-induced death (REID) was assessed by PCXMC 2.0 Rotation software. Results The largest contribution to the organ dose and effective dose at Zref 83 cm positioned in the dental CBCT x-ray beam centerline was from the salivary glands (738.29μGy, 7.38 μSv). The different organ doses showed the maximum values at the different Zref locations, and the largest contribution to the organ dose and effective dose of all simulated positions was from the thyroid (928.77μGy, 37.5 μSv). The REID values in the 10-year olds (22.6 × 10 − 7 , female; 19 × 10 − 7 , male) were approximately double than those in 30-year olds (10.4 × 10 − 7 , female; 8.88 × 10 − 7 , male) for all cancers. The highest change during age range from 10 to 30 was shown in breast cancer of females. Conclusions Although individual cancer risk estimates as a function of gender and age are small, the concern about the risks from dental CBCT is related to the rapid increase in its use for orthodontic practice, especially in children patients.

Displays composed of micro-light-emitting diodes (micro-LEDs) are regarded as promising next-generation self-luminous screens and have advantages such as high contrast, high brightness, and high color purity. The luminescence of such a display is similar to that of a Lambertian light source. However, owing to reduction in the light source area, traditional secondary optical lenses are not suitable for adjusting the light field types of micro-LEDs and cause problems that limit the application areas. This study presents the primary optical designs of dielectric and metal films to form highly reflective thin-film coatings with low absorption on the light-emitting surfaces of micro-LEDs to optimize light distribution and achieve full-angle utilization. Based on experimental results with the prototype, that have kept low voltage variation rates, low optical losses characteristics, and obtain the full width at half maximum (FWHM) of the light distribution is enhanced to 165° and while the center intensity is reduced to 63% of the original value. Hence, a full-angle micro-LEDs with a highly reflective thin-film coating are realized in this work. Full-angle micro-LEDs offer advantages when applied to commercial advertising displays or plane light source modules that require wide viewing angles.

Gap junctions are present in both vertebrates and invertebrates from nematodes to mammals. Although the importance of gap junctions has been documented in many biological processes, the molecular mechanisms underlying gap junction dynamics remain unclear. Here, using the C. elegans PLM neurons as a model, we show that UNC-44/ankyrin acts upstream of UNC-33/CRMP in regulation of a potential kinesin VAB-8 to control gap junction dynamics, and loss-of-function in the UNC-44/UNC-33/VAB-8 pathway suppresses the turnover of gap junction channels. Therefore, we first show a signal pathway including ankyrin, CRMP, and kinesin in regulating gap junctions.

High-mobility group box 1 (HMGB1) is a nuclear protein that can be secreted or released into the extracellular environment during cellular stress, functioning as a damage-associated molecular pattern molecule. This study investigates the role of HMGB1 in adipocyte development and metabolism, explicitly examining its interaction with β3-adrenergic receptor-mediated lipolysis and caveolin-1 (CAV1) regulation, which may influence cardiovascular risk factors. Using 3T3-L1 preadipocytes and mouse embryonic fibroblasts, we demonstrated that HMGB1 expression increases progressively during adipogenesis, reaching peak levels in mature adipocytes. While exogenous HMGB1 treatment did not affect preadipocyte proliferation or differentiation, it inhibited lipolysis in mature adipocytes. Mechanistically, HMGB1 suppressed β3-adrenergic receptor agonist CL-316,243-induced hormone-sensitive lipase activation by reducing protein kinase A-mediated phosphorylation and attenuating extracellular signal-regulated kinase signaling without affecting upstream cyclic AMP levels. We discovered a novel regulatory mechanism wherein CAV1 physically interacts with HMGB1 in mature adipocytes, with c-Src-dependent CAV1 phosphorylation functioning as a negative regulator of HMGB1 secretion. This finding was confirmed in CAV1-deficient models, which displayed increased HMGB1 secretion and diminished lipolytic activity both in vitro and in vivo. Furthermore, administering HMGB1-neutralizing antibodies to wild-type mice enhanced fasting-induced lipolysis, establishing circulating HMGB1 as a crucial antilipolytic factor. These findings reveal HMGB1’s previously uncharacterized role in adipose tissue metabolism as a negative regulator of lipolysis through CAV1-dependent mechanisms. This work provides new insights into adipose tissue metabolism regulation and identifies potential therapeutic targets for obesity-related metabolic disorders and cardiovascular diseases.

We consider an environment in which a principal hires an agent and evaluates his productivity over time. The problem is embedded in a continuous-time model with both hidden action and hidden information, where the principal must induce the agent to exert effort to facilitate her learning process. The value of committing to a deadline is examined in this environment, and factors which make the deadline more profitable are identified. Our framework generates a unique recursive equilibrium structure under no commitment which can be exploited to obtain a full characterization of the unique pure-strategy equilibrium. The analysis allows us to evaluate the exact value of commitment for any given set of parameters and provides insight into when it is beneficial to commit to an evaluation deadline at the outset of a relationship.

Background Given the rising prevalence of depression among older adults and the associated increase in caregiving responsibilities, understanding factors influencing caregiver burden is crucial. Previous research has not extensively explored the impact of caregivers’ attributional styles, that is, how individuals interpret the causes of life events, on their care burden. Aim This study examined the relationship between caregivers’ attributional styles and their care burden for older patients with depression. Methods This cross-sectional study enrolled older adults aged ≥ 65 years diagnosed with depression and their caregivers. Depression was diagnosed according to the DSM-V criteria for Major Depressive Disorder or Persistent Depressive Disorder. Caregivers completed the Chinese Depression Caregiver Burden Scale (CDCBS) to assess care burden, the Hamilton Depression Rating Scale (HAM-D) to evaluate patient symptom severity, the Center for Epidemiological Studies Depression Scale (CES-D) for measuring caregivers’ depression, and the Chinese Depression Patient Caregiver Attribution Style Scale (CDPCAS) to assess attributional styles. Hierarchical regression analysis was used to identify the factors independently associated with the caregiver’s subjectively assessed care burden. Results The sample included 146 caregivers of geriatric patients with depression. Most depression patients were women (74.7%) with a mean age of 74.3 years, whereas the mean age of caregivers was 57.7 years. Hierarchical regression analysis identified that caregivers’ gender ( β = − 0.14, p  = .044), educational level ( β  = 0.19, p  = .008), caregivers’ own depression assessed by the Center for Epidemiological Studies Depression Scale ( β  = 0.41, p  < .001), and attributional styles, particularly manipulation ( β  = 0.29, p  < .001) and illness/stress attributional style ( β  = 0.23, p  = .002) as independent factors associated with care burden. Patient symptom severity assessed using the Hamilton Depression Scale was not significantly correlated with care burden after controlling for attributional styles. Conclusions Certain attributional styles, particularly the manipulation and illness/stress attributional styles, significantly increased self-reported care burden. These findings highlight the need for educational resources to change the attribution style, along with support systems and accessible mental health services for caregivers to potentially ease the care burden.