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Abstract Hepatic iron overload is often concurrent with nonalcoholic fatty liver disease (NAFLD). Dysmetabolic iron overload syndrome (DIOS) is characterized by an increase in the liver and body iron stores and metabolic syndrome components. Increasing evidences suggest an overlap between NAFLD with iron overload and DIOS; however, the mechanism how iron is involved in their pathogenesis remains unclear. Here we investigated the role of iron in the pathology of a rat model of NAFLD with iron overload. Rats fed a Western (high-fat and high-fructose) diet for 26 weeks represented hepatic steatosis with an increased body weight and dyslipidemia. Addition of dietary iron overload to the Western diet feeding further increased serum triglyceride and cholesterol, and enhanced hepatic inflammation; the affected liver had intense iron deposition in the sinusoidal macrophages/Kupffer cells, associated with nuclear translocation of NFκB and upregulation of Th1/M1-related cytokines. The present model would be useful to investigate the mechanism underlying the development and progression of NAFLD as well as DIOS, and to elucidate an important role of iron as one of the "multiple hits” factors.

BACKGROUND: We hypothesized that treatment delays might be an effect modifier regarding risks and benefits of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT). METHODS: We used the dataset of the SWIFT-DIRECT trial, which randomized 408 patients to IVT+MT or MT alone. Potential interactions between assignment to IVT+MT and expected time from onset-to-needle (OTN) as well as expected time from door-to-needle (DTN) were included in regression models. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes included mRS shift, mortality, recanalization rates, and (symptomatic) intracranial hemorrhage at 24 hours. RESULTS: We included 408 patients (IVT+MT 207, MT 201, median age 72 years (IQR 64-81), 209 (51.2%) female). The expected median OTN and DTN were 142 min and 54 min in the IVT+MT group and 129 min and 51 min in the MT alone group. Overall, there was no significant interaction between OTN and bridging IVT assignment regarding either the functional (adjusted OR (aOR) 0.76, 95% CI 0.45 to 1.30) and safety outcomes or the recanalization rates. Analysis of in-hospital delays showed no significant interaction between DTN and bridging IVT assignment regarding the dichotomized functional outcome (aOR 0.48, 95% CI 0.14 to 1.62), but the shift and mortality analyses suggested a greater benefit of IVT when in-hospital delays were short. CONCLUSIONS: We found no evidence that the effect of bridging IVT on functional independence is modified by overall or in-hospital treatment delays. Considering its low power, this subgroup analysis could have missed a clinically important effect, and exploratory analysis of secondary clinical outcomes indicated a potentially favorable effect of IVT with shorter in-hospital delays. Heterogeneity of the IVT effect size before MT should be further analyzed in individual patient meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03192332.

Purpose: To report a case of disappearance of lens epithelial cells (LECs) detected at the time of treatment for intraocular lens (IOL) dislocation 12 months after cataract surgery. Observations: A 59-year-old male underwent phacoemulsification with implantation of a posterior chamber acrylic IOL for posterior subcapsular cataract without any complications. Twelve months after cataract surgery, the IOL was dislocated inferiorly from the capsular bag due to rubbing the eye strongly, without capsular deviation. Fibrotic changes around the anterior capsular margin and posterior capsular opacification were not observed. During IOL repositioning, adhesions between the anterior and posterior capsules or zonule weakness were not observed. Six months after repositioning, the in-the-bag IOL dislocated into the anterior chamber because of zonular dialysis caused by strong eye rubbing again. Several days after scleral fixation of the IOL, the intraocular pressure decreased, possibly due to leakage from the wound. On inquiring about details, it was informed that the patient had a habit of sleeping in the prone position, with his face touching the pillow. After discontinuing this habit, his visual status stabilized. Conclusions and Importance: LEC may rarely disappear 12 months after cataract surgery. Although LEC survival is affected by various factors, minor trauma, such as slight eye rubbing and sleeping in a prone position, may influence IOL stability in the capsular bag and be related to early postoperative LEC disappearance.

A model that maps the requisite skills, or knowledge components, to the contents of an online course is necessary to implement many adaptive learning technologies. However, developing a skill model and tagging courseware contents with individual skills can be expensive and error prone. We propose a technology to automatically identify latent skills from instructional text on existing online courseware called SMART (Skill Model mining with Automated detection of Resemblance among Texts). SMART is capable of mining, labeling, and mapping skills without using an existing skill model or student learning (aka response) data. The goal of our proposed approach is to mine latent skills from assessment items included in existing courseware, provide discovered skills with human-friendly labels, and map didactic paragraph texts with skills. This way, mapping between assessment items and paragraph texts is formed. In doing so, automated skill models produced by SMART will reduce the workload of courseware developers while enabling adaptive online content at the launch of the course. In our evaluation study, we applied SMART to two existing authentic online courses. We then compared machine-generated skill models and human-crafted skill models in terms of the accuracy of predicting students' learning. We also evaluated the similarity between machine-generated and human-crafted skill models. The results show that student models based on SMART-generated skill models were equally predictive of students' learning as those based on human-crafted skill models--as validated on two OLI (Open Learning Initiative) courses. Also, SMART can generate skill models that are highly similar to human-crafted models as evidenced by the normalized mutual information (NMI) values.

Background We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment.Methods Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02.Results The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients.Conclusions Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1).Trial registration number jRCTc030190195.

UVA-EpiHiper is a national scale agent-based model to support the US COVID-19 Scenario Modeling Hub (SMH). UVA-EpiHiper uses a detailed representation of the underlying social contact network along with data measured during the course of the pandemic to initialize and calibrate the model. In this paper, we study the role of heterogeneity on model complexity and resulting epidemic dynamics using UVA-EpiHiper. We discuss various sources of heterogeneity that we encounter in the use of UVA-EpiHiper to support modeling and analysis of epidemic dynamics under various scenarios. We also discuss how this affects model complexity and computational complexity of the corresponding simulations. Using round 13 of the SMH as an example, we discuss how UVA-EpiHiper was initialized and calibrated. We then discuss how the detailed output produced by UVA-EpiHiper can be analyzed to obtain interesting insights. We find that despite the complexity in the model, the software, and the computation incurred to an agent-based model in scenario modeling, it is capable of capturing various heterogeneities of real-world systems, especially those in networks and behaviors, and enables analyzing heterogeneities in epidemiological outcomes between different demographic, geographic, and social cohorts. In applying UVA-EpiHiper to round 13 scenario modeling, we find that disease outcomes are different between and within states, and between demographic groups, which can be attributed to heterogeneities in population demographics, network structures, and initial immunity.

This paper introduces MorphoGen — an integrated reliability-based topology optimization and nonlinear finite element analysis system for 2D and 3D domains. The system’s key innovation is its seamless prototyping of scientific formulations for computational problems in topology optimization. Its layered and object-oriented architecture, based on the template method design pattern, facilitates effortless modifications of algorithms and the introduction of new types of finite elements, materials, and analyses. MorphoGen also offers flexible handling of objective functions and constraints during topological optimization, enhancing its adaptability. It empowers researchers and practitioners to explore a wide range of engineering challenges, fostering a deeper understanding of complex structural behaviors and efficient design solutions.There are many topology optimization software and open source codes, especially based on the classical SIMP method. Unlike these codes our package is freely distributed among users and since it is distributed on the MIT licence, which allows for its easy modification depending on the particular needs of the users. For this purpose, we use the topology optimization algorithm proposed for the first time in our previous paper (Blachowski et al., 2020). The algorithm is based on a fully stress design-based optimality criteria and can be applied for topology optimization of either linearly elastic and elastoplastic structures. Additionally, the novelty of the proposed system is related to its ability of solving optimal topology under various constraints such as displacement, stresses and fatigue in both deterministic and probabilistic cases.Another application are modular structures, which reduce design complexity and manufacturing costs as well as rapid reconfiguration. However, in the realm of structural optimization, modular systems are more challenging due to various: modes of operation of the modules and the stresses configurations. Moreover, this area of research is dramatically less explored.Thus the effectiveness of MorphoGen for structural engineering is demonstrated with examples of topological shape optimization of two Extremely Modular Systems: a planar robotic manipulator Arm-Z and spatial free-form ramp Truss-Z.

The spread of COVID-19 has drastically increased the number of people wearing masks in public areas and the opportunities to evaluate others’ faces based on limited information. This study investigates the cognitive bias in judging the attractiveness of faces partially hidden by sanitary masks. Experiment 1 revealed that men rated women's faces as more attractive when wearing masks, specifically in the context of rating women as romantic partners; however, this mask bias was absent when men rated women as friends. On the other hand, women did not show the mask bias irrespective of the assumed social relationship. Experiment 2 demonstrated that the mask bias among elderly men was less affected by the assumed social relationship (or the possibility of reproduction), compared to young men, though they showed the bias itself. These results suggest that the cognitive strategies related to reproduction underlie the attractiveness judgment of the partial faces.

This study investigates deposition of different aluminum alloys and the influence of added elements on their mechanical properties. Focusing on wire and arc additive manufacturing (WAAM), this study aimed to address the constraints of conventional fabrication, particularly in the context of multi-material applications. WAAM was utilized for the precise deposition of 5000 series aluminum alloys onto robust 7000 series counterparts, and the results were analyzed to characterize dissimilar aluminum alloy interactions. The deposition process employed an advanced WAAM system equipped with an industrial robot, dual-axis positioner, and cold metal transfer welder, coupled with A5356 wires and A5052/A7075 plates as materials. Controlled manipulation of wire feed speed and torch speed resulted in the formation of 61 layers in a spiral configuration. Elemental analyses, hardness tests, and tensile testing were performed, revealing a distinct transition layer, which indicates an interplay between dissimilar alloys during deposition. Heat treatment interventions not only unveil the recovery of 7000 series alloy hardness but also demonstrate the feasibility of multimaterial parts with enhanced functionalities. The resulting tensile strength surpasses common 5000 series aluminum alloy benchmarks. The study evaluates interfaces under accuracy considerations, highlighting the practical applications of dissimilar aluminum alloy additive manufacturing. The study reveals an intricate interplay of dissimilar aluminum alloys, pushing the boundaries of WAAM applications. The research not only expands the technical understanding of dissimilar aluminum alloys but also provides practical insights into harnessing WAAM's potential for innovative, functional additive manufacturing. We anticipate that the findings can drive advancements in alloy fabrication techniques and has implications for industries reliant on aluminum alloys across diverse applications.

The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Center (BRC) program to assist researchers with analyzing the growing body of genome sequence and other omics-related data. In this report, we describe the merger of the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD) and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) https://www.bv-brc.org/. The combined BV-BRC leverages the functionality of the bacterial and viral resources to provide a unified data model, enhanced web-based visualization and analysis tools, bioinformatics services, and a powerful suite of command line tools that benefit the bacterial and viral research communities.

Language proficiency is identified as one of the most important factors for successful migrant integration. Japan has had a sizeable increase of migrants in the past few years, and these migrants needed to build their Japanese proficiency. Focusing on municipalities in the 23 Tokyo wards, we surveyed what types of Japanese as a Second Language (JSL) programs are available, and how this information is disseminated to the public. It was encouraging that the central government and the government agencies of Tokyo have created language policies and produced handbooks for JSL teachers. All except one ward in Tokyo offer information about JSL programs in their respective ward, and many programs were run by the municipalities or by volunteer groups, suggesting an institutionalized move for supporting language education for migrants. We also identified two points that need to be considered for a better language education system for migrants: (a) a need for a certification program for JSL teachers and (b) a need for developing a language proficiency test that does not assume studying in an academic program.

Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc.Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction.Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance.Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction.

We investigated the asymmetric reduction of β-keto esters using aquatic plants as whole-cell biocatalysts under darkness and illumination by fluorescent light. The (S)- β-hydroxy esters were obtained with high enantiomeric excess (ee) values. Regardless of the light conditions, the amount of (R)- β-hydroxy ester produced did not change significantly as the substrate concentration increased, whereas the yield of (S)- β-hydroxy ester increased substantially. Moreover, increasing the quantity of plants resulted in a significant increase in the production of (S)- β-hydroxy ester and a slight increase in the production of (R)- β-hydroxy ester, reducing the ee value. The reaction proceeded more efficiently for substrates bearing bulkier ester moieties, of which the tert-butyl ester gave the best results. Ultimately, we concluded that aquatic plants can be used as whole-cell biocatalysts for preparing optically active β-hydroxy esters. This result represents a new use of aquatic plants and contributes to the achievement of carbon neutrality.

Abstract Background Public health professionals have prepared and distributed many messages and materials to convince the public to adopt healthy behaviors or reduce risky behaviors. However, health promotion materials do not always have the desired effect due to a lack of ability to engage target audience. This study examined the effectiveness of humor appeal (i.e. using humor as an advertising technique to attract attention and increase acceptance of the message) in health promotion materials and how to use it effectively. Methods Total 17 printable posters with different frames (loss- vs. gain-framed) × tones (humorous vs. non-humorous) × topics (advance care planning, cancer screening, donor registry, smoking cessation, and physical activity) were created and evaluated for comprehensibility, persuasiveness, and resistance through two web-based surveys. Participants who were Japanese adults aged 25–64 years were randomly assigned one of the posters (200 people each) and asked to rate it. The overall score was calculated as the persuasiveness score (EHPM 2017;22:69) minus the resistance score (EHPM 2022;27:20). Results In the advance care planning case, the highest overall score was found in the gain-framed humorous poster, followed by the loss-framed humorous poster, and the non-humorous poster (p = 0.007). In the other 4 cases, the posters using humorous illustrations received a significantly lower scores than the non-humorous poster(s). Conclusion The use of humor appeal can help improve the acceptability and persuasiveness of the message when dealing with a little-known resistance-prone health topic. Humor appeal will provide an effective hook to direct public attention to what they do not know or care about in public health communication.