Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer???s disease

The absence of effective therapeutics against Alzheimer???s disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-?? (A??), metal-A??, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets??? reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.ope

YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment

Among cancer cells, indoleamine 2, 3-dioxygenase1 (IDO1) activity has been implicated in improving the proliferation and growth of cancer cells and suppressing immune cell activity. IDO1 is also responsible for the catabolism of tryptophan to kynurenine. Depletion of tryptophan and an increase in kynurenine exert important immunosuppressive functions by activating regulatory T cells and suppressing CD8+ T and natural killer (NK) cells. In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). YH29407 treatment alone and anti-PD-1 (aPD-1) combination treatment induced significant tumor suppression compared with competing drugs. In particular, combination treatment showed the best anti-tumor effects, with most tumors reduced and complete responses. Our observations suggest that improved anti-tumor effects were caused by an increase in T cell infiltration and activity after YH29407 treatment. Notably, an immune depletion assay confirmed that YH29407 is closely related to CD8+ T cells. RNA-seq results showed that treatment with YH29407 increased the expression of genes involved in T cell function and antigen presentation in tumors expressing ZAP70, LCK, NFATC2, B2M, and MYD88 genes. Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8+ T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1

Predictive Process Adjustment by Detecting System Status of Vacuum Gripper in Real Time during Pick-Up Operations

In manufacturing systems, pick-up operations by vacuum grippers may fail owing to manufacturing errors in an object’s surface that are within the allowable tolerance limits. In such situations, manual interference is required to resume system operation, which results in considerable loss of time as well as economic losses. Although vacuum grippers have many advantages and are widely used in the industry, it is highly difficult to directly monitor the current machine status and provide appropriate recovery feedback for stable operation. Therefore, this paper proposes a method to detect the success or failure of a suction operation in advance by analyzing the amount of outlet air pressure in the Venturi line. This was achieved by installing an air pressure sensor on the Venturi line to predict whether the current suction action will be successful. Through empirical experiments, it was found that downward movements in the z-axis of the vacuum gripper can easily rectify a faulty gripper suction operation. Real-time monitoring results verified that predictive process adjustment of the pick-up operation can be performed by modifying the z-position of the vacuum gripper

Enhanced adsorption capacity of ZIF-8 for chemical warfare agent simulants caused by its morphology and surface charge

Abstract The effective separation of toxic chemicals, including chemical warfare agents (CWAs), from the environment via adsorption is of great importance because such chemicals pose a significant threat to humans and ecosystems. To this end, the development of effective porous adsorbents for CWA removal has received significant attention. Understanding the specific interactions between adsorbents and CWAs must precede for the development of effective adsorbents. Herein, we report the relationship between the adsorption capacity of porous ZIF-8 and its morphological and surface characteristics. Four types of ZIF-8, which have different morphologies (such as cubic, rhombic dodecahedron, and leaf- and plate-shaped samples), were selectively prepared. The four types of ZIF-8 were found to have different surface charges owing to dissimilarly exposed components on the surfaces and additionally incorporated components. The specific surface charges of ZIF-8 were found to be closely related to their adsorption capacities for CWA simulants such as 2-chloroethyl ethyl sulfide (CEES) and dimethyl methyl phosphonate (DMMP). Cubic ZIF-8, with the most positive surface charge among four ZIF-8 samples, exhibited the highest adsorption capacity for CEES and DMMP via the effective polar interaction. Moreover, ZIF-8 exhibited excellent recyclability without losing its adsorption capacity and without critical morphological or structural changes

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As mechanical systems become more complicated and have diverse sub-modules, various sensor data are collected for the real-time health status monitoring of a system. However, because the collected sensor data are extremely large and contain irrelevant noise to the fault condition of the system, a technique of extracting important data fluctuations should be applied to detect the failure of the system. In general, unsupervised discretization techniques based on data distribution are used to extract fault patterns. However, the methods to extract significant features related to the state changes of a system are not simple. Therefore, we extract fault patterns by applying a supervised discretization method using not only the similarity between measurements but also the system state information. To verify the fault detection performance of the proposed method, acceleration sensor data were collected from a bearing-shaft system and analyzed using the proposed supervised discretized technique

Bromelain effectively suppresses Kras-mutant colorectal cancer by stimulating ferroptosis

Here, we investigated the possible anti-cancer properties of bromelain in Kras mutant human colorectal carcinoma cell lines and a mouse model harboring a Kras mutation. Cell growth and proliferation were significantly reduced in the Kras mutant colorectal carcinoma cell lines following treatment with 50 μg/mL bromelain as assessed by crystal violet staining and a proliferation assay. To identify the molecules responsible for this action, the expression levels of genes involved in signaling pathways and miRNAs were analyzed by real-time PCR. Among the genes tested, down-regulation of ACSL-4 and up-regulation of miRNAs targeting ASCL-4 were observed in Caco2 cells. Compared to the Kras wild-type colorectal carcinoma cell lines, Kras mutant colorectal carcinoma cell lines exhibited a remarkably up-regulated expression of ACSL-4, which is responsible for ferroptosis sensitivity. Moreover, the knockdown of ACSL-4 by a specific shRNA inhibited erastin-induced ferroptosis in Kras mutant DLD-1 cells as assessed by propidium iodide staining and lipid reactive oxygen species measurement. Our findings indicate that bromelain effectively exerts cytotoxic effects in Kras mutant colorectal cancer cells compared to in Kras wild-type colorectal cancer cells. Differential expression of ACSL-4 is responsible for the differential action of bromelain in regulating ferroptotic cell death

The influence of contralateral circulation on computational fluid dynamics of intracranial arteries: simulated versus measured flow velocities

Abstract Background This study aimed to retrospectively evaluate the influence of contralateral anterior circulation on computational fluid dynamics (CFD) of intracranial arteries, by comparing the CFD values of flow velocities in unilateral anterior circulation with the measured values from phase-contrast magnetic resonance angiography (PC-MRA). Methods We analyzed 21 unilateral anterior circulation models without proximal stenosis from 15 patients who performed both time-of-flight MRA (TOF-MRA) and PC-MRA. CFD was performed with the inflow boundary condition of a pulsatile flow of the internal carotid artery (ICA) obtained from PC-MRA. The outflow boundary condition was given as atmospheric pressure. Simulated flow velocities of the middle cerebral artery (MCA) and anterior cerebral artery (ACA) from CFD were compared with the measured values from PC-MRA. Results The velocities of MCA were shown to be more accurately simulated on CFD than those of ACA (Spearman correlation coefficient 0.773 and 0.282, respectively). In four models with severe stenosis or occlusion of the contralateral ICA, the CFD values of ACA velocities were significantly lower (< 50%) than those measured with PC-MRA. ACA velocities were relatively accurately simulated in the models including similar diameters of both ACAs. Conclusion It may be necessary to consider the flow condition of the contralateral anterior circulation in CFD of intracranial arteries, especially in the ACA. Relevance statement Incorporating the flow conditions of the contralateral circulation is of clinical importance for an accurate prediction of a rupture risk in Acom aneurysms as the bidirectional flow and accurate velocity of both ACAs can significantly impact the CFD results. Key points • CFD simulations using unilateral vascular models were relatively accurate for MCA. • Contralateral ICA steno-occlusion resulted in an underestimation of CFD velocity in ACA. • Contralateral flow may need to be considered in CFD simulations of ACA. Graphical Abstrac

Effectiveness of vehicle reassignment in a large-scale overhead hoist transport system

Although simulation is a popular tool for modelling and analysing modern manufacturing systems, to model shop floor control systems (SFCSs) in simulation requires quite costly efforts, since they are responsible for resolving various decision problems, such as deadlock, part dispatching, and resource conflict. The objective of the paper is to address a conceptual framework necessary to generate a WITNESS simulation model automatically from graph-based process plans and resource configurations. A graph-based process plan is used to capture part operations, their related resource requirements, and their temporal precedence relationships. A WITNESS simulation model is a graphical representation of shop floor resources with the part flow logic embedded within each resource element. To generate a WITNESS model, a process plan is automatically converted into a machine-centred part routeing graph (MCPRG) and then a transport-tending part routeing graph (TTPRG). The MCPRG implies part flows among machines, in which a node represents a machine and an edge represents a part route. The TTPRG implies part flows among machines and material handling devices, in which a node represents either machine or material handler, and an edge represents a part route. From the TTPRG, the part&apos;s input and output rules for each resource can be automatically extracted and plugged into the WITNESS model. The approach proposed in the paper enables manufacturers to generate a simulation model rapidly and effectively for performance measurement, such as bottleneck identification, work in progress, throughput times, dynamic resource utilization, and deadlock, of the SFCSs.close111

Harnessing low energy photons (635 nm) for the production of H2O2 using upconversion nanohybrid photocatalysts

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A Case of a Rapidly Progressive Small Bowel Lymphoma with High Ki-67 Expression

Primary intestinal lymphoma is a rare disease. It accounts for approximately 1∼4% of gastrointestinal malignancy. Extranodal lymphoma of the intestine mainly arises from B cells. Diffuse large B-cell lymphoma is the most common type of the disease. Approximately 40% of intestinal lymphoma can be cured, while 60% have varied disease progression. Ki-67 proliferation has been recently used as an index of cell growth to predict the progression of the disease. Reported herein is a case of a rapidly progressive small bowel diffuse large B-cell lymphoma in a 51-year-old man with a high Ki-67 expression level. He visited the emergency department because of hematochezia. Abdominal computed tomography revealed distal small bowel segmental wall thickening. He underwent operation due to spontaneous small bowel perforation. The result of the pathological examination of the resected specimen was compatible with diffuse large B-cell lymphoma. The Ki-67 index within 5 months was 90%