TRIM22 facilitates autophagosome-lysosome fusion by mediating the association of GABARAPs and PLEKHM1.

Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM proteins contribute to protein quality control by regulating the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and macroautophagy/autophagy. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. Herein, we identified a novel function of TRIM22 in the regulation of autophagy. TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, thereby inducing the autophagic clearance of protein aggregates, independent of its E3 ubiquitin ligase activity. Furthermore, a TRIM22 variant associated with early-onset familial Alzheimer disease interferes with autophagosome-lysosome fusion and autophagic clearance. These findings suggest TRIM22 as a critical autophagic regulator that orchestrates autophagosome-lysosome fusion by scaffolding autophagy-related proteins, thus representing a potential therapeutic target in neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; ADAOO: AD age of onset; AICD: APP intracellular domain; APP: amyloid beta precursor protein; BSA: bovine serum albumin; cDNAs: complementary DNAs; CQ: chloroquine; CTF: carboxyl-terminal fragment; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GST: glutathione S-transferase; HA: hemagglutinin; HOPS: homotypic fusion and protein sorting; IFN: interferon; IL1A/IL-1α: interleukin 1 alpha; KO: knockout; MTORC1: mechanistic target of rapamycin kinase complex 1; NFKBIA/IκBα: NFKB inhibitor alpha; NFE2L2/NRF2: NFE2 like bZIP transcription factor; PBS: phosphate-buffered saline; PI3K: class I phosphoinositide 3-kinase; PLA: proximity ligation assay; PLEKHM1: pleckstrin homology and RUN domain containing M1; PSEN1: presenilin 1; SEM: standard errors of the means; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SNCA: synuclein alpha; SNP: single nucleotide polymorphism; TBS: tris-buffered saline; TNF/TNF-α: tumor necrosis factor; TRIM: tripartite motif; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.

Optical monitoring of the plant growth status using polarimetry.

Polarimetry is a powerful characterization technique that uses a wealth of information from electromagnetic waves, including polarization. Using the rich information provided by polarimetry, it is being actively studied in biomedical fields such as cancer and tumor diagnosis. Despite its importance and potential in agriculture, polarimetry for living plants has not been well studied. A Stokes polarimetric imaging system was built to determine the correlation between the polarization states of the light passing through the leaf and the growth states of lettuce. The Stokes parameter s3 associated with circular polarization increased over time and was strongly correlated with the growth of lettuce seedlings. In the statistical analysis, the distribution of s3 followed the generalized extreme value (GEV) probability density function. Salt stress retarded plant growth, and the concentration of treated sodium chloride (NaCl) showed a negative correlation with the location parameter µ of GEV. The clear correlation reported here will open the possibility of polarization measurements on living plants, enabling real-time monitoring of plant health.

Negative dispersion of a form birefringence in subwavelength gratings.

An achromatic response is required in most optical systems for wideband and straightforward configurations. The chromatic response of the optical system depends on the optical dispersion of the elements in the system. Here we study the dispersion of subwavelength grating (SWG) known to have a form birefringence. The birefringence of SWG was numerically analyzed with Bloch wave analysis (BWA) and finite element method (FEM). The sandwiched SWG with two identical substrates was studied for practical applications. We successfully demonstrated the negative dispersion form birefringence of SWG with an optimal duty cycle. This extraordinary dispersion was also shown considering the intrinsic dispersion of materials. Dispersion- and the angular response were in a tradeoff relationship while they depended on periodicity. The optical interference between the grating and the substrates can be eliminated by controlling the duty cycle. Our analysis offers optimal SWG with achromatic birefringence and high transparency, promising in the widespread applications of polarization control devices.

Status of Medications Prescribed for Psychiatric Disorders in Korean Pediatric and Adolescent Patients.

While mental health services for children are increasing, few psychiatric drugs have been approved for such use. We analyzed claim data from 19,557 South Korean pediatric and adolescent patients (<20 years) who were diagnosed with schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, attention deficit-hyperactivity disorder (ADHD), or a tic disorder. Among these diseases, depressive episodes were the most common, followed by an anxiety disorder, ADHD, bipolar disorder, tic disorder, and schizophrenia. For each disease, prescriptions were categorized as full-label (approved indication with pediatric dosing in the package insert (PI)), partial-label (approved indication without pediatric dosing in the PI), and contraindication (contraindicated for the specific pediatric age in the PI). For schizophrenia, major depressive disorder, and anxiety disorder, more than 50% of the patients were prescribed partial-labeled medications. Additionally, more than 5% of patients with major depressive disorder were prescribed medications that were contraindicated for their age group. Our findings reveal that children with full-labeled psychiatric conditions are commonly administered drugs that are not explicitly approved for either their disease state or age, including off-label and unlicensed drugs. To use pharmaceuticals more safely, expanding drug indications using real-world data are needed.

Prevalence of Anemia in Pediatric Patients According to Asthma Control: Propensity Score Analysis.

PURPOSE: To investigate whether the degree of asthma control is associated with anemia in pediatric patients. PATIENTS AND METHODS: A cross-sectional study was performed using a dataset from the Health Insurance Reviews & Assessment Service (HIRA) of South Korea in 2016, which included children and adolescent patients diagnosed with asthma. Binary logistic regression was used to assess the association between asthma control and the prevalence of anemia. RESULTS: A total of 236,429 patients under 18 years old were included in the study, including 233,975 patients with controlled and 2454 with uncontrolled asthma. Binary logistic regression after adjustment for confounding factors showed that patients with uncontrolled asthma had a 2.64-fold higher prevalence of anemia than those with well-controlled asthma (OR = 2.64, 95% CI: 2.16-3.22). While there was no effect of gender on the results, there was a statistically significant association between the prevalence of anemia and asthma control in patients under 13 years old. CONCLUSION: These findings suggest that the prevalence of anemia is inversely correlated with asthma control in pediatric patients. Further studies are necessary to obtain pathophysiological insight into the relationship between severe inflammatory diseases and anemia.

Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration.

Autophagy, a main degradation pathway for maintaining cellular homeostasis, and redox homeostasis have recently been considered to play protective roles in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Increased levels of reactive oxygen species (ROS) in neurons can induce mitochondrial damage and protein aggregation, thereby resulting in neurodegeneration. Oxidative stress is one of the major activation signals for the induction of autophagy. Upon activation, autophagy can remove ROS, damaged mitochondria, and aggregated proteins from the cells. Thus, autophagy can be an effective strategy to maintain redox homeostasis in the brain. However, the interaction between redox homeostasis and autophagy is not clearly elucidated. In this review, we discuss recent studies on the relationship between redox homeostasis and autophagy associated with neurodegenerative diseases and propose that autophagy induction through pharmacological intervention or genetic activation might be a promising strategy to treat these disorders.

Anti-contamination SMART (Spectrum Monitoring Apparatus with Roll-to-roll Transparent film) window for optical diagnostics of plasma systems.

Optical emission spectroscopy is widely used in semiconductor and display manufacturing for plasma process monitoring. However, because of the contamination of the viewport, quantitative analysis is extremely difficult; therefore, qualitative analysis is used to detect species in the process. To extend plasma monitoring in advanced precise processes, the contamination problem of the viewport must be solved. We propose a new spectrum monitoring apparatus with a roll-to-roll transparent film window for optical diagnostics of a plasma system. By moving a transparent film in front of the viewport, contamination in the emission light path becomes negligible. However, the speed of the film should be optimized to reduce the maintenance period and to minimize measurement errors. We calculated the maximum thickness of SiO2, Si3N4, ITO, and the Ar/CHF3 plasma contaminant to suppress the electron temperature error measured by the line-intensity-ratio within 2% at 2 eV. The thickness of the Si3N4, ITO, and Ar/CHF3 plasma contaminant should be thinner than 12.5 nm, 7.5 nm, and 100 nm, respectively.

Dependence of the birefringence of polystyrene film on the stretching conditions.

We investigated the dependence of the birefringence of polystyrene (PS) film with a negative optical birefringence on the stretching conditions. We varied the stretching ratio (SR), stretching speed (SS), and stretching temperature (ST), and measured the inplane birefringence and the Nz coefficient of the PS film. The inplane birefringence was increased with greater SR and SS but decreased with greater ST. The Nz coefficient of the stretched PS film was around zero and showed similar dependence on the stretching conditions like inplane birefringence.

Broadening the reflection bandwidth of polymer-stabilized cholesteric liquid crystal via a reactive surface coating layer.

We report a method of broadening the reflection bandwidth of polymer-stabilized cholesteric liquid crystal (PSCLC). The top substrate was consecutively coated with a polyimide (PI) and a reactive mesogen (RM) layer, while the bottom substrate was coated with only PI. We exposed the top substrate with the RM coating to UV light. The reflection bandwidth of the PSCLC samples where the top substrate was over-coated with RM was significantly broader than the samples where both substrates were coated with PI. In addition to the effect of the UV intensity gradient, the RM-coated top substrate has a chemical affinity to bulk RM, promoting formation of the pitch gradient and broadening the reflection bandwidth in the sample.

Predicting augmented renal clearance using estimated glomerular filtration rate in critically-ill children
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AIMS: Measured glomerular filtration rate (mGFR) is often used to identify augmented renal clearance (ARC). However, in the clinical setting, estimated GFR (eGFR) is obtained more quickly and inexpensively. We aimed to determine whether eGFR can identify ARC by evaluating the correlation between the eGFR and vancomycin trough level (VTL). MATERIALS AND METHODS: We retrospectively reviewed the records of patients aged ≤ 18 years who underwent vancomycin therapeutic drug monitoring at our tertiary hospital from July 2009 to June 2014. VTL, serum creatinine concentration, eGFR, and clinical factors affecting VTL were analyzed. RESULTS: Of 101 patients, 76 (75.25%) had a subtherapeutic VTL. Patient age (p = 0.006), the daily vancomycin dose (p = 0.041) and dosing interval (p = 0.006), and eGFR (p < 0.001) affected the VTL. Multivariate analysis showed a significant relationship between eGFR and VTL (adjusted R2, 0.812; p < 0.001). An increased eGFR (odds ratio, 1.002; 95% confidence interval, 1.001 - 1.003; p = 0.001) was a risk factor for a subtherapeutic vancomycin level. The cutoff eGFR value predicting a subtherapeutic vancomycin level was 110.51 mL/min/1.73m2 (area under the curve, 0.753). CONCLUSIONS: The eGFR correlates with the VTL, and the eGFR cutoff value can predict a subtherapeutic vancomycin level. eGFR is a reliable and efficient alternative to mGFR for identifying ARC.
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Bee Venom Mitigates Cisplatin-Induced Nephrotoxicity by Regulating CD4(+)CD25(+)Foxp3(+) Regulatory T Cells in Mice.

Cisplatin is used as a potent anticancer drug, but it often causes nephrotoxicity. Bee venom (BV) has been used for the treatment of various inflammatory diseases, and its renoprotective action was shown in NZB/W mice. However, little is known about whether BV has beneficial effects on cisplatin-induced nephrotoxicity and how such effects might be mediated. In the present study, the BV-injected group showed a significant increase in the population of Tregs in spleen. Although there was no significant difference in the numbers of Tregs 3 days after cisplatin injection between the BV- and PBS-injected groups, more migration of Tregs into the kidney was observed 6 hours after cisplatin administration in BV group than in PBS group. In addition, BV-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, proinflammatory cytokines, and macrophage infiltration into the kidney 3 days after cisplatin administration. These renoprotective effects were abolished by the depletion of Tregs. The anticancer effect of repeated administrations of cisplatin was not affected by BV injection. These results suggest that BV has protective effects on cisplatin-induced nephrotoxicity in mice, at least in part, through the regulation of Tregs without a big influence on the antitumor effects of cisplatin.

Electroacupuncture induces Fos expression in the nucleus tractus solitarius via cholecystokinin A receptor signaling in rats.

OBJECTIVES: Cholecystokinin, a satiety hormone, acts on cholecystokinin A receptor on vagal afferent neurons that project to the nucleus tractus solitarius, resulting in inhibition of feeding. Cholecystokinin is known to be released by electroacupuncture stimulation at certain body sites which elicits profound psychophysiological responses. Our previous study has revealed the involvement of cholecystokinin and cholecystokinin A receptor in the electroacupuncture stimulation-induced modulation of feeding. The aim of the present study was to examine whether electroacupuncture stimulation at the acupuncture point ST36 (Joksamni) activates the nucleus tractus solitarius neurons and whether such effect is mediated by cholecystokinin A receptor. METHODS: Using an immunofluorescent analysis of Fos, a neuronal activation marker, we compared the Fos immunoreactivity of the nucleus tractus solitarius among three groups of Sprague-Dawley rats: (1) control (48 hour fasting + saline pre-treatment + no electroacupuncture stimulation); (2) SalEA (48 hour fasting + saline pre-treatment + ST36 electroacupuncture stimulation); (3) LorEA (48 hour fasting + pre-treatment of cholecystokinin A receptor antagonist, lorglumide + ST36 electroacupuncture stimulation). RESULTS: ST36 electroacupuncture stimulation significantly reduced 30 minute food intake (p<0.05, SalEA versus control) and increased Fos expression in the nucleus tractus solitarius (p<0.01, SalEA versus control). The effects of electroacupuncture on food intake and Fos were blocked by a lorglumide pre-treatment (p>0.05, LorEA versus control). DISCUSSION: Our finding suggests that ST36 electroacupuncture stimulation activates the nucleus tractus solitarius neurons via cholecystokinin A receptor signaling pathway, which may be the underlying central mechanism of electroacupuncture-induced satiety effect.

Therapeutic strategy for in-stent restenosis based on the restenosis pattern after drug-eluting stent implantation.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the outcomes of repeated percutaneous coronary intervention (PCI) based on the restenosis pattern in drug-eluting stent (DES) failure. SUBJECTS AND METHODS: From April 2003 to March 2006, all 67 patients (67 lesions) at our 3 centers who had DES in-stent restenosis (ISR) were enrolled. The patients were divided into 3 groups: group I had focal edge restenosis, group II had focal body restenosis, and group III had non-focal restenosis. All patients were treated with conventional PCI including plain old balloon angioplasty (POBA), cutting balloon angioplasty (CBA), and repeated DES implantation (Re-DES). Angiographic and clinical one year follow-up results for the 3 groups were evaluated. RESULTS: Sixteen patients were enrolled in group I, 36 in group II, and 15 in group III. Baseline clinical and angiographic characteristics and the proportion of patients in each group receiving each type of treatment strategy were not significantly different among the groups. Within each group, a comparison of angiographic and clinical outcomes for each therapeutic modality revealed that restenosis rates were not statistically different. Although rates of major adverse cardiac events (MACE) were not statistically different between groups I and II, in group III, MACE were 3-fold higher for the POBA (4/4, 100.0%) and CBA (4/4, 100.0%) subgroups than for Re-DES (1/3, 33.3%) (p=0.06), but the differences did not reach statistical significance. CONCLUSION: THE PRESENT STUDY SUGGESTS THAT TREATMENT OF DES ISR SHOULD BE INDIVIDUALIZED ACCORDING TO RESTENOSIS PATTERN: any PCI strategy appears appropriate for focal ISR patterns, while Re-DES might be a better choice for non-focal ISR patterns.

Disc size regulation in the brood cell building behavior of leaf-cutter bee, Megachile tsurugensis.

The leaf-cutter bee, Megachile tsurugensis, builds a brood cell in a preexisting tunnel with leaf discs that she cuts in decreasing sizes and assembles them like a Russian matryoshka doll. By experimentally manipulating the brood cell, it was investigated how she regulates the size of leaf discs that fit in the brood cell's internal volume. When the internal volume was artificially increased by removing a bulk of leaf discs, she decreased the leaf disc size, although increasing it would have made the leaf disc more fitting in the increased internal volume. As a reverse manipulation, when the internal volume was decreased by inserting a group of inner layers of preassembled leaf discs to a brood cell, she decreased the leaf disc size, so that the leaf disc could fit in the decreased internal volume. These results suggest that she uses at least two different mechanisms to regulate the disc size: the use of some internal memory about the degree of building work accomplished in the first and of sensory feedback of dimensional information at the construction site in the second manipulation, respectively. It was concluded that a stigmergic mechanism, an immediate sensory feedback from the brood cell changed by the building work, alone cannot explain the details of the bee's behavior particularly with respect to her initial response to the first manipulation. For a more complete explanation of the behavior exhibited by the solitary bee, two additional behavioral elements, reinforcement of building activity and processing of dimensional information, were discussed along with stigmergy.

Tea polyphenol inhibits allostimulation in mixed lymphocyte culture.

Green tea polyphenols are known to protect allogenic donor tissues from acute rejection by their recipients. This immunosuppressive effect may be generated by a unique chemical property of the major component, epigallocatechin-o-gallate (EGCG), which can block specific cell surface molecules of the donor tissues. To test this hypothesis, we examined the effects of EGCG on the murine mixed lymphocyte reactions. EGCG treatment of stimulator cells significantly attenuated the proliferation of responder T cells. The proliferation did not recover upon the secondary stimulations by fresh untreated cells or exogenous IL-2. Flow cytometric analyses showed that EGCG treatment decreased the staining intensities of various cell surface molecules including MHC II, which plays a major role in antigen presentation, and B7.1, B7.2, and their ligand, CD28, which are required for costimulatory signals in T-cell activation. These results suggest that an anergic state of alloreactive T cells may be induced by either weakening of antigen signaling or blockage of costimulatory signals with EGCG. Other possible mechanisms behind the immunosuppressive effect and a potential use of EGCG treatment of donor tissues in transplantation medicine are discussed.

Hibernation, reversible cell growth inhibition by epigallocatechin-3-O-gallate.

Epigallocatechin-3-O-gallate (EGCg) and related polyphenolic compounds found in tea are known to have antioxidative activities. However, they also have pro-oxidative activities such as generation of hydrogen peroxide. In this report, we investigated the effect on cells and showed the potential usage of EGCg in cell preservation. H(2)O(2) was generated from EGCg at concentrations of more than 300 microg/mL for 6 h at 37 degrees C, and high cytotoxicity for L929 cells were shown. In contrast, in the presence of 1 microg/mL catalase, the amount of generated H(2)O(2) was significantly low and cytotoxicity decreased markedly. This indicates that catalase eliminated H(2)O(2) generated by degradation of EGCg. Although H(2)O(2) generation was prevented, L929 cell proliferation was slightly inhibited in proportion to the concentrations of EGCg. L929 was exposed able to be 300 microg/mL to EGCg and 1 microg/mL catalase for maximum 18 days. EGCg inhibited the growth of L929 cells, and cell proliferation was restarted immediately after medium change for removing EGCg. We concluded that EGCg had a reversible growth inhibition when H(2)O(2) was eliminated from cell cultures.

Maternal investment and size-number trade-off in a bee, Megachile apicalis, in seasonal environments.

Maternal investment in offspring size and number differed between spring- and summer-emerging individual females of Megachile apicalis, a solitary multivoltine bee. Data from experimentally initiated female populations indicated that spring-emerging females produced a relatively large number of progeny but allocated a small amount of food to each, resulting in small progeny. Adult females of larger body sizes provisioned food at a greater rate than did smaller females, and this body-size effect was significant in spring-emerging females. The large body size of these females allowed them to increase the number of progeny produced under the abundant floral resources that occurred during the spring. Conversely, summer-emerging females produced fewer progeny under the diminishing resources for brood production, but allocated each with more food, producing larger progeny, most of which emerged in the spring of the following year. Field data using trap-nests also indicated the same pattern of seasonal offspring size allocation found in the experimental populations. This maternal investment strategy entails a trade-off between the size and number of progeny, so that the daughters upon emergence can best perform in their brood production under the seasonally variable environments where they reproduce.