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Abstract During neuronal pruning, phagocytes engulf shed cellular debris to avoid inflammation and maintain tissue homeostasis. How phagocytic receptors recognize degenerating neurites had been unclear. Here, we identify two glucosyltransferases Alg8 and Alg10 of the N-glycosylation pathway required for dendrite fragmentation and clearance through genetic screen. The scavenger receptor Draper (Drpr) is N-glycosylated with complex- or hybrid-type N-glycans that interact specifically with galectins. We also identify the galectins Crouching tiger (Ctg) and Hidden dragon (Hdg) that interact with N-glycosylated Drpr and function in dendrite pruning via the Drpr pathway. Ctg and Hdg are required in hemocytes for expression and function, and are induced during dendrite injury to localize to injured dendrites through specific interaction with exposed phosphatidylserine (PS) on the surface membrane of injured dendrites. Thus, the galectins Ctg and Hdg bridge the interaction between PS and N-glycosylated Drpr, leading to the activation of phagocytosis.

Glioblastoma multiforme (GBM) is one of the most prevalent and lethal primary central nervous system malignancies. GBM is notorious for its high rates of recurrence and therapy resistance and the PI3K/Akt pathway plays a pivotal role in its malignant behavior. Crebanine (CB), an alkaloid capable of penetrating the blood–brain barrier (BBB), has been shown to have inhibitory effects on proinflammatory molecules and multiple cancer cell lines via pathways such as PI3K/Akt. This study aims to investigate the efficacy and mechanisms of CB treatment on GBM. It is the first study to elucidate the anti-tumor role of CB in GBM, providing new possibilities for GBM therapy. Through a series of experiments, we demonstrate the significant anti-survival, anti-clonogenicity, and proapoptotic effects of CB treatment on GBM cell lines. Next-generation sequencing (NGS) is also conducted and provides a complete list of significant changes in gene expression after treatment, including genes related to apoptosis, the cell cycle, FoxO, and autophagy. The subsequent protein expressions of the upregulation of apoptosis and downregulation of PI3K/Akt are further proved. The clinical applicability of CB to GBM treatment could be high for its BBB-penetrating feature, significant induction of apoptosis, and blockage of the PI3K/Akt pathway. Future research is needed using in vivo experiments and other therapeutic pathways shown in NGS for further clinical or in vivo studies.

Abstract Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4-based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.

Reactions of N,N′-bis(3-methylpyridyl)oxalamide (L1), N,N’-bis(3-methylpyridyl)adipoamide (L2) and N,N’-bis(3-methylpyridyl)sebacoamide (L3) with tricarboxylic acids and Cu(II) salts afforded {[Cu(L1)(1,3,5-HBTC)]·H2O}n (1,3,5-H3BTC = 1,3,5-benzenetricarboxylic acid), 1, {[Cu1.5(L2)1.5(1,3,5-BTC)(H2O)2]·6.5H2O}n, 2, [Cu(L2)0.5(1,3,5-HBTB)]n (1,3,5-H3BTB = 1,3,5-tri(4-carboxyphenyl)benzene), 3, [Cu4(L3)(OH)2(1,3,5-BTC)2]n, 4, {[Cu3(L3)2(1,3,5-BTB)2]·2.5MeOH·2H2O}n, 5, and {[Cu3(L3)2(1,3,5-BTB)2 ]·DMF·2H2O}n, 6, which have been structurally characterized by using single crystal X-ray crystallography. Complexes 1–4 form a 2D layer with the {44.62}-sql topology, a 2D layer with the (4.62)2(42.62.82)-bex topology, a three-fold interpenetrated 3D net with the (412·63)-pcu topology and a 3D framework with the (410·632·83)(42·6)2(43·63) topology, respectively, whereas 5 and 6 are 3D frameworks with the (63)2(64·82)(68·85·102) topology. Complex 5 shows a better iodine adsorption factor of 290.0 mg g−1 at 60 °C for 360 min than the other ones, revealing that the flexibility of the spacer ligand governs the structural diversity and the adsorption capacity.

TRIM28/KAP1/TIF1β is a crucial epigenetic modifier. Genetic ablation of trim28 is embryonic lethal, although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, several lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. Here, we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs). The TRIM28-K304Q knock-in cells were created in K562 erythroleukemia cells by CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein nuclease 9) gene editing method. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from wild-type K562 cells. The expression levels of embryonic-related globin gene and a platelet cell marker integrin-beta 3 were increased in TRIM28-K304Q mutant cells, indicating the induction of differentiation. In addition to the differentiation-related genes, many zinc-finger-proteins genes and imprinting genes were activated in TRIM28-K304Q cells; they were inhibited by wild-type TRIM28 via binding with KRAB-ZNFs. These results suggest that acetylation/deacetylation of K304 in TRIM28 constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation as demonstrated by the acetylation mimic TRIM28-K304Q.

Autophagy and the ubiquitin–proteasome system (UPS) are cellular quality control processes, but their coordination remains unclear. Here, the authors show that branched ubiquitination of VPS34 functions as a switch between UPS and autophagy and has an important role in lipid metabolism in the liver.

Extended red emission (ERE) is a broad feature in the spectral region of 500–900 nm commonly observed in a wide range of circumstellar and interstellar environments. Although the observational constraints for ERE are well established, definitive identifications of the carriers and associated processes complying with these constraints remain unanswered. We report a plausible two-step model involving far-ultraviolet (UV)-irradiated single-layer graphene (SLG), considered as large polycyclic aromatic hydrocarbons, to meet these constraints and supported by laboratory experiments. The far-UV-treated SLG, producing structural defects and graphene quantum dots, showed photoluminescence excitation spectrum extending from the far-UV to UV–visible region, hence meeting the requirements of far-UV light and high photon conversion efficiency. Furthermore, a photoluminescence band shifted from ∼585 to ∼750 nm for high-dose-exposed SLG agrees with the observed redshift of the ERE band in regions under a greater far-UV radiation density.

A shift in dengue cases toward the adult population, accompanied by an increased risk of severe cases of dengue in the elderly, has created an important emerging issue in the past decade. To understand the level of past DENV infection among older adults after a large dengue outbreak occurred in southern Taiwan in 2015, we screened 1498 and 2603 serum samples from healthy residents aged ≥ 40 years in Kaohsiung City and Tainan City, respectively, to assess the seroprevalence of anti-DENV IgG in 2016. Seropositive samples were verified to exclude cross-reaction from Japanese encephalitis virus (JEV), using DENV/JEV-NS1 indirect IgG ELISA. We further identified viral serotypes and secondary DENV infections among positive samples in the two cities. The overall age-standardized seroprevalence of DENV-IgG among participants was 25.77% in Kaohsiung and 11.40% in Tainan, and the seroprevalence was significantly higher in older age groups of both cities. Although the percentages of secondary DENV infection in Kaohsiung and Tainan were very similar (43.09% and 44.76%, respectively), DENV-1 and DENV-2 spanned a wider age range in Kaohsiung, whereas DENV-2 was dominant in Tainan. As very few studies have obtained the serostatus of DENV infection in older adults and the elderly, this study highlights the need for further investigation into antibody status, as well as the safety and efficacy of dengue vaccination in these older populations.

Background/purpose: We reported an outbreak of Staphylococcus haemolyticus (SH) infection in a group of young patients (mean age 21.6) simultaneously hospitalized due to a mass-burn incident. This study analyzed the clinical features of these patients and the microbiological characteristics of the outbreak. Methods: All 50 patients hospitalized for burns were enrolled, and their clinical differences were analyzed based on culture results. A drug sensitivity test and pulsed-field gel electrophoresis (PFGE) were conducted to analyze the microbiological difference between SH isolates from the mass-burn casualty patients (the study group) and SH isolates from other patients hospitalized during the same period (the control group) with the intention of identifying the strain of SH outbreak. Results: Patients with isolated SH (N = 36) had a significantly higher disease severity (higher revised Baux score, APACHE II score, and concurrent bacteremia rate), and a significantly poorer clinical outcome (longer ICU and hospital stay, and longer MV usage). Significant differences in the phenotype (antibiotics drug sensitivity test) and genotype (PFGE typing) were observed between the study and control groups. The dominant PFGE type C identified among the study group was related to poorer outcomes in a subgroup analysis. Conclusion: A dominant PFGE type of SH infection was found in these mass-burn casualty patients. Pathogenesis or virulence factors may have contributed to our results. Further study of isolated SH should be conducted. Keywords: Burn, Outbreak, Outcome, Pulsed-field gel electrophoresis (PFGE), Staphylococcus haemolyticus (SH)

Integrative medicine comprising a tumor-associated antigen vaccine and chemotherapeutic regimens has provided new insights into cancer therapy. In this study, the AB-type diblock copolymers poly(ethylene glycol)–polylactide (PEG–PLA) were subjected to the dispersion of poorly water-soluble molecules in aqueous solutions. The physicochemical behavior of the chemotherapeutic agent DBPR114 in the PEG–PLA-polymeric aqueous solution was investigated by dynamic light scattering (DLS) technology. In vitro cell culture indicated that replacing the organic solvent DMSO with PEG–PLA polymeric micelles could maintain the anti-proliferative effect of DBPR114 on leukemia cell lines. A murine tumor-associated antigen vaccine model was established in tumor-bearing mice to determine the effectiveness of these formulas in inducing tumor regression. The results demonstrated that the therapeutic treatments effectively reinforced each other via co-delivery of antitumor drug/antigen agents to synergistically integrate the efficacy of cancer therapy. Our findings support the potential use of polymeric micellar systems for aqueous solubilization and expansion of antitumor activity intrinsic to DBPR114 and tumor-associated antigen therapy.

This study presents a noncontact electrocardiogram (ECG) measurement system to replace conventional ECG electrode pads during ECG measurement. The proposed noncontact electrode design comprises a surface guard ring, the optimal input resistance, a ground guard ring, and an optimal voltage divider feedback. The surface and ground guard rings are used to reduce environmental noise. The optimal input resistor mitigates distortion caused by the input bias current, and the optimal voltage divider feedback increases the gain. Simulated gain analysis was subsequently performed to determine the most suitable parameters for the design, and the system was combined with a capacitive driven right leg circuit to reduce common-mode interference. The present study simulated actual environments in which interference is present in capacitive ECG signal measurement. Both in the case of environmental interference and motion artifact interference, relative to capacitive ECG electrodes, the proposed electrodes measured ECG signals with greater stability. In terms of R–R intervals, the measured ECG signals exhibited a 98.6% similarity to ECGs measured using contact ECG systems. The proposed noncontact ECG measurement system based on capacitive sensing is applicable for use in everyday life.

In recent years, many researchers have examined dynamic optimization problems (DOPs). The key challenge lies in the fact that the optimal solution of a DOP typically changes over time. This paper focuses on using query-based learning dynamic particle swarm optimization (QBLDPSO) to solve DOPs. QBLDPSO is mainly used for improving multi-population-based PSO; our QBL mechanism includes two learning strategies that integrate the concepts of diversity and memory into PSO. The first learning strategy, QBL quantum parameter adaptation (QBLQPA), is used to apply the concept of diversity to the multi-population based algorithm. This is different from typical diversity-based PSO approaches, which passively maintain the diversity of particles in the solution space. We actively adapt the ratio of quantum particles and neutral particles to achieve diversity without analyzing the distribution of optima in the solution space. The second learning strategy is query-based learning optima prediction (QBLOP). Although QBLOP exploits the concept of memory, we do not need to analyze the history of all particles. We select the k nearest particles to the current best solution and use a minimum encompassing circle as the possible prediction region. Our experimental results are based on the generalized dynamic benchmark generator (GDBG), which is adopted as a benchmark for the DOP. The proposed method outperforms two state-of-the-art multi-population-based PSO methods with the average improvements of 11.37% and 8% using QBLQPA. In particular, for the recurrent problems in GDBG, our method improves performance by 35.06%.

Introduction: Dizziness and balance impairment are common symptoms of mild traumatic brain injury (mTBI). Acid-sensing ion channel 3 (ASIC3) is expressed in the vestibular and proprioceptive systems and associated with balance functions. However, whether the genetic variants of ASIC3 are associated with people who suffer dizziness and balance impairment after mTBI remained unknown.Materials and methods: A total of 200 people with mTBI and 109 non-mTBI controls were recruited. Dizziness, balance functions, and the ability to perform daily activities were assessed by Dizziness Handicap Inventory (DHI), and objective balance functions were investigated by the postural stability test. Three diseases-related genetic variants of ASIC3 were determined through polymerase chain reaction and followed by restriction fragment length polymorphism. The Student's t-test and Mann-Whitney U-test were used for normal and abnormal distributed data, respectively. The regression was applied to adjust gender and age. The normality of continuous data was evaluated by Shapiro-Wilk test.Results: In the mTBI people, the rs2288645-A allele carriers exhibited a significantly worse physical domain DHI score (A-allele carriers: 11.39 ± 8.42, non-A carriers: 8.76 ± 7.87, p = 0.03). The rs4148855-GTC deletion carriers an exhibited significantly worse overall postural stability (GTC deletion carriers: 0.53 ± 0.33, non-carriers: 0.46 ± 0.20, p = 0.03). In the controls, rs2288646-A allele carriers were significant worse in the medial-to-lateral postural stability (A-allele carriers: 0.31 ± 0.17, non-A carriers: 0.21 ± 0.10, p = 0.01).Conclusion: The present study demonstrated that ASIC3 genetic variants were associated with certain aspects of balance functions and dizziness questionnaires in people of mTBI and non-mTBI. It provides a possible evidence that ASIC3 could be a new target for the management of the balancing disorders. However, further investigations are warranted to elucidate the underlying mechanisms and clinical significance.

This article presents data that were obtained through measuring the impact of the Min oscillation on membrane proteins in Escherichia coli by quantitative protemoics analysis. We isolated inner membranes from the wild-type and mutant strains to generate proteomics datasets based on NanoLC-nanoESI-MS/MS mass spectrometry using the isobaric tags for relative and absolute quantitation (iTRAQ) method. The datasets included the raw spectral files from four sample replicates and the processed files using Proteome Discoverer that contained a total of 40,072 MS/MS spectra with confident peptide identifier (FDR

Frailty Index, defined as an individual's accumulated proportion of listed health-related deficits, is a well-established metric used to assess the health status of old adults; however, it has not yet been developed in Taiwan, and its local related structure factors remain unclear. The objectives were to construct a Taiwan Frailty Index to predict mortality risk, and to explore the structure of its factors.Analytic data on 1,284 participants aged 53 and older were excerpted from the Social Environment and Biomarkers of Aging Study (2006), in Taiwan. A consensus workgroup of geriatricians selected 159 items according to the standard procedure for creating a Frailty Index. Cox proportional hazard modeling was used to explore the association between the Taiwan Frailty Index and mortality. Exploratory factor analysis was used to identify structure factors and produce a shorter version-the Taiwan Frailty Index Short-Form.During an average follow-up of 4.3 ± 0.8 years, 140 (11%) subjects died. Compared to those in the lowest Taiwan Frailty Index tertile (< 0.18), those in the uppermost tertile (> 0.23) had significantly higher risk of death (Hazard ratio: 3.2; 95% CI 1.9-5.4). Thirty-five items of five structure factors identified by exploratory factor analysis, included: physical activities, life satisfaction and financial status, health status, cognitive function, and stresses. Area under the receiver operating characteristic curves (C-statistics) of the Taiwan Frailty Index and its Short-Form were 0.80 and 0.78, respectively, with no statistically significant difference between them.Although both the Taiwan Frailty Index and Short-Form were associated with mortality, the Short-Form, which had similar accuracy in predicting mortality as the full Taiwan Frailty Index, would be more expedient in clinical practice and community settings to target frailty screening and intervention.

In this study, we used a systems biology approach to investigate changes in the proteome and metabolome of shrimp hemocytes infected by the invertebrate virus WSSV (white spot syndrome virus) at the viral genome replication stage (12 hpi) and the late stage (24 hpi). At 12 hpi, but not at 24 hpi, there was significant up-regulation of the markers of several metabolic pathways associated with the vertebrate Warburg effect (or aerobic glycolysis), including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis, glutaminolysis and amino acid biosynthesis. We show that the PI3K-Akt-mTOR pathway was of central importance in triggering this WSSV-induced Warburg effect. Although dsRNA silencing of the mTORC1 activator Rheb had only a relatively minor impact on WSSV replication, in vivo chemical inhibition of Akt, mTORC1 and mTORC2 suppressed the WSSV-induced Warburg effect and reduced both WSSV gene expression and viral genome replication. When the Warburg effect was suppressed by pretreatment with the mTOR inhibitor Torin 1, even the subsequent up-regulation of the TCA cycle was insufficient to satisfy the virus's requirements for energy and macromolecular precursors. The WSSV-induced Warburg effect therefore appears to be essential for successful viral replication.

A series of new conjugated compounds with a –SCH2– linkage were synthesized by chemical methods from imidazole and coumarin derivatives. The experimental results indicate that of the twenty newly synthesized imidazole–coumarin conjugates, three of them exhibited appealing EC50 values (5.1–8.4 μM) and selective indices >20 against hepatitis C virus. Their potency and selectivity were increased substantially by modification of their structure with two factors: imidazole nucleus with a hydrogen atom at the N(1) position and coumarin nucleus with a substituent, such as Cl, F, Br, Me, and OMe. These guidelines provide valuable information for further development of conjugated compounds as anti-viral agents.

BACKGROUND:Mammalian M6A, a member of the proteolipid protein (PLP/DM20) family expressed in neurons, was first isolated by expression cloning with a monoclonal antibody. Overexpression of M6A was shown to induce filopodium formation in neuronal cells; however, the underlying mechanism of is largely unknown. Possibly due to gene duplication, there are two M6A paralogs, M6Aa and M6Ab, in the zebrafish genome. In the present study, we used the zebrafish as a model system to investigate the role of zebrafish M6Ab in filopodium formation in PC12 cells and neurite outgrowth in zebrafish embryos. METHODOLOGY/PRINCIPAL FINDINGS:We demonstrated that zebrafish M6Ab promoted extensive filopodium formation in NGF-treated PC12 cells, which is similar to the function of mammalian M6A. Phosphorylation at serine 263 of zebrafish M6Ab contributed to this induction. Transfection of the S263A mutant protein greatly reduced filopodium formation in PC12 cells. In zebrafish embryos, only S263D could induce neurite outgrowth. CONCLUSIONS/SIGNIFICANCE:Our results reveal that the phosphorylation status of zebrafish M6Ab at serine 263 is critical for its role in regulating filopodium formation and neurite outgrowth.