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Fatal pathogenic organisms have been detected by various point‐of‐care tests (PoCTs) in clinical samples. PoCTs based on portable electrical devices are able to detect organisms in simple and rapid method. Although electrical PoCT devices show ultra sensitivity when detecting pathogens in standard samples, their industrialization has been limited due to low reproducibility, sensitivity, and specificity, resulting from nonspecific binding issues by media. In this research, a perpendicular N‐heterocyclic carbene self‐assembled monolayer (NHC‐SAM) conjugated on graphene micropattern field‐effect transistors (NGMFETs) is first demonstrated for monitoring pathogens. Two single bonds of NHCSAM on GM are investigated via density functional theory (DFT) and surface analyses. Bioreceptors are conjugated on the side gate‐modulated NGMFET for ultra‐stable on‐site detection. The side‐gated BNGMFETs system displayed remarkable performance in the detection of the following: i) SARS‐CoV‐2 spike protein S1 (limit of detection (LOD): ≈10 pg mL−1) in CTM, ii) O. tsutsugamushi Ab (LOD: ≈1 pg mL−1), and iii) E. coli (LOD: 10° CFU mL−1) in serum. Compared to commercial methodology, the platform presents 102 times higher LODs towards those pathogens in clinical samples with higher reproducibility. Based on these results, side‐gated BNGMFETs can be utilized as universal PoCT during pandemics. [ABSTRACT FROM AUTHOR]

In the N-degron pathway, N-recognins recognize cognate substrates for degradation via the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). We have recently shown that the autophagy receptor SQSTM1/p62 (sequestosome 1) is an N-recognin that binds the N-terminal arginine (Nt-Arg) as an N-degron to modulate autophagic proteolysis. Here, we show that the N-degron pathway mediates pexophagy, in which damaged peroxisomal fragments are degraded by autophagy under normal and oxidative stress conditions. This degradative process initiates when the Nt-Cys of ACAD10 (acyl-CoA dehydrogenase family, member 10), a receptor in pexophagy, is oxidized into Cys sulfinic (CysO2) or sulfonic acid (CysO3) by ADO (2-aminoethanethiol (cysteamine) dioxygenase). Under oxidative stress, the Nt-Cys of ACAD10 is chemically oxidized by reactive oxygen species (ROS). The oxidized Nt-Cys2 is arginylated by ATE1-encoded R-transferases, generating the RCOX N-degron. RCOX-ACAD10 marks the site of pexophagy via the interaction with PEX5 and binds the ZZ domain of SQSTM1/p62, recruiting LC3+-autophagic membranes. In mice, knockout of either Ate1 responsible for Nt-arginylation or Sqstm1/p62 leads to increased levels of peroxisomes. In the cells from patients with peroxisome biogenesis disorders (PBDs), characterized by peroxisomal loss due to uncontrolled pexophagy, inhibition of either ATE1 or SQSTM1/p62 was sufficient to recover the level of peroxisomes. Our results demonstrate that the Cys-N-degron pathway generates an N-degron that regulates the removal of damaged peroxisomal membranes along with their contents. We suggest that tannic acid, a commercially available drug on the market, has a potential to treat PBDs through its activity to inhibit ATE1 R-transferases. Abbreviations: ACAA1, acetyl-Coenzyme A acyltransferase 1; ACAD, acyl-Coenzyme A dehydrogenase; ADO, 2-aminoethanethiol (cysteamine) dioxygenase; ATE1, arginyltransferase 1; CDO1, cysteine dioxygenase type 1; ER, endoplasmic reticulum; LIR, LC3-interacting region; MOXD1, monooxygenase, DBH-like 1; NAC, N-acetyl-cysteine; Nt-Arg, N-terminal arginine; Nt-Cys, N-terminal cysteine; PB1, Phox and Bem1p; PBD, peroxisome biogenesis disorder; PCO, plant cysteine oxidase; PDI, protein disulfide isomerase; PTS, peroxisomal targeting signal; R-COX, Nt-Arg-CysOX; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNP, sodium nitroprusside; UBA, ubiquitin-associated; UPS, ubiquitinproteasome system. [ABSTRACT FROM AUTHOR]

This research investigated the influence of child characteristics, parenting behaviours and teacher-child relationships in order to ascertain peer victimization among 297 Korean preschool children. Peer victimization, child social behaviours and teacher-child relationships were assessed through teacher reports. Parents completed parenting behaviour questionnaires. Results suggested independent contributions from neglectful/rejected parenting, aggression, withdrawal and conflict in teacher-child relationships. Moreover, parental neglect/rejection moderated the association between aggression and peer victimization. Implications of the results for intervention initiatives are discussed. (Contains 3 tables and 1 figure.)

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-[alpha] (ER- [alpha], encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-[alpha]-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-[alpha] and the progesterone receptor (PR), MEL-18 overexpression restored ER-[alpha] expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B- mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer., Introduction Estrogen receptor-[alpha] (ER-[alpha]), a hormone-dependent nuclear receptor encoded by ESR1, is the most common clinical marker used for breast cancer prognosis and the classification of breast cancer subtypes. Approximately [...]