Erratum: Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the treatment of non-small cell lung cancer.

[This corrects the article on p. 2598 in vol. 13, PMID: 37424807.].

Free Fibular Osteocutaneous Flap Combined With Simultaneous Tendon Reconstruction for Midfoot Restoration After Myoepithelial Carcinoma Resection.

ABSTRACT: Myoepithelial carcinomas of soft tissue are rare, and most are malignant. The optimal treatment is surgical excision. The arches of the foot are a composite structure responsible for weight bearing and pressure distribution, so it is a vast challenge in reconstruction. We report a case of reconstruction of the midfoot with a free fibular bone flap and tendon graft. We review the literature to compare various options in foot reconstructions and sort out the outcomes of different bone flaps. The free fibula osteocutaneous flap is the superior choice for midfoot reconstruction owing to its sufficient length, strength, flexible skin paddles, easy-to-withstand osteotomy, and simultaneous tendon graft harvesting.

One-Step Synthesis of Graphene-Covered Silver Nanowires with Enhanced Stability for Heating and Strain Sensing.

Solution-processed silver nanowire (AgNW) networks have been considered as promising electrode candidates for next-generation electronic devices. However, they suffer from poor thermal and electrical stability and low mechanical properties, hindering their practical applications. In this work, graphene nanosheets are successfully introduced into AgNW via a facile one-step solvothermal process. Benefiting from increased conductive paths, the resultant AgNW/graphene films exhibit high electrical conductivity. More importantly, the interlocking NW morphology can be maintained under high temperature and applied voltage due to suppressed Ag migration, which is enabled by the introduction of graphene. This feature leads to enhanced thermal and electrical stability, making them suitable for use as transparent heaters. Furthermore, the composite films present excellent mechanical performance, and negligible resistance change is observed after 10 000 repeated bending cycles. To demonstrate their feasibility toward sensor applications, sandwiched strain sensors are designed, which can endure larger tensile strains and show higher sensitivity and repeatability compared with pure AgNW-based device. Furthermore, various hand gestures can be easily recognized by the resultant sensors based on unique combinations of sensing response. This work not only provides a low-cost method to realize large-scale synthesis of AgNW/graphene composites but also offers guidance to prepare high-performance electrodes for advanced electronics.

High-fat diet-induced increase in glucocorticoids contributes to adipogenesis in obese mice.

BACKGROUND: This study was designed to examine how glucocorticoids (GCs) induced by a long-term ingestion of high-fat diet (HFD) mediate the HFD-induced adipose expansion and obesity. MATERIAL AND METHODS: To address this goal, we used a unique L/L mouse model that fails to induce its corticosterone (CORT) level, a major type of GCs in rodents, after prolonged exposure to an HFD. RESULTS: We found that, after receiving a 12-week HFD feeding, the L/L mice show less weight gain, milder adipose expansion, and higher plasma levels of triglycerides than the wild-type mice. These changes were reversed by replenishing CORT to L/L mice. When examining the expression levels of various molecules linked to lipid uptake and de novo lipogenesis in CORT-induced adipose expansion, we observed a reduction in the expression of adipose preadipocyte factor 1 (Pref-1), a key regulator in adipogenesis. In 3T3-L1 preadipocyte-like cells, dexamethasone, an agonist of the glucocorticoid receptor, also reduced expressions of Pref-1 and facilitated intracellular accumulation of lipids. CONCLUSIONS: Our results suggest that fat ingestion-induced release of CORT contributes to adipose expansion and development of obesity and highlight the pathogenic role of CORT-mediated downregulation of adipose Pref-1 in diet-induced obesity.

Impact of class cancellations on parents' and children' adaptation following an outbreak of the Omicron variant during the COVID-19 pandemic in Taiwan in April 2022.

OBJECTIVE: To explore the impact on Taiwanese parents and children following an outbreak of the Omicron variant during the COVID-19 pandemic. METHODS: Data were collected following class cancellations mandated by the Ministry of Education due to an outbreak of the Omicron variant of COVID-19 in April 2022. A national parent organization developed self-report survey questionnaire, "Impact of the Pandemic-related School Closures/Class Cancellations" (IPRSCCC), assessed parents' perceived impact of school cancellations on their child/children' and on their adaptation. The online survey was available between May 4 and May 9, 2022, in 20 districts throughout Taiwan. RESULTS: A total of 2126 parents representing 2592 children responded. Total scores on the IPRSCCC were significantly higher for parents of children whose classes were cancelled (n = 891) compared with parents whose children continued in-person classes (n = 1053). Parents perceived the class cancellations of the child/children disrupted daily routine, learning loss and impacted academic motivation. They also reported emotional stress and no time for rest, which were associated with parental burnout. However for these parents, there were no significant differences in scores between parents living in low and high socioeconomic areas. Only the subscale score for disrupted daily routine was significantly higher for fathers, and emotional stress was significantly higher for parents with two, or ≥ 3 children. When academic impacts were examined using national examination scores for 12th grade students, the percent of students with scores of ≤ 6 in English, Chinese, and mathematics was higher in 2022 than in 2020. CONCLUSIONS: Higher IPRSCCC scores for parents of children whose classes were cancelled provides additional evidence of the impact of disruptions of in-person classes due to the COVID-19 pandemic. Examination scores confirmed class cancellations impacted academic performance.

Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.

Fluorogenic Aptamer Optimizations on a Massively Parallel Sequencing Platform.

F luorogenic ap tamers (FAPs) have become an increasingly important tool in cellular sensing and pathogen diagnostics. However, fine-tuning FAPs for enhanced performance remains challenging even with the structural details provided by X-ray crystallography. Here we present a novel approach to optimize a DNA-based FAP (D-FAP), Lettuce, on repurposed Illumina next-generation sequencing (NGS) chips. When substituting its cognate chromophore, DFHBI-1T, with TO1-biotin, Lettuce not only shows a red-shifted emission peak by 53 nm (from 505 to 558 nm), but also a 4-fold bulk fluorescence enhancement. After screening 8,821 Lettuce variants complexed with TO1-biotin, the C14T mutation is found to exhibit an improved apparent dissociated constant ( vs. 0.82 µM), an increased quantum yield (QY: 0.62 vs. 0.59) and an elongated fluorescence lifetime (τ: 6.00 vs. 5.77 ns), giving 45% more ensemble fluorescence than the canonical Lettuce/TO1-biotin complex. Molecular dynamic simulations further indicate that the π-π stacking interaction is key to determining the coordination structure of TO1-biotin in Lettuce. Our screening-and-simulation pipeline can effectively optimize FAPs without any prior structural knowledge of the canonical FAP/chromophore complexes, providing not only improved molecular probes for fluorescence sensing but also insights into aptamer-chromophore interactions.

Two-photon autofluorescence lifetime assay of rabbit photoreceptors and retinal pigment epithelium during light-dark visual cycles in rabbit retina.

Two-photon excited fluorescence (TPEF) is a powerful technique that enables the examination of intrinsic retinal fluorophores involved in cellular metabolism and the visual cycle. Although previous intensity-based TPEF studies in non-human primates have successfully imaged several classes of retinal cells and elucidated aspects of both rod and cone photoreceptor function, fluorescence lifetime imaging (FLIM) of the retinal cells under light-dark visual cycle has yet to be fully exploited. Here we demonstrate a FLIM assay of photoreceptors and retinal pigment epithelium (RPE) that reveals key insights into retinal physiology and adaptation. We found that photoreceptor fluorescence lifetimes increase and decrease in sync with light and dark exposure, respectively. This is likely due to changes in all-trans-retinol and all-trans-retinal levels in the outer segments, mediated by phototransduction and visual cycle activity. During light exposure, RPE fluorescence lifetime was observed to increase steadily over time, as a result of all-trans-retinol accumulation during the visual cycle and decreasing metabolism caused by the lack of normal perfusion of the sample. Our system can measure the fluorescence lifetime of intrinsic retinal fluorophores on a cellular scale, revealing differences in lifetime between retinal cell classes under different conditions of light and dark exposure.

Imbalance in Unc80 RNA Editing Disrupts Dynamic Neuronal Activity and Olfactory Perception.

A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with developmental and physiological needs. Yet, the functions of many editing sites are still to be defined. The Unc80 gene stands out in this context due to its brain-specific expression and the evolutionary conservation of its codon-altering editing event. The precise biological functions of Unc80 and its editing, however, are still largely undefined. In this study, we first demonstrated that Unc80 editing occurs in an ADAR2-dependent manner and is exclusive to the brain. By employing the CRISPR/Cas9 system to generate Unc80 knock-in mouse models that replicate the natural editing variations, our findings revealed that mice with the "gain-of-editing" variant (Unc80G/G) exhibit heightened basal neuronal activity in critical olfactory regions, compared to the "loss-of-editing" (Unc80S/S) counterparts. Moreover, an increase in glutamate levels was observed in the olfactory bulbs of Unc80G/G mice, indicating altered neurotransmitter dynamics. Behavioral analysis of odor detection revealed distinctive responses to novel odors-both Unc80 deficient (Unc80+/-) and Unc80S/S mice demonstrated prolonged exploration times and heightened dishabituation responses. Further elucidating the olfactory connection of Unc80 editing, transcriptomic analysis of the olfactory bulb identified significant alterations in gene expression that corroborate the behavioral and physiological findings. Collectively, our research advances the understanding of Unc80's neurophysiological functions and the impact of its editing on the olfactory sensory system, shedding light on the intricate molecular underpinnings of olfactory perception and neuronal activity.

Evaluating the Margins of Breast Cancer Tumors by Using Digital Breast Tomosynthesis with Deep Learning: A Preliminary Assessment.

BACKGROUND: The assessment information of tumor margins is extremely important for the success of the breast cancer surgery and whether the patient undergoes a second operation. However, conducting surgical margin assessments is a time-consuming task that requires pathology-related skills and equipment, and often cannot be provided in a timely manner. To address this challenge, digital breast tomosynthesis technology was utilized to generate detailed cross-sectional images of the breast tissue and integrate deep learning algorithms for image segmentation, achieving an assessment of tumor margins during surgery. METHODS: this study utilized post-operative tissue samples from 46 patients who underwent breast-conserving treatment, and generated image sets using digital breast tomosynthesis for the training and evaluation of deep learning models. RESULTS: Deep learning algorithms effectively identifying the tumor area. They achieved a Mean Intersection over Union (MIoU) of 0.91, global accuracy of 99%, weighted IoU of 44%, precision of 98%, recall of 83%, F1 score of 89%, and dice coefficient of 93% on the training dataset; for the testing dataset, MIoU was at 83%, global accuracy at 97%, weighted IoU at 38%, precision at 87%, recall rate at 69%, F1 score at 76%, dice coefficient at 86%. CONCLUSIONS: The initial evaluation suggests that the deep learning-based image segmentation method is highly accurate in measuring breast tumor margins. This helps provide information related to tumor margins during surgery, and by using different datasets, this research method can also be applied to the surgical margin assessment of various types of tumors.

The Role of Central Oxytocin in Autonomic Regulation.

Oxytocin (OXT), a neuropeptide originating from the hypothalamus and traditionally associated with peripheral functions in parturition and lactation, has emerged as a pivotal player in the central regulation of the autonomic nervous system (ANS). This comprehensive ANS, comprising sympathetic, parasympathetic, and enteric components, intricately combines sympathetic and parasympathetic influences to provide unified control. The central oversight of sympathetic and parasympathetic outputs involves a network of interconnected regions spanning the neuroaxis, playing a pivotal role in the real-time regulation of visceral function, homeostasis, and adaptation to challenges. This review unveils the significant involvement of the central OXT system in modulating autonomic functions, shedding light on diverse subpopulations of OXT neurons within the paraventricular nucleus of the hypothalamus and their intricate projections. The narrative progresses from the basics of central ANS regulation to a detailed discussion of the central controls of sympathetic and parasympathetic outflows. The subsequent segment focuses specifically on the central OXT system, providing a foundation for exploring the central role of OXT in ANS regulation. This review synthesizes current knowledge, paving the way for future research endeavors to unravel the full scope of autonomic control and understand multifaceted impact of OXT on physiological outcomes.

OTUB1 contributes to the stability and function of Influenza A virus NS2.

The influenza A virus (IAV) consists of 8 single-stranded, negative-sense viral RNA (vRNA) segments. After infection, vRNA is transcribed, replicated, and wrapped by viral nucleoprotein (NP) to form viral ribonucleoprotein (vRNP). The transcription, replication, and nuclear export of the viral genome are regulated by the IAV protein, NS2, which is translated from spliced mRNA transcribed from viral NS vRNA. This splicing is inefficient, explaining why NS2 is present in low abundance after IAV infection. The levels of NS2 and its subsequent accumulation are thought to influence viral RNA replication and vRNP nuclear export. Here we show that NS2 is ubiquitinated at the K64 and K88 residues by K48-linked and K63-linked polyubiquitin (polyUb) chains, leading to the degradation of NS2 by the proteasome. Additionally, we show that a host deubiquitinase, OTUB1, can remove polyUb chains conjugated to NS2, thereby stabilizing NS2. Accordingly, knock down of OTUB1 by siRNA reduces the nuclear export of vRNP, and reduces the overall production of IAV. These results collectively demonstrate that the levels of NS2 in IAV-infected cells are regulated by a ubiquitination-deubiquitination system involving OTUB1 that is necessary for optimal IAV replication.

Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals.

BACKGROUND: The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats. METHODS: Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[ 18 F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT. RESULTS: MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction. CONCLUSION: Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[ 18 F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.

Discrepancies Among Hospitals and Regions in the Provision of Low-Value Care.

BACKGROUND: Low-value care is a critical issue in terms of patient safety and fiscal policy; however, little has been known in Asia. For the purpose of better understanding the extent of low-value care on a national level, the utilization, costs and associated characteristics of selected international recommendations were assessed in this study. METHODS: This retrospective cohort study used the National Health Insurance claims data during 2013-2017 to evaluate the low-value care utilization. Adult beneficiaries who enrolled in the National Health Insurance program and received at least one of the low-value services in hospitals were included. We measured seven procedures derived from the international recommendations at the hospital level, and a composite measure was created by summing the total utilization of selected services to determine the overall prevalence and corresponding cost. The generalized estimating equation model was adopted to estimate the association. RESULTS: A total of 1,970,496 episodes of low-value care was identified among 1,218,146 beneficiary-year observations and 2,054 hospital-year observations. Overall, the utilization rate of the composite measure increased from 150.70 to 186.23 episodes per 10,000 beneficiaries with the growth in cost from US$5.40 to US$6.90 million. Low-value care utilization was proportional to the volume of outpatient visits and length of stay. Also, hospitals with a large volume of outpatient visits (aOR [95% CI], 2.10 [1.26 to 3.49] for Q2- Q3, 2.88 [1.45 to 5.75] for ≥Q3) and a higher proportion of older patients (aOR [95% CI], 1.06 [1.02 to 1.11]) were more likely to have high costs. CONCLUSION: The utilization and corresponding cost of low-value care appeared to increase annually despite the relatively lower prevalence compared to other countries. Multicomponent interventions such as recommendations, de-implementation policies and payment reforms are considered effective ways to reduce low-value care. Repeated measurements would be needed to evaluate the effectiveness of interventions.

Multicenter study of the efficacy and safety of electrocautery-enhanced lumen-apposing metal stents for the internal drainage of pancreatic fluid collections.

Pancreatic fluid collections (PFCs) including pancreatic pseudocyst (PP) and walled-off necrosis (WON) are complications after acute pancreatitis. We aimed to evaluate the efficacy and safety of endoscopic ultrasound (EUS)-guided lumen-apposing metal stent (LAMS) placement to manage PFCs. Between June 2019 and May 2023, patients with symptomatic PFCs who underwent EUS-guided electrocautery-enhanced LAMS drainage were enrolled retrospectively from eight tertiary centers in Taiwan. In total, 33 [14 (42.42%) PP and 19 (57.58%) WON] patients were enrolled. Gallstones (27.27%) and abdominal pain (72.73%) were the most common etiology and indication for drainage. The technical and clinical success rates were 100% and 96.97%, respectively, and the mean procedure time was 30.55 (± 16.17) min. Complications included one (3.03%) case of self-limited bleeding; there were no cases of mortality. Seven (21.21%) patients had recurrence. Patients with disconnected pancreatic duct syndrome (DPDS) had a higher recurrence rate than those without (71.43% vs. 38.46%, p = 0.05). After replacing LAMSs with transmural double-pigtail plastic stents (DPSs) in the DPDS patients, the DPS migration rate was higher in the patients with recurrence (100% vs. 33.33%, p = 0.04). In conclusion, drainage of symptomatic PFCs with EUS-guided electrocautery-enhanced LAMS appears to be efficient and safe. Replacing LAMSs with DPSs in DPDS patients was associated with a lower recurrence rate.

Consensus statements on endoscopic ultrasound-guided tissue acquisition. Guidelines from the Asian Endoscopic Ultrasound Group.

OBJECTIVES: This consensus was developed by the Asian EUS Group (AEG), who aimed to formulate a set of practice guidelines addressing various aspects of endoscopic ultrasound-guided tissue acquisition (EUS-TA). METHODS: The AEG initiated the development of consensus statements and formed an expert panel comprising surgeons, gastroenterologists, and pathologists. Three online consensus meetings were conducted to consolidate the statements and votes. The statements were presented and discussed in the first two consensus meetings and revised according to comments. Final voting was conducted at a third consensus meeting. The Grading of Recommendations, Assessment, Development, and Evaluation system was adopted to define the strength of the recommendations and quality of evidence. RESULTS: A total of 20 clinical questions and statements regarding EUS-TA were formulated. The committee recommended that fine-needle biopsy (FNB) needles be preferred over conventional fine-needle aspiration (FNA) needles for EUS-TA of subepithelial lesions. For solid pancreatic masses, rapid on-site evaluation is not routinely recommended when FNB needles are used. For dedicated FNB needles, fork-tip and Franseen-tip needles have essentially equivalent performance. CONCLUSION: This consensus provides guidance for EUS-TA, thereby enhancing the quality of EUS-TA.

Temporal changes in biomarkers of neutrophil extracellular traps and NET-promoting autoantibodies following adenovirus-vectored, mRNA, and recombinant protein COVID-19 vaccination.

Neutrophil extracellular traps (NETs) play a role in innate pathogen defense and also trigger B-cell response by providing antigens. NETs have been linked to vaccine-induced thrombotic thrombocytopenia. We postulated a potential link between NET biomarkers, NET-promoting autoantibodies, and adverse events (AEs) after COVID-19 vaccine boosters. Healthy donors (HDs) who received ChAdOx1-S (A), mRNA-1273 (M), or recombinant protein (MVC-COV1901) vaccines at the National Taiwan University Hospital between 2021 and 2022 were recruited. We measured serial NET-associated biomarkers, citrullinated-histone3 (citH3), and myeloperoxidase (MPO)-DNA. Serum citH3 and MPO-DNA were significantly or numerically higher in HDs who reported AEs (n = 100, booster Day 0/Day 30, p = 0.01/p = 0.03 and p = 0.30/p = 0.35, respectively). We also observed a positive correlation between rash occurrence in online diaries and elevated citH3. A linear mixed model also revealed significantly higher citH3 levels in mRNA-1273/ChAdOx1-S recipients than MVC-COV1901 recipients. Significant positive correlations were observed between the ratios of anti-heparin platelet factor 4 and citH3 levels on Booster Day 0 and naïve and between the ratios of anti-NET IgM and citH3 on Booster Day 30/Day 0 in the AA-M and MM-M group, respectively. The increased levels of citH3/MPO-DNA accompanied by NET-promoting autoantibodies suggest a potential connection between mRNA-1273/ChAdOx1-S vaccines and cardiovascular complications. These findings provide insights for risk assessments of future vaccines.