Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in Alzheimer's disease models.

Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in AD models.

Next-generation sequencing using tissue specimen collected with a 1.1 mm-diameter cryoprobe in patients with lung cancer.

BACKGROUND AND OBJECTIVE: Next-generation sequencing (NGS) analysis is considered standard for lung cancer diagnosis in clinical practice. Little is known about the feasibility of NGS using tumour tissue sampled with a 1.1 mm-diameter cryoprobe. We aimed to investigate the suitability of specimens obtained by transbronchial cryobiopsy (TBC) using a 1.1 mm-diameter cryoprobe for NGS analysis. METHODS: Patients with lung cancer who underwent TBC using a 1.1 mm-diameter cryoprobe for NGS testing between October 2020 and April 2023 were enrolled. A 4.0- or 3.0 mm-diameter bronchoscope with radial probe endobronchial ultrasound and virtual bronchoscopic navigation was used to detect peripheral lung lesions. All procedures were performed under fluoroscopic guidance. Data were analysed retrospectively. RESULTS: A total of 56 patients underwent TBC using a 1.1 mm cryoprobe for NGS testing, during the study period. Most patients (98%) were in the advanced stage of lung cancer (recurrent or inoperable disease of stages III or IV). The diagnostic yield of NGS for DNA and RNA sequencing was 95% each (53 of 56). Moderate bleeding was noted in three patients (5%) and none of the study patients developed life-threatening complications, such as pneumothorax or lung infection. CONCLUSION: TBC using a 1.1 mm-diameter cryoprobe is a useful and safe tool for NGS analysis, for both DNA and RNA sequencing.

Analysis of particulate matter-induced alteration of genes and related signaling pathways in the respiratory system.

Airborne particulate matter (PM) is a global environmental risk factor threatening human health and is a major cause of cardiovascular and respiratory disease-associated death. Current studies on PM exposure have been limited to large-scale cohort and epidemiological investigations, emphasizing the need for detailed individual-level studies to uncover specific differentially expressed genes and their associated signaling mechanisms. Herein, we revealed that PM exposure significantly upregulated inflammatory and immune responses, such as cytokine-mediated signaling pathways, complement system, and the activation and migration of immune cells in gene set enrichment analysis of our RNA sequencing (RNAseq) data. Remarkably, we discovered that the broad gene expression and signaling pathways mediated by macrophages were predominantly expressed in the respiratory system following PM exposure. Consistent with these observations, individual PMs, classified by aerodynamic size and origin, significantly promoted macrophage recruitment to the lungs in the mouse lung inflammation model. Additionally, we confirmed that RNAseq observations from the respiratory system were reproduced in murine bone marrow-derived macrophages and the alveolar macrophage cell line MH-S after individual PM exposure. Our findings demonstrated that PM exposure augmented broad inflammatory and immune responses in the respiratory system and suggested the reinforcement of global strategies for reducing particulate air pollution to prevent respiratory diseases and their exacerbation.

16S rRNA Next-Generation Sequencing May Not Be Useful for Examining Suspected Cases of Spontaneous Bacterial Peritonitis.

Background and Objectives: Ascites, often associated with liver cirrhosis, poses diagnostic challenges, particularly in detecting bacterial infections. Traditional methods have limitations, prompting the exploration of advanced techniques such as 16S rDNA next-generation sequencing (NGS) for improved diagnostics in such low-biomass fluids. The aim of this study was to investigate whether the NGS method enhances detection sensitivity compared to a conventional ascites culture. Additionally, we aimed to explore the presence of a microbiome in the abdominal cavity and determine whether it has a sterile condition. Materials and Methods: Ten patients with clinically suspected spontaneous bacterial peritonitis (SBP) were included in this study. A traditional ascites culture was performed, and all ascites samples were subjected to 16S ribosomal RNA gene amplification and sequencing. 16S rRNA gene sequencing results were interpreted by comparing them to positive and negative controls for each sample. Results: Differential centrifugation was applied to all ascites samples, resulting in very small or no bacterial pellets being harvested. The examination of the 16S amplicon sequencing libraries indicated that the target amplicon products were either minimally visible or exhibited lower intensity than their corresponding negative controls. Contaminants present in the reagents were also identified in the ascites samples. Sequence analysis of the 16S rRNA gene of all samples showed microbial compositions that were akin to those found in the negative controls, without any bacteria isolated that were unique to the samples. Conclusions: The peritoneal cavity and ascites exhibit low bacterial biomass even in the presence of SBP, resulting in a very low positivity rate in 16S rRNA gene sequencing. Hence, the 16S RNA sequencing method does little to enhance the rate of positive samples compared to traditional culture methods, including in SBP cases.

Novel Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus in Wild Birds, South Korea.

We isolated 5 highly pathogenic avian influenza A(H5N1) clade 2.3.4.4.b viruses from wild waterfowl feces in South Korea during November 2022. Whole-genome sequencing and phylogenetic analysis revealed novel genotypes produced by reassortment with Eurasian low pathogenicity avian influenza viruses. Enhanced surveillance will be required to improve prevention and control strategies.

TNEA therapy promotes the autophagic degradation of NLRP3 inflammasome in a transgenic mouse model of Alzheimer's disease via TFEB/TFE3 activation.

BACKGROUND: The impairment in the autophagy-lysosomal pathway (ALP) and the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome represent two molecular events leading to neurodegeneration and neuroinflammation in Alzheimer's disease (AD), a devastating neurodegenerative disorder without a cure. Previously we demonstrated the cognitive-enhancing effect of a combined electroacupuncture (EA) therapy termed TNEA in a transgenic mouse model of AD, involving activation of transcription factor EB (TFEB), a master regulator of ALP. However, whether and how TNEA inhibits NLRP3 inflammasome via TFEB-mediated ALP in AD remains to be investigated. METHODS: 5xFAD mice overexpressing amyloid-ß (Aß) were treated with TNEA or EA on its composing acupoints (GB13 and GV24). The changes in the signaling pathways regulating NLRP3 inflammasome, the association of NLRP3 inflammasome with ALP, and the roles of TFEB/TFE3 in mice brains were determined by immunoblots, immunohistochemistry and AAV-mediated knockdown assays. RESULTS: TNEA inhibits the activation of NLRP3 inflammasome and the release of active interleukin 1ß (IL1B) in the hippocampi of 5xFAD mice. Mechanistically, TNEA promoted the autophagic degradation of inflammasome components via activating both TFEB and TFE3 by modulating kinases including AMPK and AKT. The composing acupoints in TNEA showed synergistic effects on regulating these molecular events and memory improvement. CONCLUSION: Our findings suggest that TNEA attenuates AD-associated memory impairment via promoting TFEB/TFE3-mediated autophagic clearance of Aß and NLRP3 inflammasome, and partially reveal the molecular basis of combined acupoints therapy originated from ancient wisdom.

Heel bone mineral density and various oral diseases: a bidirectional Mendelian randomization.

INTRODUCTION: Observational studies demonstrated that the relationship between bone mineral density and oral diseases is mixed. To access the association between heel bone mineral density and various oral diseases, we conducted the Mendelian randomization analysis to explore the association. MATERIALS AND METHODS: Two-sample bidirectional Mendelian analysis was used to explore the relationship between heel bone mineral density and various oral diseases. The inverse-variance weighted (IVW) was used as the primary effect estimate, and various methods were applied to test the reliability and stability of the results, namely MR-Egger, weighted median, simple mode, and weighted mode. RESULTS: This study showed that there was a negative relationship between heel BMD and periodontitis when heel BMD was used as an exposure factor and periodontitis as an outcome factor (IVW OR = 0.85; 95% CI, 0.75-0.95; p = 0.005). Bidirectional Mendelian randomization showed that there was no statistically significant association between periodontitis and heel bone mineral density when chronic periodontitis was the exposure factor (p > 0.05). And there was no significant relationship between heel bone mineral density and other oral diseases (dental caries, diseases of pulp and periapical tissues, impacted teeth, cleft lip, and cleft palate, oral and oropharyngeal cancer) (p > 0.05). CONCLUSION: This study showed that there was a negative relationship between heel bone density and periodontitis, and the decrease in heel bone density could promote the occurrence of periodontitis. In addition, there was no statistically significant relationship between heel bone density and other oral diseases.

Ecological factors affecting first-time mothers' satisfaction with Sanhujoriwons (postpartum care centres) from South Korea: a cross-sectional and correlational study.

BACKGROUND: In South Korea, commercial postpartum care centres, known as Sanhujoriwons, have emerged as important institutions aiding mothers' physical recovery after childbirth. Although previous studies have measured mothers' satisfaction level with Sanhujoriwons, this study applies Bronfenbrenner's ecological model to identify the factors influencing first-time mothers' satisfaction with Sanhujoriwons. METHODS: This descriptive correlational study involved 212 first-time mothers admitted to Sanhujoriwons for two weeks with their new-borns (healthy babies weighing at least 2.5 kg) after giving birth after 37 weeks of pregnancy. Data were collected using a self-report questionnaire at five postpartum care centres in the metropolitan area of South Korea from October to December 2021, on the day of the mothers' discharge. This study considered ecological factors such as perceived health status, postpartum depression, childcare stress, maternal identity at the individual level; partnership with Sanhujoriwon staff at the microsystem level; and the Sanhujoriwons' education support system at the exo-system level. The data were analysed using descriptive statistics, t-test, one-way ANOVA, correlation analysis, and hierarchical regression analysis using the SPSS 25.0 Win program. RESULTS: The mean score of satisfaction with Sanhujoriwons was 59.67 ± 10.14 out of 70, indicating a high level of satisfaction. The hierarchical regression analysis showed that satisfaction with Sanhujoriwons was significantly affected by the perceived health status (ß = 0.19, p < 0.001), partnership between mothers and the caregivers (ß = 0.26, p < 0.001), and education support system of the Sanhujoriwons (ß = 0.47, p < 0.001). The explanatory power of the model for these variables was 62.3%. CONCLUSIONS: Our results indicate that not only the mother's health status but also the educational support system of postpartum care centres and partnerships are important for improving first-time mothers' satisfaction with postpartum care centres. Thus, when developing an intervention program for postpartum care centres, practitioners should focus on developing various kinds of support and strategies to improve the physical health condition of mothers, build partnerships between mothers and care staff, and improve the quality of the educational support offered to mothers. Further studies to develop and test the effectiveness of such intervention programs are strongly suggested.

Graft Extrusion of 3 Millimeters Is Acceptable at a Minimum of 5-Year Outcomes for Lateral Meniscal Allograft Transplantation.

PURPOSE: To determine the acceptable amount of graft extrusion based on long-term radiographic outcomes in lateral meniscal allograft transplantation (MAT). METHODS: 94 lateral MAT patients with a minimum 5-year follow-up period were reviewed. Graft extrusion was measured on MRI scans taken 1 year after surgery, and the study population was divided according to the amount of extrusion: group A, extrusion <3 mm; group B, 3 mm ≤ extrusion <5 mm; and group C, extrusion ≥5 mm. For radiographic evaluation, the bilateral lateral joint space widths (JSWs) were measured on a standing 45° flexion posteroanterior radiograph. To standardize the measurements, the affected JSW was divided by the contralateral JSW. The change in the standardized JSW (ΔJSWstd) between the preoperative and latest follow-up assessments was analyzed according to the three groups. Multiple regression analysis was performed to control other related factors, such as lower limb alignment and cartilage status at the time of MAT. The acceptable amount of graft extrusion was calculated using a receiver operating characteristic (ROC) curve for the third quartile of ΔJSWstd. Clinical outcomes were evaluated using the Lysholm score and were compared among the groups. RESULTS: The mean follow-up duration was 8.3 ± 3.1 years. There were 54, 25, and 15 patients in group A, group B, and group C, respectively. In multiple regression analysis, both group B and group C had significant associations with ΔJSWstd and their beta coefficients were comparable (group B, P < .001, ß = .642; group C, P < .001, ß = 0.613). No significant difference in ΔJSWstd was found between group B and group C (P = .494). On the basis of the ROC curve, the acceptable amount of graft extrusion was 3.74 mm (sensitivity, 81.8%; specificity, 77.8%). There were no differences in the Lysholm scores among the three groups (P = .329). CONCLUSIONS: ΔJSWstd differed between graft extrusion <3 mm (group A) and graft extrusion ≥3 mm (group B and group C). However, there was no significant difference in ΔJSWstd between group B and group C. No significant difference in clinical outcomes was found according to graft extrusion. This study gave supporting evidence for the currently recognized acceptable amount of graft extrusion (3 mm). LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Signal intensity of lateral meniscal allografts deteriorates over time: a longitudinal MRI analysis during a minimum follow-up of 8 years.

PURPOSE: To evaluate the serial change of magnetic resonance imaging (MRI) signal intensity (SI) of lateral meniscal allografts in a long-term period of > 8 years and to determine whether the SI change adversely affected clinical outcomes. METHODS: Thirty-three lateral meniscal allograft transplantation (LMAT) patients with MRI taken > 8 years after surgery were included. The allograft was assessed using MRI at five serial time points (1, 2-4, 4-6, 6-8, and > 8 years after surgery), based on the following grading system: grade 1, globular increased SI not adjacent to the articular surface; grade 2, linear SI within the meniscus; and grade 3, increased SI extended to the articular surface. MRI evaluation was performed for three locations of the allograft (anterior horn, mid-body, and posterior horn), and the serial changes of allograft SI at each location were analyzed using the generalized estimating equation (GEE) with cumulative logit link function. The patients were classified according to SI change at each location (stationary group and deterioration group), and the two groups were compared in terms of clinical outcomes using the Lysholm score. RESULTS: The mean follow-up duration was 9.2 ± 1.2 years. During that period, SI of the allograft deteriorated over time, regardless of the location (anterior horn, p = 0.034; mid-body, p = 0.002; posterior horn, p < 0.001). The amount of SI deterioration at each location of the graft differed with a borderline significance (p = 0.050, GEE), and the proportion of grade 3 SI was higher at the posterior horn (36.4%) than at the other locations at the last follow-up (p < 0.001, chi-square test). However, no significant differences in the Lysholm scores were found between the stationary group and the deterioration group at all locations. CONCLUSION: SI of the meniscal allograft deteriorated over time at all locations during the long-term follow-up. Deterioration of the graft was more prominent at the posterior horn than at the other locations. SI deterioration did not adversely affect the clinical outcomes, which should be interpreted with caution, considering the small sample size of this study. In the prognosis of lateral MAT, SI deterioration at the posterior horn is a more determining factor than that at the other part of the allograft. Therefore, SI at the posterior horn needs to be examined with special concern. LEVEL OF EVIDENCE: III.

Age alone does not affect the joint survivorship after arthroscopic partial meniscectomy for degenerative medial meniscus tears: a propensity-score matched survival analysis.

PURPOSE: To evaluate the effect of age itself on the joint survivorship after arthroscopic partial meniscectomy (APM) for degenerative medial meniscus tears (DMTs). METHODS: Patients undergoing APM for DMTs during 1999-2010 were retrospectively reviewed. The inclusion criteria were as follows: (1) DMTs identified on preoperative MRI scans, (2) no definite history of trauma, and (3) follow-up duration more than 5 years. In evaluation of the joint survivorship, the endpoint was defined as conversion to arthroplasty (or realignment osteotomy) or progression to Kellgren-Lawrence grade 4. The study population was divided into older and younger groups by a cutoff age at which the difference in the joint survival rates was maximized, using a time-dependent receiver operating characteristic (ROC) curve. The two groups were then matched based on propensity scores. The joint survival rates were compared between the groups using Kaplan-Meier analysis, before and after propensity score matching (PSM). RESULTS: A total of 633 knees were included. The cutoff age was calculated as 60 years. Before PSM, 239 knees were allocated to the older group (≥ 60 years) and 394 knees to the younger group (< 60 years). A significant difference in the joint survival rates was noted between the groups (log-rank test, p < 0.001). After PSM, 183 knees remained in each group. The difference in the survival rates was no more statistically significant (n.s.). The latest Lysholm scores of the older and the younger groups before PSM were 72.2 ± 20.8 and 79.9 ± 19.6, respectively (p < 0.001); however, the scores after PSM were 73.2 ± 20.3 and 77.4 ± 20.5, respectively (n.s.). CONCLUSIONS: Joint survivorship after APM was affected by other factors associated with the aging process, such as cartilage status and meniscal tear pattern, rather than age itself. Advanced age should not be the only reason for precluding APM in treatment of DMTs. APM is a viable option when treating DMTs in elderly patients if adopted with caution. According to this study, a surgeon should assess the age-related factors when he considers APM in elderly patients. LEVEL OF EVIDENCE: III.

Combinatorial MAB-Based Joint Channel and Spreading Factor Selection for LoRa Devices.

Long-Range (LoRa) devices have been deployed in many Internet of Things (IoT) applications due to their ability to communicate over long distances with low power consumption. The scalability and communication performance of the LoRa systems are highly dependent on the spreading factor (SF) and channel allocations. In particular, it is important to set the SF appropriately according to the distance between the LoRa device and the gateway since the signal reception sensitivity and bit rate depend on the used SF, which are in a trade-off relationship. In addition, considering the surge in the number of LoRa devices recently, the scalability of LoRa systems is also greatly affected by the channels that the LoRa devices use for communications. It was demonstrated that the lightweight decentralized learning-based joint channel and SF-selection methods can make appropriate decisions with low computational complexity and power consumption in our previous study. However, the effect of the location situation of the LoRa devices on the communication performance in a practical larger-scale LoRa system has not been studied. Hence, to clarify the effect of the location situation of the LoRa devices on the communication performance in LoRa systems, in this paper, we implemented and evaluated the learning-based joint channel and SF-selection methods in a practical LoRa system. In the learning-based methods, the channel and SF are decided only based on the ACKnowledge information. The learning methods evaluated in this paper were the Tug of War dynamics, Upper Confidence Bound 1, and ϵ-greedy algorithms. Moreover, to consider the relevance of the channel and SF, we propose a combinational multi-armed bandit-based joint channel and SF-selection method. Compared with the independent methods, the combinations of the channel and SF are set as arms. Conversely, the SF and channel are set as independent arms in the independent methods that are evaluated in our previous work. From the experimental results, we can see the following points. First, the combinatorial methods can achieve a higher frame success rate and fairness than the independent methods. In addition, the FSR can be improved by joint channel and SF selection compared to SF selection only. Moreover, the channel and SF selection dependents on the location situation to a great extent.

Effect of White Noise on Pain Response, Heart Rate, and Oxygen Saturation During Heel Puncture in Premature Infants: A Randomized Controlled Trial.

OBJECTIVE: This study aimed to investigate the effect of white noise on pain response, heart rate, and oxygen saturation during heel puncture in premature infants. METHODS: A randomized, controlled, pretest-posttest design was used. The participants were premature infants admitted to the neonatal intensive care unit of a university hospital in Gyeonggi Province. Sixty premature infants were assigned to either an experimental (n = 30) or control (n = 30) group. The experimental group was exposed to white noise during heel puncture, and the measured variables were pain response, heart rate, and oxygen saturation. The data were analyzed using the independent t test, chi-squared test, and analysis of covariance. RESULTS: Premature infants in the experimental group had a lower pain response and heart rate than the control group (F = 81.26, P < .01; F = 7.05, P = .01), and higher oxygen saturation than the control group (F = 4.76, P = .03). CONCLUSION: These results demonstrated that the white noise intervention is an effective nursing intervention to reduce the pain response and stabilize heart rate and oxygen saturation in premature infants during heel puncture.

Difference in Joint Stability Between Small Posterior Malleolar Fragments With Fixation and Those Without Fixation: A Biomechanical Cadaver Study.

The indication for the surgical treatment of ankle fractures that involve a posterior malleolar fragment remains controversial. This cadaver study assessed the biomechanical results of rotation stiffness of Haraguchi type 1 posterior malleolar fragments with or without cannulated screw fixation. Twelve anatomic lower-extremity specimens from 6 cadavers were tested. Six right legs were subjected to posterior malleolus osteotomy (Haraguchi type I) followed with (group A; n = 3) or without (group B; n = 3) fixation using a cannulated screw. Ankle joint stability was measured under both external rotation force and axial loading, and the passive resistive torque was measured in both groups. The mean torque value in group A was 0.1093 Nm/º, while that in group B was 0.0537 Nm/º. There was a significant intergroup difference (p = .004). In group B, the torque value was further increased in the latter rotation period (about 40-60 degrees). Group A proved more stable under experimental conditions than group B. Fixation in type I posterior malleolar fragments produced improved stability in ankle rotation, even for posterior malleolar fragments involving <25% of the articular surface, and has been considered an effective aid in treatment.

Adaptive R&D contract for urgently needed drugs: Lessons from COVID-19 vaccine development.

This paper analyzes an incentive contract for new vaccine research and development (R&D) under pandemic situations such as COVID-19, considering the R&D contract's adaptability to the pandemic. We study how the public sector (government) designs the adaptive R&D contract and offers it to pharmaceutical enterprises. An agency-theoretic model is employed to explore the contract whose terms are an upfront grant as a fixed fee and a sales tax credit as an incentive tool, examining how the values of related parameters affect contract term determinations. We found that the adaptability factor derived from urgent policies such as emergency use authorization (EUA) as well as tax credits, can be utilized as practical incentive tools that lead vaccine developers to increase their effort levels for R&D success. We also found that public-private state-emergency contracts may not follow the conventional wisdom. Counterintuitively, dependency on tax credits (incentive part) decrease as the client's degree of risk averseness increases in the emergency contract.

[Research progress and maturity assessment of continuous manufacturing of traditional Chinese medicine].

The pharmaceutical manufacturing model is gradually changing from intermittent manufacturing to continuous manufacturing and intelligent manufacturing. This paper briefly reviewed the supervision and research progress in continuous pharmaceutical manufacturing in China and abroad and described the definition and advantages of continuous pharmaceutical manufacturing. The continuous manufacturing of traditional Chinese medicine(TCM) at the current stage was summarized in the following three terms: the enhancement of the continuity of intermittent manufacturing operations, the integration of continuous equipment to improve physical continuity between units, and the application of advanced process control strategies to improve process continuity. To achieve continuous manufacturing of TCM, the corresponding key technologies, such as material property characterization, process modeling and simulation, process analysis technology, and system integration, were analyzed from the process and equipment, respectively. It was proposed that the continuous manufacturing equipment system should have the characteristics of high speed, high response, and high reliability, "three high(H~3)" for short. Considering the characteristics and current situation of TCM manufacturing, based on the two dimensions of product quality control and production efficiency, a maturity assessment model for continuous manufacturing of TCM, consisting of operation continuity, equipment continuity, process continuity, and quality control continuity, was proposed to provide references for the application of continuous manufacturing technology for TCM. The implementation of continuous manufacturing or the application of key continuous manufacturing technologies in TCM can help to systematically integrate advanced pharmaceutical technology elements and promote the uniformity of TCM quality and the improvement of production efficiency.

Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy.

Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 µM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP+-treated PC12 cells, CB6 inhibited cell apoptosis and increased cell viability by inducing autophagy. In MPTP-induced mouse model of PD, oral administration of CB6 (10, 20 mg· kg-1· d-1, for 21 days) significantly improved motor dysfunction and prevented the loss of dopaminergic neurons in the striatum and substantia nigra pars compacta. Collectively, compound CB6 is a brain-permeable autophagy enhancer via PIK3C3 complex activation, which may help the prevention or treatment of PD.

TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2.

Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-∆-12,14-prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d-PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.

Ecological factors influencing parenting self-efficacy among working mothers with a child under 36 month old in South Korea: a cross-sectional and correlational study.

BACKGROUND: Parenting self-efficacy is an essential component for parents to successfully perform their role and is important for mother and child well-being. To support parenting self-efficacy amongst working mothers, it is necessary to understand the factors influencing parenting self-efficacy amongst this group. However, the majority of previous studies regarding factors influencing parenting self-efficacy did not focus on working mothers. Therefore, this study aimed to identify the factors influencing parenting self-efficacy of working mothers using an ecological framework. METHODS: The research design was a cross-sectional, correlational study. The participants were 298 working mothers with a child under 3 years of age, who were recruited from ten nurseries. Data were collected from August 8 to September 22, 2017 using structured questionnaires, including the Parenting Sense of Competency scale, a one-item Short Form Health Survey scale, the Maternal Role Satisfaction scale, the Parenting Stress Inventory, the Work and Parent Role Conflict scale, the Parenting Alliance Inventory, the Social Support scale, and the Childbirth and Parenting Friendly System scale. The study process of this study was approved by the Institutional Review Board. Collected data were analyzed by SPSS 23.0 Win program with descriptive statistics, t-test, one way ANOVA, Pearson correlation coefficient, and hierarchical multiple regression. RESULTS: Working mothers who were the primary caregiver had higher parenting self-efficacy compared to those who were not the primary caregiver (ß = .13, p = .022). At the individual level, the higher maternal role satisfaction, the higher parenting self-efficacy of working mothers (ß = .27, p < .001). In the micro-system level, higher parenting support by a spouse was associated with higher parenting self-efficacy of working mothers (ß = .19, p = .002). CONCLUSIONS: Educational interventions for increasing the awareness and satisfaction of maternal role and various strategies for fathers' active participation in parenting should be developed. In addition, practical interventions that reduce the burden of parenting while supporting parenting self-efficacy of working mothers who are the primary caregiver should also be considered.

Insufficient Correction and Preoperative Medial Tightness Increases the Risk of Varus Recurrence in Open-Wedge High Tibial Osteotomy.

PURPOSE: To assess serial changes of limb alignment after open wedge high tibial osteotomy (HTO) using the weightbearing line (WBL) ratio in the midterm, with a focus on varus recurrence. METHODS: Patients undergoing open wedge HTO from January 2010 to December 2016 were retrospectively reviewed. Those without serial postoperative weightbearing long-leg alignment films, those who showed remained varus alignment after osteotomy, and those who had <2 years of follow-up were excluded. In terms of immediate postoperative limb alignment (≤3 months) measured using WBL ratio, cases were categorized into 4 groups: <50%, undercorrection; 50% to 57%, insufficient correction; 57% to 67%, planned correction; and >67%, overcorrection. To determine risk factors for varus recurrence (WBL ratio <50%), immediate postoperative WBL ratio category and preoperative valgus and varus stress angles (which represent medial and lateral tightness of the joint, respectively) were investigated using logistic regression analysis, taking other related factors into account. Clinical outcomes according to varus recurrence were measured using Hospital for Special Surgery (HSS) scores. RESULTS: A total of 148 cases were included. Varus recurrence was noted in 40 cases (27.0%), with a mean follow-up of 49.7 ± 21.8 months (range 24 to 102 months). The incidence of varus recurrence was different according to WBL ratio category: 10/10 (100.0%) in undercorrection; 16/33 (48.5%) in insufficient correction; 13/58 (22.4%) in planned correction; and 1/47 (2.1%) in overcorrection. Based on logistic regression analysis, insufficient correction and preoperative valgus stress angle were found to be significant risk factors (P = .038, and .008, respectively). With valgus stress angle <2°, 7 of 10 insufficient correction cases showed varus recurrence (P = .005). However, HSS scores did not differ according to varus recurrence (P = .363). CONCLUSION: Insufficient correction and preoperative medial tightness increased the risk of varus recurrence. Especially in cases where preoperative valgus stress angle was <2°, insufficient correction was strongly associated with varus recurrence. However, no significant differences in clinical outcomes were observed according to varus recurrence in the midterm. LEVEL OF EVIDENCE: III, retrospective cohort study.