Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons.

Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.

Dweck's Social-Cognitive Model of Achievement Motivation in Science.

Dweck's social-cognitive model has long been used as a basis for achievement motivation research. However, few studies have examined the comprehensive model with interactions between perceived ability and achievement goals, and even fewer studies have focused on this model in a science academic context. With a sample of undergraduates (n = 1,036), the relations among mindsets, science academic self-efficacy, achievement goals, and achievement-related outcomes in science were examined. Fixed mindset related to performance goals. Growth mindset related to mastery goals and the number of courses completed. There was a significant indirect effect of growth mindset on interest value via mastery goals. Contrary to Dweck's model, the relation of performance goals to outcomes did not vary as a function of science academic self-efficacy. The findings provide empirical evidence for a more nuanced understanding of Dweck's model. They provide practical insights for how to support undergraduate students who are pursuing science-related career.

Patterns, predictors, and outcomes of situated expectancy-value profiles in an introductory chemistry course.

Using latent profile analysis, we identified profiles of expectancy beliefs, perceived values, and perceived costs among 1433 first- and second-year undergraduates in an introductory chemistry course for STEMM majors. We also investigated demographic differences in profile membership and the relation of profiles to chemistry final exam achievement, science/STEMM credits completed, and graduating with a science/STEMM major. Four motivational profiles were identified: Moderately Confident and Costly (profile 1), Mixed Values-Costs/Moderate-High Confidence (profile 2), High Confidence and Values/Moderate-Low Costs (profile 3), and High All (profile 4). Underrepresented students in STEMM were more likely to be in profile 2 relative to profile 3. First-generation college students were more likely to be in profile 4 than profile 3. Finally, students likely to be in profile 3 had higher final exam grades than the other profiles and were more likely to graduate with a science major compared to profile 1. There were no differences in graduating science major between profile 3 and the other two profiles. Thus, profile 3 was most adaptive for both proximal (final exam) and distal (graduating with a science major) outcomes. Results suggest that supporting motivation early in college is important for persistence and ultimately the talent development of undergraduate STEMM students.

Development of new tools to study membrane-anchored mammalian Atg8 proteins.

ABBREVIATIONS: A:C autophagic membrane:cytosol; ALS amyotrophic lateral sclerosis; ATG4 autophagy related 4; Atg8 autophagy related 8; BafA1 bafilomycin A1; BNIP3L/Nix BCL2 interacting protein 3 like; CALCOCO2/NDP52 calcium binding and coiled-coil domain 2; EBSS Earle's balanced salt solution; GABARAP GABA type A receptor-associated protein; GST glutathione S transferase; HKO hexa knockout; Kd dissociation constant; LIR LC3-interacting region; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; NLS nuclear localization signal/sequence; PE phosphatidylethanolamine; SpHfl1 Schizosaccharomyces pombeorganic solute transmembrane transporter; SQSTM1/p62 SQSTM1/p62; TARDBP/TDP-43 TAR DNA binding protein; TKO triple knockout.

Regulation of α-synuclein homeostasis and inflammasome activation by microglial autophagy.

Autophagy clears protein aggregates, damaged cellular organelles, and pathogens through the lysosome. Although autophagy is highly conserved across all cell types, its activity in each cell is specifically adapted to carry out distinct physiological functions. The role of autophagy in neurons has been well characterized; however, in glial cells, its function remains largely unknown. Microglia are brain-resident macrophages that survey the brain to remove injured neurons, excessive synapses, protein aggregates, and infectious agents. Current studies have demonstrated that dysfunctional microglia contribute to neurodegenerative diseases. In Alzheimer's disease animal models, microglia play a critical role in regulating amyloid plaque formation and neurotoxicity. However, how microglia are involved in Parkinson's disease (PD) remains poorly understood. Propagation of aggregated α-synuclein via cell-to-cell transmission and neuroinflammation have emerged as important mechanisms underlying neuropathologies in PD. Here, we review converging evidence that microglial autophagy maintains α-synuclein homeostasis, regulates neuroinflammation, and confers neuroprotection in PD experimental models.

AKT, a Key Transmitter of HIF-1α and AR Signaling Pathways, Has a Critical Role in the Apigetrin-Mediated Anti-Cancer Effects in Prostate Cancer Cells.

Apigetrin is a flavonoid glycoside phytochemical that is derived from various herbs and exhibits several beneficial biological activities, including anti-oxidant, anti-inflammatory, anti-obesity, and anti-cancer effects. In the present study, we elucidated the anti-cancer effect and targeting mechanism of apigetrin in LNCaP and PC-3 cells through various experiments, including cell viability by CELLOMAXTM Viability Assay kit, cell migration by scratch wound assays, and 2D-and 3D- cell growth assay. Apigetrin inhibited the viability, migration, proliferation, and growth of cells in long-term 2D- and 3D- cultures cell growth. A high dose of apigetrin induced apoptosis, as evidenced by increased cleavage of poly ADP-ribose polymerase (PARP) and caspase-3 (c-cas3) in both LNCaP and PC-3 cells. Furthermore, apigetrin inhibited AR, PSA, HIF-1α, and VEGF expression in LNCaP and PC-3 cells. Apigetrin also suppressed the hypoxia-induced HIF-1α expression in these cells. Furthermore, apigetrin reduced hypoxia-induced VEGF secretion in the culture medium and inhibited hypoxia-induced tube formation of HUVECs. Silencing of AKT revealed that the anti-cancer activity of apigetrin is mediated via AKT. Thus, our data suggest that apigetrin exerts anti-cancer effects by inhibiting AKT, a central key of HIF-1α and AR signaling, in early-and late-stage prostate cancer cells.

Feasibility and acceptability of a digital tele-guided intervention targeting components of the addictive appetite model for bulimia nervosa and binge-eating disorder in Korea.

OBJECTIVE: We aimed to evaluate the feasibility, acceptability, and potential impact of a tele-guided digital-based intervention based on the addictive appetite model of recurrent binge eating. METHOD: Female college students with bulimia nervosa (BN) or binge-eating disorder (BED) (n = 22) received a 6-week guided intervention targeting addictive processes and emotion regulation. The feasibility of the intervention was evaluated, and the outcomes were assessed at baseline, the end of the intervention, and 1-month follow-up. RESULTS: Of the participants, 86.4% (n = 19) completed the intervention. The self-help materials were viewed 6.03 ± 3.06 times per week, and the duration of using the self-help materials was 113.16 ± 160.19 min/week. The intervention group experienced a significant reduction with a moderate effect on binge eating at the end of the intervention (Hedges' g = 0.58), and the effects lasted through follow-up (Hedges' g = 0.82). DISCUSSION: The results suggest that the digital intervention targeting a maintenance mechanism of recurrent binge eating was feasible and acceptable for patients with BN and BED, proving the potential for symptom improvement. PUBLIC SIGNIFICANCE: The addictive appetite model provides the framework for new interventions to improve treatments for BN and BED. This study found that the digital intervention based on the model was feasible and acceptable for patients with BN and BED.

Co-Development of Adolescents' Cooperative and Competitive Attitudes: How it Predicts Mental Health and Academic Achievement.

This study used nationally representative longitudinal data in South Korea to examine how joint changes in adolescents' (N = 7324; Mage ≈ 11 years) cooperative and competitive attitudes from sixth to ninth grade relate to mental health and achievement in 10th grade. The parallel process model showed that both cooperative and competitive attitudes declined over time. Higher cooperative attitudes at baseline indicated higher competitive attitudes, and a faster decline in cooperative attitudes indicated a faster decline in competitive attitudes. The intercept of cooperative attitudes was positively related to mental health but negatively related to achievement. Opposite patterns were found for the intercept of competitive attitudes. These findings highlight the usefulness of considering the co-development of cooperative and competitive attitudes.

Cooperative and Competitive Attitudes During Adolescence and Their Social and Academic Outcomes.

Individuals develop diverse social attitudes during adolescence. This study focused on adolescents' cooperative and competitive attitudes from grades 7-11 and their outcomes in grade 12. The sample included 6,908 South Korean adolescents (47.6% girls, mean age = 12.83, range = 12-15). Latent cross-lagged models revealed negative directional associations between cooperative and compet itive attitudes for grades 7-10, but no significant associations for grades 10-11. Cooperative attitudes contributed more to social than academic outcomes, whereas competitive attitudes more positively predicted academic outcomes. The results suggest that educators who support early to mid-adolescents' cooperative or competitive attitudes need to strike a delicate balance as these attitudes do not change independently and both have distinct strengths and weaknesses.

Lactiplantibacillusplantarum ATG-K2 Exerts an Anti-Obesity Effect in High-Fat Diet-Induced Obese Mice by Modulating the Gut Microbiome.

Obesity is a major health problem. Compelling evidence supports the beneficial effects of probiotics on obesity. However, the anti-obesity effect of probiotics remains unknown. In this study, we investigated the anti-obesity effects and potential mechanisms of Lactiplantibacillus plantarum ATG-K2 using 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice. 3T3-L1 cells were incubated to determine the effect of lipid accumulation with lysate of L. plantarum ATG-K2. Mice were fed a normal fat diet or HFD with L. plantarum ATG-K2 and Orlistat for 8 weeks. L. plantarum ATG-K2 inhibited lipid accumulation in 3T3-L1 adipocytes, and reduced body weight gain, WAT weight, and adipocyte size in HFD-induced obese mice, concurrently with the downregulation of PPARγ, SREBP1c, and FAS and upregulation of PPARα, CTP1, UCP1, Prdm16, and ND5. Moreover, L. plantarum ATG-K2 decreased TG, T-CHO, leptin, and TNF-α levels in the serum, with corresponding gene expression levels in the intestine. L. plantarum ATG-K2 modulated the gut microbiome by increasing the abundance of the Lactobacillaceae family, which increased SCFA levels and branched SCFAs in the feces. L. plantarum ATG-K2 exhibited an anti-obesity effect and anti-hyperlipidemic effect in 3T3-L1 adipocytes and HFD-induced obese mice by alleviating the inflammatory response and regulating lipid metabolism, which may be influenced by modulation of the gut microbiome and its metabolites. Therefore, L. plantarum ATG-K2 can be a preventive and therapeutic agent for obesity.

Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice.

Heterogeneity in the etiopathology of autism spectrum disorders (ASD) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.

Lactobacillus plantarum HAC01 ameliorates type 2 diabetes in high-fat diet and streptozotocin-induced diabetic mice in association with modulating the gut microbiota.

Type 2 diabetes mellitus (T2DM) is a serious metabolic disorder that occurs worldwide; however, this condition can be managed with probiotics. We assessed the potential therapeutic effects of Lactobacillus plantarum HAC01 on hyperglycemia and T2DM and determined their potential mechanisms using mice with high-fat diet (HFD) and streptozotocin (STZ)-induced diabetes. The diabetic model was established with an HFD and 50 mg kg-1 STZ. L. plantarum HAC01 was then administered for 10 weeks. Body weight, food and water intake, biochemical parameters, and homeostasis model assessment for insulin resistance (HOMA-IR) were measured. Oral glucose tolerance test and histological analysis were performed, and the glucose metabolism-related gene expression and signaling pathways in the liver were determined. Fecal microbiota and serum short-chain fatty acids (SCFAs) were also analyzed. L. plantarum HAC01 significantly lowered blood glucose and HbA1c levels and improved glucose tolerance and HOMA-IR. Additionally, it increased the insulin-positive ß-cell area in islets and decreased the mRNA expression levels of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, which are associated with gluconeogenesis. L. plantarum HAC01 also increased the phosphorylation of AMPK and Akt, which are involved in glucose metabolism in the liver. Notably, L. plantarum HAC01 increased the Akkermansiaceae family and increased SCFAs in serum. L. plantarum HAC01 could alleviate hyperglycemia and T2DM by regulating glucose metabolism in the liver, protecting the islet ß-cell mass, and restoring the gut microbiota and SCFAs. L. plantarum HAC01 may thus be an effective therapeutic agent for T2DM.

Autophagy activity contributes to the impairment of social recognition in Epac2-/- mice.

Autophagy is a lysosomal degradation pathway that regulates cellular homeostasis. It is constitutively active in neurons and controls the essential steps of neuronal development, leading to its dysfunction in neurodevelopmental disorders. Although mTOR-associated impaired autophagy has previously been reported in neurodevelopmental disorders, there is lack of information about the dysregulation of mTOR-independent autophagy in neurodevelopmental disorders. In this study, we investigated whether the loss of Epac2, involved in the mTOR-independent pathway, affects autophagy activity and whether the activity of autophagy is associated with social-behavioral phenotypes in mice with Epac2 deficiencies. We observed an accumulation of autophagosomes and a significant increase in autophagic flux in Epac2-deficient neurons, which had no effect on mTOR activity. Next, we examined whether an increase in autophagic activity contributed to the social behavior exhibited in Epac2-/- mice. The social recognition deficit observed in Epac2-/- mice recovered in double transgenic Epac2-/-: Atg5+/- mice. Our study suggests that excessive autophagy due to Epac2 deficiencies may contribute to social recognition defects through an mTOR-independent pathway.

Stereotype Threat in High School Classrooms: How It Links to Teacher Mindset Climate, Mathematics Anxiety, and Achievement.

As stereotype threat was initially examined in experimental settings, the effects of such threats have often been tested by temporarily manipulating social identity threats. This study expands the literature by examining 9th-grade adolescents' naturalistic stereotype threat, using data from the National Study of Learning Mindsets in the United States (n ~= 6040, age: 13-17, Mage = 14.31, 6.9% Black boys, 6.5% Black girls, 13.1% Latinos, 12.3% Latinas, 31.5% White boys, 29.7% White girls). The results indicate that Black and Latinx students experience higher levels of stereotype threat in high school mathematics classrooms than do their White peers. When students perceive that their teachers have created fixed mindset climates, they experience greater stereotype threat. Stereotype threat, in turn, negatively predicts Black and Latino boys and White girls' later achievement via anxiety. These findings highlight the importance of creating mathematics classrooms that cultivate a growth mindset and minimize social identity threat.

Current Status of Clinical Practice Guidelines in Korea.

BACKGROUND: The development process of clinical practice guidelines (CPGs) must adhere to development standards and must be supported and steered by a representative and consistent governing body. We aimed to investigate the current status of the most recent CPGs published in Korea through surveys of medical professional societies and literature searches. METHODS: We collected CPGs developed in Korea in the past 5 years through several electronic database searches (MEDLINE, Embase, and KoreaMed), hand searches, and surveys of medical society memberships from the Korean Academy Medical Societies. Three authors selected Korean CPGs according to our inclusion/exclusion criteria and extracted data from selected CPGs about general characteristics, characteristics of CPGs for setup, evidence evaluation, and the finalization phase. RESULTS: Out of 2,337 articles searched from various sources and 66 documents collected by survey, 129 guidelines (122 by database searching and 7 by survey) were selected. During the recent 5 years, the yearly numbers of CPGs developed were around 25. A single organization was the most frequent CPG development body (42, 32.6%). The most common development methodologies described in the CPGs included were de novo (53, 41.1%) followed by adaptation (48, 37.2%) and hybrid (4, 3.1%). Systematic literature searching was performed in most of the guidelines (79.8%). The evidence level was reported in 104 guidelines (80.6%). There were 77 guidelines (59.7%) that reported an update plan. Fifty guidelines were published in Korean (41.0%), and 46 guidelines were published in English only (37.7%). CONCLUSION: Among CPGs developed in Korea in the last 5 years, the proportion adhering to CPG development standards has increased, but there is still room for improvement.

The Role of Stereotype Threat in Ethnically Minoritized Students' Science Motivation: A Four-Year Longitudinal Study of Achievement and Persistence in STEM.

Grounded in expectancy-value and stereotype threat theories, this four-year longitudinal study examined associations between changes in stereotype threat and motivation (self-efficacy, task values, and perceived costs) among 425 undergraduates from racial/ethnic groups typically underrepresented in science, technology, engineering, and mathematics (STEM). Growth analyses indicated that students' stereotype threat and perceived cost of studying science increased during college, whereas science self-efficacy, intrinsic value, and attainment value declined. Parallel growth analyses suggested that higher initial stereotype threat related to a faster decline in attainment value and faster increase in perceived costs throughout college. Higher initial levels and a steeper increase in stereotype threat related to lower STEM GPA. Higher initial levels and a slower decline in motivation variables related to higher STEM GPA and more completed STEM courses. These findings provide empirical evidence for the relations between stereotype threat and motivation among underrepresented minority students during a key developmental period.

Longitudinal relations between South Korean adolescents' academic self-efficacy and values in mathematics and English.

BACKGROUND: Students' motivation generally declines over time. Some researchers have suggested that the parallel decline in academic self-efficacy and values may be as a result of the longitudinal reciprocal relations between these two motivational constructs. However, little empirical evidence has supported this speculation. Further, all prior evidence has been provided based on samples of students from Western countries (Europe, United States). AIMS: The current study was designed to examine the reciprocal relation between academic self-efficacy and values with a sample from another culture, namely South Korea. SAMPLE: We used nationally representative longitudinal data of 6,908 students in seventh grade (Mage  = 12.83 years). METHODS: We analysed the data tracking our sample from 7th grade to 11th grade. Latent cross-lagged models of academic self-efficacy and values in mathematics and English for 5 years were tested, while controlling for gender, achievement, and family income. RESULTS: In both mathematics and English domains, there emerged significant unidirectional paths from prior values to later self-efficacy from Grades 8 to 11. For English, significant unidirectional paths from prior self-efficacy to later values additionally emerged from Grades 8 to 9. That is, significant reciprocity between self-efficacy and values was found for English from Grades 8 to 9. CONCLUSIONS: Relatively consistent paths from prior values to later self-efficacy were identified among Korean adolescents, distinct from prior work focusing on students from Western countries. The results underscore the importance of considering different educational contexts and suggest the critical role of values in the development of Korean adolescents' academic self-efficacy.

A Retrospective Analysis Evaluating the Outcome of Parenteral Nutrition in the Treatment of Anorexia Nervosa in Korea.

The objective of this study was to investigate the clinical efficacy of parenteral nutrition (PN) as supplemental feeding for patients with anorexia nervosa (AN). This study was conducted by reviewing the medical records of patients with AN who were hospitalized at a non-specialized ward. A total of 129 patients with AN were recruited, consisting of 67 patients received PN with oral refeeding and 62 patients received oral refeeding alone. We compared the weight gain at discharge and after discharge between the groups. As a result, at admission, the patients given supplementary PN had lower body mass indices and lower caloric intake than the patients without PN. The mean duration of PN was 8.5 days, which amounted to about a third of the average hospital stay with no difference between the groups. Both groups had similar weight gains during hospitalization, but the patients with PN had higher weight gains than the patients without PN at one and three months after discharge. In conclusion, the results suggest that supplementary PN in the early stage of refeeding might initiate weight gain in AN when nasogastric tube feeding is not possible. Randomized controlled trials are needed to be further tested of PN in treatment of AN.

Nonmuscle myosin IIB regulates Parkin-mediated mitophagy associated with amyotrophic lateral sclerosis-linked TDP-43.

C-terminal fragments of Tar DNA-binding protein 43 (TDP-43) have been identified as the major pathological protein in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how they affect cellular toxicity and neurodegeneration, including the modulation process remains unknown. This study revealed that the C-terminal fragment of TDP-43 (TDP-25) was localized primarily to mitochondria and caused abnormal mitochondrial morphology, inducing Parkin-mediated mitophagy. Also, we discovered that the knockdown of selective autophagy receptors, such as TAX1BP, Optineurin, or NDP52 caused TDP-25 accumulation, indicating that TDP-25 was degraded by mitophagy. Interestingly, myosin IIB, a nonmuscle type of myosin and actin-based motor protein, is mostly colocalized to TDP-25 associated with abnormal mitochondria. In addition, myosin IIB inhibition by siRNA or blebbistatin induced mitochondrial accumulation of insoluble TDP-25 and Tom20, and reduced neuronal cell viability. Our results suggest a novel role of myosin IIB in mitochondrial degradation of toxic TDP-25. Therefore, we proposed that regulating myosin IIB activity might be a potential therapeutic target for neurodegenerative diseases associated with TDP-43 pathology.

Brassicasterol from Edible Aquacultural Hippocampus abdominalis Exerts an Anti-Cancer Effect by Dual-Targeting AKT and AR Signaling in Prostate Cancer.

In the Compendium of Materia Medica, seahorse (Hippocampus) is considered effective for the reinforcement of kidney and men's health. However, the role of seahorse on human health lacks scientific evidence. Therefore, we evaluated the effect of seahorse on human prostate cancer using various in vitro methods and identified bioactive compound. Seahorse lipid extract (SHL) decreased androgen receptor (AR) and prostate-specific antigen (PSA) expression in dihydrotestosterone (DHT)-induced LNCaP cells of prostate cancer. Gas Chromatography (GC)-mass spectrometry data showed that brassicasterol was present in H. abdominalis. Brassicasterol downregulated the expression of AR and PSA in DHT-induced LNCaP cells. Brassicasterol induced apoptosis accompanied by sub-G1 phase arrest and inhibited migration in LNCaP cells. We confirmed that AKT and AR mediated the anti-cancer effect of brassicasterol using siRNA transfection. Brassicasterol exerts an anti-cancer effect in AR-independent cancer as well as in AR-dependent cells by AKT inhibiting. Our findings suggest that SHL has the anticancer potential via inhibition of AR and demonstrated that brassicasterol from H. abdominalis exerted an anti-cancer effect by dual-targeting AKT and AR signaling in prostate cancer.