Large-scale bidirectional Mendelian randomization study identifies new gut microbiome significantly associated with immune thrombocytopenic purpura.

Introduction: A variety of studies have shown a link between the gut microbiota and autoimmune diseases, but the causal relationship with Henoch-Schönlein purpura (HSP) and immune thrombocytopenic purpura (ITP) is unknown. Methods: This study investigated the bidirectional causality between gut microbiota and HSP and ITP using Mendelian randomization (MR). Large-scale genetic data of gut microbiota at phylum to species level from the MiBioGen consortium and the Dutch Microbiome Project were utilized. Genome-wide association studies (GWAS) summary statistics for HSP and ITP came from FinnGen R10. Various MR methods were applied to infer causal relationships, including inverse variance weighted (IVW), maximum likelihood (ML), cML-MA, MR-Egger, weighted median, weighted model, and MR-PRESSO. Multiple sensitivity analyses and Bonferroni correction were conducted to enhance robustness and reliability. Results: Based on the IVW estimates, 23 bacterial taxa were identified to have suggestive associations with HSP and ITP. Remarkably, after Bonferroni correction, family Alcaligenaceae (OR = 2.86, 95% CI = 1.52-5.37; IVW, p = 1.10 × 10-3, ML, p = 1.40 × 10-3) was significantly associated with ITP as a risk factor, while family Bacteroidales S24 7group (OR = 0.46, 95% CI = 0.29-0.74; IVW, p = 1.40 × 10-3) was significantly associated with ITP as a protective factor. No significant associations between HSP and ITP and gut microbiota were found in reverse analyses. Conclusion: Our study provides evidence of causal effects of gut microbiota on HSP and ITP, highlighting the importance of further research to clarify the underlying mechanisms and develop targeted therapeutic interventions for these autoimmune diseases.

LINC00894 inhibited neuron cellular apoptosis and regulated activating transcription factor 3 expression.

LINC00894 may be associated with synaptic function, but its biology function in neural cells is still unknown. In this study, LINC00894 knockdown decreased the EdU incorporated into newly synthesized DNA and cell viability in MTT or CCK-8 assay in HEK-293T and BE(2)-M17 (M17) neuroblastoma cells. And LINC00894 knockdown increased cellular apoptosis in Annexin V-FITC staining, the expression of activated Caspase3 and the level of reactive oxygen species (ROS) both in HEK-293T and M17 cells. Moreover, LINC00894 also protected cells from hydrogen peroxide induced apoptosis in in vitro models. Utilizing RNA sequencing (RNA-seq) integrated with quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunoblot, we identified that LINC00894 affected activating transcription factor 3 (ATF3) expression in HEK-293T, M17, and SH-SY5Y neuroblastoma cells. Finally, we found that ectopic expression of ATF3 restored cell proliferation and inhibited cell apoptosis in LINC00894 downregulated M17 cells. While knockdown of ATF3 also significantly increased the cell viability inhibition and apoptosis promotion induced by LINC00894 knockdown in M17 cells. Our results from in vitro models revealed that LINC00894 could promote neuronal cell proliferation and inhibit cellular apoptosis by affecting ATF3 expression.

Reciprocal relationships among parental psychological control, emotion regulation ability, and subjective well-being of adolescents: Disentangling between- and within-person effects.

BACKGROUND: Although research has demonstrated that parental psychological control is associated with the subjective well-being of adolescents, the lack of longitudinal studies that investigate whether or not bidirectional associations exist between the two and their potential mediating mechanisms has continued to date. In addition, previous studies have not rigorously distinguished between- and within-person effects. Thus, this study investigated longitudinal bidirectional associations between parental psychological control and the subjective well-being of adolescents. The study further examined the mediating role of emotion regulation ability. METHODS: A total of 1365 Chinese adolescents (boys: 53.2 %; Mage = 14.68 years, SD = 1.56) participated in a three-wave longitudinal study with annual assessments. Random intercept cross-lagged panel models were utilized to separate between- and within-person variation. RESULTS: After controlling for between-person variance, the results revealed that adolescents with low levels of subjective well-being reported high levels of parental psychological control after one year. Emotion regulation ability played a bidirectional mediating role in the relationship between psychological control and subjective well-being. That is, psychological control and subjective well-being mutually influenced each other through emotion regulation ability. LIMITATIONS: Assessments of the key study variables were provided by adolescents. Moreover, the study considered a combination of the mothers' and fathers' use of psychological control without differentiating between paternal and maternal psychological control. CONCLUSIONS: The findings highlight the importance of interventions that target emotion regulation ability, which contributes to breaking the negative cycle between controlling parenting and the well-being of adolescents.

Endogenous Retroviruses Unveiled: A Comprehensive Review of Inflammatory Signaling/Senescence-Related Pathways and Therapeutic Strategies.

Endogenous retroviruses (ERVs), a subset of genomic transposable elements (TEs) in a broader sense, have remained latent within mammalian genomes for tens of millions of years. These genetic elements are typically in a silenced state due to stringent regulatory mechanisms. However, under specific conditions, they can become activated, triggering inflammatory responses through diverse mechanisms. This activation has been shown to play a potential role in various neurological disorders, tumors, and cellular senescence. Consequently, the regulation of ERV expression through various methods holds promise for clinical applications in disease treatment. ERVs also engage in interactions with a variety of exogenous viruses, thereby influencing the outcomes of viral infectious diseases. This article comprehensively reviews the pathogenic cascade of ERVs, encompassing activation, inflammation, associated diseases, senescence, and interplay with viruses. Additionally, it outlines therapeutic strategies targeting ERVs with the aim of offering novel research directions for understanding the relationship between ERVs and diseases, along with corresponding treatment modalities.

Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury.

Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.

Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.

Antiparasitic efficacy of flavonoids identified from Psoralea corylifolia against Tetrahymena piriformis in guppy (Poecilia reticulate).

Tetrahymena piriformis belongs to the ciliated protists (ciliates), causing severe economic losses in aquaculture. Chemical drugs currently used usually have toxic side effects, and there is no specific drug against Tetrahymena. Therefore, it is an urgent need to identify new antiparasitic lead compounds. In the present study, the in vitro parasiticidal activity of ethyl acetate (EtOAc) extracts and water extracts from 22 selected traditional Chinese medicines (TCMs) were evaluated against T. piriformis. The EtOAc extract of P. corylifolia turned out to be the most active with the minimum parasiticidal concentration of 100 mg/L within 3 h. Thus, it was separated into 12 fractions by the first-dimensional (D1) normal phase liquid chromatography (NPLC), meanwhile combining with in vitro antiparasitic tests for activity tracking. Subsequently, 8 flavonoids were identified in the active fractions by the second-dimensional (D2) reverse phase liquid chromatography (RPLC) tandem high-resolution mass spectrometry. According to the results, 5 flavonoids were selected for in vitro antiparasitic test, of which isobavachalcone showed the minimum parasiticidal concentration of 3.125 mg/L in 2 h. Bathing treatment of infected guppies with isobavachalcone could significantly reduce the burden of T. piriformis, obtaining a 24-h median effective concentration (24-h EC50) value of 1.916 mg/L. And the concentration of isobavachalcone causing guppies to die within 24 h is 39 times than that of 24-h EC50. The results demonstrated that isobavachalcone has the potential to be developed into a novel commercial fish drug against T. piriformis.

Extended Black Hole Thermodynamics from Extended Iyer-Wald Formalism.

In recent years, there has been significant interest in the field of extended black hole thermodynamics, where the cosmological constant and/or other coupling parameters are treated as thermodynamic variables. Drawing inspiration from the Iyer-Wald formalism, which reveals the intrinsic and universal structure of conventional black hole thermodynamics, we illustrate that a proper extension of this formalism also unveils the underlying theoretical structure of extended black hole thermodynamics. As a remarkable consequence, for any gravitational theory described by a diffeomorphism invariant action, it is always possible to construct a consistent extended thermodynamics using this extended formalism.

Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes.

Chronic adipose tissue inflammation accompanied by macrophage accumulation and activation is implicated in the pathogenesis of insulin resistance and type 2 diabetes in humans. The transcriptional coregulator CREBZF is a key factor in hepatic metabolism, yet its role in modulating adipose tissue inflammation and type 2 diabetes remains elusive. The present study demonstrates that overnutrition-induced CREBZF links adipose tissue macrophage (ATM) proinflammatory activation to insulin resistance. CREBZF deficiency in macrophages, not in neutrophils, attenuates macrophage infiltration in adipose, proinflammatory activation, and hyperglycemia in diet-induced insulin-resistant mice. The coculture assays show that macrophage CREBZF deficiency improves insulin sensitivity in primary adipocytes and adipose tissue. Mechanistically, CREBZF competitively inhibits the binding of IκBα to p65, resulting in enhanced NF-κB activity. In addition, bromocriptine is identified as a small molecule inhibitor of CREBZF in macrophages, which suppresses the proinflammatory phenotype and improves metabolic dysfunction. Furthermore, CREBZF is highly expressed in ATM of obese humans and mice, which is positively correlated with proinflammatory genes and insulin resistance in humans. This study identifies a previously unknown role of CREBZF coupling ATM activation to systemic insulin resistance and type 2 diabetes.

RIP1/3-dependent programmed necrosis induces intestinal injury in septic rats.

The regulation of various types of cell death may help to restore the normal physiological function of cells and play a protective role in sepsis. In the current study, we explore the role of programmed cell necrosis in sepsis and the underlying mechanisms. The septic rat model is established by Cecal-ligation and perforation (CLP), and the in vitro model is established by LPS in IEC-6 cells. Our results demonstrate that receptor-interacting protein 1 (RIP1) is significantly upregulated in the ileum of septic rats and LPS-treated IEC-6 cells at both the mRNA and protein levels. Nec-1, an inhibitor of RIP1, reduces the protein levels of RIP1, p-RIP3, and phosphorylated mixed-lineage kinase domain-like (MLKL) (serine 358) and relieves intestinal injury in CLP-induced septic rats with decreased IL-6 and TNF-α levels. The in vitro experiments further reveal that LPS induces the colocalization of RIP1 and RIP3, resulting in the phosphorylation and translocation of MLKL to the plasma membrane in IEC-6 cells. LPS also facilitates ROS production in IEC-6 cells, but this effect is further reversed by Nec-1, si-RIP1 and si-RIP3. Furthermore, LPS-induced necrosis in IEC-6 cells is counteracted by NAC. Thus, we conclude that RIP1/RIP3-dependent programmed cell necrosis participates in intestinal injury in sepsis and may be associated with RIP1/RIP3-mediated ROS.

Does childhood psychological maltreatment encourage you to become a cyberbullying perpetrator? The mediating role of negative affect and the moderating role of meaning in life.

Objective: With the development of information and communication technology, cyberbullying among Chinese college students has become more frequent, bringing many negative consequences to both society and students themselves. Childhood psychological maltreatment may be one of the influencing factors of cyberbullying, but its internal mechanism remains poorly understood. This study aimed to explore the relationship between childhood psychological maltreatment and cyberbullying among college students and to further explore the mediating effect of negative emotion and the moderating effect of meaning in life. Methods: In this study, 656 college students (48.7% males) were recruited to complete anonymous questionnaires assessing their perceptions of child psychological maltreatment, negative affect, meaning in life and cyberbullying. SPSS23.0 and Hayes PROCESS macro for SPSS were used to conduct statistical analysis. Results: (1) Childhood psychological maltreatment was significantly positively associated with cyberbullying; (2) Negative affect played a partially mediating role between childhood psychological maltreatment and cyberbullying; and (3) Meaning in life moderated the direct association between childhood psychological maltreatment and cyberbullying and moderated the association between negative affect and cyberbullying. Conclusion: In this study, a moderated mediation model was constructed and the internal mechanism of childhood psychological maltreatment and cyberbullying among college students was found. The results provided both theoretical contributions and practical suggestions for preventing cyberbullying.

Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials.

This meta-analysis investigated the effect of physical exercise (PE) on the levels of oxidative biomarkers in randomized controlled trials (RCTs) involving healthy subjects. We searched five databases for articles until May 1, 2023. A random-effect meta-analysis, subgroup analysis, meta-regressions as well as trim and fill method were conducted using STATA 11.0, involving ten articles. According to the results of the meta-analysis, PE had no significant effect on superoxide dismutase (SOD), glutathione peroxidase, and catalase levels. PE induced significant increase in total antioxidant status (standardized mean difference [SMD] 1.53, 95% CI 0.73-2.32), and PE could significantly reduce the level of malondialdehyde (MDA) (SMD -1.11, 95% CI -2.15 to -0.06). Sensitivity analyses and subgroup analyses showed that male participants, body mass index (BMI) <25, exercise duration between 1 and 12 weeks, resistance exercise or multicomponent exercise, and exercise of low or moderate intensity were associated with a significant PE-induced decrease in MDA concentrations. Meta-regression analysis identified the age of the participants as a confounder of the effect of PE on SOD levels. The older age of the subjects was associated in a gradient fashion with incident SOD levels. Further RCTs are required to investigate the optimal PE protocol for people of different ages and BMI as well as the effect of PE on oxidative stress.

Cyberchondria and Chinese Adolescent Mental Health in the Age of COVID-19 Pandemic.

One of the far-reaching impacts of the COVID-19 pandemic is that it has become the fertile soil of cyberchondria. Adolescents' mental health was severely hit by this by-product of the COVID-19 pandemic both due to the direct effects and its indirect effects on security. This study investigated whether and how cyberchondria was associated with Chinese adolescents' mental health (i.e., well-being and depressive symptoms). Based on a large Internet sample (N = 1,108, 67.5 percent female, Mage = 16.78 years), cyberchondria, psychological insecurity, mental health, and a series of covariates were assessed. Preliminary analyses were conducted in SPSS Statistics software and main analyses were conducted in Mplus. Path analyses indicated that (a) cyberchondria was negatively associated with well-being (b = -0.12, p = 0.001) and positively associated with depressive symptoms (b = 0.17, p < 0.001); (b) psychological insecurity could fully mediate the association between cyberchondria and mental health (indirect effect well-being = -0.15, 95% confidence interval [CI -0.19 to -0.12] and indirect effect depressive symptoms = 0.15, 95% CI [0.12 to 0.19]); (c) the two dimensions (social insecurity and uncertainty) of psychological insecurity could play the mediating role in the associations between cyberchondria and mental health, uniquely and parallelly; and (d) these results did not vary by gender. This study suggests that cyberchondria may arouse individuals' psychological insecurity about interpersonal interaction and the development of events, which ultimately decreases their well-being and increases the risk of depressive symptoms. These findings facilitate the establishment and implementation of relevant prevention and intervention programs.

Proline hydroxylation of CREB-regulated transcriptional coactivator 2 controls hepatic glucose metabolism.

Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes.

Casein Kinase 1δ Phosphorylates TDP-43 and Suppresses Its Function in Tau mRNA Processing.

BACKGROUND: Neurofibrillary tangle aggregated from anomalous hyperphosphorylated tau is a hallmark of Alzheimer's disease (AD). Trans-active response DNA-binding protein of 43 kDa (TDP-43) enhances the instability and exon (E) 10 inclusion of tau mRNA. Cytoplasmic inclusion of hyperphosphorylated TDP-43 in the neurons constitutes the third most prevalent proteinopathy of AD. Casein kinase 1δ (CK1δ) is elevated in AD brain and phosphorylates TDP-43 in vitro. OBJECTIVE: To determine the roles of CK1δ in phosphorylation, aggregation, and function of TDP-43 in the processing of tau mRNA. METHODS: The interaction and colocalization of TDP-43 and CK1δ were analyzed by co-immunoprecipitation and immunofluorescence staining. TDP-43 phosphorylation by CK1δ was determined in vitro and in cultured cells. RIPA-insoluble TDP-43 aggregates obtained by ultracentrifugation were analyzed by immunoblots. The instability and E10 splicing of tau mRNA were studied by using a reporter of green fluorescence protein tailed with 3'-untranslational region of tau mRNA and a mini-tau gene and analyzed by real-time quantitative PCR and reverse transcriptional PCR. RESULTS: We found that CK1δ interacted and co-localized with TDP-43. TDP-43 was phosphorylated by CK1δ at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells, which was mutually enhanced. CK1δ overexpression promoted the aggregation of TDP-43 and suppressed its activity in enhancing the instability and E10 inclusion of tau mRNA. CONCLUSION: CK1δ phosphorylates TDP-43, promotes its aggregation, and inhibits its activity in promoting the instability of tau mRNA and inclusion of tau E10. Elevated CK1δ in AD brain may contribute to TDP-43 and tau pathologies directly or indirectly.

Peer Victimization and Subjective Well-Being Among Chinese Adolescents: Moderated Mediation by Forgiveness and Self-Esteem.

Considerable developmental research has shown an association between peer victimization and subjective well-being among adolescents. However, the mediating processes and protective factors that constrain this association are less understood. To fill these gaps, we investigated whether self-esteem mediates the association between peer victimization and subjective well-being and whether forgiveness moderates the direct and indirect associations of peer victimization with adolescents' subjective well-being via self-esteem. A large sample of 2,758 adolescents (Mage = 13.53 years, SD = 1.06) from 10 middle schools in China participated in this study. Participants provided data on demographic variables, peer victimization, self-esteem, forgiveness, and subjective well-being by answering anonymous questionnaires. After controlling for demographic covariates, we found that self-esteem mediated the relationship between peer victimization and subjective well-being. Furthermore, as a protective factor, forgiveness moderated the relationship between peer victimization and self-esteem. Consistent with the protective-reactive model, when adolescents experienced more peer victimization, those with higher forgiveness levels exhibited a greater decline in self-esteem, and low self-esteem was then associated with decreased subjective well-being. These findings demonstrate the utility of examining both mediating and moderating factors in this relationship and highlight the negative impact of peer victimization on adolescent self-worth and the limited role of forgiveness as a protective factor.

Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression.

BACKGROUND AND AIMS: NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity. APPROACH AND RESULTS: Here, we show that CREBZF is a key mechanism of liver fibrosis checkpoint that promotes hepatocyte injury and exacerbates diet-induced NASH in mice. CREBZF deficiency attenuated liver injury, fibrosis, and inflammation in diet-induced mouse models of NASH. CREBZF increases HSC activation and fibrosis in a hepatocyte-autonomous manner by stimulating an extracellular matrix protein osteopontin, a key regulator of fibrosis. The inhibition of miR-6964-3p mediates CREBZF-induced production and secretion of osteopontin in hepatocytes. Adeno-associated virus -mediated rescue of osteopontin restored HSC activation, liver fibrosis, and NASH progression in CREBZF-deficient mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced NASH mouse models and humans with NASH. CONCLUSIONS: Osteopontin signaling by CREBZF represents a previously unrecognized intrahepatic mechanism that triggers liver fibrosis and contributes to the severity of NASH.

The regrouping of Luminal B (HER2 negative), a better discriminator of outcome and recurrence score.

BACKGROUND: Breast cancer (BC) remains the leading cause of cancer-related deaths worldwide. High recurrence risk Luminal BC receives adjuvant chemotherapy in addition to standard hormone therapy. Considering the heterogeneity of Luminal B BC, a more accurate classification model is urgently needed. METHODS: In this study, we retrospectively reviewed the data of 1603 patients who were diagnosed with HER2-negative breast invasive ductal carcinoma. According to the expression level of PR and Ki-67 index, the Luminal B (HER2-negative) BCs were divided into three groups: ER+PR-Ki67low (ER-positive, PR-negative, and Ki-67 index <20%), ER+PR+Ki67high (ER-positive, PR-positive, and Ki-67 index ≥20%), and ER+PR-Ki67high (ER-positive, PR-negative, and Ki-67 index ≥20%). The cox proportional hazards regression model was used to evaluate the correlation between each variable and outcomes. Besides, discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve and log-rank χ2 value. RESULTS: The analysis results showed that there was a significant correlation between subtypes using this newly defined classification and overall survival (p < 0.001) and disease-free survival (DFS) (p < 0.001). Interestingly, patients in the ER+PR-Ki67high subgroup have the worst survival outcome in Luminal B (HER2-negative) subtype, similar to Triple-negative patients. Besides, the ER+PR+Ki67high has worse 5-year DFS compared with Luminal A group. There was a significant relationship between the regrouping subtype and the recurrence score index (RI) (p < 0.001). Moreover, the results showed that patients in ER+PR-Ki67high subtype were more likely to have high RI for distance recurrence (RI-DR) and local recurrence (RI-LRR). Our newly defined classification has a better discrimination ability to predict survival outcome and recurrence score of Luminal B (HER2-negative) BC patients, which may help in clinical decision-making for individual treatment.

Developmental Trajectories of Adolescent Internet Addiction: Interpersonal Predictors and Adjustment Outcomes.

Despite the burgeoning literature on adolescent internet addiction (IA), the majority of studies have relied on cross-sectional designs and variable-centered analytical approaches. Therefore, little is understood about the heterogeneous developmental trajectories of adolescent IA as well as its antecedents and outcomes. This longitudinal study adopted growth mixture modeling (GMM), a person-centered approach, to identify the distinct trajectories of IA among adolescents during a three-year period. We further examined the interpersonal predictors along with a series of outcomes of different trajectories. Participants included 1,365 Chinese adolescents (Mage = 14.68 years, SD = 1.56; 46.8% girls) from two junior high schools and two senior high schools. The GMM results indicated three distinct trajectories: low-increasing (56.7%), moderate-declining (37.6%), and high-declining (5.7%) groups. In terms of interpersonal predictors, adolescents who reported poorer relationships with their parents, teachers, and schoolmates were more likely to belong to the high-declining and moderate-declining groups. In terms of outcomes, the high-declining and moderate-declining groups exhibited an increase in mental health problems (i.e., more depressive symptoms, lower self-esteem, and lower subjective well-being) and delinquent behaviors, even after controlling for their baseline levels. These findings highlight the heterogeneity of IA trajectories among adolescents, the predictive role of interpersonal factors, and different adjustment outcomes associated with IA trajectories. Therefore, prevention and intervention programs involving interpersonal relationships may be promising for adolescents at high or moderate risk of IA.

Broadband multimode 3 dB optical power splitter using tapered couplers.

A design of a 1 × 2 multimode 3 dB optical power splitter using tapered couplers is proposed and investigated in this paper. As an example, a 1 × 2 splitter processing five-lowest order transverse-electric-polarized modes is designed and optimized by utilizing finite difference time domain method and particle swarm optimization algorithm. To verify the feasibility of this novel design, the optimized device is fabricated on a silicon-on-insulator platform. The coupling lengths of tapered couplers are respectively 6.5 µm, 6.0 µm, 3.5 µm, 5.0 µm, 5.0 µm, 7.5 µm, 6.0 µm, 5.0 µm, and 8.0 µm. Measurement results reveal that, for the fabricated splitter, the power uniformity varies from 0.041 to 0.88 dB, the crosstalk ranges from -23.96 to -14.12 dB, and the insertion loss changes from 0.089 to 1.50 dB within a bandwidth from 1520 to 1600 nm.