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Aim: Rheumatoid arthritis (RA) is an autoimmune disorder marked by an overgrowth of joint tissue and inflammation of the synovium. The mammalian target of rapamycin (mTOR), functioning as a serine/threonine protein kinase, is recognized for its role in controlling cell proliferation, metabolism, and inflammatory responses. While there is some evidence hinting at a link between RA and proteins downstream of mTOR, the findings are not definitive. In light of this, we have undertaken a Mendelian randomization (MR) analysis to investigate the potential connection between mTOR and RA. Methods: A two-sample MR study was performed by utilizing significant single nucleotide polymorphisms (SNPs) derived from a comprehensive genome-wide association study (GWAS) dataset, which included 58,284 samples of RA and 3,301 samples of mTOR-related proteins, as instrumental variables (IVs). The primary MR analysis techniques employed were inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression. Additionally, sensitivity analyses were carried out on the IVs to evaluate heterogeneity and pleiotropy using MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Furthermore, to validate the robustness of the findings, replication analyses were also conducted using another RA GWAS dataset focusing on European populations. Results: The main findings indicated that there is no causal link between mTOR-related proteins and RA. The genetically elevated levels of mTOR-related proteins do not appear to raise the risk of RA [AKT (p = 0.721), ATF6 (p = 0.369), ATG7 (p = 0.112), BECN1 (p = 0.599), EIF4A3 (p = 0.652), EIF4B (p = 0.989)]. Additionally, the Cochran’s Q test did not detect any heterogeneity across all proteins. The MR-PRESSO analysis also found no evidence of pleiotropy. The replication cohort confirmed these results, showing once more that there is no connection between mTOR and RA, which suggests that the initial findings are both robust and reliable. Conclusions: Although earlier research has hinted at a possible link between mTOR pathway proteins and RA, our study does not endorse a causal relationship between the two. Additional studies are required to clarify the intricate mechanisms that drive RA and to determine the role of mTOR signaling in the disease process.

Multifoci focusing has always been a problem that researchers continue to pay attention to and urgently needs to be solved. Metasurfaces display unprecedented capabilities and flexibilities to solve this problem. In this work, Pancharatnam–Berry (PB)‐phase‐based plasmonic metasurfaces are presented to realize wavelength‐selective directional focusing on the same focal plane. Ultrathin meta‐atoms with the half‐wave plate effect have only three layers, and 360° phase modulation is obtained by axially rotating gold strip based on PB phase. Two metasurfaces are designed to verify our strategy. Above all, a wavelength‐selective directional focusing metasurface is presented to converge right‐handed circularly polarized wave with wavelengths of 187, 271, and 355 μm at different predetermined positions at 810 μm. Next, the second metasurface exhibits the function that three vortex beams carrying orbital angular momentums with different topological charges can be produced under the irradiation of incident wave at the aforementioned wavelengths. In this research, a solid step is paved toward practical applications of flat photonics.

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by the overproliferation of synovial fibroblast‐like synoviocytes (FLSs) in the lining, leading to chronic inflammation and progressive joint damage. RA pathogenesis involves lymphocyte infiltration, increased synovial cell proliferation, and impaired cell death. This study investigated the effects of rapamycin on RA‐FLSs and explored the underlying molecular mechanisms. Methods The optimal drug concentration and time for rapamycin administration were determined using a cell counting kit‐8 assay. The concentration of rapamycin varied from 1 to 25 nmol/L. The mRNA expression levels of protein kinase B (AKT), mammalian target of rapamycin (mTOR), B cell lymphoma 2 (Bcl‐2), and Bcl‐2‐associated X protein (Bax) were quantified by real‐time polymerase chain reaction. Protein expression (p‐AKT, AKT, p‐mTOR, mTOR, pS6 kinase [S6K], S6K, p‐4E‐binding protein 1 [4EBP1], 4EBP1, Bcl‐2, Bax, caspase 3, caspase 9, cyclin‐dependent kinase 2 [CDK2], and CD1) were detected by Western blotting analysis. Results Rapamycin suppresses RA‐FLS proliferation and induces apoptosis in a dose‐dependent manner. Rapamycin significantly elevated the protein expression of Bax (p

Background and objectivesObservational studies have suggested that a multitude of pathological processes and biomolecules are involved in the initiation and development of epilepsy, and ULK3 is linked to the nervous system. However, it remains uncertain whether this association between ULK3 and epilepsy is causal and the direction of any causal relationship. This study employs a two-sample Mendelian randomization (MR) method to investigate the relationship between ULK3 and the risk of epilepsy.MethodsWe analyzed genome-wide association study (GWAS) summary statistics for ULK3 (sample size = 3,301), focal epilepsy (sample size = 39,348), and generalized epilepsy (sample size = 33,446). Bidirectional MR analyses were conducted to explore these relationships. We selected a set of single nucleotide polymorphisms (SNPs) with an association threshold of less than 1 × 10−5 as instrumental variables for further analysis. Various MR methods, including Inverse Variance Weighted, Weighted Median, MR-Egger Regression, Simple Model, Weighted Model, and Robust Adjustment Profile Score were used. Sensitivity analyses were performed to ensure the robustness of the results.ResultsOur MR analyses revealed a causal relationship where an increased level of ULK3 was associated with a decreased risk of focal epilepsy (odds ratio = 0.92, 95% confidence interval: 0.86–1.00, p = 0.041). No significant heterogeneity (Q = 7.85, p = 0.165) or horizontal pleiotropy (Egger regression intercept = 0.0191, p = 0.415) was detected. However, in the reverse analysis, we found no significant causal effect of focal epilepsy on ULK3 (p > 0.05). Furthermore, no significant causation was identified between ULK3 and generalized epilepsy (p > 0.05).ConclusionThis study suggests a causal relationship between ULK3 and the risk of focal epilepsy from a genetic perspective. Nevertheless, further investigation is needed to understand the role of ULK3 in epilepsy fully.

IntroductionObservational studies suggest associations between gut microbiota and polymyositis (PM) and dermatomyositis (DM), but causal relationships are unclear. We investigate the causal effects of gut microbiota on PM and DM, providing insights hoping to provide insights for future treatment and prevention.MethodsSummary statistics of gut microbiota were obtained from a multi-ethnic Genome Wide Association Studies (GWAS) meta-analysis, including 119 taxa from 18,340 Europeans. PM/DM statistics were extracted from GWAS analyses. Mendelian randomization (MR) with IVW, MR-Egger, and weighted median methods was performed. Sensitivity analyses addressed heterogeneity and pleiotropy. Of the 119 bacterial genera studied, six showed causal links.ResultsAlloprevotella (OR: 3.075, 95% CI: 1.127–8.386, p = 0.028), Ruminococcaceae UCG003 (OR: 4.219, 95% CI: 1.227–14.511, p = 0.022), Dialister (OR: 0.273, 95% CI: 0.077–0.974, p = 0.045) were associated with PM. Anaerotruncus (OR: 0.314, 95% CI: 0.112–0.882, p = 0.028), Ruminococcaceae UCG002 (OR: 2.439, 95% CI: 1.173–5.071, p = 0.017), Sutterella (OR: 3.392, 95% CI: 1.302–8.839, p = 0.012) were related to DM. Sensitivity analyses validated these associationsDiscussionWe establish causal relationships between Ruminococcaceae, Sutterella, Anaerotruncus with DM, Alloprevotella, Ruminococcaceae UCG003, and Dialister with PM. Common microbiota, like Ruminococcaceae, have significant clinical implications. These findings open up greater possibilities for the gut microbiota to contribute to the development of PM/DM and for future monitoring of the gut microbiota in patients with PM/DM.

Early childhood education and care (ECEC) serves as a crucial foundation for children’s holistic growth and lifelong learning. Despite its significance, comparative analyses of leading ECEC documents across cultures remain limited. To address this gap, our study conducts a comparative analysis to identify key aspects and examine similarities and differences in national ECEC documents from China and Finland. Methodologically, we used a triangle of researchers from China and Finland. We employed qualitative content analysis to systematically identify, examine, and compare the key aspects in these two countries from the leading ECEC documents, i.e., the Chinese national ECEC guidelines and the Finnish ECEC national core curriculum. The findings reveal numerous similarities alongside notable differences. Both countries place a high value on ECEC, emphasizing principles that shape the learning environment and use diverse pedagogical methods. However, nuanced variations exist in the approaches. The Chinese documents feature more specific guidelines tailored to different age groups, accompanied by detailed pedagogical suggestions, while the Finnish national core curriculum offers general guidelines for all preschool age groups, complemented by the unique feature of individual development plans for each child. The findings have significant implications for policymakers, ECEC educators, and practitioners in international contexts. Future studies are needed to further explore the specific pedagogies in ECEC between these two nations and to analyze how the curriculum and educational guidelines are implemented in pedagogical practices.

Abstract Background Epidemiological studies have shown a close association between osteoarthritis (OA) and cardiovascular disease (CVD), but reliable evidence needs to be provided. We performed a two‐sample Mendelian randomization (MR) study to examine the potential causal effect between OA and CVD. Methods Exposures were self‐reported OA, knee osteoarthritis (KOA), and hip osteoarthritis (HOA). The outcomes were 12 CVDs, including heart failure, atrial fibrillation, coronary artery disease, pulmonary embolism, stroke and its subtypes, myocardial infarction, coronary heart disease, and primary hypertension. All outcomes were obtained from published genome‐wide association studies. The inverse‐variance weighted method was used as the primary MR analysis. Heterogeneity tests and sensitivity analyses were conducted to validate the accuracy of the MR results. Results Self‐reported OA increased the incidence of small vessel stroke (odds ratio [OR] = 1.25, 95% confidence interval [CI]: 1.02–1.52, p = 0.03) and primary hypertension (1.01 [1.00–1.02], p

When individuals pursuing personal goals encounter setbacks and failures, they often fall into a conflict between disengaging from and striving toward the goal, defined as an action crisis. The present study investigated the influence and mechanism of self-transcendence meaning of life (STML) on goal disengagement and reengagement during a high versus a low action crisis. Study 1 included situations with different action crises. In Study 1, participants with high STML exhibited significantly higher goal disengagement and reengagement during high action crisis compared with low action crisis. Study 2 replicated the findings in Study 1 using participants’ personal goals by questionnaires, and further exhibited that action crisis had negative effect on self-efficacy for participants with low STML, and this process subsequently reduced goal adjustment. Interestingly, no mediation effect of self-efficacy was found between action crisis and goal adjustment among participants with high STML. Findings from the present study suggest that releasing obsessions and adopting a dialectical relationship between success and failure may help individuals in high action-crisis situations, and self-efficacy may provide flexibility and autonomy.

Abstract The nucleosome surface contains an area with negative electrostatic potential known as the acidic patch, which functions as a binding platform for various proteins to regulate chromatin biology. The dense clustering of acidic residues may impact their effective pKa and thus the electronegativity of the acidic patch, which in turn could influence nucleosome-protein interactions. We here set out to determine the pKa values of residues in and around the acidic patch in the free H2A-H2B dimer using NMR spectroscopy. We present a refined solution structure of the H2A-H2B dimer based on intermolecular distance restraints, displaying a well-defined histone-fold core. We show that the conserved histidines H2B H46 and H106 that line the acidic patch have pKa of 5.9 and 6.5, respectively, and that most acidic patch carboxyl groups have pKa values well below 5.0. For H2A D89 we find strong evidence for an elevated pKa of 5.3. Our data establish that the acidic patch is highly negatively charged at physiological pH, while protonation of H2B H106 and H2B H46 at slightly acidic pH will reduce electronegativity. These results will be valuable to understand the impact of pH changes on nucleosome-protein interactions in vitro, in silico or in vivo.

Ubiquitination of histone H2A can occur on distinct lysine residues, but how each site is recognised by the specific E3 ligase remains poorly understood. Here the authors demonstrate that the E3 ligase RNF168 binds the acidic patch on the nucleosome surface, directing the E2 to the target lysine K13/K15.

Overparenting is an emerging topic in parenting research and has gained increasing attention in media. Most studies have focused on adolescents and young adults in Western countries, while it remains unclear whether overparenting is related to young children's outcomes in non-Western contexts. The present study aimed to examine the mechanism by which overparenting was associated with Chinese young children's social preference. The study surveyed 283 Chinese parents of children aged 36-83 months (mean age = 58.61) to examine parenting practices and child social preference. The results suggested that parents' psychological control and parent--child relationship had serial mediating effects on the relationship between overparenting and young children's social preference in terms of shyness and unsociability. The present study further raised the importance of parenting during early childhood and generated practical implications for parents in China and beyond, encouraging parents to reflect on how their beliefs and practices may influence child outcomes from the early years.

Prosocial behavior refers to a broad category of actions that benefit other people or the society. Compared with other factors that affect prosocial performance, prosocial outcomes, consisting of prosocial gains and prosocial non-losses have received less attention up to now. In the current research, we explored the influences of different types of expected outcomes and regulatory focus on prosocial performance. Studies 1a and 1b examined the differences in prosocial performance elicited by prosocial gain (e.g., enhancing others' access to clean water) and prosocial non-loss outcomes (e.g., protecting others from suffering dirty water). We found that the expected prosocial non-loss outcomes induced greater prosocial performance compared with the expected prosocial gain outcomes. Studies 2a and 2b examined the effects of dispositional and situational regulatory focus on prosocial loss aversion. We found that differences in prosocial performance between two expected prosocial outcomes were reduced when promotion focus was primed; whereas a primed prevention focus did not significantly increase this difference. Additionally, participants displayed a greater prosocial loss aversion in the prevention focus condition than in the promotion focus condition. The reason for the non-significant interaction between regulatory focus and expected prosocial outcome was discussed.

This document provides a comparative study of early childhood education and care (ECEC) national documents in China and Finland. It analyzes the key aspects and similarities and differences in the ECEC guidelines of both countries. The findings show that both China and Finland prioritize ECEC and emphasize principles that shape the learning environment and use diverse pedagogical methods. However, there are nuanced variations in their approaches, with China providing more specific guidelines tailored to different age groups and Finland offering general guidelines for all preschool age groups. The study has implications for policymakers, educators, and practitioners in international contexts. [Extracted from the article]