Therapeutic potential of cannabidiol (CBD) in anxiety disorders: A systematic review and meta-analysis.

Cannabidiol (CBD), as one of the phytocannabinoids, has a wide range of therapeutic properties for various neuropsychiatric disorders due to central nervous system effects. These therapeutic properties demonstrated by preclinical and clinical studies encompass more than just anticonvulsant, anti-arthritic, analgesic, anti-inflammatory, antioxidant, antitumor, antiemetic, antipsychotic and neuroprotective effects. It has been hypothesized that CBD holds potential in the treatment of various neuropsychiatric and anxiety disorders. Thus, PRISMA was used as a guide for our systematic review. Eight of the 1550 articles screened in June 2023 were eligible for meta-analysis. Based on the 316 participants included in these eight articles, this meta-analysis revealed a substantial significant impact of CBD on anxiety with a considerable effect size (Hedges' g = -0.92, 95% CI -1.80 to -0.04). In addition, this meta-analysis focuses on the efficacy of CBD in treating anxiety disorders such as generalized anxiety disorder (GAD), social anxiety disorder (SAD), and post-traumatic stress disorder (PTSD). However, caution should be exercised in interpreting our findings due to the limited size of the clinical sample, and additional trials ought to be carried out if deemed necessary.

Childhood Adversities and Caregiving for Older Parents: Building Capacity for a Caring Society.

OBJECTIVES: This study investigates the relationships between childhood adversities and the provision of informal care for older parents in later life in China. METHODS: The data came from 4 waves of the China Health and Retirement Longitudinal Study (N = 20,047). Using multilevel logistic regression models, we examined the relationships between adverse experiences in childhood and both the propensity and intensity of caregiving for older parents. Drawing on the regression results, we then estimated the total number of caregivers for older parents in China. RESULTS: Experiencing 1 additional childhood adversity was associated with a decrease of 8% in the odds of providing informal care (p < .001). The association between childhood adversity and caregiving remained significant after sociodemographic factors and later-life outcomes were controlled for. We estimated that 58.3 million middle-aged adults in China were providing care for parents in 2020. Had people experienced 1 fewer adversity in their childhood, there would have been 2.2 million more caregivers in 2020. Had they experienced 2 fewer adversities, there would have been 3.4 million more caregivers. DISCUSSION: The factors associated with informal caregiving can be traced back to early-life experiences. To address the shortage of informal care supply, it is crucial to foster a caring culture from the very beginning of human development.

Enhancing Strategy of the Small-Polaron Conductivity in LaCrO3: First-Principles Calculations and Experimental Validation.

LaCrO3 (LCO) has promising applications as a p-type conductive material in the fields of transparent conducting oxes, high-temperature sensors, and magnetohydrodynamic power generators. However, the easy volatility of the Cr element, along with the issues of low electrical conductivity caused by the small-polaron conduction mechanism and wide band gap, has hindered the widespread application of LCO. In this work, based on band engineering and defect engineering, we screened doping schemes through first-principles calculations that can reduce Cr volatility by enhancing the Cr-O bond energy. We also aimed to promote small-polaron hopping and improve the electrical conductivity by introducing impurity levels. Additionally, we conducted a thorough analysis of the small-polaron conductivity mechanism. Through the solid-state method, we successfully prepared codoped LCO with Ca and Zn. The Zn dopants effectively enhanced the Cr-O bond strength, suppressed the Cr volatility, and improved high-temperature stability. The Zn dopants introduced additional impurity energy levels within the band gap, significantly changing the mobility of small polarons. Through optimal doping concentration, the La0.7Ca0.3Cr0.95Zn0.05O3 sample demonstrated a significant enhancement in electrical conductivity compared to La0.7Ca0.3CrO3, increasing from 7 to 60 at 1000 K. Additionally, the impurity energy levels enhanced the asymmetry near the Fermi level, resulting in an increased Seebeck coefficient (S). This is beneficial for the production of high-temperature sensors. The output voltage of an LCO thermocouple module reaches up to 58 mV at 2170 K, indicating that the performance optimization strategy employed in this work has significant implications for the regulation and application of oxide electrical materials.

Structure elucidation and anticancer activity of a heteropolysaccharide from white tea.

White tea, one of the six traditional teas in China, is made only through natural withering and low-temperature drying processes. It demonstrates diverse pharmacological and health-promoting effects, including antioxidant, antiviral, anticancer, and hypolipidemic activities. Despite the significance of polysaccharides in white tea leaves, their fine structure and physiological functions remain unexplored. In this study, the polysaccharide fragment WTP-80a with anticancer activity was isolated and purified from white tea through water extraction, alcohol precipitation, DEAE-52 ion exchange column chromatography, and sephacryl S-200 dextran gel column chromatography. WTP-80a exhibited a molecular weight of 1.14 × 105 Da and consisted of galactose (Gal), arabinose (Ara), rhamnose (Rha), and glucuronic acid (Glc-UA). The main chain skeleton of WTP-80a contained 3,6)-ß-Galp-(1→, 3)-α-Galp-(1→, 5)-α-Araf-(1 â†’ and 3)-α-Glcp-UA-(1→. Branch chains included α-Araf-(1 â†’ and ß-Rhap-(1 â†’ connected to the C3 and C6 positions of →3,6)-ß-Galp-(1→, respectively. In vitro anticancer experiments revealed that WTP-80a effectively hindered the proliferation, colony formation, migration, and invasion of B16F10 cells. Additionally, it induced apoptosis in B16F10 cells by blocking the G2/M phase, increasing active oxygen content, and reducing mitochondrial membrane potential. These findings provide a solid theoretical foundation for the application of white tea polysaccharides as anticancer products.

Bioinformatics analysis for the identification of Sprouty-related EVH1 domain-containing protein 3 expression and its clinical significance in thyroid carcinoma.

The poorly differentiated thyroid carcinoma (THCA) subtype is associated with an aggressive disease course, a less favorable overall prognosis, and an increased risk of distant organ metastasis. In this study, our objective was to explore the potential utility of the Sprouty-related EVH1 domain-containing protein 3 (SPRED3) as a biomarker for early diagnosis and prognosis in THCA patients. The differentially expressed prognostic-related genes associated with THCA were identified by querying The Cancer Genome Atlas (TCGA) database. The difference in the expression of the SPRED3 gene between thyroid carcinoma (THCA) tissues and normal tissues was analyzed using data from The Cancer Genome Atlas (TCGA) and further validated through immunohistochemistry. Univariate and multivariate Cox regression models were used, along with clinical information from THCA patients, to analyze the prognostic value of the SPRED3 gene in THCA patients. Functional enrichment analysis was subsequently performed to elucidate the molecular mechanisms underlying the regulatory effects of the SPRED3 gene on thyroid carcinoma. Additionally, we calculated the percentage of infiltrating immune cells in THCA patients and evaluated their correlation with SPRED3 gene expression. Compared with those in noncancerous thyroid tissue, the gene and protein expression levels of SPRED3 were found to be elevated in thyroid carcinoma tissues. Furthermore, the expression of SPRED3 in thyroid carcinoma exhibited significant correlations with tumor location, histological grade, pathological stage, and tumor node metastasis classification (TNM) stage. Univariate and multivariate Cox proportional hazards (Cox) regression analyses demonstrated that SPRED3 could serve as an independent prognostic factor for predicting the overall survival of THCA patients. The results of functional enrichment analysis suggested the potential involvement of SPRED3 in the regulation of extracellular matrix organization, epidermal development, signaling receptor activator activity, skin development, receptor ligand activity, glycosaminoglycan binding, neuroactive ligand‒receptor interaction, the IL-17 signaling pathway, and the PI3K-Akt signaling pathway. Additionally, there were significant correlations between the expression level of the SPRED3 gene and the infiltration of various immune cells (eosinophils, central memory T cells, neutrophils, macrophages, and NK cells) within the thyroid tumor microenvironment. SPRED3 can be used as a prognostic biomarker in patients with THCA could potentially be therapeutic target for THCA.

Optically-Trapped Nanodiamond-Relaxometry Detection of Nanomolar Paramagnetic Spins in Aqueous Environments.

Probing electrical and magnetic properties in aqueous environments remains a frontier challenge in nanoscale sensing. Our inability to do so with quantitative accuracy imposes severe limitations, for example, on our understanding of the ionic environments in a diverse array of systems, ranging from novel materials to the living cell. The Nitrogen-Vacancy (NV) center in fluorescent nanodiamonds (FNDs) has emerged as a good candidate to sense temperature, pH, and the concentration of paramagnetic species at the nanoscale, but comes with several hurdles such as particle-to-particle variation which render calibrated measurements difficult, and the challenge to tightly confine and precisely position sensors in aqueous environment. To address this, we demonstrate relaxometry with NV centers within optically-trapped FNDs. In a proof of principle experiment, we show that optically-trapped FNDs enable highly reproducible nanomolar sensitivity to the paramagnetic ion, (\mathrm{Gd}^{3+}). We capture the three distinct phases of our experimental data by devising a model analogous to nanoscale Langmuir adsorption combined with spin coherence dynamics. Our work provides a basis for routes to sense free paramagnetic ions and molecules in biologically relevant conditions.

Solvent-polarity dependence of ultrafast excited-state dynamics of trans-4-nitrostilbene.

Ultrafast excited-state dynamics of the simplest nitrostilbenes, namely trans-4-nitrostilbene (t-NSB), was studied in solvents of various polarities with ultrafast broadband time-resolved fluorescence and transient absorption spectroscopies, and by quantum-chemical computations. The results revealed that the initially excited S1(ππ*) state deactivation dynamics is strongly influenced by the solvent polarity. Specifically, the t-NSB S1-state lifetime decreases by three orders of magnitude from ∼60 ps in high-polarity solvents to ∼60 fs in nonpolar solvents. The strong solvent-polarity dependence arises from the differences in dipole moments among the S1 and relevant states, including the major intersystem crossing (ISC) receiver triplet states, and therefore, the solvent polarity can modulate their relative energies and ISC rates. In nonpolar solvents, the sub-100 fs lifetime is due to a combination of efficient ISC and internal conversion. In medium-polarity solvents, the S1-state population decays via a competing ISC relaxation mechanism in a biphasic manner, and the ISC rates are found to obey the inverse energy gap law of the strong coupling case. In high-polarity solvents, the S1 state is stabilized to a much lower energy such that ISC becomes energetically infeasible, and the S1 state decays via barrier crossing along the torsion angle of the central ethylenic bond to the nonfluorescent perpendicular configuration. Regardless of the initial S1-state deactivation pathways in various solvents, the excited-state population is ultimately trapped in the metastable T1-state perpendicular configuration, at which a slower ISC occurs to bring the system to the ground state and bifurcate into either trans or cis form of NSB.

Association of ApoE gene polymorphisms with serum lipid levels and the risk of type 2 diabetes mellitus in the Chinese Han population of central China.

Background: Apolipoprotein E (ApoE) is involved in lipid transformation and metabolism. Although some studies have examined the association between ApoE polymorphisms and the risk of type 2 diabetes mellitus (T2DM), the findings differ depending on the location and population. Methods: A total of 1,738 participants, including 743 patients with T2DM and 995 controls without T2DM, were enrolled from central China, and ApoE polymorphisms, 388T > C (rs429358) and 526C > T (rs7412), were genotyped. The association between ApoE alleles and T2DM and blood lipid levels was analyzed. Logistic regression analysis was performed to evaluate the interactions between ApoE polymorphisms and various factors, such as age, sex, and prevalence of hypertension in patients with T2DM. Results: The genotype ɛ3/ɛ4 and ɛ4 alleles of ApoE were associated with T2DM risk in the Chinese Han population in central China. Moreover, in patients with T2DM, participants in the E4 (ɛ3/ɛ4, ɛ4/ɛ4) group had significantly higher lipid profiles than those in the E3 (ɛ3/ɛ3) group, whereas participants in the E2 group (ɛ2/ɛ2, ɛ2/ɛ3) showed lower total cholesterol, low-density lipoprotein cholesterol, and ApoE-A1 levels than those in the E3 (ɛ3/ɛ3) group. The results from the current study may help in understanding ApoE polymorphisms and lipid profiles in the Chinese Han population.

Gene polymorphism in IL17A and gene-gene interaction in the IL23R/IL17A axis are associated with susceptibility to coronary artery disease.

AIMS: Studies have confirmed that the IL-23R/IL-17A axis plays an important role in the development of autoimmune and inflammatory diseases. However, its role in coronary artery disease (CAD) remains unclear. Here, we conducted a large sample case-control study to investigate the association between the IL23R/IL17A axis and CAD in the Chinese Han population. METHODS: Two SNPs, rs2275913: G>A (IL17A) and rs6682925: T>C (IL23R), were genotyped in 3042 CAD cases and 3216 controls using the high-resolution melt technology (HRM). Logistic regression analyses were used to adjust the traditional risk factors for CAD and perform the gene interaction analyses. Multiple linear regression analyses were used to study the relationships between the selected SNPs and the levels of serum lipids. In addition, meta-analysis also was performed for the association between rs6682925 and rs2275913 with CAD in different popolations. RESULTS: Our case-control and meta-analysis for single SNPs demonstrated that the frequencies of the alleles and the distribution of the genotypes had no significant differences in CAD cases compared with controls. In the stratified analysis, we observed that the frequency of the IL17A rs2275913-A allele was more epidemic in early-onset CAD than in the controls (Padj = 0.005, OR = 1.209, 95% CI: 1.059-1.382), and the minor allele C of rs6682925 was associated with a decreased level of serum total cholesterol under a recessive model (Padj = 0.011). We demonstrated a significant interaction between rs6682925 and rs2275913 and CAD in the Chinese Han population. Four genotypes (CTGG, CCAA, CCAG, CCGG) were significantly associated with CAD (Padj = 2.94 × 10-4, OR = 0.619, 95% CI: 0.478-0.803; Padj = 0.01, OR = 1.808, 95% CI: 1.152-1.869; Padj = 6 × 10-6, OR = 2.179, 95% CI: 1.558-3.049; Padj = 0.001, OR = 1.883, 95% CI: 1.282-2.762, respectively). CONCLUSION: Our study found no single SNP of rs2275913 in IL17A and rs6682925 in IL23R was associated with CAD in the Chinese population, but the interaction of them were significantly associated with CAD susceptibility, highlighting the key role of the IL-23R/IL-17A axis in the development of CAD. In addition, we also found rs2275913 was associated with early-onset CAD and rs6682925 was associated with total cholesterol levels, which will contribute to the clinical stratified management of this common disease.

NINJ2 deficiency inhibits preadipocyte differentiation and promotes insulin resistance through regulating insulin signaling.

OBJECTIVE: Genetic variants in ninjurin-2 (NINJ2; nerve injury-induced protein 2) confer risk of ischemic strokes and coronary artery disease as well as endothelial activation and inflammation. However, little is known about NINJ2's in vivo functions and underlying mechanisms. METHODS: The phenotypes of NINJ2 knockout mice were analyzed, and mechanisms of NINJ2 that regulate body weight, insulin resistance, and glucose homeostasis and lipogenesis were investigated in vivo and in vitro. RESULTS: This study found that mice lacking NINJ2 showed impaired adipogenesis, increased insulin resistance, and abnormal glucose homeostasis, all of which are risk factors for strokes and coronary artery disease. Mechanistically, NINJ2 directly interacts with insulin receptor/insulin-like growth factor 1 receptor (INSR/IGF1R), and NINJ2 knockdown can block insulin-induced mitotic clonal expansion during preadipocyte differentiation by inhibiting protein kinase B/extracellular signal-regulated kinase (AKT/ERK) signaling and by decreasing the expression of key adipocyte transcriptional regulators CCAAT/enhancer-binding protein ß (C/EBP-ß), C/EBP-α, and peroxisome proliferator-activated receptor γ (PPAR-γ). Furthermore, the interaction between NINJ2 and INSR/IGF1R is needed for maintaining insulin sensitivity in adipocytes and muscle via AKT and glucose transporter type 4. Notably, adenovirus-mediated NINJ2 overexpression can ameliorate diet-induced insulin resistance in mice. CONCLUSIONS: In conclusion, these findings reveal NINJ2 as an important new facilitator of insulin receptors, and the authors propose a unique regulatory mechanism between insulin signaling, adipogenesis, and insulin resistance.

Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and liver fibrosis through the IGF1R/EGR1/PDGF-BB signaling pathway.

BACKGROUND: Liver fibrogenesis is orchestrated by the paracrine signaling interaction between several resident cell types regulating the activation of hepatic stellate cells (HSCs). However, the molecular mechanisms underlying paracrine regulation are largely unknown. The aim of this study is to elucidate the role of Ninjurin2 in the crosstalk between hepatocytes and HSCs and better understand the implications of Ninjurin2 in liver fibrosis. METHODS: Ninj2 knockout mice (Ninj2-/-) and hepatocyte-specific Ninj2 overexpression mice (Ninj2Hep-tg) were constructed and followed by the induction of liver fibrosis using methionine- and choline-deficient (MCD) diet. The relationship between Ninjurin2 and liver fibrosis phenotype was evaluated in vivo by measurement of fibrotic markers and related genes. We used an in vitro transwell cell co-culture model to examine the impact of Ninjurin2 in hepatocytes on the crosstalk to HSCs. The interaction of Ninjurin2 and IGF1R and the regulation of PI3K-AKT-EGR1 were analyzed in vivo and in vitro. Finally, an inhibitory Ninjurin2 peptide was injected intravenously via the tail vein to investigate whether inhibiting of Ninjurin2 cascade can attenuate MCD diet-induced liver fibrosis in mice. RESULTS: We found that hepatic Ninjurin2 expression was significantly increased in fibrotic human liver and MCD diet-induced liver injury mouse models. In the mouse model, hepatocyte-specific overexpression of Ninj2 exacerbates MCD-induced liver fibrosis, while global Ninj2 knockout reverses the phenotype. To mimic hepatocyte-HSC crosstalk during liver fibrosis, we used co-culture systems containing hepatocytes and HSCs and determined that Ninjurin2 overexpression in hepatocytes directly activates HSCs in vitro. Mechanistically, Ninjurin2 directly interacts with insulin-like growth factor 1 receptor (IGF1R) and increases the hepatocyte secretion of the fibrogenic cytokine, platelet-derived growth factor-BB (PDGF-BB) through IGF1R-PI3K-AKT-EGR1 cascade. Inhibition of PDGFRB signaling in HSCs can abolish the profibrogenic effect of Ninjurin2. In addition, we demonstrated that a specific inhibitory Ninjurin2 peptide containing an N-terminal adhesion motif mitigates liver fibrosis and improves hepatic function in the mouse models by negatively regulating the sensitivity of IGF1R to IGF1 in hepatocytes. CONCLUSION: Hepatic Ninjurin2 plays a key role in liver fibrosis through paracrine regulation of PDGF-BB/PDGFRB signaling in HSCs, and the results suggesting Ninjurin2 may be a potential therapeutic target.

Two Novel Functional Mutations in Promoter Region of SCN3B Gene Associated with Atrial Fibrillation.

The sodium voltage-gated channel beta subunit 3 (SCN3B) plays a crucial role in electrically excitable cells and conduction tissue in the heart. Some previous studies have established that genetic modification in sodium voltage-channel genes encoding for the cardiac ß-subunits, such as SCN1B, SCN2B, SCN3B and SCN4B, can result in atrial fibrillation (AF). In the current study, we identified two rare variants in 5'UTR (NM_018400.4: c.-324C>A, rs976125894 and NM_018400.4: c.-303C>T, rs1284768362) of SCN3B in two unrelated lone AF patients. Our further functional studies discovered that one of them, the A allele of c.-324C>A (rs976125894), can improve transcriptional activity and may raise SCN3B expression levels. The A allele of c.-324C>A (rs976125894) has higher transcriptional activity when it interacts with GATA4, as we confirmed transcription factor GATA4 is a regulator of SCN3B. To the best of our knowledge, the current study is the first to demonstrate that the gain-of-function mutation of SCN3B can produce AF and the first to link a mutation occurring in the non-coding 5'UTR region of SCN3B to lone AF. The work also offers empirical proof that GATA4 is a critical regulator of SCN3B gene regulation. Our findings may serve as an encyclopedia for AF susceptibility variants and can also provide insight into the investigation of the functional mechanisms behind AF variants discovered by genetic methods.

Label-Aware Distribution Calibration for Long-Tailed Classification.

Real-world data usually present long-tailed distributions. Training on imbalanced data tends to render neural networks perform well on head classes while much worse on tail classes. The severe sparseness of training instances for the tail classes is the main challenge, which results in biased distribution estimation during training. Plenty of efforts have been devoted to ameliorating the challenge, including data resampling and synthesizing new training instances for tail classes. However, no prior research has exploited the transferable knowledge from head classes to tail classes for calibrating the distribution of tail classes. In this article, we suppose that tail classes can be enriched by similar head classes and propose a novel distribution calibration (DC) approach named as label-aware DC (). transfers the statistics from relevant head classes to infer the distribution of tail classes. Sampling from calibrated distribution further facilitates rebalancing the classifier. Experiments on both image and text long-tailed datasets demonstrate that significantly outperforms existing methods. The visualization also shows that provides a more accurate distribution estimation.

Separation of memory span and learning rate: Evidence from behavior and spontaneous brain activity in older adults.

It is unclear how the ability to initially acquire information in a first learning trial relates to learning rate in subsequent repeated trials. The separation of memory span and learning rate is an important psychological dilemma that remains unaddressed. Given the potential effects of aging on memory and learning, this study investigated the separation of memory span and learning rate from behavior and spontaneous brain activity in older adults. We enrolled a total of 758 participants, including 707 healthy older adults and 51 mild cognitive impairment (MCI) patients. Sixty-five participants out of 707 completed resting-state functional magnetic resonance imaging (fMRI) scanning. Behaviorally, memory span and learning rate were not correlated with each other in the paired-associative learning test (PALT) but were negatively correlated in the auditory verbal learning test (AVLT). This indicated that the relationship between memory span and learning rate for item memory might be differentially affected by aging. Interaction analysis confirmed that these two capacities were differentially affected by test type (associative memory vs. item memory). Additionally, at three progressive brain activity indexes (ALFF, ReHo, and DC), the right brain regions (right inferior temporal gyrus and right middle frontal gyrus) were more negatively correlated with memory span, whereas, the left precuneus was more positively correlated with learning rate. Regarding pathological aging, none of the correlations between memory span and learning rate were significant in either PALT or AVLT in MCI. This study provides novel evidence for the dissociation of memory span and learning rate at behavioral and brain activity levels, which may have useful applications in detecting cognitive deficits or conducting cognitive interventions.

Global Limb Anatomic Staging System Score correlates with the clinical outcomes in chronic limb threatening ischemia patients.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) affects millions of people and causes health care burden around the globe. Global Limb Anatomic Staging System (GLASS) was proposed as a new anatomic system for integrating the complexity of threatened limb. METHODS: We retrospectively classified computed tomography angiography images of threatened limbs into GLASS stages between January 2018 and April 2020. Comorbidities, limb treatments, and outcomes including amputation-free survival (AFS), reintervention and mortality were compared and the likelihood of benefit from revascularization was estimated according to GLASS. Kaplan-Meier estimate was used to determine the rates of endpoint events at 1 year. Multivariate analysis was performed to identify predictors of those outcomes. RESULTS: In our study, 285 threatened limbs in 263 patients were stratified including GLASS stage I disease (N.=53, 19%), stage II (N.=129; 45%) and stage III (N.=103; 36%) disease. The percentage of limbs undergoing endovascular revascularization and minor amputation increased significantly with increasing GLASS stage. On Kaplan-Meier analysis, increasing GLASS stage was associated with 1-year reduced AFS (stage I: 96.1%, stage II: 94.1%, stage III: 83.9%; log rank P=0.016). The percentage of 1-year reintervention rate in infrapopliteal GLASS grade 3-4 (15%) was significantly higher than the percentage of reintervention in infrapopliteal GLASS grade 0-2 (5%) (Log rank P=0.002). Infrapopliteal GLASS grade 3 and 4 was the independent predictor of reduced AFS. CONCLUSIONS: GLASS stage correlated with intensity of limb treatment and with clinical outcomes at 1 year. Infrapopliteal GLASS grade 3 and 4 independently predicted the reduced amputation-free survival.

Functional rare variant in a C/EBPbeta binding site in NINJ2 gene increases the risk of coronary artery disease.

OBJECTIVE: NINJ2 regulates activation of vascular endothelial cells, and genome-wide association studies showed that variants in NINJ2 confer risk to stroke. However, whether variants in NINJ2 are associated with coronary artery disease (CAD) is unknown. METHODS: We genotyped rs34166160 in NINJ2 in two independent Chinese GeneID populations which included 2,794 CAD cases and 4,131 controls, and performed genetics association studies. Functional studies were also performed to reveal the mechanisms. RESULTS: Allele rs34166160 significantly confers risk to CAD in the GeneID Hubei population which contained 1,440 CAD cases and 2,660 CAD-free controls (observed P-obs = 6.39 × 10-3 with an odds ratio (OR) was 3.39, adjusted P-adj = 8.12 × 10-3 with an OR of 3.10). The association was replicated in another population, GeneID Shandong population contained 1,354 CAD cases and 1,471 controls (P-obs = 3.33 × 10-3 with an OR of 3.14, P-adj = 0.01 with an OR of 2.74). After combining the two populations, the association was more significant (P-obs = 1.57 × 10-5 with an OR of 3.58, P-adj = 3.41 × 10-4 with an OR of 2.80). In addition, we found that rs34166160 was associated with the mRNA expression level of NINJ2 and the flanking region of rs34166160 can directly bind with transcriptional factor CCAAT-box/enhancer-binding protein beta, and the risk A allele has more transcription activity than non-risk C allele with or without LPS in HUVEC cells. CONCLUSIONS: Our study demonstrates that the functional rare variant rs34166160 in NINJ2 confers risk to CAD for the first time, and these findings further expand the range of the pathology of CAD and atherosclerosis.

NPF transporters in synaptic-like vesicles control delivery of iron and copper to seeds.

Accumulation of iron in seeds is essential for both plant reproduction and human nutrition. Transport of iron to seeds requires the chelator nicotianamine (NA) to prevent its precipitation in the plant vascular tissues. However, how NA is transported to the apoplast for forming metal-NA complexes remains unknown. Here, we report that two members of the nitrate/peptide transporter family, NAET1 and NAET2, function as NA transporters required for translocation of both iron and copper to seeds. We show that NAET1 and NAET2 are predominantly expressed in the shoot and root vascular tissues and mediate secretion of NA out of the cells in resembling the release of neurotransmitters from animal synaptic vesicles. These findings reveal an unusual mechanism of transmembrane transport in plants and uncover a fundamental aspect of plant nutrition that has implications for improving food nutrition and human health.

Correction: Study of reference intervals for free triiodothyronine, free thyroxine, and thyroid-stimulating hormone in an elderly Chinese Han population.

[This corrects the article DOI: 10.1371/journal.pone.0239579.].

Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry.

BACKGROUND AND AIMS: Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. APPROACH AND RESULTS: We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. CONCLUSIONS: Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.

Comparison of conbercept and ranibizumab combined mitomycin C-augmented trabeculectomy for neovascular glaucoma.

PURPOSE: To compare the efficacy and security of conbercept and ranibizumab combined with trabeculectomy and panretinal photocoagulation for neovascular glaucoma (NVG). METHODS: One hundred and sixty patients with NVG were randomly divided into a conbercept group comprised of 80 patients and a ranibizumab group comprised of 80 patients. The postoperative and preoperative visual acuities, intraocular pressures frequency of anti-glaucoma medications, and surgical complications were recorded. The expressions of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (FLT-1), and placenta-like growth factor (PLGF) in the aqueous humor were determined using an enzyme-linked immunosorbent assay. Examining the fundus and obtaining photographs used indirect ophthalmoscopy. Kaplan-Meier and log-rank analyses estimated the success rates. RESULTS: All patient follow-up periods were at 1 year. The differences observed in IOP and the frequencies of anti-glaucoma medications at various follow-up time points were not statistically significant (all P > 0.05). The differences observed in both the group visual acuities at various follow-up time points were not statistically significant (P > 0.05). Rates of surgery complications were 18.75% and 25.00% in the conbercept group and ranibizumab group, respectively. The expressions of VEGF, FLT-1, and PLGF significantly decreased (all P < 0.05). The recurrence percentages were 30.00% and 36.25% after conbercept and ranibizumab treatment, respectively. CONCLUSION: The conbercept effects were similar with that of ranibizumab. Intravitreal injection of conbercept was effective for NVG treatment, which provides a new therapeutic drug for NVG treatment.