Ephrin B2 (EFNB2) potentially protects against intervertebral disc degeneration through inhibiting nucleus pulposus cell apoptosis.

Nucleus pulposus (NP) cell apoptosis is a significant indication of accelerated intervertebral disc degeneration; however, the precise mechanism is unelucidated as of yet. Ephrin B2 (EFNB2), the only gene down-regulated in the three degraded intervertebral disc tissue microarray groups (GSE70362, GSE147383 and GSE56081), was screened for examination in this study. Subsequently, EFNB2 was verified to be down-regulated in degraded NP tissue samples. Interleukin-1 (IL-1ß) treatment of NP cells to simulate the IDD environment indicated that IL-1ß treatment decreased EFNB2 expression. In degenerative NP cells stimulated by IL-1ß, EFNB2 knockdown significantly increased the rate of apoptosis as well as the apoptosis-related molecules cleaved-caspase-3 and the Bax to Bcl-2 ratio. EFNB2 was found to promote AKT, PI3K, and mTOR phosphorylation; the PI3K/AKT signaling role was investigated using the PI3K inhibitor LY294002. EFNB2 overexpression significantly increased PI3K/AKT pathway activity in IL-1ß-stimulated NP cells than the normal control. Moreover, EFNB2 partially alleviated NP cell apoptosis induced by IL-1ß, reduced the cleaved-cas3 level, and decreased the Bax/Bcl-2 ratio after the addition of the inhibitor LY294002. Additionally, EFNB2 overexpression inhibited the ERK1/2 phosphorylation; the effects of EFNB2 overexpression on ERK1/2 phosphorylation, degenerative NP cell viability, and cell apoptosis were partially reversed by ERK signaling activator Ceramide C6. EFNB2 comprehensively inhibited the apoptosis of NP cells by activating the PI3K/AKT signaling and inhibiting the ERK signaling, obviating the exacerbation of IDD. EFNB2 could be a potential target to protect against degenerative disc changes.

Tocilizumab Successfully Treating Refractory Hearing Impairment in a Patient With Cogan Syndrome: A Case Report and Review of the Literature.

Cogan syndrome (CS) is a rare systemic vasculitis characterized primarily by nonsyphilitic interstitial keratitis and vestibular and auditory dysfunction. In this article, we report the case of a 31-year-old male diagnosed with CS for 1 year. He was admitted to the hospital with fever, dizziness, headache, tinnitus, and hearing loss. After being treated with glucocorticoids, cellular immunosuppressants, and infliximab therapy, his symptoms were greatly relieved except for hearing loss. Then, he attempted to use tocilizumab (TCZ) which was ultimately effective in controlling the auditory dysfunction. In addition, we found 4 cases of TCZ for CS through a literature review and compared them with our patient. Although glucocorticoids are still the first-line treatment for CS, TCZ therapy provides fresh hope for patients who have refractory hearing impairment with hormone resistance, or whose hormone dosages cannot be lowered to maintenance levels.

Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects.

Phosphoinositide 3-kinases (PI3Ks) modify lipids by the phosphorylation of inositol phospholipids at the 3'-OH position, thereby participating in signal transduction and exerting effects on various physiological processes such as cell growth, metabolism, and organism development. PI3K activation also drives cancer cell growth, survival, and metabolism, with genetic dysregulation of this pathway observed in diverse human cancers. Therefore, this target is considered a promising potential therapeutic target for various types of cancer. Currently, several selective PI3K inhibitors and one dual-target PI3K inhibitor have been approved and launched on the market. However, the majority of these inhibitors have faced revocation or voluntary withdrawal of indications due to concerns regarding their adverse effects. This article provides a comprehensive review of the structure and biological functions, and clinical status of PI3K inhibitors, with a specific emphasis on the development strategies and structure-activity relationships of dual-target PI3K inhibitors. The findings offer valuable insights and future directions for the development of highly promising dual-target drugs targeting PI3K.

Dibromomethane Knitted Highly Porous Hyper-Cross-Linked Polymers for Efficient High-Pressure Methane Storage.

Hyper-cross-linked polymers (HCPs) with ultra-high porosity, superior physicochemical stability, and excellent cost-effectiveness are attractive candidates for methane storage. However, the construction of HCPs with BET surface areas exceeding 3000 m2 g-1 remains extremely challenging. In this work, a newly developed DBM-knitting method with a slow-knitting rate is employed to increase the cross-linking degree, in which dichloromethane (DCM) is replaced by dibromomethane (DBM) as both solvent and electrophilic cross-linker, resulting in highly porous and physicochemically stable HCPs. The BET surface areas of DBM-knitted SHCPs-Br are 44%-120% higher than that of DCM-knitted SHCPs-Cl using the same building blocks. Remarkably, SHCP-3-Br exhibits an unprecedentedly high porosity (SBET = 3120 m2 g-1) among reported HCPs, and shows a competitive volumetric 5-100 bar working methane capacity of 191 cm3 (STP) cm-3 at 273 K calculated by using real packing density, which outperforms sate-of-art metal-organic framework (MOFs) at comparable conditions. This facile and versatile low-knitting-rate strategy enables effective improvement in the porosity of HCPs for porosity-desired applications.

Sirolimus for the treatment of patients with refractory connective tissue disease-related thrombocytopenia: a pilot study.

OBJECTIVE: CTD-related immune thrombocytopenia (CTD-ITP) represents an unmet medical need because the drugs that are available are only partly effective and have considerable side-effects. The aim of this study was to assess the efficacy and safety of sirolimus in refractory CTD-ITP patients. METHODS: We did a single-arm, open-label, pilot study of sirolimus in patients with CTD-ITP unresponsive to, or intolerant of, conventional medications. Patients received oral sirolimus for 6 months at a starting dose of 0.5-1 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/ml. The primary efficacy end point was changes in platelet count, and overall response assessed according to the ITP International Working Group Criteria. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. RESULTS: Between November 2020 and February 2022, 12 consecutively hospitalized patients with refractory CTD-ITP were enrolled and prospectively followed. Of these, six patients (50%) achieved complete response, two (16.7%) achieved partial response, and four (33.3%) were no response under therapy. Three of four patients with primary Sjögren's syndrome and two of three patients with systemic lupus erythematosus achieved overall response. One of two patients with overlapping Sjögren's syndrome and systemic lupus erythematosus achieved complete response at 6 months. No severe drug-related toxicities were observed. CONCLUSION: Our results do support sirolimus as an alternative regimen for refractory CTD-ITP patients, including systemic lupus erythematosus and primary SS.

Small-molecule LRRK2 inhibitors for PD therapy: Current achievements and future perspectives.

Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that orchestrates a diverse array of cellular processes, including vesicle transport, autophagy, lysosome degradation, neurotransmission, and mitochondrial activity. Hyperactivation of LRRK2 triggers vesicle transport dysfunction, neuroinflammation, accumulation of α-synuclein, mitochondrial dysfunction, and the loss of cilia, ultimately leading to Parkinson's disease (PD). Therefore, targeting LRRK2 protein is a promising therapeutic strategy for PD. The clinical translation of LRRK2 inhibitors was historically impeded by issues surrounding tissue specificity. Recent studies have identified LRRK2 inhibitors that have no effect on peripheral tissues. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides a summary of the structure and biological functions of LRRK2, along with an overview of the binding modes and structure-activity relationships (SARs) of small-molecule inhibitors targeting LRRK2. It offers valuable references for developing novel drugs targeting LRRK2.

Loss of APOO (MIC26) aggravates obesity-related whitening of brown adipose tissue via PPARα-mediated functional interplay between mitochondria and peroxisomes.

BACKGROUND: Mitochondrial dysfunction and aberrant structure in adipose tissue occur in obesity and obesity-linked brown adipose tissue (BAT) whitening; however, whether this aberrant architecture contributes to or is the result of obesity is unknown. Apolipoprotein O (APOO) is a constitutive protein of the mitochondrial cristae organizing system complex. This study aimed to characterize the physiological consequences of APOO deficiency in vivo. METHODS: APOO expression was analyzed in different human and murine adipose depots, and mice lacking APOO in adipocytes (ApooACKO) are developed to examine the metabolic consequences of adipocyte-specific APOO ablation in vitro and in vivo. RESULTS: Results showed that APOO expression is reduced in BAT from both diet-induced and leptin-deficient obese mice. APOO-knockout mice showed increased adiposity, BAT dysfunction and whitening, reduced non-shivering thermogenesis, and blunted responses to cold stimuli. APOO deficiency disrupted mitochondrial structure in brown adipocytes and impaired oxidative phosphorylation, thereby inducing a shift from oxidative to glycolytic metabolism, increasing lipogenic enzyme levels and BAT whitening. APOO inactivation inhibited thermogenesis in BAT by reducing mitochondrial long-chain fatty acid oxidation. It also disturbed peroxisomal biogenesis and very long-chain fatty acid oxidation via peroxisome proliferator-activated receptor α. CONCLUSIONS: Altogether, APOO deficiency in adipocytes aggravates BAT whitening and diet-induced obesity; thus, APOO could be a therapeutic target for obesity.

Intrathecal injection of methotrexate combined with dexamethasone for Cogan's syndrome with neurological involvement: A case report and literature review.

Cogan's syndrome (CS) is a rare autoimmune disease in which approximately 10%-13% of people with the condition develop neurological symptoms. While glucocorticoids are the standard of care for patients with CS, disease-modifying anti-rheumatic drugs (DMARDs) and biologics agents are more widely used to treat the systemic and vestibular auditory manifestations of CS. Herein, we report a rare case of CS with central nervous system damage who failed to respond to systemic use of glucocorticoids and DMARDs. However, his symptoms were successfully improved by intrathecal injection of methotrexate (MTX) and dexamethasone. To our knowledge, the use of intrathecal injections of MTX and dexamethasone to treat CS has not been reported in any literature. Therefore, the present case may provide a new idea for clinicians to treat central nervous system symptoms in patients with CS.

Diagnostic serum biomarkers associated with ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune rheumatic disease that mostly affects the axial skeleton. This study aimed to investigate reliable diagnostic serum biomarkers for AS. Serum samples were collected from 20 AS patients and 20 healthy controls (HCs) and analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The differential metabolites between the AS patients and HCs were profiled using univariate and multivariate statistical analyses. Pathway analysis and a heat map were also conducted. Random forest (RF) analysis and the least absolute shrinkage and selection operator (LASSO) were used to establish predictive and diagnostic models. After controlling the variable importance in the projection (VIP) value > 1 and false discovery rate (FDR) < 0.05, a total of 61 differential metabolites were identified from 995 metabolites, which exhibited significant differences in the pathway analysis and heat map between the AS patients and HCs. RF as a predictive model also identified differential metabolites with 95% predictive accuracy and a high area under the curve (AUC) of 1. A diagnostic model comprising nine metabolites (cysteinylglycine disulfide, choline, N6, N6, N6-trimethyllysine, histidine, sphingosine, fibrinopeptide A, glycerol 3-phosphate, 1-linoleoyl-GPA (18:2), and fibrinopeptide A (3-16)) was generated using LASSO regression, capable of distinguishing HCs from AS with a high AUC of 1. Our results indicated that the UPLC-MS/MS analysis method is a powerful tool for identifying AS metabolite profiles. We developed a nine-metabolites-based model serving as a diagnostic tool to separate AS patients from HCs, and the identified diagnostic biomarkers appeared to have a diagnostic value for AS.

Cytokines and chemokines involved in HLA-B27-positive ankylosing spondylitis-associated acute anterior uveitis.

Purpose: Acute anterior uveitis (AAU) is the most common extra-articular symptom of ankylosing spondylitis (AS). This study aims to reveal the cytokines and chemokines involved in the immunopathogenesis of human leucocyte antigen (HLA)-B27+ AS-associated AAU. Methods: Twenty-one HLA-B27+ AS-associated AAU patients and 21 healthy controls (HCs) were recruited for this study. Serum cytokine concentrations in all 42 subjects were determined by the Meso Scale Discovery (MSD) electrochemiluminescence method. In each sample, 34 cytokines, 10 chemokines, eight angiogenesis mediators, and four vascular injury mediators were measured. The differences in cytokine and chemokine concentrations were compared between the two groups. Results: Concentrations of serum IL-3, TNF-α, IL-6, IL-17D, IL-22, IP10/CXCL10, MIP-3α/CCL20, sFlt-1/VEGFR-1, CRP, and MCP-4/CCL13 were significantly higher in patients with HL-B27+ AS-associated AAU than in HCs (p < 0.05). In contrast, concentrations of serum IL-4, IL-8, MIP-1α/CCL3, Eotaxin-3/CCL26, PlGF, VEGF-C, and VEGF-D were significantly lower in patients with HL-B27+ AS-associated AAU than in HCs (p < 0.05). Conclusions: Significant differences were detected in the levels of several cytokines and chemokines in the serum of HLA-B27+ AS-associated AAU compared with HCs. Some novel differential cytokines and chemokines that have not been reported in other kinds of uveitis were also identified. These results reveal the underlying pathogenesis of HLA-B27+ AS-associated AAU and could potentially aid in clinical diagnosis.

[Effect of positive end-expiratory pressure on cardiac function in patients with early left ventricular diastolic dysfunction: a prospective cohort study].

OBJECTIVE: To evaluate the effect of positive end-expiratory pressure (PEEP) ventilation on cardiac function in patients with early left ventricular (LV) diastolic dysfunction undergoing laparoscopic radical gastrectomy. METHODS: Patients who underwent laparoscopic radical gastrectomy under elective general anesthesia from July 2021 to February 2022 at the Subei People's Hospital were enrolled [age 60-75 years old, American Society of Anesthesiologists (ASA) grade I-II, and left ventricular ejection fraction (LVEF) > 0.50]. Transthoracic echocardiography (TTE) was performed before operation, and the peak early diastolic velocity (E peak) and peak late diastolic velocity (A peak) at the mitral ostium were recorded and the E/A and E peak deceleration time (DT) were calculated. Then isovolumic relaxation time (IVRT) and early peak mitral annular diastolic velocity (e') were recorded and left ventricular E/e' (LVE/e') was calculated. According to the E/A, mitral e', LVE/e', DT, and IVRT, the patients were divided into early LV diastolic dysfunction group (E/A < 1, mitral e' < 7 cm/s, LVE/e' > 14, DT > 200 ms, and IVRT > 100 ms) and normal cardiac function group (1 < E/A < 2, 160 ms < DT < 240 ms, and 70 ms < IVRT < 90 ms), with 35 patients in each group. Both groups were received fixed 5 cmH2O (1 cmH2O ≈ 0.098 kPa) PEEP 5 minutes after the beginning of the pneumoperitoneum until the end of the procedure. A volume controlled ventilation was used with a tidal volume (VT) of 7 mL/kg, an inspired oxygen concentration of 0.60, and an inspiratory to expiratory ratio of 1:2. Left and right myocardial systolic and diastolic function related parameters, including LVEF, LV global longitudinal strain (LVGLS), tricuspid annulus plane systolic migration (TAPSE), the peak early diastolic velocity (E peak) at the mitral and tricuspid valve ostia and the peak early diastolic velocity (e') at the corresponding annulus were measured by transesophageal echocardiography (TEE) before tracheal intubation (T0), 5 minutes after the pneumoperitoneum (T1), 5 minutes after PEEP ventilation (T2), 30 minutes after PEEP ventilation (T3), and 5 minutes after the end of pneumoperitoneum (T4), respectively. The left and right ventricular myocardial performance index (LVMPI/RVMPI) was calculated. RESULTS: Finally, 60 patients were included in the analysis, including 28 patients in the early LV diastolic dysfunction group and 32 patients in the normal cardiac function group. Compared with those at T0, mean arterial pressure (MAP), LVEF, mitral e', LVGLS, tricuspid e' and TAPSE were significantly lower in the normal cardiac function group at T1, and the early LV diastolic dysfunction group at T1, T2, and T3, and LVMPI, LVE/e', RVE/e', and RVMPI were significantly higher. At T4, the LVE/e' and the RVE/e' were significantly higher in the early LV diastolic dysfunction group than those at T0 (LVE/e': 16.52±1.26 vs. 14.32±1.09, and RVE/e': 18.71±1.74 vs. 16.51±1.93, respectively, both P < 0.05), Mitral e' and tricuspid e' were significantly lower than those at T0 [mitral e' (m/s): 0.07±0.01 vs. 0.09±0.01, tricuspid e' (m/s): 0.06±0.01 vs. 0.08±0.01, both P < 0.05]. Compared with the normal cardiac function group, MAP, LVEF, mitral e', LVGLS, tricuspid e', and TAPSE at T1, T2, and T3 were significantly lower in the early LV diastolic dysfunction group, while LVMPI, LVE/e', RVE/e', and RVMPI were significantly higher. At T4, the LVE/e' and the RVE/e' were significantly higher in the early LV diastolic dysfunction group than those in the normal cardiac function group (LVE/e': 16.52±1.26 vs. 9.87±1.25, RVE/e': 18.71±1.74 vs. 10.97±1.70, both P < 0.05). Mitral e' and tricuspid e' were significantly lower in the normal cardiac function group [mitral e' (m/s): 0.07±0.01 vs. 0.11±0.02, tricuspid e' (m/s): 0.06±0.01 vs. 0.10±0.02, both P < 0.05]. CONCLUSIONS: In early LV diastolic dysfunction patients, compared with patients with normal cardiac function, 5 cmH2O PEEP can further exacerbate left and right myocardial systolic and diastolic function in patients during pneumoperitoneum; when the pneumoperitoneum was ended, 5 cmH2O PEEP only worsen left and right myocardial diastolic function in patients, and did not affect left and right myocardial systolic function.

Inflamed adipose tissue: A culprit underlying obesity and heart failure with preserved ejection fraction.

The incidence of heart failure with preserved ejection fraction is increasing in patients with obesity, diabetes, hypertension, and in the aging population. However, there is a lack of adequate clinical treatment. Patients with obesity-related heart failure with preserved ejection fraction display unique pathophysiological and phenotypic characteristics, suggesting that obesity could be one of its specific phenotypes. There has been an increasing recognition that overnutrition in obesity causes adipose tissue expansion and local and systemic inflammation, which consequently exacerbates cardiac remodeling and leads to the development of obese heart failure with preserved ejection fraction. Furthermore, overnutrition leads to cellular metabolic reprogramming and activates inflammatory signaling cascades in various cardiac cells, thereby promoting maladaptive cardiac remodeling. Growing evidence indicates that the innate immune response pathway from the NLRP3 inflammasome, to interleukin-1 to interleukin-6, is involved in the generation of obesity-related systemic inflammation and heart failure with preserved ejection fraction. This review established the existence of obese heart failure with preserved ejection fraction based on structural and functional changes, elaborated the inflammation mechanisms of obese heart failure with preserved ejection fraction, proposed that NLRP3 inflammasome activation may play an important role in adiposity-induced inflammation, and summarized the potential therapeutic approaches.

[Community structure of phyllosphere fungi associated with dominant tree species in a broad-leaved Korean pine forest of Changbai Mountain, Northeast China]. / é•¿ç™½å±±é˜”å¶çº¢æ¾æž—ä¼˜åŠ¿æ ‘ç§å¶é™ çœŸèŒç¾¤è½ç»“æž„.

Forest is the main component of terrestrial ecosystems that harbors about 40% of the existing species on the earth. As a vital component of biodiversity, phyllosphere microbes in the canopy play a critical and unique role in maintaining plant health, improving host resistance, and influencing global biogeochemical cycle. However, the studies on the community structure of phyllosphere fungi in natural forests are scarce as compared to that on rhizosphere microbes. Consequently, we know litter about how phyllosphere fungi associates with leaf traits. In this study, we analyzed fungal community composition of canopy leaves of six dominant tree species (i.e., Pinus koraiensis, Tilia amurensis, Quercus mongolica, Acer mono, Fraxinus mandshurica, and Ulmus japonica), in a broad-leaved Korean pine forest of Changbai Mountain Nature Reserve in Jilin Province, using high-throughput sequencing. We compared the differences of phyllosphere fungal community structure and functional groups of different dominant tree species. Moreover, 14 key leaf functional traits of their host trees were measured to investigate the relationships between fungal community composition and leaf functional traits. We found that the dominant phyla and class of phyllosphere fungi were Ascomycota and Basidiomycota, and Dothideomycetes and Taphrinomycetes, respectively. Results of LEfSe analysis indicated that all the tree species except Ulmus japonica had significant biomarkers, such as the Eurotiomycetes of Pinus koraiensis and the Ascomycetes of Quercus mongolica. The main functional groups of phyllosphere fungi were pathotroph. The results of redundancy and envfit analysis showed that functional traits related to plant nutrient acquisition as well as resistance to diseases and pests were the main factors influencing the community structure of phyllosphere fungi.

Aloe gel glucomannan induced colon cancer cell death via mitochondrial damage-driven PINK1/Parkin mitophagy pathway.

Mitophagy can selectively remove damaged mitochondria, which is critical in regulating mitochondrial homeostasis in diseases, such as cancer. Herein, we found that Aloe gel glucomannan (AGP) significantly inhibited the proliferation of colon cancer cells. RNA-seq analysis revealed that AGP upregulated autophagy, lysosome and mitochondrial fission signal pathways in colon cancer cell line CT26. Notably, AGP induced the accumulation of impaired and reactive oxygen species (ROS)-generating mitochondria, which triggered excessive mitophagy. Interestingly, the mitophagy activator enhanced AGP-induced mitophagy and cytotoxicity, whereas the mitophagy inhibitor reversed the influence of AGP. Furthermore, activation of PINK1/Parkin mitophagy pathway and transcription factor EB (TFEB) signaling was dependent on ROS overproduction. Taken together, these results indicated that AGP induced cytotoxic mitophagy through ROS-related PINK1/Parkin pathway and TFEB activation in CT26 cells. The research would provide theoretical basis for the development of AGP as a promising anticancer agent.

ANGPTL3 Is Involved in the Post-prandial Response in Triglyceride-Rich Lipoproteins and HDL Components in Patients With Coronary Artery Disease.

It is well-established that there exists an inverse relationship between high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels in the plasma. However, information is lacking on the impact of post-prandial triglyceride-rich lipoproteins (TRLs) on the structure of HDL subclasses in patients with coronary artery disease (CAD). In this study, the data of 49 patients with CAD were analyzed to evaluate dynamic alterations in post-prandial lipid profiles using nuclear magnetic resonance-based methods. An enzyme-linked immunosorbent assay was used to quantify the serum angiopoietin-like protein 3 (ANGPTL3). After glucose supplementation, the expression of hepatic ANGPTL3 was evaluated both in vitro and in vivo. Compared to fasting levels, the post-prandial serum TG level of all participants was considerably increased. Although post-prandial total cholesterol in HDL (HDL-C) remained unchanged, free cholesterol in HDL particles (HDL-FC) was significantly reduced after a meal. Furthermore, the post-prandial decrease in the HDL-FC level corresponded to the increase in remnant cholesterol (RC), indicating the possible exchange of free cholesterol between HDL and TRLs after a meal. Moreover, CAD patients with exaggerated TG response to diet, defined as TG increase >30%, tend to have a greater post-prandial increase of RC and decrease of HDL-FC compared to those with TG increase ≤30%. Mechanistically, the fasting and post-prandial serum ANGPTL3 levels were significantly lower in those with TG increase ≤30% than those with TG increase >30%, suggesting that ANGPTL3, the key lipolysis regulator, may be responsible for the different post-prandial responses of TG, RC, and HDL-FC.

Glycerophospholipid metabolism is involved in rheumatoid arthritis pathogenesis by regulating the IL-6/JAK signaling pathway.

To explore the metabolic mechanism of differential plasma interleukin (IL)-6 expression in patients with rheumatoid arthritis (RA). A total of 240 RA patients were enrolled in the non-target metabolomics study cohort and 69 healthy volunteers were included as healthy controls (HCs). Plasma IL-6 levels were detected by electrochemiluminescence assay. Plasma metabolites were detected by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Patients with active RA (n = 20) and remissive RA (n = 20) and 20 HCs were enrolled in the targeted validation cohort. Metabolites identified by non-target metabolomics were quantitatively analyzed by ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry. Effects of 1-oleoyl-sn-glycero-3-phosphocholine (OGPC) associated with IL-6 on MH7A cells were assessed. After 24-h or 48-h induction by TNF-α, the supernatants were collected for IL-6 quantification by enzyme-linked immunosorbent assay. Furthermore, Western blot was performed to investigate the relative JAK2 and p-JAK2 expressions. With an increasing IL-6 level, OGPC shown to be related to the glycerophospholipid metabolism pathway by Kyoto Encyclopedia of Genes and Genomes analysis displayed a significant decrease. In the validating RA cohort, the OGPC concentrations in remissive RA group and active RA group decreased compared with HC group. OGPC down-regulated IL-6 secretion and p-JAK2 expression in TNF-α-induced MH7A cells in vitro. In conclusion, glycerophospholipid metabolism is the main metabolic pathway associated with the differential IL-6 expression in RA patients. The down-regulated OGPC is a promoting factor for the increased IL-6 plasma level in RA patients, which further affects the downstream JAK signaling pathway.

Antisolvent-assisted Crystallization of Centimeter-sized Lead-free Bismuth Bromide Hybrid Perovskite Single Crystals with X-ray Sensitive Merits.

Hybrid bismuth halides perovskites have emerged as promising candidates for X-ray detection, due to the strong absorptivity of high-energy X-ray photons, high resistivity, large carrier diffusion length and low toxicity. However, the mostly investigated hybrid bismuth iodides single crystals are usually opaque and require a harsh synthesis process. Herein, novel one-dimensional (1D) pentamethylenediamine bismuth bromide (PDA)BiBr5 single crystals were synthesized via an antisolvent-assisted crystallization method at room temperature. Bulk (PDA)BiBr5 single crystals have sizes of 10×1.3×1.5 mm3 and high transparency. They are shown to have low density of defects of 2.0×1010  cm-3 and obvious photoconductivity. Moreover, they exhibit large bulk resistivity of 2.13×1011 â€…Ω cm and good X-ray attenuation coefficient. Consequently, the vertical structured (PDA)BiBr5 single crystal X-ray photoconductor produces a sensitivity of 3.8 µC Gyair -1  cm-2 . This study provides a facile strategy for synthesizing bulk hybrid bismuth bromides single crystals with potential X-ray detection application.

Estimating the rate of overdiagnosis with prostate cancer screening: evidence from the Finnish component of the European Randomized Study of Screening for Prostate Cancer.

PURPOSE: Screening for prostate cancer may have limited impact on decreasing prostate cancer-related mortality. A major disadvantage is overdiagnosis, whereby lesions are identified that would not have become evident during the man's lifetime if screening had not taken place. The present study aims to estimate the rate of overdiagnosis using Finnish data from the European randomized trial of prostate cancer screening. METHODS: We used data from 80,149 men randomized to a screening or a control group, distinguishing four birth cohorts. We used the "catch-up method" to identify when the difference in the cumulative incidence of prostate cancer between the screening and control groups had stabilized, implying that the screening has no further effect. We define the overdiagnosis rate to be the relative excess cumulative incidence in the screened group at that point. As an independent method, we also examined the diagnosis rates of T1c tumors as an indicator of early tumors detected by PSA. RESULTS: The estimates of overdiagnosis rates from the catch-up method using the full period of available follow-up ranged between cohorts from 2.3% to 15.4%, and the T1c analysis gave very similar results. CONCLUSION: Some overdiagnosis has occurred, but there is uncertainty about its extent. A long follow-up is required to demonstrate the full impact of screening. We evaluated the overdiagnosis rates at a population level, associated with being offered screening, taking account of contamination (screening among the controls). The overall evaluation of screening should incorporate mortality benefit, cost-effectiveness, and quality of life.

5-Ammoniumvaleric acid stabilized mixed-dimensional perovskite submicron platelets with white light emission.

Low-dimensional Pb-Br and Pb-Cl perovskite single crystals have aroused considerable attention due to their broadband white-light emission. But their synthesis involving halogenation of organic amines, dissolution of lead oxide and a slow cooling process is quite complicated. Herein, we report white light emission from mixed-dimensional AVA x (MAPbCl3) perovskite submicron platelets formed by one-step solution processing. It is found that the presence of 5-ammoniumvaleric acid (5-AVA) with a zwitterionic functional group is crucial for modulating the morphology and structural dimensionality of perovskites. Importantly, AVA x (MAPbCl3) perovskites exhibit distinctive structural dimensionality dependent broadband emission, indicating the formation of self-trapped excited states. The AVA2(MAPbCl3) perovskite exhibits white-light emission with a color rendering index (CRI) of 85 and a correlated color temperature (CCT) of 8624 K, yielding "cold" white light. Moreover, the mixed-dimensional perovskite exhibits good stability for more than 30 days. With this report, we aim to provide a facile approach for synthesizing stable low-dimensional perovskite nanostructures for making advanced optoelectronic devices.