Cut-off values of haemoglobin and clinical outcomes in incident peritoneal dialysis: the PDTAP study.

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.

Morphology, genetic characterization and phylogeny of Moniliformis tupaia n. sp. (Acanthocephala: Moniliformidae) from the northern tree shrew Tupaia belangeri chinensis Anderson (Mammalia: Scandentia).

A new species of Moniliformis, M. tupaia n. sp. is described using integrated morphological methods (light and scanning electron microscopy) and molecular techniques (sequencing and analysing the nuclear 18S, ITS, 28S regions and mitochondrial cox1 and cox2 genes), based on specimens collected from the intestine of the northern tree shrew Tupaia belangeri chinensis Anderson (Scandentia: Tupaiidae) in China. Phylogenetic analyses show that M. tupaia n. sp. is a sister to M. moniliformis in the genus Moniliformis, and also challenge the systematic status of Nephridiacanthus major. Moniliformis tupaia n. sp. represents the third Moniliformis species reported from China.

Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension.

OBJECTIVE: To analyse the relationship between the polymorphisms of the H-type hypertensive methylenetetrahydrofolate reductase (MTHFR) C677T gene and neutrophil gelatinase-associated lipocalin (NGAL) in early kidney injury. METHOD: A total of 279 hospitalised patients with hypertension were selected and grouped according to their homocysteine (Hcy) level. If their blood Hcy level was ≥ 10 µmol/L they were assigned to the H-type hypertensive group, and if it was < 10 µmol/L they were assigned to the non-H-type hypertensive group. Blood lipid indexes, renal function indexes and blood glucose indexes were collected, and the differences between the two groups were compared. Furthermore, MTHFR C677T genotype distribution and allele frequency and Hcy level of MTHFR C677T genotype were compared, and logistic multiple regression analysis was conducted for the correlation of different genotypes of MTHFR C677T and the early kidney injury marker NGAL. RESULTS: In the non-H-type hypertensive group, the levels of Hcy and NGAL, cystatin, blood urea nitrogen, serum creatinine, uric acid, serum ß2-microglobulin and urinary microalbumin-to-creatinine ratio increased significantly, and the glomerular filtration rate level decreased significantly, when compared with the H-type hypertensive group, with statistical differences (p < 0.05). The H-type hypertensive group and the non-H-type hypertensive group had significant differences in the CC, CT and TT genotypes and allele frequencies at the MTHFR C677T locus. The MTHFR C677T gene mutation rate of the H-type hypertensive group was significantly higher than that of the non-H-type hypertensive group. The H-type hypertensive group had higher levels of the TT genotype and CT genotype Hcy. There was a statistical difference (p < 0.05). CONCLUSION: Methylenetetrahydrofolate reductase C677T polymorphism is correlated with the Hcy level, and its gene polymorphism will affect the Hcy level. Methylenetetrahydrofolate reductase C677T polymorphism has an interactive effect with NGAL. Screening NGAL and reducing Hcy levels are valuable methods for the prevention and treatment of early renal injury in patients with H-type hypertension and help improve the prognosis of patients and their quality of life.

The Effect of Angiotensin Receptor Blockers on In-Stent Restenosis After Stent Implantation: A Meta-Analysis.

AIM: Angiotensin receptor blockers (ARBs) have been shown to inhibit restenosis in vitro and in vivo, but the evidence found in humans is inconsistent. This study aimed to evaluate the effectiveness of ARBs in preventing in-stent restenosis after percutaneous coronary intervention (PCI). METHOD: Databases including the Cochrane Library, MEDLINE, Web of Science, EMBASE, and CNKI were searched to collect randomised controlled trials on ARBs inhibiting restenosis that were published before October 2022. A total of 1,056 patients enrolled in eight trials were included in the study. RESULTS: The ARBs group showed lower target lesion revascularisation than the control group (RR 0.54; 95% CI 0.34-0.86; p=0.01), but the restenosis incidence between these two groups was not statistically significant (RR 0.85; 95% CI 0.65-1.11; p>0.05). CONCLUSION: This study found that ARBs might have a potential effect on reducing target lesion revascularisation after PCI in coronary heart disease patients but has no impact on angiographic restenosis.

Free Water MR Imaging of White Matter Microstructural Changes is a Sensitive Marker of Amyloid Positivity in Alzheimer's Disease.

BACKGROUND: Extracellular free water (FW) resulting from white matter degeneration limits the sensitivity of diffusion tensor imaging (DTI) in predicting Alzheimer's disease (AD). PURPOSE: To evaluate the sensitivity of FW-DTI in detecting white matter microstructural changes in AD. To validate the effectiveness of FW-DTI indices to predict amyloid-beta (Aß) positivity in mild cognitive impairment (MCI) subtypes. STUDY TYPE: Retrospective. POPULATION: Thirty-eight Aß-negative cognitively healthy (CH) controls (68.74 ± 8.28 years old, 55% female), 15 Aß-negative MCI patients (MCI-n) (68.87 ± 8.83 years old, 60% female), 29 Aß-positive MCI patients (MCI-p) (73.03 ± 7.05 years old, 52% female), and 29 Aß-positive AD patients (72.93 ± 9.11 years old, 55% female). FIELD STRENGTH/SEQUENCE: 3.0T; DTI, T1 -weighted, T2 -weighted, T2 star-weighted angiography, and Aß PET (18 F-florbetaben or 11 C-PIB). ASSESSMENT: FW-corrected and standard diffusion indices were analyzed using trace-based spatial statistics. Area under the curve (AUC) in distinguishing MCI subtypes were compared using support vector machine (SVM). STATISTICAL TESTS: Chi-squared test, one-way analysis of covariance, general linear regression analyses, nonparametric permutation tests, partial Pearson's correlation, receiver operating characteristic curve analysis, and linear SVM. A P value <0.05 was considered statistically significant. RESULTS: Compared with CH/MCI-n/MCI-p, AD showed significant change in tissue compartment indices of FW-DTI. No difference was found in the FW index among pair-wise group comparisons (the minimum FWE-corrected P = 0.114). There was a significant association between FW-DTI indices and memory and visuospatial function. The SVM classifier with tissue radial diffusivity as an input feature had the best classification performance of MCI subtypes (AUC = 0.91), and the classifying accuracy of FW-DTI was all over 89.89%. DATA CONCLUSION: FW-DTI indices prove to be potential biomarkers of AD. The classification of MCI subtypes based on SVM and FW-DTI indices has good accuracy and could help early diagnosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Predictive value of monocyte to HDL-C ratio for coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease.

We aimed to investigate the predictive validity of monocyte to high-density lipoprotein cholesterol ratio (MHR) for coronary artery lesions (CALs) and intravenous immunoglobulin (IVIG) resistance in complete Kawasaki disease (KD). MHR values of a total of 207 complete KD patients were calculated and analyzed with regard to their clinical characteristics and outcomes. We compared the differences in clinical data and laboratory parameters between CAL+ group and CAL- group as well as between IVIG-resistant group and IVIG-responsive group. Spearman's correlation analysis was applied to evaluate the correlation between C-reactive protein (CRP) and MHR. Multivariate logistic regression was used to identify risk factors of CALs and IVIG resistance. Receiver operating characteristic (ROC) curve analysis was chosen to determine the optimal cut-off value of MHR and its validity in predicting CALs and IVIG resistance. The MHR level was significantly higher in the CAL+ group, with cut-off value of 1.30 g/L, yielding a sensitivity of 0.753 and specificity of 0.805, as well as in IVIG-resistant group, with cut-off value of 1.03 g/L, yielding a sensitivity of 0.97 and specificity of 0.485. Multivariate logistic regression showed that MHR was an independent risk factor for CALs but not for IVIG resistance. According to the Spearman's correlation analysis, CRP was positively correlated with the MHR. CONCLUSIONS: As a practical, cost-effective inflammatory biomarker, MHR has a significantly predictive value in complete KD children complicated with CALs and IVIG-resistance. Paying more attention to the changes of MHR in KD children may contribute to better understanding of KD development and prognosis in clinical practice. WHAT IS KNOWN: • CALs are the most prevalent serious sequela of KD, and approximately 10%~20% of patients do not respond to IVIG therapy. • MHR could be a convenient biomarker to predict the development and progression of CVDs. It has been reported that the MHR is a new prognostic biomarker in several CVDs. WHAT IS NEW: • MHR has a significantly predictive value in KD children complicated with CALs and IVIG-resistance. • Compared with the molecular and immunological biomarkers that have been reported, MHR has the characteristics of practical, cost-effective, higher sensitivity and specificity, which can be used as a predictive indicator in complete KD patients.

Correlation Study of Chronic Renal Insufficiency and Long-Term Prognosis of Patients with Acute Ischemic Cerebral Apoplexy After Intravenous rt-PA Thrombolysis.

Objective: To investigate the correlation between chronic renal insufficiency and the long-term prognosis of patients with acute ischemic cerebral apoplexy after intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis. Methods: 290 patients (194 males and 96 females) with acute cerebral infarction who received intravenous rt-PA thrombolysis were admitted to Ningbo Medical Center Lihuili Hospital from May 2018 to December 2020. Their clinical baseline data were recorded. According to the estimated glomerular filtration rate (eGFR) level, patients were divided into the control group (252 cases) and the chronic kidney disease (CKD) group (38 cases). The prognosis of patients was evaluated by a modified Rankin Scale (mRS) 90 days after cerebral apoplexy by telephone interview or outpatient following-up (mRS ≤ 2 reflected good prognosis, mRS >2 reflected unfavorable prognosis). Multivariate logistic regression was used to analyze the prognosis risk relationship of acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis with CKD. Results: Acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis with CKD were older ((79.08 ± 8.96) years vs (65.84 ± 13.31) years, P = .00052, 95% CI = 0.00031-0.00072) than who without CKD, and were more likely to be suffering from hypertension (94.7% (36/38) and 66.3% (167/252), P = .00023, 95% CI = 0.00011-0.00033), atrial fibrillation (50.0% (19/38) and 26.6% (67/252), P = .007, 95% CI = 0.001-0.009), high Uric acidemia (68.4% (26/38) and 17.9% (45/252), P = .00044, 95% CI = 0.00027-0.00061), hyperhomocysteinemia (47.4% (18/38) and 13.1% (33/252), P = .00032, 95% CI=0.00022-0.00053), history of malignant tumor (13.2% (5/38) and 4.4% (11/252), P = .044, 95% CI = 0.0023-0.0053), cardiogenic embolism (Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of cerebral infarction) (47.4% (18/38) and 29.0% (73/252), P = .038, 95% CI = 0.029-0.055). The mortality rate of the CKD group was higher than the control group (13.2% (5/38) and 4.0% (10/252), P = .033, 95% CI = 0.021-0.053), and the good prognosis rate in the CKD group was significantly lower than in the control group (42.1% (16/38) and 73.8% (186/252), P = .00032, 95% CI = 0.00012-0.00043). Multivariate logistic regression analysis showed that CKD was an independent risk factor for acute ischemic cerebral apoplexy patients undergoing intravenous rt-PA thrombolysis (OR = 4.606, 95%CI 1.176~18.041, P = .028, 95% CI = 0.022-0.043). Conclusion: CKD is an independent risk factor for acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis.

Bidirectional or unidirectional? Longitudinal associations between external stressors, perceived spousal support, and marital instability.

Based on three annual waves of data from 268 Chinese newlyweds (Mage = 29.59, SD = 3.25 for husbands; Mage = 28.08, SD = 2.51 for wives), the present study examined the bidirectional associations between external stressors, perceived spousal support, and marital instability by using a three-wave, cross-lagged approach. Results indicated bidirectional associations between external stressors and marital instability, and a unidirectional association linking marital instability to perceived spousal support. Additionally, external stressors at Wave 2 mediated the association between external stressors at Wave 1 and marital instability at Wave 3. Taken together, the present study contributes to an emerging body of research aimed at clarifying: (a) the directionality of the associations between external stressors, perceived spousal support, and marital instability; (b) how external stressors cumulatively affect the development of marital instability. Our study extends the Vulnerability-Stress-Adaptation (VSA) model and has developmental implications for promoting marital relationships in non-Western couples.

Paclitaxel-based supramolecular hydrogel loaded with mifepristone for the inhibition of breast cancer metastasis.

Breast cancer is the leading cause of cancer death among women and almost all of the breast cancer-caused mortality is related to metastasis. It has been reported that glucocorticoid facilitates the metastasis of breast cancer in mice, and mifepristone can antagonize the effect of glucocorticoid. Paclitaxel is one of the important drugs in the treatment of breast cancer. Mifepristone combined with paclitaxel could be an effective strategy for inhibiting breast cancer metastasis. However, their inherent defects, in terms of short blood circulation half-life and lack of tumor targeting, not only limit their effectiveness but also cause adverse reactions. Therefore, our aim is to explore a novel protocol against breast cancer metastasis, further optimize its therapeutic efficacy by a nanodelivery system, and explore its mechanism. Herein, a paclitaxel-conjugated and mifepristone-loaded hydrogel (PM-nano) was prepared by self-assembly. Its characterizations were studied. The antimetastatic effect was evaluated in vitro and in vivo and its mechanism was also explored by western blot assay. The resultant PM-nano was developed with favorable water solubility and good biocompatibility. Moreover, PM-nano displayed increased cell uptake properties and stimulated drug release in the tumor micro-acidic environment. The PM-nano was more effective in inhibiting the proliferation and metastasis of breast cancer than other groups in vitro and in vivo. The PM-nano might inhibit metastasis through glucocorticoid receptor/receptor tyrosine kinase-like orphan receptor 1 and MMPs. Taken together, PM-nano showed superior antimetastatic effects against breast cancer and excellent biocompatibility in vitro and in vivo, providing a new option for limiting metastasis.

Two-Photon Excited Fluorescent 3,3'-Diamino-5,5'-Diboryl-2,2'-Bithienyls Featuring a Quadrupolar Structure.

The quest for fluorophores exhibiting large two-photon absorption cross sections and high fluorescence efficiency is an important topic. Two 2,2'-bithienyl derivatives are disclosed which contain two N,N-disubstituted amino and two dimesitylboryl groups at 3,3'- and 5,5'-positions, respectively. Despite the great steric effect of amino groups, the bithienyl skeleton still adopts a coplanar geometry. Herein, they are characterized by a quadrupolar structure and display good fluorescence efficiency and large two-photon absorption cross sections up to 473 GM.

Telemedicine and Clinical Outcomes in Peritoneal Dialysis: A Propensity-Matched Study.

INTRODUCTION: Telemedicine (TM) has shown to provide potential benefits on clinical outcomes in patients with chronic kidney disease but limited evidences published in the peritoneal dialysis (PD) population. This study aimed to explore the long-term effects of TM on the mortality and technique failure. METHODS: The Peritoneal Dialysis Telemedicine-assisted Platform Cohort Study (PDTAP Study) was conducted prospectively in 27 hospitals in China since 2016. Patient and practice data were collected through the doctor-end of the TM app (Manburs) for all participants. TM including self-monitoring records, on-line education materials, and real-time physician-patient contact was only performed for the patient-end users of the Manburs. The primary outcome was all-cause mortality. The secondary outcomes were cause-specific mortality and all-cause and cause-specific permanent transfer to hemodialysis. RESULTS: A total of 7,539 PD patients were enrolled between June 2016 and April 2019, with follow-up till December 2020. Patients were divided into two cohorts: TM group (39.1%) and non-TM group (60.9%). A propensity score was used to create 2,160 matched pairs in which the baseline covariates were well-balanced. There were significantly lower risks of all-cause mortality (HR 0.59 [0.51, 0.67], p < 0.001), CVD mortality (HR 0.59 [0.49, 0.70], p < 0.001), all-cause transfer to hemodialysis (0.57 [0.48, 0.67], p < 0.001), transfer to hemodialysis from PD-related infection (0.67 [0.51, 0.88], p = 0.003), severe fluid overload (0.40 [0.30, 0.55], p < 0.001), inadequate solute clearance (0.49 [0.26, 0.92], p = 0.026), and catheter-related noninfectious complications (0.41 [0.17, 0.97], p = 0.041) in the TM group compared with the non-TM group. CONCLUSION: This study indicated real-world associations between TM usage and reduction in patient survival and technique survival through a multicenter prospective cohort.

Chiral Triarylborane-Based Small Organic Molecules for Circularly Polarized Luminescence.

Circularly polarized luminescence (CPL) has shown promising application potentials in 3D display, optical data storage, smart sensors/probers, CPL lasers, and light source for asymmetric photosynthesis. In the last decade, the CPL-active small organic molecules (CPL-SOMs) have attracted rapidly increasing research interest owing to the great advantages of SOMs, such as high luminescence efficiency, facile modification of chemical structure, fine emission wavelength tuning, precise relationships between structure and properties, and as well as easy fabrication. Promoted by the unique effects of boryl group, such as strong electron-accepting ability, great steric effect, and Lewis acidity to bind with Lewis bases, we herein summarized our recent research results about the creation of CPL-SOMs by modification of chiral scaffolds, such as [2.2]paracyclophane, [5]/[7]helicene, and binaphthyl, with boryl group. The preliminary results have well demonstrated that the chiral triarylborane-based SOMs exhibit promising CPL properties, such as intense CPL in combination of high luminescence dissymmetry factor (|glum |) with high fluorescence efficiency, solvent-induced sign inversion, facile emission wavelength tuning, high fluorescence efficiency in the solid, and substituent-induced sign inversion.

Cadinane-Type Sesquiterpenoids with Cytotoxic Activity from the Infected Stems of the Semi-mangrove Hibiscus tiliaceus.

Eight new cadinane sesquiterpenoids (1-8), along with two known compounds (9 and 10), were isolated from infected stems of the semi-mangrove plant, Hibiscus tiliaceus. The structures of compounds 1-8 were elucidated through the analysis of their 1D and 2D NMR and MS data, and their absolute configurations were determined by comparing their experimental and calculated ECD spectra and by single-crystal X-ray diffraction. The two confused known compounds (9 and 10) were resolved using single-crystal X-ray crystallography. Compounds 1-3 have novel norsesquiterpene carbon skeletons arising from a ring contraction rearrangement. All obtained isolates were evaluated against the HepG2 and Huh7 cell lines, and compounds 1b, 2b, 4, 6, and 8 showed cytotoxic activity toward both cell lines, with IC50 values ranging from 3.5 to 6.8 µM.

Cadinane-type sesquiterpenoid dimeric diastereomers hibisceusones A-C from infected stems of Hibiscus tiliaceus with cytotoxic activity against triple-negative breast cancer cells.

Three new cadinane-type sesquiterpenoid dimeric diastereomers (1-3) named hibisceusones A-C were obtained from the infected stems of Hibiscus tiliaceus. The structures were determined by NMR spectroscopy and MS techniques, and the absolute configurations were assigned by ECD and single-crystal X-ray diffraction techniques. Compounds 1-3 are diastereomers, and contain a 1,4-dioxane ring linearly fused to different cadinane-type polycyclic skeletons. This is the first time that such a structure has been identified in natural products. Compounds 1-3 exhibited cytotoxic activities, and 2 showed a significantly high anti-triple-negative breast cancer (TNBC) effect. The anti-cancer effect of compound 2 was 3-4 fold higher than that of 1 and 3. The anti-cancer effect was generated via the induction of the apoptosis of the MDA-MB-231 cells by inhibiting the PI3Kα pathway.

Arabidopsis MYB4 plays dual roles in flavonoid biosynthesis.

Flavonoids are major secondary metabolites derived from the plant phenylpropanoid pathway that play important roles in plant development and also have benefits for human health. So-called MBW ternary complexes involving R2R3-MYB and basic helix-loop-helix (bHLH) transcription factors along with WD-repeat proteins have been reported to regulate expression of the biosynthetic genes in the flavonoid pathway. MYB4 and its closest homolog MYB7 have been suggested to function as repressors of phenylpropanoid metabolism. However, the detailed mechanism by which they act has not been fully elucidated. Here, we show that Arabidopsis thaliana MYB4 and its homologs MYB7 and MYB32 interact with the bHLH transcription factors TT8, GL3 and EGL3 and thereby interfere with the transcriptional activity of the MBW complexes. In addition, MYB4 can also inhibit flavonoid accumulation by repressing expression of the gene encoding Arogenate Dehydratase 6 (ADT6), which catalyzes the final step in the biosynthesis of phenylalanine, the precursor for flavonoid biosynthesis. MYB4 potentially represses not only the conventional ADT6 encoding the plastidial enzyme but also the alternative isoform encoding the cytosolic enzyme. We suggest that MYB4 plays dual roles in modulating the flavonoid biosynthetic pathway in Arabidopsis.

NEIL3 may act as a potential prognostic biomarker for lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death. This study aimed to develop and validate reliable prognostic biomarkers and signature. METHODS: Differentially expressed genes were identified based on three Gene Expression Omnibus (GEO) datasets. Based on 1052 samples' data from our cohort, GEO and The Cancer Genome Atlas, we explored the relationship of clinicopathological features and NEIL3 expression to determine clinical effect of NEIL3 in LUAD. Western blotting (22 pairs of tumor and normal tissues), Real-time quantitative PCR (19 pairs of tumor and normal tissues), and immunohistochemical analyses (406-tumor tissues subjected to microarray) were conducted. TIMER and ImmuCellAI analyzed relationship between NEIL3 expression and the abundance of tumor-infiltrating immune cells in LUAD. The co-expressed-gene prognostic signature was established based on the Cox regression analysis. RESULTS: This study identified 502 common differentially expressed genes and confirmed that NEIL3 was significantly overexpressed in LUAD samples (P < 0.001). Increased NEIL3 expression was related to advanced stage, larger tumor size and poor overall survival (p < 0.001) in three LUAD cohorts. The proportions of natural T regulatory cells and induced T regulatory cells increased in the high NEIL3 group, whereas those of B cells, Th17 cells and dendritic cells decreased. Gene set enrichment analysis indicated that NEIL3 may activate cell cycle progression and P53 signaling pathway, leading to poor outcomes. We identified nine prognosis-associated hub genes among 370 genes co-expressed with NEIL3. A 10-gene prognostic signature including NEIL3 and nine key co-expressed genes was constructed. Higher risk-score was correlated with more advanced stage, larger tumor size and worse outcome (p < 0.05). Finally, the signature was verified in test cohort (GSE50081) with superior diagnostic accuracy. CONCLUSIONS: This study suggested that NEIL3 has the potential to be an immune-related therapeutic target and an independent predictor of LUAD prognosis. We also developed a prognostic signature for LUAD with a precise diagnostic accuracy.

Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy.

OBJECTIVES: Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive. METHODS: Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system. RESULTS: A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM. CONCLUSIONS: The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.

Abscisic acid suppresses the activation of NLRP3 inflammasome and oxidative stress in murine allergic airway inflammation.

Abscisic acid (ABA), a well-known natural phytohormone reportedly exerts anti-inflammatory and anti-oxidative properties in diabetes and colitis. However, the efficacy of ABA against allergic airway inflammation and the underlying mechanism remain unknown. Herein, an OVA-induced murine allergic airway inflammation model was established and treated with ABA in the presence or absence of PPAR-γ antagonist GW9662. The results showed that ABA effectively stunted the development of airway inflammation, and concordantly downregulated OVA-induced activation of NLRP3 inflammasome, suppressed oxidative stress and decreased the expression of mitochondrial fusion/fission markers including Optic Atrophy 1 (OPA1), Mitofusion 2 (Mfn2), dynamin-related protein 1 (DRP1) and Fission 1 (Fis1). Moreover, ABA treatment further increased OVA-induced expression of PPAR-γ, while GW9662 abrogated the inhibitory effect of ABA on allergic airway inflammation as well as on the activation of NLRP3 inflammasome and oxidative stress. Consistently, ABA inhibited the activation of NLRP3 inflammasome, suppressed oxidative stress and mitochondrial fusion/fission in LPS-stimulated Raw264.7 cells via PPAR-γ. Collectively, ABA ameliorates OVA-induced allergic airway inflammation in a PPAR-γ dependent manner, and such effect of ABA may be associated with its inhibitory effect on NLRP3 inflammasome and oxidative stress. Our results suggest the potential of ABA or ABA-rich food in protecting against asthma.

SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode ß-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

K562 cell-derived exosomes suppress the adhesive function of bone marrow mesenchymal stem cells via delivery of miR-711.

A failure of bone marrow mesenchymal stem cells (BM-MSCs) to adhere to hematopoietic cells is an essential cause of the progression of chronic myelogenous leukemia and is also a cause of failure of bone marrow (BM) transplantation, but the exact mechanisms of this have not been fully elucidated. Recent studies have indicated that microRNAs (miRNAs) are contained in leukemia-derived exosomes and are involved in modulating the BM microenvironment. In this study, we found that K562 cell-derived exosomes transfer miR-711 to BM-MSCs and suppress the adhesive function of BM-MSCs. Using qRT-PCR, we also confirmed a significantly higher level of miR-711 in exosomes derived from K562 cells than in exosomes derived from parental cells. The BM-MSCs co-cultured with exosomes derived from K562 cells showed a lower adhesion rate than did controls. We further demonstrated that exosomal transfer of miR-711 induced decreased adhesive abilities by inhibiting expression of adhesion molecule CD44 in BM-MSCs. In conclusion, our study reveals that K562 cell-derived exosomal miR-711 can be transferred to BM-MSCs and weaken adhesive abilities by silencing the expression of the adhesion molecule CD44.