Role of cytoplasmic dynein in the axonal transport of microtubules and neurofilaments

Recent studies have shown that the transport of microtubules (MTs) and neurofilaments (NFs) within the axon is rapid, infrequent, asynchronous, and bidirectional. Here, we used RNA interference to investigate the role of cytoplasmic dynein in powering these transport events. To reveal transport of MTs and NFs, we expressed EGFP-tagged tubulin or NF proteins in cultured rat sympathetic neurons and performed live-cell imaging of the fluorescent cytoskeletal elements in photobleached regions of the axon. The occurrence of anterograde MT and retrograde NF movements was significantly diminished in neurons that had been depleted of dynein heavy chain, whereas the occurrence of retrograde MT and anterograde NF movements was unaffected. These results support a cargo model for NF transport and a sliding filament model for MT transport

SOAPsplice: Genome-Wide ab initio Detection of Splice Junctions from RNA-Seq Data

RNA-Seq, a method using next generation sequencing technologies to sequence the transcriptome, facilitates genome-wide analysis of splice junction sites. In this paper, we introduce SOAPsplice, a robust tool to detect splice junctions using RNA-Seq data without using any information of known splice junctions. SOAPsplice uses a novel two-step approach consisting of first identifying as many reasonable splice junction candidates as possible, and then, filtering the false positives with two effective filtering strategies. In both simulated and real datasets, SOAPsplice is able to detect many reliable splice junctions with low false positive rate. The improvement gained by SOAPsplice, when compared to other existing tools, becomes more obvious when the depth of sequencing is low. SOAPsplice is freely available at http://soap.genomics.org.cn/soapsplice.html

Ube2L6 promotes M1 macrophage polarization in HFD-fed obese mice via ISGylation of STAT1 to trigger STAT1 activation

Introduction: In obesity-related type 2 diabetes mellitus (T2DM), M1 macrophages aggravate chronic inflammation and insulin resistance. ISG15-conjugation enzyme E2L6 (Ube2L6) has been demonstrated as a promoter of obesity and insulin resistance. This study investigated the function and mechanism of Ube2L6 in M1 macrophage polarization in obesity. Methods: Obesity was induced in Ube2L6AKO mice and age-matched Ube2L6flox/flox control mice by high-fat diet (HFD). Stromal vascular cells (SVCs) were isolated from epididymal white adipose tissue of mice. Polarization induction was performed in mouse bone marrow-derived macrophages (BMDMs) by exposure to IFN-γ, lipopolysaccharide (LPS), or IL-4. F4/80 expression was assessed by immunohistochemistry staining. Expression of M1/M2 macrophage markers and target molecules was determined by flow cytometry, RT-qPCR, and Western blotting, respectively. Protein interaction was validated by co-immunoprecipitation (Co-IP) assay. The release of TNF-α and IL-10 was detected by ELISA. Results: The polarization of pro-inflammatory M1 macrophages together with an increase in macrophage infiltration were observed in HFD-fed mice, which could be restrained by Ube2L6 knockdown. Additionally, Ube2L6 deficiency triggered the repolarization of BMDMs from M1 to M2 phenotypes. Mechanistically, Ube2L6 promoted the expression and activation of signal transducer and activator of transcription 1 (STAT1) through interferon-stimulated gene 15 (ISG15)-mediated ISGlylation, resulting in M1 macrophage polarization. Conclusion: Ube2L6 exerts as an activator of STAT1 via post-translational modification of STAT1 by ISG15, thereby triggering M1 macrophage polarization in HFD-fed obese mice. Overall, targeting Ube2L6 may represent an effective therapeutic strategy for ameliorating obesity-related T2DM

Biventricular longitudinal strain as a predictor of functional improvement after D-shant device implantation in patients with heart failure

BackgroundThe creation of an atrial shunt is a novel approach for the management of heart failure (HF), and there is a need for advanced methods for detection of cardiac function response to an interatrial shunt device. Ventricular longitudinal strain is a more sensitive marker of cardiac function than conventional echocardiographic parameters, but data on the value of longitudinal strain as a predictor of improvement in cardiac function after implantation of an interatrial shunt device are scarce. We aimed to investigate the exploratory efficacy of the D-Shant device for interatrial shunting in treating heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), and to explore the predictive value of biventricular longitudinal strain for functional improvement in such patients.MethodsA total of 34 patients were enrolled (25 with HFrEF and 9 with HFpEF). All patients underwent conventional echocardiography and two-dimensional speckle tracking echocardiogram (2D-STE) at baseline and 6 months after implantation of a D-Shant device (WeiKe Medical Inc., WuHan, CN). Left ventricular global longitudinal strain (LVGLS) and right ventricular free wall longitudinal strain (RVFWLS) were evaluated by 2D-STE.ResultsThe D-Shant device was successfully implanted in all cases without periprocedural mortality. At 6-month follow-up, an improvement in New York Heart Association (NYHA) functional class was observed in 20 of 28 patients with HF. Compared with baseline, patients with HFrEF showed significant reduced left atrial volume index (LAVI) and increased right atrial (RA) dimensions, as well as improved LVGLS and RVFWLS, at 6-month follow-up. Despite reduction in LAVI and increase in RA dimensions, improvements in biventricular longitudinal strain did not occur in HFpEF patients. Multivariate logistic regression demonstrated that LVGLS [odds ratio (OR): 5.930; 95% CI: 1.463–24.038; P = 0.013] and RVFWLS (OR: 4.852; 95% CI: 1.372–17.159; P = 0.014) were predictive of improvement in NYHA functional class after D-Shant device implantation.ConclusionImprovements in clinical and functional status are observed in patients with HF 6 months after implantation of a D-Shant device. Preoperative biventricular longitudinal strain is predictive of improvement in NYHA functional class and may be helpful to identify patients who will experience better outcomes following implantation of an interatrial shunt device

The mediating role of negative symptoms in “secondary factors” determining social functioning in chronic schizophrenia

BackgroundChronic schizophrenia is significantly influenced by negative symptoms, with several known contributors to secondary negative symptoms. However, the impact of these factors and negative symptoms on social functioning warrants further exploration.MethodsWe assessed the clinical symptoms, antipsychotic adverse reactions, and social functioning of 283 hospitalized patients with chronic schizophrenia using various standardized interviews and scales. We conducted multiple regression and mediation analyses to elucidate the impact of secondary factors on negative symptoms, and the relationship among these “secondary factors,” negative symptoms, and social functioning.ResultsOur findings identified depressive symptoms, extrapyramidal symptoms, and positive symptoms as significant contributors to secondary negative symptoms. We found that negative symptoms play a notable mediating role in the effect of depressive and positive symptoms on social functioning. However, the relationship between positive symptoms, negative symptoms, and social functioning proved to be intricate.ConclusionOur findings propose that negative symptoms act as pivotal mediators in the correlation between “secondary factors” (including the depressive symptoms and positive symptoms) and social functioning. The treatment of chronic schizophrenia necessitates focusing on key factors such as depressive and positive symptoms, which might significantly contribute to the development of secondary negative symptoms. Further research is essential to clarify the complex relationship among positive symptoms, negative symptoms, and social functioning in schizophrenia