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The excitation-contraction (E-C) coupling in heart cells governed by L-type Ca 2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (JSR). During heart failure, LCC-RyR signaling became defective, leading to degraded Ca 2+ transients and compromised contractile strength. In the present study, we investigated the structural and molecular mechanisms underlying the compromised LCC-RyR signaling in rat heart failure models produced by transverse aortic constriction surgery. Stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of JSRs and those of JSR-coupled TTs were both decreased in failing heart cells. The TT-JSR junctional structures, known as couplons, were displaced or missing from the Z-line areas. Moreover, the spatial span of individual couplons was markedly reduced in failing heart cells. Knockdown of junctophilin-2 (JP2), a TT-SR linker protein down-regulated in heart failure, fully reproduced the structural deformation and decreased/desynchronized Ca 2+ release, indicating that JP2 down-regulation is at least partially responsible for the structural and functional defects of E-C coupling in heart failure. In searching for upstream regulator of JP2, we found that microRNA-mediated suppression of JP2 expression underlied both TT-SR structural uncoupling and LCC-RyR functional uncoupling. These results revealed molecular and structural mechanisms underlying the defective E-C coupling in failing heart cells, and suggested new therapeutic targets against heart failure.

Aims The contraction of a heart cell is controlled by Ca2+-induced Ca2+ release between L-type Ca2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (SR). During heart failure, LCC–RyR signalling becomes defective. The purpose of the present study was to reveal the ultrastructural mechanism underlying the defective LCC–RyR signalling and contractility. Methods and results In rat models of heart failure produced by transverse aortic constriction surgery, stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of junctional SRs and those of SR-coupled TTs were both decreased in failing heart cells. The TT–SR junctions were displaced or missing from the Z-line areas. Moreover, the spatial span of individual TT–SR junctions was markedly reduced in failing heart cells. Numerical simulation and junctophilin-2 knockdown experiments demonstrated that the decrease in junction size (and thereby the constitutive LCC and RyR numbers) led to a scattered delay of Ca2+ release activation. Conclusions The shrinking and eventual absence of TT–SR junctions are important mechanisms underlying the desynchronized and inhomogeneous Ca2+ release and the decreased contractile strength in heart failure. Maintaining the nanoscopic integrity of TT–SR junctions thus represents a therapeutic strategy against heart failure and related cardiomyopathies.

In this study, we explored different spontaneous functional connectivity patterns between the anterior prefrontal cortex and other brain regions in nonmedicated patients with obsessive-compulsive disorder in a resting state, and examined the relationship between the abnormal spontaneous functional connectivity patterns of the anterior prefrontal cortex and clinical symptoms in patients with obsessive-compulsive disorder. Twenty nonmedicated patients with obsessive-compulsive disorder and 20 sex-matched and age-matched healthy individuals underwent resting state functional MRI scanning. Compared with the healthy controls, significantly increased positive functional connectivity with the right anterior prefrontal cortex was observed in the right insula and the middle cingulate cortex in patients with obsessive-compulsive disorder. Our findings suggest that abnormal intrinsic or spontaneous functional connectivity in the cognitive control system in a resting state may underlie the pathophysiology of obsessive-compulsive disorder.

Background Major depressive disorder (MDD) is a highly heritable psychiatric disease, and the existing literature is not robust enough to allow us to evaluate whether MDD-associated biomarkers are state-independent heritable endophenotypes or state markers related to depression per se. Methods Twenty two patients diagnosed with MDD, 22 siblings, as well as 26 gender-, age-, and education-matched healthy subjects, participated in the resting-state functional magnetic resonance imaging (fMRI) analysis. We compared the differences in the fractional amplitude of low-frequency fluctuation (fALFF) among the three groups and investigated the correlation between clinical measurements and fALFF in the regions displaying significant group differences. Results Both the MDD and siblings groups showed an increased fALFF in the left middle frontal gyrus (l-MFG, Brodmann Area, BA 10) compared to the healthy controls. The MDD groups demonstrated an increased fALFF in the right dorsal medial frontal gyrus (r-DMFG, BA 9) and a decreased fALFF in the bilateral lingual gyrus relative to siblings and healthy controls. Limitations Medication effects, an inability to control subjects' thoughts during imaging. Conclusions Our results suggest that the dysfunction in the l-MFG may represent an imaging endophenotype which may indicate a risk for MDD. The r-DMFG may play a critical role in depressive symptomatology and may reveal therapeutic target for MDD.

Previous case-control and family-based association studies have implicated the SLC6A4 gene in obsessive-compulsive disorder (OCD). Little research, however, has examined this gene's role in obsessive-compulsive symptoms (OCS) in community samples. The present study genotyped seven tag SNPs and two common functional tandem repeat polymorphisms (5-HTTLPR and STin2), which together cover the whole SLC6A4 gene, and investigated their associations with OCS in normal Chinese college students (N = 572). The results revealed a significant gender main effect and gender-specific genetic effects of the SLC6A4 gene on OCS. Males scored significantly higher on total OCS and its three dimensions than did females (ps

Recent years, microRNAs (miRNAs) have attracted scholars' attention extensively. MiRNAs are a class of 21-25-nucleotide non-coding RNAs that have been implicated in regulating gene transcription and expression. Thus, alteration of miRNA is involved in many human activities and diseases. The function of miRNA is varied dependence on cell type and target mRNA. MiRNAs play important roles in the process of injury and repair through affecting cell phenotypes, such as development, division, proliferation, apoptosis and regeneration. Recently, miRNA-based findings seem to be promising implications for diagnosis and therapy.

Spontaneous brain activity or off-line activity after memory encoding is associated with memory consolidation. A few recent resting-state functional magnetic resonance imaging (RS-fMRI) studies indicate that the RS-fMRI could map off-line memory consolidation effects. However, the gene effects on memory consolidation process remain largely unknown. Here we collected two RS-fMRI sessions, one before and another after an episodic memory encoding task, from two groups of healthy young adults, one with apolipoprotein E (APOE) e2/e3 and the other with APOE e3/e4. The ratio of regional homogeneity (ReHo), a measure of local synchronization of spontaneous RS-fMRI signal, of the two sessions was used as an index of memory-consolidation. APOE e3/e4 group showed greater ReHo ratio within the medial temporal lobe (MTL). The ReHo ratio in MTL was significantly correlated with the recognition memory performance in the APOE e3/e4 group but not in e2/e3 group. Additionally, APOE e3/e4 group showed lower ReHo ratio in the occipital and parietal picture-encoding areas. Our results indicate that APOE e3/e4 group may have a different off-line memory consolidation process compared to e2/e3 group. These results may help generate future hypotheses that the off-line memory consolidation might be impaired in Alzheimer’s disease.

Resting-state fMRI (RS-fMRI) has been drawing more and more attention in recent years. However, a publicly available, systematically integrated and easy-to-use tool for RS-fMRI data processing is still lacking. We developed a toolkit for the analysis of RS-fMRI data, namely the RESting-state fMRI data analysis Toolkit (REST). REST was developed in MATLAB with graphical user interface (GUI). After data preprocessing with SPM or AFNI, a few analytic methods can be performed in REST, including functional connectivity analysis based on linear correlation, regional homogeneity, amplitude of low frequency fluctuation (ALFF), and fractional ALFF. A few additional functions were implemented in REST, including a DICOM sorter, linear trend removal, bandpass filtering, time course extraction, regression of covariates, image calculator, statistical analysis, and slice viewer (for result visualization, multiple comparison correction, etc.). REST is an open-source package and is freely available at http://www.restfmri.net.

G-Quadruplexes have been proved to exist in 5'-untranslated region (5'-UTR), promoter, intron and exon regions of many human genes. Here we report an intramolecular G-quadruplex formed by a G-rich sequence in the 3'-flanking region of signal transducers and activators of transcription 3 (STAT3) gene. The results showed that this G-rich sequence could affect the expression of STAT3. When the STAT3 G-quadruplex was stabilized by a novel non-planar ligand Cepharanthine (CEP), the decreased expression of STAT3 was observed in primary cultured cardiomyocytes. We also demonstrated that the down-regulation of STAT3 was most likely occurred at the transcriptional level. Our results provide a new clue for studying the G-quadruplex formation, recognition and function in the 3'-flanking region of gene.

G-quadruplex is a kind of special secondary structure of nuclei acids, which exists in genome DNA and RNA and preferentially located in functional regions such as telomeres, promoters, 5' untranslated region (5' UTR) of mRNA and so on. G-quadruplex has been implicated by a lot of studies as an important structure in many biological processes including gene stability, telomere synthesis, transcriptional or translational regulation of gene expression and recombination. We here review the recent studies of G-quadruplex in genome DNA, RNA and G-quadruplex oligonucleotides, focusing on their biological function.

BACKGROUND: Prior research has shown that the amygdala of carriers of the short allele (s) of the serotonin transporter (5-HTT) gene (5-HTTLPR) have a larger response to negative emotional stimuli and higher spontaneous activity during the resting state than non-carriers. However, recent studies have suggested that the effects of 5-HTTLPR may be specific to different ethnic groups. Few studies have been conducted to address this issue. METHODOLOGY/PRINCIPAL FINDINGS: Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted on thirty-eight healthy Han Chinese subjects (l/l group, n = 19; s/s group, n = 19) during the resting state and during an emotional processing task. Compared with the s/s group, the l/l group showed significantly increased regional homogeneity or local synchronization in the right amygdala during the resting state (|t|>2.028, p