Structural remodeling in related brain regions in patients with facial synkinesis

Facial synkinesis is a troublesome sequelae of facial nerve malfunction.It is difficult to recover from synkinesis,despite improved surgical techniques for isolating the peripheral facial nerve branches.Furthermore,it remains unclear whether long-term dysfunction of motor control can lead to irreversible plasticity-induced structural brain changes.This case-control study thus investigated the structural brain alterations associated with facial synkinesis.The study was conducted at Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,China.Twenty patients with facial synkinesis(2 male and 18 female,aged 33.35±6.97 years)and 19 healthy volunteers(2 male and 17 female,aged 33.21±6.75 years)underwent magnetic resonance imaging,and voxel-based and surface-based morphometry techniques were used to analyze data.There was no significant difference in brain volume between patients with facial synkinesis and healthy volunteers.Patients with facial synkinesis exhibited a significantly reduced cortical thickness in the contralateral superior and inferior temporal gyri and a reduced sulcal depth of the ipsilateral precuneus compared with healthy volunteers.In addition,sulcal depth of the ipsilateral precuneus was negatively correlated with the severity of depression.These findings suggest that there is a structural remodeling of gray matter in patients with facial synkinesis after facial nerve malfunction.This study was approved by the Ethics Review Committee of the Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,China(approval No.2017-365-T267)on September 13,2017,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR1800014630)on January 25,2018.

Changes in microRNAs expression are involved in age-related atrial structural remodeling and atrial fibrillation

Background Small noncoding microRNAs regulate gene expression in cardiac development and disease and have been implicated in the aging process and in the regulation of extracellular matrix proteins. However, their role in age-related cardiac remodeling and atrial fibrillation （AF） was not well understood. The present study was designed to decipher molecular mechanisms underlying age-related atrial structural remodeling and AF. Methods Three groups of dogs were studied： adult and aged dogs in sinus rhythm and with persistent AF induced by rapid atrial pacing. The expressions of microRNAs were measured by quantitative real-time polymerase chain reaction. Pathohistological and ultrastructural changes were tested by light and electron microscopy. Apoptosis index of myocytes was detected by TUNEL. Results Samples of atrial tissue showed the abnormal pathohistological and ultrastructural changes, the accelerated fibrosis, and apoptosis with aging and/or in AF dogs. Compared to the adult group, the expressions of microRNAs-21 and -29 were significantly increased, whereas the expressions of microRNAs-1 and -133 showed obvious downregulation tendency in the aged group. Compared to the aged group, the expressions of microRNAs-1, -21, and -29 was significantly increased in the old group in AF; contrastingly, the expressions of microRNA-133 showed obvious downregulation tendency. Conclusion These multiple aberrantly expressed microRNAs may be responsible for modulating the transition from adaptation to pathological atrial remodeling with aging and/or in AE

Effects of trimetazidine on atrial structural remodeling and platelet activation in dogs with atrial fibrillation

Atrial fibrillation （AF） is one of the most common .arrhythmias in clinical practice. AF results in electrophysiological alterations which involve increased atrial effective refractory period and atrial effective refractory period dispersion, reduced rate adaptation of atrial effective refractory period, and slowed atrial conduction. These variances promote their own maintenance-AF begets AF.1 Previous study suggested that Ca^2＋ overload and metabolic derangement contributed to electrophysiological remodeling in AF. However, we did not demonstrate a persistent disturbance in energy metabolism during AF in our previous study,

Qingxuan Jiangya Decoction(清眩降压汤) Prevents Blood Pressure Elevation and Ameliorates Vascular Structural Remodeling via Modulating TGF-β 1/Smad Pathway in Spontaneously Hypertensive Rats

Objective:To elevate the effects of Qingxuan Jiangya Decoction(清眩降压汤,QXJYD)on hypertension and vascular structural remodeling(VSR)in spontaneously hypertensive rats(SHRs),and investigate the underlying mechanisms.Methods:SHRs(n=8)were given intra-gastric administration with 60 mg/kg of QXJYD or saline,daily for 8 weeks,while rats in SHR-control(n=8)and WKY(n=8)groups were received equal volumes of saline solution.Systolic blood pressures(SBP),diastolic blood pressures(DBP)and mean blood pressures(MBP)were measured once a week.The levels of angiotensinⅡ(AngⅡ),endothelin 1(ET-1)and plasma renin activity(PRA)were tested by enzyme-linked immunosorbent assay(ELISA)and radioimmunoassay,respectively.The effect of QXJYD on VSR was determined by examining the media thickness and the ex vivo contractility of thoracic aortic.The proliferation and fibrosis of vascular smooth muscle cells(VSMCs)were examined via immunohistochemical(IHC)staining for proliferating cell nuclear antigen(PCNA),collagen Ⅰ and collagen Ⅲ,respectively.The mRNA and protein expressions of transforming growth factor β1(TGF-β1),Smad3 and phosphorylation of Smad3 in thoracic aorta tissues were determined by real-time polymerase chain reaction(PCR)and Western blot assay,respectively.Results:QXJYD treatment led to a significant decrease of the elevation of blood pressure in SHRs and reduced the levels of AngⅡ,ET-1 and PRA in the serum(P<0.05).In addition,QXJYD treatment remarkably ameliorated VSR and vascular function in SHRs.Moreover,QXJYD inhibited VSMC proliferation and fibrosis by suppressing the expression of PCNA,collagen Ⅰ and collagen Ⅲ in thoracic aortic.Furthermore,QXJYD inhibited the expression of TGF-β1,Smad3 and the phosphorylation of Smad3,respectively(P<0.05).Conclusion:QXJYD reversed VSR by inhibiting VSMC proliferation and collagen deposition via regulation of TGF-β1/Smad signaling pathway,which may,in part,illuminate its anti-hypertensive activities.

Calpain I inhibition prevents atrial structural remodeling in a canine model with atrial fibrillation

Background Atrial fibrillation （AF） is accompanied by atrial structural remodeling. Calpain activity is induced during AE To test a causal relationship between calpain activation and atrial structural changes, N-acetyI-Leu-Leu-Met （ALLM）, a calpain inhibitor, was utilized in a canine AF model. Methods Fifteen dogs were randomly divided into 3 groups： sham-operated group, control group and calpain inhibitor group; each with 5 dogs. Sustained AF was induced by rapid right atrium pacing at 600 beats per minute for 3 weeks. ALLM was administered at a dosage of 1.0 mg-kg-l-d1 in the calpain inhibitor group. Three weeks later, the proteolysis, protein expression of TnT and myosin, calpain I localization and expression and structural changes were examined in left atrial free walls, right atrial free walls and the interatrial septum respectively. Atrial size and contractile function were also measured by echocardiography. Results Long-term rapid atrial pacing induced marked structural changes such as enlarged atrial volume, myolysis, degradation of TnT and myosin, accumulation of glycogen and changes in mitochondrial shape and size, which were paralleled by an increase in calpain activity. The positive correlation between calpain activity and the degree of myolysis （rs=0.90 961, P〈0.0001） was demonstrated. In addition to structural abnormalities, pacing-induced atrial contractile dysfunction was observed in this study. The pacing-induced atrial structural alterations and loss of contractility were partially prevented by the calpain inhibitor ALLM. Conclusions Activation of calpain represents key features in the progression towards overt structural remodeling. Calpain inhibitor, ALLM, suppressed the increased calpain activity and reversed structural remodeling caused by sustained atrial fibrillation in the present model. Calpain inhibition may therefore provide a possibility for therapeutic intervention in AE

Effects of Qili Qiangxin capsule on lung structural remodeling in heart failure rats after myocardial infarction and its mechanism

Objective To observe the effect of Qili Qiangxin Capsule(QQC)in improving lung structural remodeling on heart failure(HF)rats after myocardial infarction(MI)and to study its possible mechanism.Methods The proximal left anterior descending branch of coronary artery was ligated using a terylene suture to establish

Renovascular hypertension causes cerebral vascular remodeling

Renovascular hypertensive rats （RHRs） were developed using the 2-kidney, 2-clip method. All RHRs at 10 weeks displayed high permeability of the cerebral surface blood vessels. Vascular casts of the RHRs showed that the vascular network was sparse. The arterioles of the RHRs at 10 weeks had smaller lumen diameters, but thicker vessel walls with hyalinosis formation compared with control animals. The endothelial cell membrane appeared damaged, and microthrombus formed. After ischemia, the infarction size was larger in RHRs than in control animals. These results suggest that cerebral arterioles in RHRs underwent structural remodeling. High blood pressure may aggravate the severity of brain injury in cerebral ischemia and affect the recovery of ischemia.

Effect of prenatal tetrandrine therapy on pulmonary vascular structural remodeling in the nitrofen-induced CDH rat model

To examine the effects of prenatal tetrandrine (Tet) therapy on pulmonary arterial structural remodeling in nitrofen-induced congenital diaphragmatic hernia (CDH) Methods CDH was induced in fetal rats by maternal administration of 100*!mg nitrofen by gavage on day 9 5 of gestation (term, day 22) Control animals received olive oil (OO) Tet (24*!mg/kg per day) or normal saline (NS) was given by gavage every day from 16 to 20 days of gestation, and fetuses were delivered by caesarean section on day 21 5 Lung sections from 3 fetuses in each group were studied The number of vessels were calculated, the external diameter (ED), medial wall thickness (MT), percent of medial wall thickness, and wall structure were evaluated by image analysis software Results In the pre-acinar arteries, CDH-NS pups had a significantly increased %MT compared with the OO-NS group ( P <0 05), while CDH-Tet animals had a reduced %MT compared with the CDH-NS rats ( P <0 05) Similar results were seen in the intra-acinar level Significant differences were observed between CDH-NS animals and OO-NS controls in the percentage of muscularized intra-acinar blood vessels ( P <0 001) Tet-treated CDH pups had a reduced percentage of muscularized intra-acinar arteries compared with CDH-NS animals Conclusions Medial hypertrophy is present in both the pre-acinar and intra-acinar arteries in the nitrofen-induced CDH rat model Tet treatment inhibits medial hypertrophy and reduces the percentage of muscularized intra-acinar vessels Prenatal Tet therapy may be efficacious in reducing the risk of PH in human newborns with CDH

Chromatin Remodeling in Stem Cell Maintenance in Arabidopsis thaliana

Pluripotent stem cells are able to both self-renew and generate undifferentiated cells for the formation of new tissues and organs. In higher plants, stem cells found in the shoot apical meristem （SAM） and the root apical meristem （RAM） are origins of organogenesis occurring post-embryonically. It is important to understand how the regulation of stem cell fate is coordinated to enable the meristem to constantly generate different types of lateral organs. Much knowledge has accumulated on specific transcription factors controlling SAM and RAM activity. Here, we review recent evidences for a role of chromatin remodeling in the maintenance of stable expression states of transcription factor genes and the control of stem cell activity in Arabidopsis.

Mechanism of chromatin remodeling revealed by the Snf2-nucleosome structure

Subject Code:C05With the support from the National Natural Science Foundation of China,a collaborative study by the research teams led by Chen Zhucheng(陈柱成)and Li Xueming(李雪明)at the School of Life Sciences,Tsinghua University,recently reported their work,titled“Mechanism of chromatin remodeling revealed

The Beauty of Being a Variant： H2A.Z and the SWR1 Complex in Plants

Numerous studies have shown that the nucleosome is a dynamic structure that strongly influences gene expression. Dynamism concerns different nucleosomal characteristics, including position, posttranslational modifications, and histone composition. Thus, within the nucleosome, canonical histones can be exchanged by histone variant proteins with specific functions--a process known as ‘histone replacement＇. The histone variant H2A.Z has an important function in transcription and, during the last few years, its role in plant development and immune response has become evident. Compiling genetic and biochemical studies from several laboratories has revealed that plants contain a multiprotein complex, similar to the SWR1/SRCAP complex from yeast and animals, involved in H2A.Z deposition. Despite intense research in different organisms, the mechanism by which H2A.Z influences transcription is still unknown. However, recent results from Arabidopsis have shown a strong inverse correlation between H2A.Z and DNA methylation, suggesting that H2A.Z might protect genes from silencing.

Histone Acetyltransferase AtGCN5/HAG1 Is a Versatile Regulator of Developmental and Inducible Gene Expression in Arabidopsis

Histone acetylation/deacetylation is a dynamic process and plays an important role in gene regulation. Histone acetylation homeostasis is regulated by antagonist actions of histone acetyltransferases （HAT） and deacetylases （HDAC）. Plant genome encodes multiple HATs and HDACs. The Arabidopsis HAT gene AtGCNS/HAGlplays an essential role in many plant development processes, such as meristem function, cell differentiation, leaf and floral organogenesis, and responses to environmental conditions such as light and cold, indicating an important role of this HAT in the regulation of both long-term developmental switches and short-term inducible gene expression. AtGCN5 targets to a large number of promoters and is required for acetylation of several histone H3 lysine residues. Recruitment of AtGCN5 to target promoters is likely to be mediated by direct or indirect interaction with DNA-binding transcription factors and/or by interaction with acetylated histone lysine residues on the targets. Interplay between AtGCN5 and other HATand HDAC is demonstrated to control specific regulatory pathways. Analysis of the role of AtGCN5 in light-inducible gene expression suggests a function of AtGCN5 in preparing chromatin commitment for priming inducible gene activation in plants.

Genome-Wide Analysis of Histone Modifications： H3K4me2, H3K4me3, H3K9ac, and H3K27ac in Oryza sativa L. Japonica

While previous studies have shown that histone modifications could influence plant growth and devel- opment by regulating gene transcription, knowledge about the relationships between these modifications and gene expression is still limited. This study used chromatin immunoprecipitation followed by high-throughput sequencing （ChlP-Seq）, to investigate the genome-wide distribution of four histone modifications： di and trimethylation of H3K4 （H3K4me2 and H3K4me3） and acylation of H3K9 and H3K27 （H3K9ac and H3K27ac） in Oryza sativa L. japonica. By analyz- ing published DNase-Seq data, this study explored DNase-Hypersensitive （DH） sites along the rice genome. The histone marks appeared mainly in generic regions and were enriched around the transcription start sites （TSSs） of genes. This analysis demonstrated that the four histone modifications and the DH sites were all associated with active transcription. Furthermore, the four histone modifications were highly concurrent with transcript regions-a promising feature that was used to predict missing genes in the rice gene annotation. The predictions were further validated by experimentally confirming the transcription of two predicted missing genes. Moreover, a sequence motif analysis was constructed in order to identify the DH sites and many putative transcription factor binding sites.

Arabidopsis MSI1 Is Required for Negative Regulation of the Response to Drought Stress

Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Altered levels of MSI1 result in pleiotropic phenotypes, reflecting the complexity of MSI1 protein functions. In order to uncover additional functions of MSI1, we performed transcriptional profiling of wild-type and plants with highly reduced MSI1 levels （msil-cs）. Surprisingly, the known functions of MSI1 could only account for a minor part of the transcriptional changes in msil-cs plants. One of the most striking unexpected observations was the up-regulation of a subset of ABA-responsive genes eliciting the response to drought and salt stress. We report that MSI1 can bind to the chromatin of the drought-inducible downstream target RD20 and suggest a new role for MSI1 in the negative regulation of the Arabidopsis drought-stress response.

Decoding the Epigenetic Language of Plant Development

Epigenetics refers to the study of heritable changes in gene expression or cellular phenotype without changes in DNA sequence. Epigenetic regulation of gene expression is accomplished by DNA methylation, histone modifications, histone variants, chromatin remodeling, and may involve small RNAs. DNA methylation at cytosine is carried out by enzymes called DNA Methyltransferases and is involved in many cellular processes, such as silencing of transposable elements and pericentromeric repeats, X-chromosome inactivation and genomic imprinting, etc. Histone modifications refer to posttranslational covalent attachment of chemical groups onto histones such as phosphorylation, acetylation, and methylation, etc. Histone variants, the non-canonical histones with amino acid sequences divergent from canonical histones, can have different epigenetic impacts on the genome from canonical histones. Higher-order chromatin structures maintained or modified by chromatin remodeling proteins also play important roles in regulating gene expression. Small non-coding RNAs play various roles in the regulation of gene expression at preas well as posttranscriptional levels. A special issue of Molecular Plant on ＇Epigenetics and Plant Development＇ （Volume 4, Number 2, 2009） published a variety of articles covering many aspects of epigenetic regulation of plant development. We have tried here to present a bird＇s-eye view of these credible efforts towards understanding the mysterious world of epigenetics. The majority of the articles are about the chromatin modifying proteins, including histone modifiers, histone variants, and chromatin remodeling pro- teins that regulate various developmental processes, such as flowering time, vernalization, stem cell maintenance, and response to hormonal and environmental stresses, etc. Regulation of expression of seed transcriptome, involvement of direct tandem repeat elements in the PHE1 imprinting in addition to PcG proteins activity, paramutation, and epigenetic barriers in species hybridization are described well. The last two papers are about the Pol V-mediated heterochromatin formation in- dependent of the 24nt-siRNA and the effect of genome position and tissue type on epigenetic regulation of gene expression. These findings not only further our current understanding of epigenetic mechanisms involved in many biological phenomena, but also pave the path for the future work, by raising many new questions that are discussed in the following lines.

Control of PHERES1 Imprinting in Arabidopsis by Direct Tandem Repeats

Genomic imprinting is an epigenetic phenomenon that causes monoallelic expression of specific genes dependent on the parent-of-origin. Imprinting of the Arabidopsis gene PHERES1 requires the function of the FERTILIZATION INDEPENDENT SEED （FIS） Polycomb group complex as well as a distally located methylated region containing a tandem triple repeat sequence. In this study, we investigated the regulation of the close PHERES1 homolog PHERES2. We found that PHERES2 is also a direct target gene of the FIS Polycomb group complex, but, in contrast to PHERES1, PHERES2 is equally expressed from maternal and paternal alleles. Thus, PHERES2 is not regulated by genomic imprinting, correlating with the lack of tandem repeats at PHERES2. Eliminating tandem repeats from the PHERES1 locus abolishes PHERES1 imprinting, demonstrating that tandem repeats are essential forPHERES1 imprinting. Taking these results together, our study shows that the recently duplicated genes PHERES1 and PHERES2 are both target genes of the FIS Polycomb group complex but only PHERES1 is regulated by genomic imprinting, which is likely caused by the presence of repeat sequences in the proximity of the PHERES1 locus.

Defining the Functional Network of Epigenetic Regulators in Arabidopsis thaliana

Development of ChiP-chip and ChlP-seq technologies has allowed genome-wide high-resolution profiling of chromatin-associated marks and binding sites for epigenetic regulators. However, signals for directing epigenetic modifiers to their target sites are not understood. In this paper, we tested the hypothesis that genome location can affect the involvement of epigenetic regulators using Chromatin Charting （CC） Lines, which have an identical transgene construct inserted at different locations in the Arabidopsis genome. Four CC lines that showed evidence for epigenetic silencing of the luciferase reporter gene were transformed with RNAi vectors individually targeting epigenetic regulators LHP1, MOM1, CMT3, DRD1, DRM2, SUVH2, CLF, and HD1. Involvement of a particular epigenetic regulator in silencing the transgene locus in a CC line was determined by significant alterations in luciferase expression after suppression of the regulator＇s expression. Our results suggest that the targeting of epigenetic regulators can be influenced by genome location as well as sequence context. In addition, the relative importance of an epigenetic regulator can be influenced by tissue identity. We also report a novel approach to predict interactions between epigenetic regulators through clustering analysis of the regulators using alterations in gene expression of putative downstream targets, including endogenous loci and transgenes, in epigenetic mutants or RNAi lines. Our data support the existence of a complex and dynamic network of epigenetic regulators that serves to coordinate and control global gene expression in higher plants.

Structure and regulation of the chromatin remodeller ISWI

Subject Code:C05With the support by the National Natural Science Foundation of China,the research team led by Dr.Chen Zhucheng(陈柱成)at the School of Life Science,Tsinghua University,Beijing,recently reported their work,titled'Structure and regulation of the chromatin remodeller ISWI',in Nature(2016,540:466—469).Chromatin is the life blueprint of eukaryotes.Chromatin remodellers utilize the energy of ATP hydrolysis to move,destabilize,eject,or restructure nucleosomes,building and rebuilding the blueprint