The putative protein kinase Stk36 is essential for ciliogenesis and CSF flow by associating with Ulk4.

Motile cilia lining on the ependymal cells are crucial for cerebrospinal fluid (CSF) flow and its dysfunction is often associated with hydrocephalus. Unc51-like-kinase 4 (Ulk4) was previously linked to CSF flow and motile ciliogenesis in mice, as the hypomorph mutant of Ulk4 (Ulk4tm1a/tm1a ) developed hydrocephalic phenotype resulted from defective ciliogenesis and disturbed ciliary motility, while the underling mechanism is largely obscure. Here, we report that serine/threonine kinase 36 (STK36), a paralog of ULK4, directly interacts with ULK4 and this was demonstrated by yeast two-hybrid (Y2H) in yeast and coimmunoprecipitation (co-IP) assays in HEK293T cells, respectively. The interaction region was confined to their respective N-terminal kinase domain. The hypomorph mutant of Stk36 (Stk36tmE4-/- ) also developed progressive hydrocephalus postnatally and dysfunctional CSF flow, with multiple defects of motile cilia, including reduced ciliary number, disorganized ciliary orientation, defected axonemal structure and inconsistent base body (BB) orientation. Stk36tmE4-/- also disturbed the expression of Foxj1 transcription factor and a range of other ciliogenesis-related genes. All these morphological changes, motile cilia defects and transcriptional dysregulation in the Stk36tmE4-/- are practically copied from that in Ulk4tm1a/tm1a mice. Taken together, we conclude that both Stk36 and Ulk4 are crucial for CSF flow, they cooperate by direct binding with their kinase domain to regulate the Foxj1 transcription factor pathways for ciliogenesis and cilia function, not limited to CSF flow. The underlying molecular mechanism probably conserved in evolution and could be extended to other metazoans.

Arabidopsis PDI11 interacts with lectin molecular chaperons calreticulin 1 and 2 through its D domain.

The endoplasmic reticulum (ER) is equipped with protein disulfide isomerases (PDIs), molecular chaperons, and other folding enzymes to ensure that newly synthesized proteins in the ER are properly folded. Molecular chaperons and PDIs can form complex to promote protein folding in the ER of mammalian cells. In plants, many PDIs associate with each other and function cooperatively in oxidative protein folding. As a plant unique protein disulfide isomerase, Arabidopsis thaliana PDI11 (AtPDI11) demonstrates oxidative protein folding activities and works synergistically with AtPDI2/5. However, whether AtPDI11 associates with molecular chaperons or AtPDIs in catalyzing disulfide formation remained unknown. Here, we find that AtPDI11 interacts with ER resident lectin chaperones calreticulin 1 (CRT1) and CRT2. Furthermore, the D domain, but not the a or a' domain of AtPDI11 provides the biding sites for its interaction with CRT1/2. Moreover, the P domain of CRT1 is responsible for its interaction with AtPDI11. Our work implies that Arabidopsis CRT1/2 may specifically recruit AtPDI11 to assist the folding of glycoproteins in the ER.

Middle cerebral arterial bifurcation aneurysms are associated with bifurcation angle and high tortuosity.

PURPOSE: To investigate the association of middle cerebral artery (MCA) bifurcation aneurysms with bifurcation morphology. MATERIALS AND METHODS: 205 patients were enrolled, including 61 patients with MCA bifurcation aneurysms and 144 non-aneurysmal subjects. Aneurysmal cases were divided into types C (aneurysm neck on extension of the parent artery centerline) and D (deviating neck). The radius of the parent artery M1 (RP) and bilateral branches (RS and RL, respectively), smaller (φS) and larger (φL) lateral angles, bifurcation angle, and arterial tortuosity from parent vessel to bilateral branches (TS and TL, respectively) were analyzed. Logistic regression and receiver operator characteristic (ROC) curve analysis were performed to identify risk factors and predictive values for MCA aneurysm presence and types. RESULTS: In aneurysmal MCA bifurcations, bifurcating angle, TS, TL and RL were significantly larger (P<0.01), while φS was significantly smaller (P<0.001) than those in controls. The bifurcation angle, TS and LogitP were better morphological parameters for predicting MCA aneurysm presence with the AUC of 0.795, 0.932 and 0.951, respectively. Significant (P<0.05) differences were observed in the bifurcation angle, φL, RP, RL and TL between types C and D aneurysmal bifurcations. TL was an independent factor in discriminating types C from D aneurysms with an AUC of 0.802. CONCLUSIONS: Bifurcation angle and arterial tortuosity from the parent artery to the branch forming a smaller angle with the parent artery have a higher value in distinguishing MCA aneurysmal from non-aneurysmal ones, and the tortuosity from the parent artery to the contralateral branch is the best indicator for distinguishing types C from D aneurysmal bifurcations.

The Rice Receptor-Like Kinases DWARF AND RUNTISH SPIKELET1 and 2 Repress Cell Death and Affect Sugar Utilization during Reproductive Development.

Cell-to-cell communication precisely controls the creation of new organs during reproductive growth. However, the sensor molecules that mediate developmental signals in monocot plants are poorly understood. Here, we report that DWARF AND RUNTISH SPIKELET1 (DRUS1) and DRUS2, two closely related receptor-like kinases (RLKs), redundantly control reproductive growth and development in rice (Oryza sativa). A drus1-1 drus2 double knockout mutant, but not either single mutant, showed extreme dwarfism and barren inflorescences that harbored sterile spikelets. The gibberellin pathway was not impaired in this mutant. A phenotypic comparison of mutants expressing different amounts of DRUS1 and 2 revealed that reproductive growth requires a threshold level of DRUS1/2 proteins. DRUS1 and 2 maintain cell viability by repressing protease-mediated cell degradation and likely by affecting sugar utilization or conversion. In the later stages of anther development, survival of the endothecium requires DRUS1/2, which may stimulate expression of the UDP-glucose pyrophosphorylase gene UGP2 and starch biosynthesis in pollen. Unlike their Arabidopsis thaliana ortholog FERONIA, DRUS1 and 2 mediate a fundamental signaling process that is essential for cell survival and represents a novel biological function for the CrRLK1L RLK subfamily.

The SUMO E3 Ligase-Like Proteins PIAL1 and PIAL2 Interact with MOM1 and Form a Novel Complex Required for Transcriptional Silencing.

The mechanism by which MORPHEUS' MOLECULE1 (MOM1) contributes to transcriptional gene silencing has remained elusive since the gene was first identified and characterized. Here, we report that two Arabidopsis thaliana PIAS (PROTEIN INHIBITOR OF ACTIVATED STAT)-type SUMO E3 ligase-like proteins, PIAL1 and PIAL2, function redundantly to mediate transcriptional silencing at MOM1 target loci. PIAL1 and PIAL2 physically interact with each other and with MOM1 to form a high molecular mass complex. In the absence of either PIAL2 or MOM1, the formation of the high molecular mass complex is disrupted. We identified a previously uncharacterized IND (interacting domain) in PIAL1 and PIAL2 and demonstrated that IND directly interacts with MOM1. The CMM2 (conserved MOM1 motif 2) domain of MOM1 was previously shown to be required for the dimerization of MOM1. We demonstrated that the CMM2 domain is also required for the interaction of MOM1 with PIAL1 and PIAL2. We found that although PIAL2 has SUMO E3 ligase activity, the activity is dispensable for PIAL2's function in transcriptional silencing. This study suggests that PIAL1 and PIAl2 act as components of the MOM1-containing complex to mediate transcriptional silencing at heterochromatin regions.

Characterization of the oxidative protein folding activity of a unique plant oxidoreductase, Arabidopsis protein disulfide isomerase-11.

Protein disulfide isomerases (PDIs) can catalyze disulfide bond formation in nascent secretory proteins and membrane proteins and can introduce correct disulfide bonds into substrate proteins containing mispaired disulfides. The functions of mammalian PDIs have been extensively studied; however, relative to mammalian PDIs, the systematic characterization of PDIs for their oxidoreductase activity in plants is still lacking. Arabidopsis protein disulfide isomerases-11 (AtPDI11), with the structure of a-a'-D, has no ortholog in animals or yeast. In this study, we demonstrated that AtPDI11 has oxidoreductase activity in vitro using a GSSG/GSH-mediated oxidative protein folding system. Moreover, the active site in the a' domain of AtPDI11 is critical for its oxidative folding activity. AtPDI11 is present in four redox forms in vivo, which are determined by the active site cysteines (Cys52 and Cys55 in the a domain, and Cys171 and Cys174 in the a' domain). Genetic evidence suggests that AtPDI11 is required for plant growth under reducing conditions. Our work provides an example for studying the oxidoreductase function of other plant PDIs.

The Receptor-Like Kinase SIT1 Mediates Salt Sensitivity by Activating MAPK3/6 and Regulating Ethylene Homeostasis in Rice.

High salinity causes growth inhibition and shoot bleaching in plants that do not tolerate high salt (glycophytes), including most crops. The molecules affected directly by salt and linking the extracellular stimulus to intracellular responses remain largely unknown. Here, we demonstrate that rice (Oryza sativa) Salt Intolerance 1 (SIT1), a lectin receptor-like kinase expressed mainly in root epidermal cells, mediates salt sensitivity. NaCl rapidly activates SIT1, and in the presence of salt, as SIT1 kinase activity increased, plant survival decreased. Rice MPK3 and MPK6 function as the downstream effectors of SIT1. SIT1 phosphorylates MPK3 and 6, and their activation by salt requires SIT1. SIT1 mediates ethylene production and salt-induced ethylene signaling. SIT1 promotes accumulation of reactive oxygen species (ROS), leading to growth inhibition and plant death under salt stress, which occurred in an MPK3/6- and ethylene signaling-dependent manner in Arabidopsis thaliana. Our findings demonstrate the existence of a SIT1-MPK3/6 cascade that mediates salt sensitivity by affecting ROS and ethylene homeostasis and signaling. These results provide important information for engineering salt-tolerant crops.

Blocking the MIR155HG/miR-155 axis reduces CTGF-induced inflammatory cytokine production and α-SMA expression via upregulating AZGP1 in hypertrophic scar fibroblasts.

Hypertrophic scarring (HS) is a pathological condition characterized by excessive fibrosis and inflammation, resulting in excessive extracellular matrix formation in the skin. MIR155HG, a long non-coding RNA, is abnormally upregulated in fibrotic tissues; however, its underlying mechanism is poorly understood. Using single-cell sequencing data, we analyzed connective tissue growth factor (CTGF) expression in various cell types in HS and normal skin tissues and MIR155HG expression in clinical samples. To investigate the mechanism of fibrosis, an in vitro model using CTGF-treated hypertrophic scar fibroblasts (HSFBs) was established and qRT-PCR, western blotting and ELISA assays were performed to investigate the expression of interleukin (IL)-1ß, IL-6, and mesenchymal markers α-smooth muscle actin (α-SMA). CTGF stimulates MIR155HG level through phosphorylated STAT3 binding to the MIR155HG promoter. We analyzed the methylation of MIR155HG, assessed the levels of miR-155-5p/-3p in CTGF-treated HSFBs and identified differentially expressed genes among HS and NS samples using the Gene Expression Omnibus RNA sequencing data. The binding between miR-155-5p/-3p and AZGP1 was confirmed using a dual-luciferase assay and inflammatory cytokine production and α-SMA expression were investigated in rescue experiments. The findings revealed that CTGF elevated inflammatory cytokine production, α-SMA and MIR155HG expression in HSFBs. MIR155HG is upregulated in HS tissues due to low DNA methylation. Mechanistically, miR-155-5p/-3p was directly bound to MIR155HG 3'UTR. MIR155HG silencing inhibited cytokine production and α-SMA expression by repressing the generation of miR-155-5p/-3p in CTGF-treated HSFBs. Bioinformatics analysis and luciferase reporter assays revealed that miR-155-5p/-3p targets AZGP1. In addition, transfection with plasmids carrying AZGP1 cDNA significantly inhibited the signaling activity of miR-155-5p/-3 p-overexpressing HSFBs. Our findings highlight the importance of the MIR155HG/miR-155/AZGP1 axis in regulating cytokine production and α-SMA in HS.

Alpha tocopherol treatment reduces the expression of Nogo-A and NgR in rat brain after traumatic brain injury.

BACKGROUND: Neurite outgrowth inhibitor-A (Nogo-A), myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein are three myelin-associated proteins that act as inhibitors to central nervous system regeneration. Neurite outgrowth inhibitor-A imposes the strongest effect on inhibiting axonal regeneration after traumatic brain injury. Alpha-tocopherol, a member of the vitamin E family, is recognized as an active antioxidative substance. Its use has not been well studied in brain injury research, especially in axonal regeneration research. METHODS: We obtained 99 intact adult male Sprague-Dawley rats (200-250 g) from the Experimental Animal Center of Central South University. We used the modified method of Freeney to generate moderate brain injury in the rats. We injected 600 mg/kg α-tocopherol intraperitoneally daily as traumatic brain injury (TBI) treatment. Then, we performed behavioral tests in the corresponding time point, examined brain tissues after hematoxylin-eosin staining to identify changes in cell morphology, and performed immunohistochemical staining and quantitative real-time polymerase chain reaction to detect the expression of NoGo and Nogo receptor (NgR) in brain tissue. RESULTS: For the Neurological Severity Scores of rats, there were obvious differences among the three groups at the corresponding time points. Standard hematoxylin-eosin staining showed that the brain structure of a sham-operated group of rats was clear, uniform, and compact. A TBI group exhibited hemorrhage, edema, inflammatory cell infiltration, condensed nuclei, and necrosis. We also saw glial cells and fibrous tissue proliferation. The α-tocopherol-treated TBI group had similar but less severe changes than the TBI group. Expression of Nogo-A and NgR increased after TBI compared with the sham-operated group. However, Nogo-A and NgR expression was significantly lower in the α-tocopherol-treated TBI group compared with the TBI group. Similarly, results showed that functional neurological deficits among rats in the α-tocopherol-treated TBI group were less pronounced than in the TBI group (model group). CONCLUSIONS: Our data demonstrate that α-tocopherol-treated rats had reduced microscopic evidence of brain damage. Alpha-tocopherol reduced Nogo-A and NgR expression in brain tissue after traumatic brain injury and promoted nerve regeneration. Alpha-tocopherol treatment of TBI rats had a neuroprotective role in their recovery.

Safety and effects of endovascular treatment of basilar tip aneurysms in patients with moyamoya diseases.

The effect and safety of endovascular treatment of basilar tip aneurysms associated with moyamoya disease are unknown. This study was to investigate the safety and effect of endovascular treatment of basilar tip aneurysms associated with moyamoya disease. Patients with moyamoya disease concurrent with basilar tip aneurysms were retrospectively enrolled and treated with endovascular embolization. The clinical and angiographic data were analyzed. Thirty patients with a basilar tip aneurysm were enrolled, including 8 (26.67%) male and 22 (73.33%) female patients aged 38 to 72 years (mean 54.4 ± 8.15). Endovascular treatment was successfully performed in 29 (96.67%) patients but failed in 1 (3.33%). Immediately after embolization, aneurysm occlusion degree was Raymond-Roy grade I in 26 (89.66%), grade II in 2 (6.90%), and grade III in 1 (3.45%). Intraprocedural complications occurred in 2 (10%) patients, including aneurysm rupture in 1 (3.33%), leading to death of the patient, and stent thrombosis in 2 (6.67%) which was successfully treated with thrombolysis. At discharge, good clinical outcome (modified Rankin Scale 0-2) was achieved in 29 (96.67%) and death in 1 (3.03%). Follow-up was performed 6 to 26 months (median 15) in 27 (93.1%) patients. Aneurysm occlusion degree was Raymond-Roy grade I in 21 (77.78%) patients, grade II in 4 (14.81%), and grade III in 2 (7.41%), not significantly (P = .67) different from those immediately after embolization. Aneurysm recurrence was found in 4 patients (14.81%). The clinical outcome was modified Rankin Scale 0 to 2 in all 27 patients, not significantly different from that at discharge. Endovascular embolization can be performed safely and effectively for basilar tip aneurysms associated with moyamoya disease even though more advanced embolization techniques are necessary.

Cerebral aneurysms at major arterial bifurcations are associated with the arterial branch forming a smaller angle with the parent artery.

Currently, the relationship of bifurcation morphology and aneurysm presence at the major cerebral bifurcations is not clear. This study was to investigate cerebral arterial bifurcation morphology and accompanied hemodynamic stresses associated with cerebral aneurysm presence at major cerebral arterial bifurcations. Cerebral angiographic data of major cerebral artery bifurcations of 554 anterior cerebral arteries, 582 internal carotid arteries, 793 middle cerebral arteries and 195 basilar arteries were used for measurement of arterial diameter, lateral and bifurcation angles and aneurysm deviation. Hemodynamic stresses were analyzed using computational fluid dynamic simulation. Significantly (P < 0.001) more aneurysms deviated toward the smaller branch and the smaller lateral angle than towards the larger branch and larger lateral angle at all four major bifurcations. At the flow direct impinging center, the total pressure was the greatest while the dynamic pressure, wall shear stress (WSS), vorticity and strain rate were the least. Peak 1 and Peak 2 were located on the branch forming a smaller and larger angle with the parent artery, respectively. The dynamic pressure (175.4 ± 18.6 vs. 89.9 ± 7.6 Pa), WSS (28.9 ± 7.4 vs. 15.7 ± 5.3 Pa), vorticity (9874.6 ± 973.4 vs. 7237.8 ± 372.7 1/S), strain rate (9873.1 ± 625.6 vs. 7648.3 ± 472.5 1/S) and distance (1.9 ± 0.8 vs. 1.3 ± 0.3 mm) between the peak site and direct flow impinging center were significantly greater at Peak 1 than at Peak 2 (P < 0.05 or P < 0.01). Moreover, aneurysms deviation and Peak 1 were always on the same side. In conclusion, the branch forming a smaller angle with the parent artery is associated with abnormally enhanced hemodynamic stresses to initiate an aneurysm at the bifurcation apex.

Risk factors for repeated recurrence of cerebral aneurysms treated with endovascular embolization.

Purpose: To explore the risk factors of recurrence after second endovascular embolization of recurrent aneurysms and the characteristics of recurrent refractory aneurysms to help clinical decision-making. Materials and methods: Forty-nine patients with recurrent aneurysms who underwent repeated embolization were retrospectively enrolled and divided into the recurrent and non-recurrent group. The risk factors of recurrence, complications and follow-up results of repeated embolization, and characteristics of recurrent refractory aneurysms were analyzed. Results: Among the 49 patients with the second embolization, 5 were lost to follow-up, 9 recurred, and 35 did not. Univariate analysis showed that aneurysm size (P = 0.022), aneurysm classification (P = 0.014), and Raymond-Roy grade after the second embolization (P = 0.001) were statistically different between the two groups. Multivariate analysis demonstrated the Raymond-Roy grade as an independent risk factor for the recurrence of aneurysms after the second embolization (P = 0.042). The complication rate after the second embolization was 4%. There were five recurrent refractory aneurysms with an average aneurysm size of 23.17 ± 10.45 mm, including three giant aneurysms and two large aneurysms. To achieve complete or near-complete embolization of the recurrent refractory aneurysms, multiple treatment approaches were needed with multiple stents or flow diverting devices. Conclusion: Aneurysm occlusion status after the second embolization is an independent risk factor for the recurrence of intracranial aneurysms. Compared with near-complete occlusion, complete occlusion can significantly reduce the risk of recurrence after second embolization. In order to achieve complete or near-complete occlusion, recurrent refractory aneurysms need multiple treatments with the use of multiple stents or flow diverting devices.

Effect of immediate blood pressure reduction on post-stroke depression in ischemic stroke patients: A substudy of CATIS trial.

BACKGROUND: Several prospective studies have identified that hypertension is an important risk factor of post-stroke depression (PSD). However, the effect of immediate antihypertensive treatment on the risk of PSD in patients with acute ischemic stroke remains unknown. METHODS: In this prespecified depression substudy of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) randomized clinical trial, a total of 642 patients with acute ischemic stroke within 48 h of onset and elevated systolic BP at 7 sites of CATIS were included. Patients were randomly assigned to receive antihypertensive treatment (n = 318) or to control group (n = 324). The primary outcome was depression (Hamilton Rating Scale for Depression score≥8) at 3-month posttreatment follow-up. RESULTS: At 24 h after randomization, the mean systolic BP was reduced by 21.6 mm Hg (12.5%) in the treatment group and 13.9 mm Hg (7.9%) in the control group (difference, -7.7 mm Hg [95% CI, -10.2 to -5.2]; P<0.001). The mean systolic BP levels at 7 days (P<0.001) and 14 days (P<0.001) after randomization in treatment group were also significantly lower than those in control group. At 3-month posttreatment follow-up, 122 patients (38.4%) in antihypertensive treatment group and 131 patients (40.4%) in control group developed PSD (odds ratio, 0.92 [95% CI, 0.67 to 1.26]; P = 0.59). LIMITATIONS: All patients in the CATIS trial were Chinese, which might limit the generalizability of our findings to other populations. CONCLUSIONS: Early antihypertensive treatment had no effect on the risk of PSD at 3 months among patients with acute ischemic stroke and elevated BP.

Generation and characterization of three induced pluripotent stem cell lines (NUIGi046-A, NUIGi046-B, NUIGi046-C) from a 51-year-old healthy individual.

Skin punch biopsy was donated by a healthy 51-year-old Caucasian male and the dermal fibroblasts were reprogrammed into human induced pluripotent stem cell (hiPSC) lines by using non-integrative Sendai viruses expressing OCT4, SOX2, KLF4 and c-MYC. Three iPSC lines (NUIGi046-A, NUIGi046-B, NUIGi046-C) highly expressed the pluripotent markers and were capable of differentiating into cells of endodermal, mesodermal, and ectodermal origin. These iPSCs can be offered as controls and in combination with genome-editing and three-dimensional (3D) system. They may be used for human disease modelling and drug screening.

Association between vein diameters, reflux characteristics, and clinical severity in patients with chronic venous insufficiency in Northwest China.

OBJECTIVE: Our goal was to summarize the relationship between vein diameters, reflux characteristics, and clinical severity in consecutive patients with chronic venous insufficiency (CVI) in Northwest China. METHODS: We evaluated 531 consecutive patients with CVI (249 women) who presented to the Department of Ultrasound of Xijing Hospital from September 2017 to July 2019. Reflux times and the mean diameters of the great saphenous, the small saphenous, and the calf perforator veins based on duplex ultrasound scans obtained in the standing position were recorded. Venous-specific assessment tools-the Heaviness, Achiness, Swelling, Throbbing, Itching (HASTI) score, the Venous Clinical Severity Score (VCSS), and the Clinical, Etiological, Anatomical, Pathophysiological (CEAP) class-were analyzed. Regression analysis was used to investigate the relationship between the clinical scores, vein diameters, and reflux times. A P value of less than .05 was considered statistically significant. RESULTS: We analyzed 531 consecutive patients with 728 limbs. The mean age was 55.24 ± 11.38 years; the mean body mass index (BMI) was 24.75 ± 3.49 kg/m2. Three hundred thirty-four patients (62.9%) presented with unilateral limb findings and 197 (37.1%), with bilateral limb involvement. No significant changes were noted in age and BMI across CEAP classes (F = 2.322 and F = 3.917, respectively; P > .05 for both). Both the HASTI score (r2 = 0.8741; P < .001) and the VCSS (r2 = 0.9257; P < .001) correlated with the CEAP class. The HASTI score strongly correlated with the mean diameters of the great saphenous and small saphenous veins (r2 = 0.9252, r2 = 0.6304, respectively; P < .001 for both) similarly to VCSS (r2 = 0.9396, r2 = 0.7195, respectively; P < .001 for both). The HASTI score and VCSS correlated equally with the mean diameters of the calf perforator veins (r = 0.7773 and r = 0.7781, respectively; P < .001 for both). In those with C6, both great saphenous vein (F = 4.608; P < .001) and small saphenous vein reflux times (F = 14.97; P < .001) were significantly higher than those in C1. Both the HASTI score and VCSS strongly associated with the reflux times of the great saphenous (r2 = 0.7706 and r2 = 0.8181, respectively; P < .001 for both) and small saphenous veins (r2 = 0.6470 and r2 = 0.7865, respectively; P < .001 for both). CONCLUSIONS: This analysis is one of the few epidemiologic studies of patients with CVI in Northwest China. Age and BMI did not correlate with CEAP class. Both the HASTI score and VCSS correlated strongly with the CEAP classification; vein diameters and reflux time in both the great saphenous vein and the small saphenous vein, indicating the validity of these outcome tools to venous hemodynamics and to CVI in general.

Factors affecting recurrence and management of recurrent cerebral aneurysms after initial coiling.

OBJECTIVE: To investigate factors affecting recurrence and effects and safety of endovascular retreatment for aneurysms recurrent after embolization. METHODS: Among 815 aneurysms treated with embolization, recurrence was in 114 aneurysms (14.0%). Forty-three recurrent aneurysms were managed with re-embolization. Procedural complications, angiographic, and clinical results of retreatment were analyzed. RESULTS: Patients with recurrent aneurysms were significantly (P < 0.01) younger than without recurrence (51.09 ± 10.46 vs. 53.88 ± 9.61 years). Recurrent aneurysms (n = 114) were significantly (P = 0.00) greater (11.12 ± 8.35 vs. 5.81 ± 3.44 mm) with a significantly (P = 0.00) greater neck (4.34 ± 2.26 vs. 2.90 ± 1.44 mm) than without recurrence. The rupture status of aneurysms significantly (P = 0.00) affected recurrence at follow-up. Significantly (P = 0.00) more aneurysms without recurrence were treated with advanced embolization techniques (81.0% vs. 62.3%) and got complete occlusion at the first embolization than those with recurrence (93.7% vs. 36.8%). In treating 43 recurrent aneurysms, stent-assisted recoiling was used in 48.8% in the first retreatment and 50% in the second and third retreatment procedures. Angiographic follow-up in 38 (88.4%) cases showed complete or near complete occlusion in 30 aneurysms, with the rest eight aneurysms experiencing a second recurrence (21.1%). Of the eight aneurysms with the second recurrence, five underwent the second endovascular retreatment, with complete aneurysm occlusion achieved in three cases (60%), near-complete occlusion in one (20%), and incomplete occlusion in one case at immediate angiography and six-month follow-up. Procedure-related complications occurred in three patients. CONCLUSIONS: Endovascular retreatment of recurrent previously coiled aneurysms is safe and effective even though advanced embolization techniques are frequently involved especially for large and giant aneurysms.

Sumoylation of SUVR2 contributes to its role in transcriptional gene silencing.

The SU(VAR)-3-9-related protein family member SUVR2 has been previously identified to be involved in transcriptional gene silencing both in RNA-dependent and -independent pathways. It interacts with the chromatin-remodeling proteins CHR19, CHR27, and CHR28 (CHR19/27/28), which are also involved in transcriptional gene silencing. Here our study demonstrated that SUVR2 is almost fully mono-sumoylated in vivo. We successfully identified the exact SUVR2 sumoylation site by combining in vitro mass spectrometric analysis and in vivo immunoblotting confirmation. The luminescence imaging assay and quantitative RT-PCR results demonstrated that SUVR2 sumoylation is involved in transcriptional gene silencing. Furthermore, we found that SUVR2 sumoylation is required for the interaction of SUVR2 with CHR19/27/28, which is consistent with the fact that SUMO proteins are necessary for transcriptional gene silencing. These results suggest that SUVR2 sumoylation contributes to transcriptional gene silencing by facilitating the interaction of SUVR2 with the chromatin-remodeling proteins CHR19/27/28.

The Cytosolic Iron-Sulfur Cluster Assembly Protein MMS19 Regulates Transcriptional Gene Silencing, DNA Repair, and Flowering Time in Arabidopsis.

MMS19 is an essential component of the cytoplasmic iron-sulfur (Fe-S) cluster assembly complex in fungi and mammals; the mms19 null mutant alleles are lethal. Our study demonstrates that MMS19/MET18 in Arabidopsis thaliana interacts with the cytoplasmic Fe-S cluster assembly complex but is not an essential component of the complex. We find that MMS19 also interacts with the catalytic subunits of DNA polymerases, which have been demonstrated to be involved in transcriptional gene silencing (TGS), DNA repair, and flowering time regulation. Our results indicate that MMS19 has a similar biological function, suggesting a functional link between MMS19 and DNA polymerases. In the mms19 null mutant, the assembly of Fe-S clusters on the catalytic subunit of DNA polymerase α is reduced but not blocked, which is consistent with the viability of the mutant. Our study suggests that MMS19 assists the assembly of Fe-S clusters on DNA polymerases in the cytosol, thereby facilitating transcriptional gene silencing, DNA repair, and flowering time control.

Progesterone alters Nogo-A, GFAP and GAP-43 expression in a rat model of traumatic brain injury.

Previous studies have demonstrated that progesterone has neuroprotective effects in the central nervous system (CNS) following traumatic brain injury (TBI). Numerous cellular mechanisms have been reported to be important in the neuroprotective effects of progesterone, including the reduction of edema, inflammation and apoptosis, and the inhibition of oxidative stress. However, the effect of progesterone on neuronal protection following TBI remains unclear. The present study aimed to investigate the effects of progesterone on the expression of Nogo-A, an inhibitor of axonal growth, glial fibrillary acidic protein (GFAP), a main component of the glial scar and growth-associated protein-43 (GAP-43), a signaling molecule in neuronal growth in TBI rats. The TBI model was produced by the weight drop method. In total, 75 rats were assigned to three groups: the sham group, TBI group with vehicle treatment and TBI group with progesterone treatment. The protein expression of Nogo-A, GFAP and GAP-43 in the cortex and the hippocampus was examined by immunocytochemistry. TBI rats significantly increased the expression of Nogo-A, GFAP, and GAP-43 at 1, 3, 7 and 14 days post-injury. Progesterone significantly decreased the expression of Nogo-A and GFAP, and upregulated the GAP-43 protein. Our findings suggested that progesterone promotes neuroprotection following TBI by inhibiting the expression of Nogo-A and GFAP, and increasing GAP-43 expression.