How to build a paraspeckle

Noncoding RNAs have recently been identified as essential components of the enigmatic nuclear suborganelles called paraspeckles

Aripiprazole, a novel antipsychotic agent : Dopamine D2 receptor partial agonist

It is obvious that DA is an important neurotransmitter in vivo. It is involved in a variety of physiological processes such as mental processes, motor function and hormone regulation. In this context, it is quite understandable that a DA D2 receptor antagonist that inhibits the DA D2 receptor regardless of the state of activity of dopaminergic neurotransmission and inhibit the physiological function of DA can have a variety of adverse effects. In contrast to DA D2 antagonists, aripiprazole acts as an antagonist at the DA D2 receptor in the state of excessive dopaminergic neurotransmission, while it acts as an agonist at the DA D2 receptor in the state of low dopaminergic neurotransmission, and thus attempts to bring the state of dopaminergic neurotransmission to normal. This activity of aripiprazole to regulate dopaminergic neurotransmission is physiologically reasonable, and can be regarded as a stabilizing effect, for which aripiprazole is called a dopamine system stabilize

A thymus-specific noncoding RNA, Thy-ncR1, is a cytoplasmic riboregulator of MFAP4 mRNA in immature T-cell lines

<p>Abstract</p> <p>Background</p> <p>Postgenomic transcriptome analyses have identified large numbers of noncoding (nc)RNAs in mammalian cells. However, the biological function of long ncRNAs in mammalian cells remains largely unknown. Our recent expression profiling of selected human long ncRNAs revealed that a majority were expressed in an organ-specific manner, suggesting their function was linked to specific physiological phenomena in each organ. We investigated the characteristics and function of ncRNAs that were specifically expressed in the thymus, the site of T-cell selection and maturation.</p> <p>Results</p> <p>Expression profiling of 10 thymus-specific ncRNAs in 17 T-cell leukemia cell lines derived from various stages of T-cell maturation revealed that HIT14168 ncRNA, named Thy-ncR1, was specifically expressed in cell lines derived from stage III immature T cells in which the neighbouring CD1 gene cluster is also specifically activated. The Thy-ncR1 precursor exhibited complex alternative splicing patterns and differential usage of the 5' terminus leading to the production of an estimated 24 isoforms, which were predominantly located in the cytoplasm. Selective RNAi knockdown of each Thy-ncR1 isoform demonstrated that microfibril-associated glycoprotein 4 (MFAP4) mRNA was negatively regulated by two major Thy-ncR1 isoforms. Intriguingly, the MFAP4 mRNA level was controlled by a hUPF1-dependent mRNA degradation pathway in the cytoplasm distinct from nonsense-mediated decay.</p> <p>Conclusions</p> <p>This study identified Thy-ncR1 ncRNA to be specifically expressed in stage III immature T cells in which the neighbouring CD1 gene cluster was activated. Complex alternative splicing produces multiple Thy-ncR1 isoforms. Two major Thy-ncR1 isoforms are cytoplasmic riboregulators that suppress the expression of MFAP4 mRNA, which is degraded by an uncharacterized hUPF1-dependent pathway.</p

Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1γ gene

Fox-1 is a regulator of tissue-specific splicing, via binding to the element (U)GCAUG in mRNA precursors, in muscles and neuronal cells. Fox-1 can regulate splicing positively or negatively, most likely depending on where it binds relative to the regulated exon. In cases where the (U)GCAUG element lies in an intron upstream of the alternative exon, Fox-1 protein functions as a splicing repressor to induce exon skipping. Here we report the mechanism of exon skipping regulated by Fox-1, using the hF1γ gene as a model system. We found that Fox-1 induces exon 9 skipping by repressing splicing of the downstream intron 9 via binding to the GCAUG repressor elements located in the upstream intron 8. In vitro splicing analyses showed that Fox-1 prevents formation of the pre-spliceosomal early (E) complex on intron 9. In addition, we located a region of the Fox-1 protein that is required for inducing exon skipping. Taken together, our data show a novel mechanism of how RNA-binding proteins regulate alternative splicing

Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: a comparative study between Azelnidipine and amlodipine on glucose tolerance and endothelial function - a crossover trial (AGENT)

<p>Abstract</p> <p>Background</p> <p>Hypertension is associated with impaired glucose tolerance and insulin resistance. Medical treatment that interferes with various steps in the renin-angiotensin system improves glucose tolerance and insulin resistance. However, it remains unclear if long-acting calcium channel blockers (CCBs) such as azelnidipine and amlodipine affect glucose tolerance and insulin resistance in clinical practice.</p> <p>Methods</p> <p>Seventeen non-diabetic patients with essential hypertension who had controlled blood pressure levels using amlodipine (5 mg/day) were enrolled in this study. After randomization, either azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks. At baseline and the end of each CCB therapy, samples of blood and urine were collected and 75 g oral glucose tolerance test (OGTT) was performed. In addition, hematopoietic progenitor cells (HPCs) were measured at each point by flow cytometry and endothelial functions were measured by fingertip pulse amplitude tonometry using EndoPAT.</p> <p>Results</p> <p>Although blood pressure levels were identical after each CCB treatment, the heart rate significantly decreased after azelnidipine administration than that after amlodipine administration (<it>P </it>< 0.005). Compared with amlodipine administration, azelnidipine significantly decreased levels of glucose and insulin 120 min after the 75 g OGTT (both <it>P </it>< 0.05). Serum levels of high-sensitivity C-reactive protein (<it>P </it>= 0.067) and interleukin-6 (<it>P </it>= 0.035) were decreased. Although endothelial functions were not different between the two medication groups, the number of circulating HPCs was significantly increased after azelnidipine administration (<it>P </it>= 0.016).</p> <p>Conclusions</p> <p>These results suggest that azelnidipine treatment may have beneficial effects on glucose tolerance, insulin sensitivity, the inflammatory state, and number of circulating progenitor cells in non-diabetic patients with essential hypertension.</p

Polyethylene Glycol-Based Synthetic Hydrogel Sealant for Closing Vitrectomy Wounds: An In Vivo and Histological Study

Purpose We conducted an in vivo study using Dutch pigmented rabbit eyes to test the usefulness of polyethylene glycol (PEG) sealant for the closure of sutureless sclerotomies in microincisional vitrectomy surgery (MIVS). Methods: Three-port, 23-gauge vitrectomy was performed on rabbit eyes. After air leakage was confirmed by the application of 0.625% povidone–iodine at the sclerotomy site, PEG sealant was subconjunctivally injected using a 27-gauge needle through conjunctival incisions to cover the sclerotomy wounds, following which it was polymerized by the application of xenon light for 60 seconds. Ophthalmological examinations and intraocular pressure measurements were conducted the day before and 1, 3, 5, and 7 days after surgery. The eyes were enucleated for histological evaluation 7 days after surgery. Results: PEG sealant was rapidly polymerized by the application of xenon light after subconjunctival injection, and it firmly sealed the sclerotomies without air leakage, as confirmed by povidone–iodine dropping, in all cases. Conjunctival and scleral wounds closed with PEG sealant were successfully attached and remained intact till the end of the follow-up period. There was no sign of postoperative hypotony or infection in any eye, and no adverse effects of PEG sealant were found. In histological examination, linear scar formation and eosinophilic staining of collagen fibers were observed at the sclerotomy sites, while the sclerotomy tunnels appeared tightly closed. Conclusions: PEG sealant can be useful for the closure of sutureless 23-gauge vitrectomy incisions in rabbits. Translational Relevance The PEG sealant may become an effective option for closing vitrectomy incisions including pediatric cases

コロンブス ノ タマゴ テキ ハッソウ ニ モトズイタ タイイ ヘンカンヨウ マット ノ シサク

We report on a new mat experimentally developed by us for changing the position of the body (named i-mat), based on an idea of a floating body. [Method] At first,4, approximately 70cm long, belts were attached to both the right and left side of the pad for tying to the beds. For a lateral position with a 30-degree tilt to the right side, the belt attached on the left side is fixed to the right bed fence and the length of the belt is adjusted so that the patient’s position becomes lateral with a 30-degree tilt. The body pressure levels (mmHg) at sites of bone were measured after position changes by using a simple body pressure-measuring device (PREDIA®) in 10 patients with an independence degree of daily living rating of C2 (group i) in whom the i-mat was used, and compared with the levels measured after position changes in patients where a mat made of urethane (Nasentpat®) was used (group N). [Results] The pressure levels in the sacral region and occipital region could be significantly lowered in group i as compared with that in group N. We also measured and compared the pressures at the major trochanter, acrominon, and iliac regions, because the high-pressure loaded region shifted to these regions on the side facing the bed in the lateral position. No significant differences in the pressure levels at the major trochanter and acrominon were found between the i and N groups. The pressure level in the iliac region in the i group was significantly higher than that that in the N group. [Conclusion] Use of this experimentally produced i-mat can significantly lower the pressure load at the sacral and occipital regions when the patient is placed in the lateral position of either side with a 30-degree tilt, as compared to that of Nasentpat®. But it appears that caution should be exercised to prevent the occurrence of bedsores in the iliac region

Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice

Mouse NEAT1 is required for paraspeckle formation in a subset of cells but is not essential for animal health and viability

Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells

In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) NEAT1 is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of NEAT1 in VSMC phenotypic modulation is unknown. Herein we showed that NEAT1 expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing NEAT1 in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of NEAT1 in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which NEAT1 knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that NEAT1 sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic "off" state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA NEAT1 in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that NEAT1 is a therapeutic target for treating occlusive vascular diseases

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K‐RAS status for unresectable colorectal liver metastasis (BECK study): Long‐term results of survival

[Background/Purpose]To investigate the long‐term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. [Methods]Recurrence and survival data with long‐term follow‐up were analyzed in the cohort of a multi‐institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). [Results]A total of 22/12 patients with K‐RAS wild‐type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left‐sided primary tumors than in right‐sided tumors (75.0% vs 30.0%, P = .022). The median follow‐up was 72.6 months. The 5‐year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5‐year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow‐up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5‐year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1‐4). [Conclusions]Conversion hepatectomy achieved a similar long‐term survival to the results of previous studies in initially resectable patients, although many of them experienced several post‐hepatectomy recurrences. Left‐sided primary was found to be the predictor for conversion hepatectomy