Miracle-dz/UniFAR-FTUs huggingface dataset:
MicroRNA-663 Regulates Human Vascular Smooth Muscle Cell Phenotypic Switch and Vascular Neointimal Formation

Rationale: Abnormal phenotypic switch of vascular smooth muscle cell (VSMC) is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. MicroRNAs (miRNAs) have emerged as important regulators for VSMC function, and we recently identified miR-663 as critical for controlling human aortic smooth muscle cell proliferation. Objective: To investigate whether miR-663 plays a role in human VSMC phenotypic switch and the development of neointima formation. Methods and Results: By using quantitative reverse-transcription polymerase chain reaction, we found that miR-663 was significantly downregulated in human aortic VSMCs on platelet-derived growth factor treatment, whereas expression was markedly increased during VSMC differentiation. Furthermore, we demonstrated that overexpression of miR-663 increased expression of VSMC differentiation marker genes, such as smooth muscle 22&agr;, smooth muscle &agr;-actin, calponin, and smooth muscle myosin heavy chain, and potently inhibited platelet-derived growth factor–induced VSMC proliferation and migration. We identified the transcription factor JunB and myosin light chain 9 as downstream targets of miR-663 in human VSMCs, because overexpression of miR-663 markedly inhibited expression of JunB and its downstream molecules, such as myosin light chain 9 and matrix metalloproteinase 9. Finally, we showed that adeno-miR-663 markedly suppressed the neointimal lesion formation by ≈50% in mice after vascular injury induced by carotid artery ligation, specifically via decreased JunB expression. Conclusions: These results indicate that miR-663 is a novel modulator of human VSMC phenotypic switch by targeting JunB/myosin light chain 9 expression. These findings suggest that targeting miR-663 or its specific downstream targets in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.
Reference Gene Selection for Quantitative Real-Time Reverse-Transcriptase PCR in Annual Ryegrass (Lolium multiflorum) Subjected to Various Abiotic Stresses

To select the most stable reference genes in annual ryegrass (Lolium multiflorum), we studied annual ryegrass leaf tissues exposed to various abiotic stresses by qRT-PCR and selected 11 candidate reference genes, i.e., 18S rRNA, E2, GAPDH, eIF4A, HIS3, SAMDC, TBP-1, Unigene71, Unigene77, Unigene755, and Unigene14912. We then used GeNorm, NormFinder, and BestKeeper to analyze the expression stability of these 11 genes, and used RefFinder to comprehensively rank genes according to stability. Under different stress conditions, the most suitable reference genes for studies of leaf tissues of annual ryegrass were different. The expression of the eIF4A gene was the most stable under drought stress. Under saline-alkali stress, Unigene14912 has the highest expression stability. Under acidic aluminum stress, SAMDC expression stability was highest. Under heavy metal stress, Unigene71 expression had the highest stability. According to the software analyses, Unigene14912, HIS3, and eIF4A were the most suitable for analyses of abiotic stress in tissues of annual ryegrass. GAPDH was the least suitable reference gene. In conclusion, selecting appropriate reference genes under abiotic stress not only improves the accuracy of annual ryegrass gene expression analyses, but also provides a theoretical reference for the development of reference genes in plants of the genus Lolium.
Bioactive Composites Consisting of PEEK and Calcium Silicate Powders

Bioactive bone-repairing materials with mechanical properties analogous to those of natural bone can be obtained through the combination of bioactive ceramic fillers with organic polymers. Previously, we developed novel bioactive microspheres in a binary CaO—SiO2 system produced through a sol—gel process as filler for the fabrication of composites. In this study, we fabricate bioactive composites in which polyetheretherketone is reinforced with 0—50 vol% 30CaO · 70SiO2 (CS) microspheres. The prepared composites reinforced with CS particles form hydroxyapatite on their surfaces in simulated body fluid. The induction periods of hydroxyapatite formation on the composites decrease with increasing amount of CS particles. The mechanical properties of the composites are evaluated by three-point bending test. The composites reinforced with 20 vol% CS particles show 123.5 MPa and 6.43 GPa in bending strength and Young’s modulus, respectively.
The natural course of bulimia nervosa and eating disorder not otherwise specified is not influenced by personality disorders.

OBJECTIVE To examine prospectively the natural course of bulimia nervosa (BN) and eating disorder not otherwise specified (EDNOS) and to test the effects of personality disorder (PD) comorbidity on the outcomes. METHOD Ninety-two female patients with current BN (N=23) or EDNOS (N=69) were evaluated at baseline enrollment in the Collaborative Longitudinal Personality Disorders Study (CLPS). Eating disorders (EDs) were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders. Personality disorders (PDs) were assessed with the Diagnostic Interview for DSM-IV PD (DIPD-IV). The course of BN and EDNOS was assessed with the Longitudinal Interval Follow-up Evaluation and the course of PDs was evaluated with the Follow-Along version of the DIPD-IV at 6, 12, and 24 months. RESULTS Probability of remission at 24 months was 40% for BN and 59% for EDNOS. To test the effects of PD comorbidity on course, ED patients were divided into groups with no, one, and two or more PDs. Cox proportional regression analyses revealed that BN had a longer time to remission than EDNOS (p<.05). The number of PDs was not a significant predictor of time to remission, nor was the presence of Axis I psychiatric comorbidity or Global Assessment of Functioning scores. Analyses using proportional hazards regression with time-varying covariates revealed that PD instability was unrelated to changes in ED. CONCLUSIONS BN has a worse 24-month course (longer time to remission) than EDNOS. The natural course of BN and EDNOS is not influenced significantly by the presence, severity, or time-varying changes of co-occurring PDs, co-occurring Axis I disorders, or by global functioning.
Sertraline and Cognitive Behavioral Therapy for Depressed Alcoholics: Results of A Placebo-Controlled Trial

Alcoholism and depression are common disorders that frequently cooccur in the same individual. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression and also had decreased drinking in some studies of heavy drinkers and alcoholics. The reported effect of serotonergic medications on alcohol intake in depressed alcoholics has not been consistent. Most previous studies have not investigated the use of an SSRI in the context of cognitive behavioral therapy (CBT), a known efficacious treatment of both alcoholism and depression. The study presented here was a randomized placebo-controlled 12-week trial of sertraline combined with individual CBT focused on both alcoholism relapse prevention and depressive symptoms. Subjects were 82 currently depressed, actively drinking alcohol-dependent individuals. Subjects had either primary (independent) major depression (70 subjects) or substance-induced mood disorder and at least 1 first-degree relative (parent, sibling, or child) with an affective disorder (12 subjects). Depression and alcohol consumption outcomes were measured weekly over 12 weeks. Sertraline was well tolerated and all subjects had decreases in both depression and alcohol use during the study compared with baseline. Subjects who received sertraline had fewer drinks per drinking day than subjects who received placebo, but other drinking outcomes were not different between the 2 treatment groups. Treatment with sertraline was associated with less depression at the end of treatment in female subjects compared with female subjects who received placebo. Less drinking during the study was associated with improved depression outcome. The findings in this study suggest that sertraline, compared with placebo, may provide some modest benefit in terms of drinking outcome and also may lead to improved depression in female alcohol-dependent subjects. Additionally, alcohol relapse prevention CBT, delivered according to manual guidelines with modifications that provide specific attention to depression, appeared to be of benefit to subjects, although this interpretation is limited by the design of the study.
RNA-programmed genome editing in human cells

Type II CRISPR immune systems in bacteria use a dual RNA-guided DNA endonuclease, Cas9, to cleave foreign DNA at specific sites. We show here that Cas9 assembles with hybrid guide RNAs in human cells and can induce the formation of double-strand DNA breaks (DSBs) at a site complementary to the guide RNA sequence in genomic DNA. This cleavage activity requires both Cas9 and the complementary binding of the guide RNA. Experiments using extracts from transfected cells show that RNA expression and/or assembly into Cas9 is the limiting factor for Cas9-mediated DNA cleavage. In addition, we find that extension of the RNA sequence at the 3′ end enhances DNA targeting activity in vivo. These results show that RNA-programmed genome editing is a facile strategy for introducing site-specific genetic changes in human cells. DOI: http://dx.doi. org/10.7554/eLife.00471. 001
Selective impairment of GABAergic synaptic transmission in the flurothyl model of neonatal seizures

Neonatal seizures can result in long‐term adverse consequences including alteration of seizure susceptibility and impairment in spatial memory. However, little is known about the effects of neonatal seizures on developmental changes occurring in synaptic transmission during the first postnatal weeks. The purpose of the present study was to examine the effect of neonatal seizures on several aspects of γ‐aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission in the developing rat hippocampus. Flurothyl was used to induce multiple recurrent seizures in rat pups during the first postnatal days. Whole‐cell patch‐clamp recordings from the hippocampal CA3 pyramidal cell and extracellular recordings from the CA3 pyramidal cell layer were made in slice preparations. In rats that experienced neonatal seizures the amplitude of spontaneous inhibitory postsynaptic currents at P15–17 was decreased by 27% compared with controls, whereas neither frequency nor the kinetic properties were altered. Neonatal seizures did not affect the timing of the developmental switch in the GABAA signaling from excitatory to inhibitory. None of the studied parameters of glutamatergic postsynaptic currents was different between the flurothyl and control groups, including the amplitude and frequency of the spontaneous excitatory postsynaptic currents, the ratio of the amplitudes and frequencies of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) and N‐methyl‐d‐aspartate (NMDA)‐mediated spontaneous postsynaptic currents, and the kinetics of AMPA and NMDA mediated postsynaptic currents in the age groups P8–10 and P15–17. We suggest that the selective depression of the amplitude of GABAergic synaptic responses may contribute to the adverse neurological and behavioral consequences that occur following neonatal seizures.
Role of Structural Barriers in the Mechanism of Alternans-Induced Reentry

Abstract— Previously, using an animal model of T-wave alternans in structurally normal myocardium, we demonstrated that repolarization can alternate with opposite phase between neighboring myocytes (ie, discordant alternans), causing spatial dispersions of repolarization that form the substrate for functional block and reentrant ventricular fibrillation (VF). However, the mechanisms responsible for cellular discordant alternans and its electrocardiographic manifestation (ie, T-wave alternans) in patients with structural heart disease are unknown. We hypothesize that electrotonic uncoupling between neighboring regions of cells by a structural barrier (SB) is a mechanism for discordant alternans. Using voltage-sensitive dyes, ventricular action potentials were recorded from 26 Langendorff-perfused guinea pig hearts in the absence (ie, control) and presence of an insulating SB produced by an epicardial laser lesion. Quantitative analysis of magnitude and phase of cellular alternans revealed that in controls, action potential duration alternated in phase at all ventricular sites above a critical heart rate (269±17 bpm), ie, concordant alternans. Also, above a faster critical heart rate threshold (335±24 bpm), action potential duration alternated with opposite phase between sites, ie, discordant alternans. In contrast, only discordant but not concordant alternans was observed in 80% of hearts with the SB, and discordant alternans always occurred at a significantly slower heart rate (by 68±28 bpm) compared with controls. Therefore, the SB had a major effect on the alternans–heart rate relation, which served to facilitate the development of discordant alternans. Whether a SB was present or not, discordant alternans produced considerable increases (by ≈170%) in the maximum spatial gradient of repolarization, which in turn formed the substrate for unidirectional block and reentry. However, by providing a structural anchor for stable reentry, discordant alternans in the presence of a SB led most often to sustained monomorphic ventricular tachycardia rather than to VF, whereas in the absence of a SB discordant alternans caused VF. SBs facilitate development of discordant alternans between cells with different ionic properties by electrotonically uncoupling neighboring regions of myocardium. This may explain why arrhythmia-prone patients with structural heart disease exhibit T-wave alternans at lower heart rates. These data also suggest a singular mechanism by which T-wave alternans forms a substrate for initiation of both VF and sustained monomorphic ventricular tachycardia.
First-Principles Calculations of Oxygen Vacancy Formation in Epitaxially Strained La1-xCaxMnO3

Using epitaxial strain as a degree of freedom is a promising way to tailor the properties in thin films of transition metal oxides. Since the ground state of such materials tend to have many competing low-energy states they are susceptible to small perturbations, potentially inducing new phenomena. Due to the choice of different substrates and growth orientations, a wide range of strain can be applied in the thin films, giving researchers the ability to fine-tune the material properties. In this work, the effect of epitaxial strain on the oxygen vacancy formation energies in different compositions of La1°xCaxMnO3 is calculated from first-principles within the DFT + U framework using the PBEsol functional. Due to the different spatial orientation of the Mn-O-bonds, it is possible to distinguish between two chemically inequivalent oxygen anions with a differing reponse to biaxial strain. This difference is reflected in the oxygen vacancy formation energies, which for all composition exhibit a different strain response. A displacement of oxygen anions towards the La/Ca-cations was found. For the intermediate compounds, the formation energies are largely influenced by which cation the oxygen is displaced towards. In combination with the reported phenomenon of surface segregation of cations, this could potentially be utilized in creating oxygen vacancy concentration gradients for use in novel electronics design.
Comparative embryogenesis of Mecoptera and Lepidoptera with special reference to the abdominal prolegs

The eruciform larvae of holometabolous insects are primarily characterized by bearing a varying number of abdominal prolegs in addition to three pairs of thoracic legs. However, whether the prolegs are evolutionarily homologous among different insect orders is still a disputable issue. We examined the embryonic features and histological structure of the prolegs of the scorpionfly Panorpa byersi Hua and Huang (Mecoptera: Panorpidae) and the Oriental armyworm Mythimna separata (Walker) (Lepidoptera: Noctuidae) to investigate whether the prolegs are homologous between these two holometabolous insect orders. In the scorpionfly, paired lateral process primordia arise on abdominal segments I–VIII (A1–A8) in line with the thoracic legs in early embryonic stages, but degenerate into triangular protuberances in later stages, and paired medial processes appear along the midventral line before dorsal closure and eventually develop into unjointed, cone‐shaped prolegs. Histological observation showed that the lumina of the prolegs are not continuous with the hemocoel, differing distinctly from that of the basic appendicular plan of thoracic legs. These results suggest that the prolegs are likely secondary outgrowths in Mecoptera. In the armyworm, lateral process primordia appear on A1–A10 in alignment with the thoracic legs in the early embryonic stages, although only the rudiments on A3–A6 and A10 develop into segmented prolegs with the lumina continuous with the hemocoel and others degenerate eventually, suggesting that the prolegs are true segmental appendages serially homologous with the thoracic legs in Lepidoptera. Therefore, we conclude that the larval prolegs are likely not evolutionarily homologous between Mecoptera and Lepidoptera. J. Morphol. 277:585–593, 2016. © 2016 Wiley Periodicals, Inc.
Liquidity Constraints and the Permanent Income Hypothesis: Pseudo Panel Estimation with German Consumption Survey Data

This paper empirically investigates the relevance of liquidity constraints and excess sensitivity in intertemporal household consumption. Using a pseudo panel that has been constructed on rich German consumption survey data, we estimate the consumption responses to permanent and transitory income shocks, as well as the presence of excess sensitivity to anticipated income changes. A switching regression approach with unknown sample separation is applied to identify the two regimes whether to be liquidity constrained or not. The results are used to test whether liquidity constraints affect the validity of the permanent income hypothesis. For households in the constrained regime, reactions to changes in transitory income are found to be significantly greater than for households in the unconstrained regime. Furthermore, we provide evidence for excess sensitivity to anticipated income changes for households in the constrained regime if total consumption, durable as well as non-durable, is considered.
Impaired CK1 Delta Activity Attenuates SV40-Induced Cellular Transformation In Vitro and Mouse Mammary Carcinogenesis In Vivo

Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data show that inactivating mutations in CK1δ impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.
Human β-defensin 3 affects the activity of pro-inflammatory pathways associated with MyD88 and TRIF

β‐Defensins are cationic host defense peptides that form an amphipathic structure stabilized by three intramolecular disulfide bonds. They are key players in innate and adaptive immunity and have recently been shown to limit the production of pro‐inflammatory cytokines in TLR4‐stimulated macrophages. In the present study, we investigate the mechanism underlying the anti‐inflammatory effect of human β‐defensin 3 (hBD3). We show that the canonical structure of hBD3 is required for this immunosuppressive effect and that hBD3 rapidly associates with and enters macrophages. Examination of the global effect of hBD3 on transcription in TLR4‐stimulated macrophages shows that hBD3 inhibits the transcription of pro‐inflammatory genes. Among the altered genes there is significant enrichment of groups involved in the positive regulation of NF‐κB including components of Toll‐like receptor signaling pathways. We confirm these observations by showing corresponding decreases in protein levels of pro‐inflammatory cytokines and cell surface molecules. In addition, we show that hBD3 reduces NF‐κB signaling in cells transfected with MyD88 or TRIF and that hBD3 inhibits the TLR4 response in both MyD88‐ and TRIF‐deficient macrophages. Taken together these findings suggest that the mechanism of hBD3 anti‐inflammatory activity involves specific targeting of TLR signaling pathways resulting in transcriptional repression of pro‐inflammatory genes.
Newer Trends in In Situ Gelling Systems for Controlled Ocular Drug Delivery

In situ -gelling systems has the great potential in the wide areas of drug delivery. The application areas of such systems are broad and these systems can be formulated not only as gels but also as in situ gelling nanospheres, microspheres and liposomes. To overcome the drawbacks associated with conventional drug delivery systems and take advantages of both solutions and gels, such as accurate dosing, ease of administration of the former and longer precorneal residence of the latter, a newer concept of in situ gelling drug delivery systems was came in light for the first time in the early 1980s. In situ gelling systems are the polymeric solutions which can be administered in solution form and immediately undergoes sol-gel phase transition in to a viscoelastic gel upon exposure to physiological conditions (e.g. pH, temperature and ionic concentration) or application of external triggers. In situ gelling systems seems to have wide applications in ocular therapy. A lot of research is going on in this area proves the fact that in situ gelling systems can be advantageous in the ocular drug delivery. In the present review we will discuss recent researches involving application of in situ gelling polymers, their applications in the various domains of drug delivery and marketed formulations based on in situ gelling systems.