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Variable superstrong coronal emission lines were observed in the spectrum of one galaxy, SDSS J095209.56+ 214313.3, and their enigmatic origin remains controversial. In this paper, we report the detection of variable broad emission bumps reminiscent of a supernova (SN) II-Plateau spectra taken a few days after the shock breakout in a second galaxy with variable superstrong coronal lines, SDSS J074820.67+471214.3. The coronal line spectrum shows unprecedentedly high ionization with superstrong [Fex]λ6376, [Fe XI]λ7894, [Fe XIV] λ5304, [S XII]λ7612, and [Ar XIV]λ4414, but without detectable optical [Fe VII] line emission. The coronal line luminosities are similar to those observed in bright Seyfert galaxies and 20 times more luminous than those reported in the hottest Type IIn SN 2005ip inferred from its strong coronal lines. The coronal lines (σ ∼ 120-240 km s-1) are much broader than the narrow emission lines (σ ∼ 40 km s-1) from the star-forming regions in the galaxy, but are nearly at the same systematic redshift. We also detected a variable non-stellar continuum emission from its Sloan Digital Sky Survey spectroscopy and Galaxy Evolution Explorer photometry. In the follow-up spectra taken 4-5 years later, the coronal lines, SN-like feature, and non-stellar continuum disappeared, while the [O III]λ.5007 intensity increased by a factor of about 10. Our analysis suggests that the coronal line region should be at least 10 light days in size and should be powered either by a steady ionizing source with a soft X-ray luminosity of at least a few 1042 erg s-1 or by a very luminous soft X-ray outburst. These findings can be more naturally explained by a star tidally disrupted by the central black hole than by an SN explosion. The similarity of the coronal line variability trend observed in the two galaxies suggests that the two transient events have the same origin, with SDSS J074820.67+471214.3 being caught at an earlier stage by the spectroscopic observation. [ABSTRACT FROM AUTHOR]

The Pik3c3 gene encodes an 887 amino acid lipid kinase, phosphoinositide-3-kinase class 3 (PIK3C3). PIK3C3 is known to regulate various intracellular membrane trafficking events. However, little is known about its functions during early embryogenesis in mammals. To investigate the function of PIK3C3 in vivo, we generated Pik3c3 null mice. We show here that Pik3c3 heterozygous are normal and fertile. In contrast, Pik3c3 homozygous mutants are embryonic lethal and die between E7.5 and E8.5 of embryogenesis. Mutant embryos are poorly developed with no evidence of mesoderm formation, and suffer from severely reduced cell proliferations. Cell proliferation defect is also evident in vitro, where mutant blastocysts in culture fail to give rise to typical colonies formed by inner cell mass. Electron microscopic analysis revealed that epiblast cells in mutant embryos appear normal, whereas the visceral endoderm cells contain larger vesicles inside the lipid droplets. Finally, we provide evidence that mTOR signaling is drastically reduced in Pik3c3 null embryos, which could be a major contributor to the observed proliferation and embryogenesis defects. [ABSTRACT FROM AUTHOR]

Based on the variational equation of the nonlinear bending theory of double-deck reticulated shallow shells, equations of large deflection and boundary conditions for a double-deck reticulated circular shallow spherical shell under a uniformly distributed pressure are derived by using coordinate transformation means and the principle of stationary complementary energy. The characteristic relationship and critical buckling pressure for the shell with two types of boundary conditions are obtained by taking the modified iteration method. Effects of geometrical parameters on the buckling behavior are also discussed. [ABSTRACT FROM AUTHOR]

Premotor circuits in the brainstem project to pools of orofacial motoneurons to execute essential motor action such as licking, chewing, breathing, and in rodent, whisking. Previous transsynaptic tracing studies only mapped orofacial premotor circuits in neonatal mice, but the adult circuits remain unknown as a consequence of technical difficulties. Here, we developed a three-step monosynaptic transsynaptic tracing strategy to identify premotor neurons controlling vibrissa, tongue protrusion, and jaw-closing muscles in the adult mouse. We registered these different groups of premotor neurons onto the Allen mouse brain common coordinate framework (CCF) and consequently generated a combined 3D orofacial premotor atlas, revealing unique spatial organizations of distinct premotor circuits. We further uncovered premotor neurons that simultaneously innervate multiple motor nuclei and, consequently, are likely to coordinate different muscles involved in the same orofacial motor actions. Our method for tracing adult premotor circuits and registering to Allen CCF is generally applicable and should facilitate the investigations of motor controls of diverse behaviors. [ABSTRACT FROM AUTHOR]

In this paper, a simple and nondestructive method of modeling 40-nm interconnects is proposed. Traditional methods based on charge-based capacitance measurement model the interconnects by fitting the capacitance or resistance curves, first by assuming one constant process parameter, such as metal thickness, and then by extracting the metal width, metal spacing, and inter-level dielectric (ILD) thickness from certain test patterns that may therefore result in model inaccuracy while the transmission and scanning electron microscopy methods are both destructive and time consuming. The proposed new methodology directly extracts the metal width based on the metal resistance test structures, and then the metal thickness, metal spacing, and ILD thickness without any presumption. It is also nondestructive and fast, with a model accuracy higher than 95%. Furthermore, with the ensured accuracy of layout parameter extraction, the necessity of an accurate interconnect model in the 40 nm technology and beyond is emphasized. [ABSTRACT FROM AUTHOR]

On the basis of our quantum mechanical calculation, we propose that homogeneous single-stranded adenine bases (Ade-DNA) form helical H aggregates, and the photoexcited states can be described as Frenkel excitons. The calculated excitonic coupling between adjacent transition dipoles is in good agreement with the measured absorption spectrum of 20-base homogeneous adenine stacks that exhibits a blue shift of 2.6 nm relative to that of the monomeric species. [ABSTRACT FROM AUTHOR]

C12H12N2O6MoMn, triclinic, P1̄ (no. 2), a = 7.0427(3) Å, b = 10.4459(7) Å, c = 10.5778(6) Å, α = 73.233(6)°, β = 83.372(4)°, γ = 77.340(4)°, V = 725.85(7) Å3, Z = 2, Rgt(F) = 0.0386, wRref(F2) = 0.0916, T = 293(2) K. [ABSTRACT FROM AUTHOR]

A number of chiral secondary amines attached to Merrifield resin or to noncrosslinked (soluble) polystyrene support were synthesized. The corresponding lithium amides, generated from these amines by treatment with BuLi, react with tropinone, a model symmetrical ketone, to give the corresponding enolates enantioselectively (ee up to 75%). The enolates were trapped either as the corresponding aldol adducts by a reaction with benzaldehyde or as ring-opening products in a reaction with a chloroformate. [ABSTRACT FROM AUTHOR]

In response to DNA damage or replication block, cells activate a battery of checkpoint signaling cascades to control cell cycle progression and elicit DNA repair in order to maintain genomic stability and integrity. Identified as a homolog of its fission yeast counterpart, human Rad9 was proposed to form a Rad9-Hus1-Rad1 protein complex to mediate checkpoint signals. However, the precise function of Rad9 in the process of checkpoint activation is not fully understood. Using the RNA interference technique, we investigated the role of Rad9 in the genotoxic stress-induced activation of S-phase checkpoint and the maintenance of chromosomal stability. We found that Rad9 knockdown reduced the phosphorylation of Rad17, Chk1 and Smc1 in response to DNA replication block and certain types of DNA damage. Immunofluorescence studies showed that the removal of Rad9 disrupted the foci formation of phosphorylated Chk1, but not ATR. Moreover, Rad9 knockdown resulted in radioresistant DNA synthesis and reduced cell viability under replication stress. Finally, removal of Rad9 by RNAi led to increased accumulation of spontaneous chromosomal aberrations. Taken together, these results suggest a critical and specific role of Rad9 in the activation of S-phase checkpoint and the maintenance of chromosome stability. [ABSTRACT FROM AUTHOR]

Animals vocalize only in certain behavioral contexts, but the circuits and synapses through which forebrain neurons trigger or suppress vocalization remain unknown. Here, we used transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of neurons in the periaqueductal gray (PAG) that gate the production of ultrasonic vocalizations (USVs) in mice (i.e. PAG-USV neurons). Activating PAG-projecting neurons in the preoptic area of the hypothalamus (POAPAG neurons) elicited USV production in the absence of social cues. In contrast, activating PAG-projecting neurons in the central-medial boundary zone of the amygdala (AmgC/MPAG neurons) transiently suppressed USV production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping in brain slices revealed that POAPAG neurons directly inhibit PAG interneurons, which in turn inhibit PAG-USV neurons, whereas AmgC/M-PAG neurons directly inhibit PAG-USV neurons. These experiments identify two major forebrain inputs to the PAG that trigger and suppress vocalization, respectively, while also establishing the synaptic mechanisms through which these neurons exert opposing behavioral effects. [ABSTRACT FROM AUTHOR]

This article concerns the dynamical behavior for a reaction-diffusion equation with integral term. First, by using bifurcation analysis and center manifold theorem, the existence of periodic steady-state solution are established for a special kernel function and a general kernel function respectively. Then, we prove the model admits periodic traveling wave solutions connecting this periodic steady state to the uniform steady state u=1 by applying center manifold reduction and the analysis to phase diagram. By numerical simulations, we also show the change of the wave profile as the coefficient of aggregate term increases. Also, by introducing a truncation function, a shift function and some auxiliary functions, the asymptotic behavior for the Cauchy problem with initial function having compact support is investigated. [ABSTRACT FROM AUTHOR]

The past decade has witnessed the gradual and steady progress of adoptive T cell therapy in treating various types of cancer. In combination with gemcitabine and carboplatin chemotherapy, we previously conducted a clinical trial, NCT00690872, to treat Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) patients with autologous EBV-expanded cytotoxic T lymphocytes (CTLs). While achieving a 2-year overall survival rate of 62.9%, this trial failed to induce an anti-tumor response in a sizable fraction of patients. Thus, the identification of benchmarks capable of evaluating CTL products and predicting clinical immunotherapeutic efficacy remains an urgent need. We conducted T cell receptor (TCR) repertoire sequencing to assess EBV-expanded infusion-ready CTL products. To depict the overall repertoire landscape, we evaluated the individual repertoire diversity by Shannon entropy, and, compared the inter-patient CDR3 similarity to estimate T cells expanded by common antigens. With a recently developed bioinformatics algorithm, termed Motif Analysis, we made a machine-learning prediction of structural regions within the CDR3 of TCRβ that associate with CTL therapy prognosis. We found that long term survivors, defined as patients surviving longer than two years, had a higher CTL repertoire diversity with reduced inter-patient similarity. Furthermore, TCR Motif Analysis identified 11 structural motifs distinguishing long term survivors from short term survivors. Specifically, two motifs with a high area under the curve (AUC) values were identified as potential predictive benchmarks for efficacious CTL production. Together, these results reveal that the presence of diverse TCR sequences containing a common core motif set is associated with a favorable response to CTL immunotherapy against EBV-positive NPC. [ABSTRACT FROM AUTHOR]

Acute hepatopancreatic necrosis disease (AHPND) is a major debilitating disease that causes massive shrimp death resulting in substantial economic losses in shrimp aquaculture. The Pir toxin proteins secreted by a unique strain of Vibrio parahaemolyticus play an essential role in the pathogenesis of AHPND. At present, most studies on the effects of Pir toxin proteins in shrimp focus on digestive tissues or organs such as hepatopancreas, stomach, etc., with none on the immune organs. In the present study, two recombinant Pir toxin proteins (rPirA and rPirB) of V. parahaemolyticus were expressed with rPirB shown to enter shrimp hemocytes. Employing pull-down and LC-MS/MS analysis, GST-rPirB was found to interact with 13 proteins in hemocytes, including histone H3 and histone H4 and among which histone H4 had the highest protein score. Further analysis using GST pull-down and Far-Western blot analysis revealed that rPirB could interact with histone H4. In addition, using the purified nucleosome protein from Drosophila S2 cells, it was found that PirB protein could specifically bind to histones. When flow cytometry was applied, it was observed that the interaction between PirB and histones in shrimp hemocytes induces apoptosis, which results in the dephosphorylation of Serine 10 in histone H3. Collectively, the current study shows that in addition to its effect on the digestive tract of shrimp, the PirB toxin protein interacts with histones to affect the phosphorylation of histone H3-S10, thereby inducing apoptosis. [ABSTRACT FROM AUTHOR]

Mooring measurements at ;1408E in the western equatorial Pacific Ocean documented greatly intensified eastward subsurface currents, which largely represent the nascent Equatorial Undercurrent, to ~67 cm s-1 in boreal summer of 2016. The eastward currents occupied the entire upper 500m while the westward surface currents nearly disappeared. Historical in situ data observed similar variations after most El Niño events. Further analysis combining satellite and reanalysis data reveals that the eastward currents observed at ~1408E are a component of an anomalous counterclockwise circulation straddling the equator, with westward current anomalies retroflecting near the western boundary and feeding southeastward current anomalies along the New Guinea coast. A 1.5-layer reduced-gravity ocean model is able to crudely reproduce these variations, and a hierarchy of sensitivity experiments is performed to understand the underlying dynamics. The anomalous circulation is largely the delayed ocean response to equatorial wind anomalies over the centralto- eastern Pacific basin emerging in the mature stage of El Niño. Downwelling Rossby waves are generated by the reflection of equatorial Kelvin waves and easterly winds in the eastern Pacific. Upon reaching the western Pacific, the southern lobes of Rossby waves encounter the slanted New Guinea island and deflect to the equator, establishing a local sea surface height maximum and leading to the detour of westward currents flowing from the Pacific interior. Additional experiments with edited western boundary geometry confirm the importance of topography in regulating the structure of this cross-equatorial anomalous circulation. [ABSTRACT FROM AUTHOR]

The origins of an observed weakly sheared nonturbulent (laminar) layer (WSL), and a strongly sheared turbulent layer above the Equatorial Undercurrent core (UCL) in the eastern equatorial Pacific are studied, based mainly on the data from the Tropical Atmosphere and Ocean mooring array. Multiple-time-scale (from 3 to 25 days) equatorial waves were manifested primarily as zonal velocity oscillations with the maximum amplitudes (from 10 to 30 cm s-1) occurring at different depths (from the surface to 85-m depths) above the seasonal thermocline. The subsurface-intensified waves led to vertically out-of-phase shear variations in the upper thermocline via destructive interference with the seasonal zonal flow, opposing the tendency for shear instability. These waves were also associated with depth-dependent, multiple-vertical-scale stratification variations, with phase lags of p/2 or p, further altering stability of the zonal current system to vertical shear. The WSL andUCL were consequently formed by coupling of multiple equatorial waves with differing phases, particularly of the previously identified equatorial mode and subsurface mode tropical instability waves (with central period of 17 and 20 days, respectively, in this study), and subsurface-intensified waves with central periods of 6, 5, and 12 days and velocity maxima at 45-, 87-, and 40-m depths, respectively. In addition, a wavelike feature with periods of 50-90 days enhanced the shear throughout the entire UCL. WSLs and UCLs seem to emerge without a preference for particular tropical instability wave phases. The generation mechanisms of the equatorial waves and their joint impacts on thermocline mixing remain to be elucidated. [ABSTRACT FROM AUTHOR]

Purpose: Alpha-blockers have been proven as an effective method for increasing the stone expulsion rate of distal ureteral stones. Limited studies have focused on doxazosin; its efficacy remained unclear. We performed this meta-analysis to investigate the efficacy and safety of doxazosin for patients diagnosed with distal ureteral stones less than 10mm.Materials and Methods: We systematically searched Ovid MEDLINE®, Cochrane Library, EMBASE, and PubMed for articles comparing doxazosin and conventional care or tamsulosin for distal ureteral stones through October 2019. The outcome measures were stone expulsive rate (SER), stone expulsive time (SET), pain episodes, analgesics consumption, and adverse events.Results: We included 12 studies involving 836 participants with distal ureteral stones less than 10mm in our review. The present meta-analysis showed doxazosin could significantly increase SER [RR=1.64,95%CI (1.32, 2.04), P  < 0.00001], shorten SET [WMD=-3.97,95% CI (-5.68, -2.27), P  < 0.00001] compared with conventional care. In the subgroup analyses, doxazosin showed no benefit in the children subgroup (<16 years old) [RR=1.63,95% CI (0.73,3.64), P  =0.23]. No statistically significant difference was observed regarding the effectiveness of doxazosin and tamsulosin in SER, SET, and safety. 9 in 286 participants reported doxazosin-related adverse events; most were mild to moderate.Conclusion: This meta-analysis may suggest that doxazosin is a safe and effective MET for distal ureteral stones less than 10mm. It is not demonstrated to have any significant difference with tamsulosin in SER, SET, and safety. However, it showed no benefits for patients<16 years old. [ABSTRACT FROM AUTHOR]

In the eastern tropical Indian Ocean, intraseasonal variability (ISV) affects the regional oceanography and marine ecosystems. Mooring and satellite observations documented two periods of unusually weak ISV during the past two decades, associated with suppressed baroclinic instability of the South Equatorial Current. Regression analysis and model simulations suggest that the exceptionally weak ISVs were caused primarily by the extreme El Niño events and modulated to a lesser extent by the Indian Ocean dipole. Additional observations confirm that the circulation balance in the Indo-Pacific Ocean was disrupted during the extreme El Niño events, impacting the Indonesian Throughflow Indian Ocean dynamics. This research provides substantial evidence for large-scale modes modulating ISV and the abnormal Indo-Pacific dynamical connection during extreme climate modes. [ABSTRACT FROM AUTHOR]

The article focuses on the deep-reaching acceleration of the ocean circulation which is mainly induced by a planetary intensification of surface winds since the early 1990s. Topics discussed include wind changes associated with the onset of a negative Pacific decadal oscillation, the use of Mann-Kendall test and examination of the spatial pattern of the acceleration of the global ocean circulation.

The morphology and ontogeny of the trilobite Changaspis elongata based on 216 specimens collected from the Lazizhai section of the Balang Formation (Stage 4, Series 2 of the Cambrian) in Guizhou Province, South China are described. The relatively continuous ontogenetic series reveals morphological changes, and shows that the species has seventeen thoracic segments in the holaspid period, instead of the sixteen as previously suggested. The development of the pygidial segments shows that their number gradually decreases during ontogeny. A new dataset of well-preserved specimens offers a unique opportunity to investigate developmental traits after segment addition is completed. The ontogenetic size progressions for the lengths of cephalon and trunk show overall compliance with Dyar's rule. As a result of different average growth rates for the lengths of cephalon, trunk and pygidium, the length of the thorax relative to the body shows a gradually increasing trend; however, the cephalon and pygidium follow the opposite trend. Morphometric analysis across fourteen post-embryonic stages reveals growth gradients with increasing values for each thoracic segment from anterior to posterior. The reconstruction of the development traits shows visualization of the changes in relative growth and segmentation for the different body parts. The new dataset and growth gradient of the trunk suggest that the thoracic segment growth dynamics of early Cambrian to Silurian trilobites follow the same general continuous, steady-state growth gradient decreasing from posterior to anterior. [ABSTRACT FROM AUTHOR]

Ubiquitination and deubiquitination are reversible processes that play crucial roles in regulating organ size in plants. However, information linking deubiquitination and seed size in rice (Oryza sativa) is limited. Here, we characterized a dominant large-grain mutant, large grain1-D (lg1-D), with a 30.8% increase in seed width and a 34.5% increase in 1,000-grain weight relative to the wild type. The lg1-D mutant had more cells oriented in the lateral direction of the spikelet hull compared with the wild type. Map-based cloning showed that LG1 encodes a constitutively expressed ubiquitin-specific protease15 (OsUBP15) that possesses deubiquitination activity in vitro. Loss-of-function and down-regulated expression of OsUBP15 produced narrower and smaller grains than the control. A set of in vivo experiments indicated that the mutant Osubp15 had enhanced protein stability relative to wild-type OsUBP15. Further experiments verified that OsDA1 directly interacted with OsUBP15. Genetic data indicated that OsUBP15 and GRAIN WIDTH 2 (GW2) were not independent in regulating grain width and size. In summary, we identified OsUBP15 as a positive regulator of grain width and size in rice and provide a promising strategy for improvement of grain yield by pyramiding OsUBP15 and gw2. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is the leading cause of death worldwide. Long noncoding RNAs (lncRNAs) are a class of noncoding transcripts of > 200 nucleotides and are increasingly recognized as playing functional roles in physiology and disease. ANRIL is a lncRNA gene mapped to the chromosome 9p21 genetic locus for CAD identified by the first series of genome-wide association studies (GWAS). However, ANRIL's role in CAD and the underlying molecular mechanism are unknown. Here, we show that the major ANRIL transcript in endothelial cells (ECs) is DQ485454 with a much higher expression level in ECs than in THP-1 monocytes. Of note, DQ485454 expression was down-regulated in CAD coronary arteries compared with non-CAD arteries. DQ485454 overexpression significantly reduced monocyte adhesion to ECs, transendothelial monocyte migration (TEM), and EC migration, which are critical cellular processes involved in CAD initiation, whereas siRNA-mediated ANRIL knockdown (KD) had the opposite effect. Microarray and follow-up quantitative RT-PCR analyses revealed that the ANRIL KD down-regulated expression of AHNAK2, CLIP1, CXCL11, ENC1, EZR, LYVE1, WASL, and TNFSF10 genes, and up-regulated TMEM100 and TMEM106B genes. Mechanistic studies disclosed that overexpression of CLIP1, EZR, and LYVE1 reversed the effects of ANRIL KD on monocyte adhesion to ECs, TEM, and EC migration. These findings indicate that ANRIL regulates EC functions directly related to CAD, supporting the hypothesis that ANRIL is involved in CAD pathogenesis at the 9p21 genetic locus and identifying a molecular mechanism underlying lncRNA-mediated regulation of EC function and CAD development. [ABSTRACT FROM AUTHOR]

Rod and cone photoreceptors are specialized retinal neurons that have a fundamental role in visual perception, capturing light and transducing it into a neuronal signal. Aberrant functioning of rod and/ or cone photoreceptors can ultimately lead to progressive degeneration and eventually blindness. In man, many rod and rod-cone degenerative diseases are classified as forms of retinitis pigmentosa (RP). Dogs also have a comparable disease grouping termed progressive retinal atrophy (PRA). These diseases are generally due to single gene defects and follow Mendelian inheritance.We collected 51 DNA samples from Miniature Schnauzers affected by PRA (average age of diagnosis ~3.9 61 years), as well as from 56 clinically normal controls of the same breed (average age~6.6 62.8 years). Pedigree analysis suggested monogenic autosomal recessive inheritance of PRA. GWAS and homozygosity mapping defined a critical interval in the first 4,796,806 bp of CFA15. Whole genome sequencing of two affected cases, a carrier and a control identified two candidate variants within the critical interval. One was an intronic SNV in HIVEP3, and the other was a complex structural variant consisting of the duplication of exon 5 of the PPT1 gene along with a conversion and insertion (named PPT1dci). PPT1dci was confirmed homozygous in a cohort of 22 cases, and 12 more cases were homozygous for the CFA15 haplotype. Additionally, the variant was found homozygous in 6 non-affected dogs of age higher than the average age of onset. The HIVEP3 variant was found heterozygous (n = 4) and homozygous wild-type (n = 1) in cases either homozygous for PPT1dci or for the mapped CFA15 haplotype. We detected the wildtype and three aberrant PPT1 transcripts in isolated white blood cell mRNA extracted from a PRA case homozygous for PPT1dci, and the aberrant transcripts involved inclusion of the duplicated exon 5 and novel exons following the activation of cryptic splice sites. No neurological signs were detected among the dogs homozygous for the PPT1dci variant. Therefore, we propose PPT1dci as causative for a non-syndromic form of PRA (PRAPPT1) that shows incomplete penetrance in Miniature Schnauzers, potentially related to the presence of the wild-type transcript. To our knowledge, this is the first case of isolated retinal degeneration associated with a PPT1 variant. [ABSTRACT FROM AUTHOR]

Nav1.5 is the α-subunit of the cardiac sodium channel complex. Abnormal expression of Nav1.5 on the cell surface because of mutations that disrupt Nav1.5 trafficking causes Brugada syndrome (BrS), sick sinus syndrome (SSS), cardiac conduction disease, dilated cardiomyopathy, and sudden infant death syndrome. We and others previously reported that Ran-binding protein MOG1 (MOG1), a small protein that interacts with Nav1.5, promotes Nav1.5 intracellular trafficking to plasma membranes and that a substitution in MOG1, E83D, causes BrS. However, the molecular basis for the MOG1/Nav1.5 interaction and how the E83D substitution causes BrS remains unknown. Here, we assessed the effects of defined MOG1 deletions and alanine-scanning substitutions on MOG1's interaction with Nav1.5. Large deletion analysis mapped the MOG1 domain required for the interaction with Nav1.5 to the region spanning amino acids 146-174, and a refined deletion analysis further narrowed this domain to amino acids 146-155. Site-directed mutagenesis further revealed that Asp-148, Arg-150, and Ser-151 cluster in a peptide loop essential for binding toNav1.5.GST pulldown and electrophysiological analyses disclosed that the substitutions E83D, D148Q, R150Q, and S151Q disrupt MOG1's interaction with Nav1.5 and significantly reduce its trafficking to the cell surface. Examination of MOG1's 3D structure revealed that Glu-83 and the loop containing Asp-148, Arg-150, and Ser-151 are spatially proximal, suggesting that these residues form a critical binding site for Nav1.5. In conclusion, our findings identify the structural elements in MOG1 that are crucial for its interaction with Nav1.5 and improve our understanding of how the E83D substitution causes BrS. [ABSTRACT FROM AUTHOR]

Background: Previous studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, findings with genome-wide significance have been rare, and not replicated. We hypothesized that whole exome sequencing (WES) of premature subjects with extremely divergent phenotypic outcomes could facilitate the identification of genetic variants or gene networks contributing disease risk. Results: The Prematurity and Respiratory Outcomes Program (PROP) recruited a cohort of > 765 extremely preterm infants for the identification of markers of respiratory morbidity. We completed WES on 146 PROP subjects (85 affected, 61 unaffected) representing extreme phenotypes of early respiratory morbidity. We tested for association between disease status and individual common variants, screened for rare variants exclusive to either affected or unaffected subjects, and tested the combined association of variants across gene loci. Pathway analysis was performed and disease-related expression patterns were assessed. Marginal association with BPD was observed for numerous common and rare variants. We identified 345 genes with variants unique to BPD-affected preterm subjects, and 292 genes with variants unique to our unaffected preterm subjects. Of these unique variants, 28 (19 in the affected cohort and 9 in unaffected cohort) replicate a prior WES study of BPD-associated variants. Pathway analysis of sets of variants, informed by disease-related gene expression, implicated protein kinase A, MAPK and Neuregulin/epidermal growth factor receptor signaling. Conclusions: We identified novel genes and associated pathways that may play an important role in susceptibility/resilience for the development of lung disease in preterm infants. [ABSTRACT FROM AUTHOR]

Ocean heat uptake is the primary heat sink of the globe and modulates its surface warming rate. In situ observations during the past half century documented obvious multidecadal variations in the upper-ocean heat content (0-400 m; OHC400) of the Indian Ocean (IO). The observed OHC400 showed an increase of (5.9 ± 2.5) 3 1021 J decade-1 during 1965-79, followed by a decrease of (-5.2 ± 2.5) 3 1021 J decade-1 during 1980-96, and a rapid increase of (13.6 ± 1.1) 3 1021 J decade21 during 2000-14. These variations are faithfully reproduced by an Indo-Pacific simulation of an ocean general circulation model (OGCM), and insights into the underlying mechanisms are gained through OGCM experiments. The Pacific wind forcing through the Indonesian Throughflow (ITF) was the leading driver of the basin-integrated OHC400 increase during 1965-79 and the decrease during 1980-96, whereas after 2000 local wind and heat flux forcing within the IO made a larger contribution. The ITF heat transport is primarily dictated by Pacific trade winds. It directly affects the south IO, after which the signatures can enter the north IO through the meridional heat transport of the western boundary current. The prevailing warming of the western-tocentral IO for 2000-14 was largely induced by equatorial easterly wind trends, Ekman downwelling off the equator, and northeasterly wind trends over the west Asia-East Africa coastal region. The increasing downward longwave radiation, probably reflecting anthropogenic greenhouse gas forcing, overcame the decreasing surface shortwave radiation and also made a significant contribution to the rapid upper-IO warming after 2000. [ABSTRACT FROM AUTHOR]

Salvianolic acid A (Sal A) has been shown to prevent and treat ischemic cardiovascular, as well as cerebral vascular diseases. However, little is known about Sal A in renal ischemia/reperfusion (I/R) injury. In this study, a renal I/R injury model in rats and a hypoxia/reoxygenation (H/R) model to damage proximal renal tubular cells (HK-2) were used to assess whether Sal A halts the development and progression of renal I/R injury. As compared with vehicle treatment, Sal A significantly attenuated kidney injury after renal I/R injury, accompanied by decreases in plasma creatinine, blood urea nitrogen levels, the number of apoptosispositive tubular cells, and kidney oxidative stress. Sal A also activated phosphorylated protein kinase B (p-Akt) and phosphorylated-mammalian target of rapamycin (p-mTOR) compared with vehicle-treated I/R injury rats. In H/R-injured HK-2 cells, Sal A can reduce the levels of reactive oxygen species in a dose-related manner. Similar to the results from in vivo experiments, in vitro Sal A also increased the protein expression of phosphorylated-eukaryotic initiation factor 4E binding protein 1 (p-4EBP1) compared with vehicle. Furthermore, the cytoprotective activity of Sal A was inhibited by LY294002 and rapamycin. These findings indicate that Sal A can ameliorate renal I/R injury and promote tubular cell survival partly via the Akt/mTOR/ 4EBP1pathway. Sal A could be a candidate compound to prevent ischemic tissue damage. [ABSTRACT FROM AUTHOR]

Network systems with clustering have been given much attention due to their wide occurrence in the real world. One focus of these studies has been on robustness of single clustered networks and interdependent clustered networks under random attack (RA) or hub-targeted attack. However, infrastructure networks could suffer from a damage that is localized, i.e. a group of neighboring nodes attacked or fail, a topic that was not studied earlier on clustered networks. In this paper, we analytically and via simulations study the robustness under localized attack (LA) of single Erdős–Rényi clustered network and interdependent clustered network. For generating networks with clustering we use two models: (i) double Poisson distribution (DPD) and (ii) fixed degree distribution (FDD). For the LA case, the DPD model shows a second order phase transition behavior for a single clustered network, while for dependent networks, the system undergoes a change of percolation phase transition from a first order (abrupt transition) to a second order (continuous) transition when the coupling strength q decreases below a critical value qc. Our results imply that single networks become significantly more vulnerable with increasing clustering coefficient c with respect to LA. This is in contrast to RA where the robustness is almost independent of c. We obtain similar results when testing different real networks. For LA on dependent networks, we also observe that the system becomes more vulnerable as c increases. This is again in contrast to RA, where for, q < qc, the system robustness is almost unaffected by increasing clustering. We also solved analytically the case of LA on random regular networks which are clustered and interdependent and find that as m (the number of clustered networks that each network depends on) or c increases, the system becomes significantly more vulnerable. We also analyzed via simulations the case of generating clustering in networks for the model of keeping a FDD, and find that the influence of clustering on the robustness of two partially interdependent networks under LA is smaller than for DPD, which is very different from these cases under RA. [ABSTRACT FROM AUTHOR]

A new type of gamma-ray spectrum is predicted in a general hadronic framework by taking into account gluon condensation (GC) effects in proton. The result presents a power law with a sharp break in the gamma-ray spectra at the TeV band. We suggest probing this GC signature in Earth-limb gamma-ray spectra using the Dark Matter Particle Explorer and the Calorimetric Electron Telescope in orbit. [ABSTRACT FROM AUTHOR]

We report co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus in a patient with pneumonia in China. The case highlights possible co-detection of known respiratory viruses. We noted low sensitivity of upper respiratory specimens for SARS-CoV-2, which could further complicate recognition of the full extent of disease. [ABSTRACT FROM AUTHOR]

Exosomes, abundant in blood, deliver various molecules to recipient cells. Endothelial cells are directly exposed to circulating substances. However, how endothelial cells respond to serum exosomes (SExos) and the implications in diabetes-associated vasculopathy have never been explored. In the present study, we showed that SExos from diabetic db/db mice (db/db SExos) were taken up by aortic endothelial cells, which severely impaired endothelial function in nondiabetic db/m+ mice. The exosomal proteins, rather than RNAs, mostly account for db/db SExos-induced endothelial dysfunction. Comparative proteomics analysis showed significant increase of arginase 1 in db/db SExos. Silence or overexpression of arginase 1 confirmed its essential role in db/db SExos-induced endothelial dysfunction. This study is a demonstration that SExos deliver arginase 1 protein to endothelial cells, representing a cellular mechanism during development of diabetic endothelial dysfunction. The results expand the scope of bloodborne substances that monitor vascular homeostasis. [ABSTRACT FROM AUTHOR]

Advances in metering and two-way communication technologies foster the studies of Home Energy Management System (HEMS). This study proposes a new HEMS, which optimally schedules the distributed residential energy resources (DRERs) in a smart home environment with varying electricity tariff and high solar penetrations. The uncertainties of solar power output are captured by using Monte Carlo sampling technique to generate multiple solar output scenarios based on the probabilistic solar radiation model. The homeowner's rigid and elastic restrictions on the operations of the automatically controlled household appliances are modelled. Based on this, an optimal DRER scheduling model is proposed to minimise the home operation cost while taking into account the homeowner's requirements. A new heuristic optimisation algorithm recently proposed by the authors, i.e. natural aggregation algorithm, is used to solve the proposed model. Simulations based on real Australian solar data are conducted to validate the proposed method. [ABSTRACT FROM AUTHOR]

Achieving both bond dissociation energies (BDEs) and their trends for the R-X bonds with R = Me, Et, i-Pr, and t-Bu reliably is nontrivial. Density functional theory (DFT) methods with traditional exchange-correlation functionals usually have large error on both the BDEs and their trends. The M06-2X functional gives rise to reliable BDEs, but the relative BDEs are determined not as accurately. More demanding approaches such as some double-hybrid functionals, for example, G4 and CCSD(T), are generally required to achieve the BDEs and their trends reliably. The fixed-node diffusion quantum Monte Carlo method (FN-DMC) is employed to calculated BDEs of these R-X bonds with X = H, CH3, OCH3, OH, and F in this work. The single Slater-Jastrow wave function is adopted as trial wave function, and pseudopotentials (PPs) developed for quantum Monte Carlo calculations are chosen. Error of these PPs is modest in wave function methods, while it is more pronounced in DFT calculations. Our results show that accuracy of BDEs with FN-DMC is similar to that of M06-2X and G4, and trends in BDEs are calculated more reliably than M06-2X. Both BDEs and trends in BDEs of these bonds are reproduced reasonably with FN-DMC. FN-DMC using PPs can thus be applied to BDEs and their trends of similar chemical bonds in larger molecules reliably and provide valuable information on properties of these molecules. [ABSTRACT FROM AUTHOR]

Objective: The correlation of the BRG1 rs1122608 single nucleotide polymorphism (SNP) with acute myocardial infarction (AMI) has been reported in American and European populations. However, whether rs1122608 acts as a protective factor or a risk factor for AMI is controversial. In this study, we aimed to detect the associations between rs1122608 and the clinical characteristics of AMI as well as susceptibility, gene-environment interactions, and risk factors for AMI in a Chinese Han population. Methods: In this study, 300 AMI patients and 300 healthy controls of Chinese Han ancestry were enrolled. PCR-RFLP was used to genotype rs1122608 SNPs. Genotypic and allelic frequencies of rs1122608 were compared between the AMI and control groups and among four AMI subgroups, which were subdivided by typical symptom, diagnosis time (DT), infarction location andserious complication. Results: Significant differences were detected between the AMI patients and the controls in both the genotypic and allelic frequencies of rs1122608 (p<0.001 for each). There were also interactions between the subjects with a minor T allele and smoking or alcohol consumption (p<0.001 for each). Conclusion: In the Chinese Han study population, the mutant GT and TT genotypes and minor T allele of rs1122608 were positively correlated with the risk of AMI. For the first time, we discovered that the GT genotype of the rs1122608 SNP is significantly correlated with diagnosis time of AMI. In addition, the interactions between the minor T allele of rs1122608 and smoking or alcohol use and between the rs1122608 CC genotype and alcohol use appear to increase the risk of AMI. [ABSTRACT FROM AUTHOR]

Floral nectaries are closely associated with biotic pollination, and the nectar produced by corolla nectaries is generally enclosed in floral structures. Although some Swertia spp. (Gentianaceae), including S. bimaculata, evolved a peculiar form of corolla nectaries (known as "gland patches") arranged in a conspicuous ring on the rotate corolla and that completely expose their nectar, little is known about the pollination of these plants. Two hypotheses were made concerning the possible effects of gland patches: visual attraction and visitor manipulation. The floral traits, mating system, and insect pollination of S. bimaculata were examined, and the pollination effects of gland patches were evaluated. A comparative study was made using Swertia kouitchensis, a species with fimbriate nectaries. Swertia bimaculata flowers were protandrous, with obvious stamen movement leading to herkogamy in the female phase and to a significant reduction in nectary-anther distance. The species is strongly entomophilous and facultatively xenogamous. The daily reward provided per flower decreased significantly after the male phase. The most effective pollinators were large dipterans, and the visiting proportion of Diptera was significantly higher in S. bimaculata than in S. kouitchensis. Most visitors performed "circling behavior" in S. bimaculata flowers. Removing or blocking the nectaries caused no reduction in visiting frequency but a significant reduction in visit duration, interrupting the circling behavior. The circling behavior was encouraged by nectar abundance and promoted pollen dispersal. Visitor species with small body size had little chance to contact the anthers or stigma, revealing a filtration effect exerted by the floral design. These results rejected the "visual attraction" hypothesis and supported the "visitor manipulation" hypothesis. The nectary whorl within a flower acted like a ring-shaped track that urged nectar foragers to circle on the corolla, making pollination in S. bimaculata flowers more orderly and selective than that in classically generalist flowers. [ABSTRACT FROM AUTHOR]

SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 μM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 μM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 μM), Jurkat (IC50 = 2.2 μM), THP1 (IC50 = 3.5 μM), U937 (IC50 = 3.9 μM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) remains one of the most lethal cancers. MicroRNA-155 (miR-155) and collagen triple helix repeat containing 1 (CTHRC1) were found to be involved in hepatocarcinogenesis, but their detailed functions in HCC are unclear. Here, we aimed to investigate the underlying role of miR-155-5p and CTHRC1 in HCC. Methods: miR-155-5p and CTHRC1 expression levels were detected by qRT-PCR, IHC and WB in HCC patients and cell lines. Dual-luciferase assay, qRT-PCR and WB were used to validate the target interaction between miR-155-5p and CTHRC1. Biological behaviors, including apoptosis, cell cycle progression, and cell proliferation, invasion and migration, were measured by flow cytometry, CCK-8 assay and Transwell tests. A xenograft model was established to examine the effects of miR-155-5p and CTHRC1 on tumor formation. WB was finally utilized to identify the role of GSK- 3β-involved Wnt/β-catenin signaling in HCC growth and metastasis. Results: Our results showed that miR-155-5p and CTHRC1 were down-regulated and up-regulated, respectively, in HCC patients and cell lines. Dual-luciferase assay verified that CTHRC1 was the direct target of miR-155-5p. Moreover, elevated miR-155-5p expression promoted apoptosis but suppressed cell cycle progression and cell proliferation, invasion and migration in vitro and facilitated tumor formation in vivo; elevated CTHRC1 expression abolished these biological effects. Additionally, miR-155-5p overexpression increased metastasis- and anti-apoptosis-related protein expression and decreased pro-apoptosis-related protein expression, while forced CTHRC1 expression conserved the expression of these proteins. Conclusion: Altogether, our data suggested that miR-155-5p modulated the malignant behaviors of HCC by targeting CTHRC1 and regulating GSK-3β-involved Wnt/β-catenin signaling; thereby, miR-155-5p and CTHRC1 might be promising therapeutic targets for HCC patients. [ABSTRACT FROM AUTHOR]

Background: Among colorectal cancer (CRC) survivors, how the prior tumor location affects the risk of subsequent primary colorectal cancer (SPCRC) and the outcome of those suffering from SPCRC remain unknown.Methods: CRC cases diagnosed from 1973 to 2012 were screened for SPCRC development using the Surveillance, Epidemiology, and End Results database. The relative risk of SPCRC was estimated using the standardized incidence ratio. Survivals were analyzed using the Kaplan-Meier and Cox regression model.Results: The overall risk of SPCRC increased by 27% in CRC survivors compared to that of the general population. The risk increased in patients with both prior right colon cancer (RCC) and left colon cancer (LCC), and was concentrated in the first 5 years after the prior diagnosis, and among young patients. Among the 6701 SPCRC patients identified, patients with prior RCC were more likely to be elderly, female, and with more low or undifferentiated disease than those with prior LCC or rectal cancer (ReC). The overall survivals differed by both prior tumor location (P < 0.0001) and age (P < 0.0001), and the difference by tumor location remained significant when adjusted or stratified by any other potential prognostic factor except age. The cancer specific survivals differed by age (P < 0.0001) rather than by prior tumor location (P = 0.455).Conclusions: The overall risk of SPCRC increased among patients with both prior RCC and LCC, but not among those with ReC. The different survival outcomes in CRC survivors suffering from SPCRC were largely explained by the patient age but not by the prior tumor location. [ABSTRACT FROM AUTHOR]

The nuclear factor κB (NF-κB) transcription factor family regulates genes involved in cell proliferation and inflammation. The promoters of these genes often contain NF-κBbinding sites (κB sites) arranged in tandem. How NF-κB activates transcription through these multiple sites is incompletely understood. We report here an X-ray crystal structure of homodimers comprising the RelA DNA-binding domain containing the Rel homology region (RHR) in NF-κB bound to an E-selectin promoter fragment with tandem κB sites. This structure revealed that two dimers bind asymmetrically to the symmetrically arranged κB sites at which multiple cognate contacts between one dimer to the corresponding DNA are broken. Because simultaneous RelA-RHR dimer binding to tandem sites in solution was anti-cooperative, we inferred that asymmetric RelA-RHR binding with fewer contacts likely indicates a dissociative binding mode. We found that both κB sites are essential for reporter gene activation by full-length RelA homodimer, suggesting that dimers facilitate DNA binding to each other even though their stable cooccupation is not promoted. Promoter variants with altered spacing and orientation of tandem κB sites displayed unexpected reporter activities that were not explained by the solution- binding pattern of RelA-RHR. Remarkably, full-length RelA bound all DNAs with a weaker affinity and specificity. Moreover, the transactivation domain played a negative role in DNA binding. These observations suggest that other nuclear factors influence full-length RelA binding toDNAby neutralizing the transactivation domain negative effect. We propose that DNA binding by NF-κB dimers is highly complex and modulated by facilitated association-dissociation processes. [ABSTRACT FROM AUTHOR]

The aim of the present study was to explore the clinical value of urinary retinol-binding protein (RBP) level in the prognosis of cirrhotic ascites by assessment of the RBP levels prior to and following ascites treatment. The levels of urinary RBP, urinary microalbumin (mAlb), serum urea nitrogen (urea) and serum creatinine (Cr), and the estimated glomerular filtration rate (eGFR) were measured in 90 patients with cirrhosis and ascites hospitalized in a single institution between May 2011 and January 2012, and in 30 healthy controls. The levels of urinary mAlb, serum urea and serum Cr were higher in the cirrhotic patients compared with the healthy controls (P<0.05). Urinary RBP levels were significantly higher and eGFR was significantly lower in the liver cirrhosis group compared with the healthy control group (P<0.01). Urinary RBP, urinary mAlb, serum urea and serum Cr increased and eGFR decreased as the severity of the ascites increased (P<0.05). Urinary RBP was significantly higher in patients whose ascites did not respond or was refractory compared with those in whom it subsided (P<0.05), exhibiting a gradual increase over time in the former and a gradual reduction over time in the latter group (P<0.05). Increased urinary RBP and decreased eGFR in the early stage of cirrhosis ascites suggested impaired renal function, which serves a role in the process of ascites formation. These results indicated that urinary RBP is a sensitive indicator of early renal injury in patients with ascites due to cirrhosis and is closely associated with the progression of cirrhotic ascites. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the frequency of gene CYP2C9*3 in Chinese populations, and to analyze the impact of CYP2C9*3 genetic polymorphism on the cholesterol-lowering effect of fluvastatin in a Chinese hyperlipidemic population. Methods: CYP2C9 genotype was determined by polymerase chain reaction - restriction fragment length polymorphism (PCR - RFLP) in 270 unrelated hyperlipidemic patients who were treated with 80 mg fluvastatin monotherapy daily for 4 weeks and 250 healthy controls. Clinical data were collected prior to treatment with fluvastatin and 4 weeks after. Results: In 270 hyperlipidemic patients, the frequency of CYP2C9*3 was 3.70 % which is significantly higher than in 250 healthy controls (2.60 %) (p < 0.01). After oral intake of fluvastatin 80 mg daily for 4 weeks, CYP2C9*1/*3 genotype was associated with a decrease in LDL-C levels (by 33.9 % in CYP2C9*1/*3 versus 24.5 % for CYP2C9*1/*1, p < 0.05) and with reduction of TC (by 36.4 % in CYP2C9*1/*3 versus 19.4 % in CYP2C9*1/*1, p < 0.05). Conclusion: The frequency of CYP2C9*3 is 3.17 % in Chinese populations, and those who carry CYP2C9*3 mutation have a high risk of hyperlipidemia. CYP2C9*3 seems to increase the lipid-lowering effects of fluvastatin. [ABSTRACT FROM AUTHOR]

Objective: We aimed to examine how spontaneous brain activity might be related to the pathophysiology of generalized anxiety disorder (GAD). Patients and methods: Using resting-state functional MRI, we examined spontaneous regional brain activity in 31 GAD patients (mean age, 36.87±9.16 years) and 36 healthy control participants (mean age, 39.53±8.83 years) matched for age, education, and sex from December 2014 to October 2015. We performed a two-sample t-test on the voxel-based analysis of the regional homogeneity (ReHo) maps. We used Pearson correlation analysis to compare scores from the Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, State-Trait Anxiety Scale-Trait Scale, and mean ReHo values. Results: We found abnormal spontaneous activity in multiple regions of brain in GAD patients, especially in the sensorimotor cortex and emotional regions. GAD patients showed decreased ReHo values in the right orbital middle frontal gyrus, left anterior cingulate cortex, right middle frontal gyrus, and bilateral supplementary motor areas, with increased ReHo values in the left middle temporal gyrus, left superior temporal gyrus, and right superior occipital gyrus. The ReHo value of the left middle temporal gyrus correlated positively with the Hamilton Anxiety Rating Scale scores. Conclusion: These results suggest that altered local synchronization of spontaneous brain activity may be related to the pathophysiology of GAD. [ABSTRACT FROM AUTHOR]

β-blockers are commonly used for the treatment of acute variceal bleeding in cirrhosis. Renin-angiotensin-aldosterone antagonists (angiotensin I-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists) are potential therapies for portal hypertension. Several studies have compared the renin-angiotensin-aldosterone system (RAAS) inhibitor and β-blocker combination therapy vs. β-blocker monotherapy, with inconsistent results. The aim of the present study was to assess the efficacy of the RAAS inhibitor and β-blocker combination therapy vs. β-blocker monotherapy for hepatic vein pressure gradient (HVPG) reduction in cirrhosis. Studies were obtained using PubMed, Embase, Medline and Cochrane library databases up to July 2015, and the weighted mean difference (WMD) in HVPG reduction was used as a measure of treatment efficacy. In total, three studies (91 patients) were included. When compared to the β-blocker monotherapy, the RAAS inhibitor and β-blocker combination therapy resulted in a significant HVPG reduction [WMD 1.70; 95% confidence interval (CI): 0.52-2.88]. However, there was no significant difference in the heart rate reduction between the monotherapy and combination therapy groups (WMD -0.11; 95% CI: -3.51-3.29). In addition, no significant difference in the hemodynamic response was observed between the two groups (WMD 1.46; 95% CI: 0.93-2.30). In conclusion, the RAAS inhibitor and β-blocker combination therapy reduces portal hypertension significantly and to a greater extent than β-blocker monotherapy. Both therapies reduced the heart rate to similar levels; however, the RAAS inhibitor and β-blocker combination therapy reduced the mean arterial pressure to a greater extent. Due to the limited number of studies included, the data available do not allow a satisfactory comparison of adverse events. Moreover, further larger-scale trials are required in order to strengthen the results of the present study. [ABSTRACT FROM AUTHOR]

Fibronectin (FN) is a primary component of the mammary mesenchymal compartment and undergoes dramatic changes during breast cancer development. Increased FN expression is associated with an invasive and metastatic breast cancer phenotype. The present study demonstrated that FN causes an epithelial-mesenchymal transition (EMT)-like morphological change in MCF-7 breast cancer cells. FN stimulation caused the downregulation of epithelial markers E-cadherin and tight junction protein ZO-1, and the upregulation of mesenchymal markers N-cadherin and vimentin. Additionally, FN promoted cell migration and invasion in MCF-7 cells, with increased expression of calpain-2 and proteolysis of focal adhesion kinase 1 (FAK), indicating calpain activation. Notably, the FN induced changes in morphology and EMT markers were reversed with the treatment of calpain-specific inhibitors, calpain inhibitor I (N-acetyl-L-leucyl-L-leucyl-L-norleucinal), calpeptin and calpain inhibitor IV. Meanwhile, the effects of FN on cell migration and invasion, as well as FAK proteolysis were markedly suppressed by calpain inhibitors. Taken together, the results of the present study indicate that calpain plays an essential role in FN-induced EMT response, and that targeting calpain signaling may be a potential strategy to reduce breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Background: Epstein Barr virus (EBV) plays a causal role in some diseases, including infectious mononucleosis, lymphoproliferative diseases and nasopharyngeal carcinoma. Detection of EBV infection has been shown to be a useful tool for diagnosing EBV-related diseases. In the present study, we compared the performance of molecular tests, including fluorescence in situ hybridization (FISH) and EBV real-time PCR, to those of serological assays for the detection of EBV infection.Methods: Thirty-eight patients with infectious mononucleosis (IM) were enrolled, of whom 31 were diagnosed with a mild type, and seven were diagnosed with IM with haemophagocytic lymphohistiocytosis and chronic active EBV infection. Twenty healthy controls were involved in the study. The atypical lymphocytes in peripheral blood were detected under a microscope and the percentage of positive cells was calculated. EBV DNA load in peripheral blood was detected using real-time PCR. The FISH assay was developed to detect the EBV genome from peripheral blood mononuclear cells (PBMC). Other diagnosis methods including the heterophil agglutination (HA) test and EBV-VCA-IgM test, to detect EBV were also compared. SPSS17.0 was used for statistical analysis.Results: In all, 5-41% atypical lymphocytes were found among the PBMC in mild IM patients, whereas 8-51% atypical lymphocytes were found in IM patients with haemophagocytic lymphohistiocytosis and chronic active EBV infection patients. There was no significant difference in the ratios of atypical lymphoma between patients of the different types. We observed that 71.2% of mild IM patients and 85.7% of IM patients with haemophagocytic lymphohistiocytosis and chronic active EBV infection patients were positive for EBV-VCA-IgM. EBV-VCA-IgM was negative in all healthy control subjects. In addition, 67.1% of mild IM patients tested heterophile antibody positive, whereas 71.4% of IM patients with haemophagocytic lymphohistiocytosis and chronic active EBV infection tested positive. EBV DNA detected using real-time PCR was observed in 89.5% of these IM patients. The EBV genome was detected by the FISH assay in 97.4% of the IM patients. The EB viral loads detected by FISH and real-time PCR increased with the severity of IM. The EBV genome was detected in almost all the PBMC of IM with haemophagocytic lymphohistiocytosis and chronic active EBV infection patients.Conclusion: Molecular tests, including FISH and EBV real-time PCR, are more sensitive than serological assays for the detection of EBV infection. The FISH assay detecting EBV copies in unfractionated whole blood is preferable and superior to plasma real-time PCR in its reflection of the absolute viral burden circulating in the patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess sensitivity and responsiveness of power Doppler ultrasound (PDUS) in detecting enthesitis for ankylosing spondylitis (AS) patients compared to clinical examinations. Twenty AS patients initiating etanerceptunderwent clinical and PDUS examinations of six bilateral entheseal sites at baseline and after 1, 2 and 3 months of treatment. Clinical and PDUS examinations identified at least one entheseal lesion in nine (45%) and 19 (95%) patients, respectively. Furthermore, of 240 entheseal sites examined in these 20 patients, PDUS detected 123 entheseal lesions (51.3% of sites), compared with only 47 entheseal lesions (19.6%) detected by clinical examination (P < 0.05). The entheseal lesions found on PDUS were most commonly identified by calcification (33.3%), tendon edema (29.2%), abnormal blood flow (25.8%), a thickened tendon (22.1%), cortical irregularity (12.9%), bony erosions (9.6%) and bursitis at the tendon insertion to the bone cortex (7.1%). Improvements in clinical symptoms and laboratory parameters, and significant decreases in PDUS scores were observed following treatment with etanercept. Improvements in PDUS scores continued during follow-up in patients who entered remission following treatment. In conclusion, PDUS improves detection of structural and inflammatory abnormalities of the enthesis in AS compared to physical examination. In addition, PDUS may be useful inascertaining medications. [ABSTRACT FROM AUTHOR]

Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs. [ABSTRACT FROM AUTHOR]

Once it enters the host cell, herpes simplex virus type 1 (HSV-1) recruits a series of host cell factors to facilitate its life cycle. Here, we demonstrate that serine/arginine-rich splicing factor 2 (SRSF2), which is an important component of the splicing speckle, mediates HSV-1 replication by regulating viral gene expression at the transcriptional and posttranscriptional levels. Our results indicate that SRSF2 functions as a transcriptional activator by directly binding to infected cell polypeptide 0 (ICP0), infected cell polypeptide 27 (ICP27), and thymidine kinase promoters. Moreover, SRSF2 participates in ICP0 pre-mRNA splicing by recognizing binding sites in ICP0 exon 3. These findings provide insight into the functions of SRSF2 in HSV-1 replication and gene expression. [ABSTRACT FROM AUTHOR]

Two novel cycloalkoxy silane compounds (ED1 and ED2) were synthesized and used as the external electron donors (EEDs) in Ziegler-Natta catalysts with diethyl 2,3-diisopropylsuccinate as internal electron donor. The results indicated that the Ziegler-Natta catalysts using ED1 and ED2 as EEDs had high catalytic activities and good stereoselectivities. The melt flow rate (MFR) and gel permeation chromatography (GPC) results revealed that the obtained polypropylene has higher MFR and lower average molecular weights than the commercial EED cyclohexyl methyl dimethoxysilane. The differential scanning calorimetry (DSC) results indicated that new isospecific active centers formed after the introduction of new external donors. The work implied that the novel EEDs could improve the hydrogen sensitivities of the catalyst system and obtain polymers with high melt flow rate. [ABSTRACT FROM AUTHOR]

Motivation: Biomedical researchers often search through massive catalogues of literature to look for potential relationships between genes and diseases. Given the rapid growth of biomedical literature, automatic relation extraction, a crucial technology in biomedical literature mining, has shown great potential to support research of gene-related diseases. Existing work in this field has produced datasets that are limited both in scale and accuracy. Results: In this study, we propose a reliable and efficient framework that takes large biomedical literature repositories as inputs, identifies credible relationships between diseases and genes, and presents possible genes related to a given disease and possible diseases related to a given gene. The framework incorporates name entity recognition (NER), which identifies occurrences of genes and diseases in texts, association detection whereby we extract and evaluate features from gene-disease pairs, and ranking algorithms that estimate how closely the pairs are related. The F1-score of the NER phase is 0.87, which is higher than existing studies. The association detection phase takes drastically less time than previous work while maintaining a comparable F1-score of 0.86. The end to- end result achieves a 0.259 F1-score for the top 50 genes associated with a disease, which performs better than previous work. In addition, we released a web service for public use of the dataset. [ABSTRACT FROM AUTHOR]

Background: The formation of new lymphatic vessels provides an additional route for tumour cells to metastasize. Therefore, inhibiting lymphangiogenesis represents an interesting target in cancer therapy. First evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with lymphangiogenesis. However, the underlying mechanisms of HDACi induced anti-lymphangiogenic properties are not fully investigated so far and in part remain unknown. Methods: Human lymphatic endothelial cells (LEC) were cultured in vitro and treated with or without HDACi. Effects of HDACi on proliferation and cell cycle progress were analysed by BrdU assay and flow cytometry. Apoptosis was measured by quantifying mono- and oligonucleosomes in the cytoplasmic fraction of cell lysates. In vitro lymphangiogenesis was investigated using the Matrigel short term lymphangiogenesis assay. The effects of TSA on cell cycle regulatory proteins and apoptosis-related proteins were examined by western blotting, immunofluorescence staining and semi-quantitative RT-PCR. Protein- and mRNA half-life of p21 were analysed by western blotting and quantitative RT-PCR. The activity of the p21 promoter was determined using a dual luciferase assay and DNA-binding activity of Sp1/3 was investigated using EMSA. Furthermore, siRNA assays were performed to analyse the role of p21 and p53 on TSA-mediated anti-lymphangiogenic effects. Results: We found that HDACi inhibited cell proliferation and that the pan-HDACi TSA induced G0/G1 arrest in LEC. Cell cycle arrest was accompanied by up-regulation of p21, p27 and p53. Additionally, we observed that p21 protein accumulated in cellular nuclei after treatment with TSA. Moreover, we found that p21 mRNA was significantly upregulated by TSA, while the protein and mRNA half-life remained largely unaffected. The promoter activity of p21 was enhanced by TSA indicating a transcriptional mechanism. Subsequent EMSA analyses showed increased constitutive Sp1/3-dependent DNA binding in response to HDACi. We demonstrated that p53 was not required for TSA induced p21 expression and growth inhibition of LECs. Interestingly, siRNA-mediated p21 depletion almost completely reversed the anti-proliferative effects of TSA in LEC. In addition, TSA induced apoptosis by cytochrome c release contributed to activating caspases-9, -7 and -3 and downregulating the anti-apoptotic proteins cIAP-1 and -2. Conclusions: In conclusion, we demonstrate that TSA - a pan-HDACi - has distinct anti-lymphangiogenic effects in primary human lymphatic endothelial cells by activating intrinsic apoptotic pathway and cell cycle arrest via p21- dependent pathways. [ABSTRACT FROM AUTHOR]