Blockholder Characteristics and Earnings Quality

This study focuses on the impact of blockholder characteristics on earnings quality. Most of the studies inliterature make the implicit assumption that blockholders are a homogeneous group. This study is one offew studies that acknowledges the heterogeneity of blockholders and attempts to understand theunexplained proportion of blockholder heterogeneity. Earnings quality is calculated using the modifiedDechow and Dichev (2002) model with fixed effects (FDD model) by Lee and Masulis (2009), and it isregressed on various blockholder characteristics. The results show that earnings quality is lower forfirms with market-driven and multilateral blockholders

Turnip mosaic potyvirus probably first spread to Eurasian brassica crops from wild orchids about 1000 years ago

Turnip mosaic potyvirus (TuMV) is probably the most widespread and damaging virus that infects cultivated brassicas worldwide. Previous work has indicated that the virus originated in western Eurasia, with all of its closest relatives being viruses of monocotyledonous plants. Here we report that we have identified a sister lineage of TuMV-like potyviruses (TuMV-OM) from European orchids. The isolates of TuMV-OM form a monophyletic sister lineage to the brassica-infecting TuMVs (TuMV-BIs), and are nested within a clade of monocotyledon-infecting viruses. Extensive host-range tests showed that all of the TuMV-OMs are biologically similar to, but distinct from, TuMV-BIs and do not readily infect brassicas. We conclude that it is more likely that TuMV evolved from a TuMV-OM-like ancestor than the reverse. We did Bayesian coalescent analyses using a combination of novel and published sequence data from four TuMV genes [helper component-proteinase protein (HC-Pro), protein 3(P3), nuclear inclusion b protein (NIb), and coat protein (CP)]. Three genes (HC-Pro, P3, and NIb), but not the CP gene, gave results indicating that the TuMV-BI viruses diverged from TuMV-OMs around 1000 years ago. Only 150 years later, the four lineages of the present global population of TuMV-BIs diverged from one another. These dates are congruent with historical records of the spread of agriculture in Western Europe. From about 1200 years ago, there was a warming of the climate, and agriculture and the human population of the region greatly increased. Farming replaced woodlands, fostering viruses and aphid vectors that could invade the crops, which included several brassica cultivars and weeds. Later, starting 500 years ago, inter-continental maritime trade probably spread the TuMV-BIs to the remainder of the world

The orphan receptor ERRα interferes with steroid signaling

The estrogen receptor-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily that has been shown to interfere with the estrogen-signaling pathway. In this report, we demonstrate that ERRα also cross-talks with signaling driven by other steroid hormones. Treatment of human prostatic cells with a specific ERRα inverse agonist reduces the expression of several androgen-responsive genes, in a manner that does not involve perturbation of androgen receptor expression or activity. Furthermore, ERRα activates the expression of androgen response elements (ARE)-containing promoters, such as that of the prostate cancer marker PSA, in an ARE-dependent manner. In addition, promoters containing a steroid response element can be activated by all members of the ERR orphan receptor subfamily, and this, even in the presence of antisteroid compounds

Endothelial dysfunction of bypass graft: Direct comparison of In Vitro and In Vivo models of ischemia-reperfusion injury

BACKGROUND: Although, ischemia/reperfusion induced vascular dysfunction has been widely described, no comparative study of in vivo- and in vitro-models exist. In this study, we provide a direct comparison between models (A) ischemic storage and in-vitro reoxygenation (B) ischemic storage and in vitro reperfusion (C) ischemic storage and in-vivo reperfusion. METHODS AND RESULTS: Aortic arches from rats were stored for 2 hours in saline. Arches were then (A) in vitro reoxygenated (B) in vitro incubated in hypochlorite for 30 minutes (C) in vivo reperfused after heterotransplantation (2, 24 hours and 7 days reperfusion). Endothelium-dependent and independent vasorelaxations were assessed in organ bath. DNA strand breaks were assessed by TUNEL-method, mRNA expressions (caspase-3, bax, bcl-2, eNOS) by quantitative real-time PCR, proteins by Western blot analysis and the expression of CD-31 by immunochemistry. Endothelium-dependent maximal relaxation was drastically reduced in the in-vivo models compared to ischemic storage and in-vitro reperfusion group, and no difference showed between ischemic storage and control group. CD31-staining showed significantly lower endothelium surface ratio in-vivo, which correlated with TUNEL-positive ratio. Increased mRNA and protein levels of pro- and anti-apoptotic gens indicated a significantly higher damage in the in-vivo models. CONCLUSION: Even short-period of ischemia induces severe endothelial damage (in-vivo reperfusion model). In-vitro models of ischemia-reperfusion injury can be limitedly suited for reliable investigations. Time course of endothelial stunning is also described

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

First-in-class humanized FSH blocking antibody targets bone and fat

Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing

Kemijski sastav te antioksidacijski, citotoksični i insekticidni potencijal valerijane Valeriana alliariifolia u Turskoj

Valeriana is a common plant species used for various healing purposes in folk medicine since antiquity. This study investigates the phytochemical profile, antioxidant, cytotoxic, and insecticidal activity of Valeriana alliariifolia Adams, a species that has traditionally been used in Turkey. For the analyses we prepared four root extracts of V. alliariifolia Adams using hexane (HM1), chloroform (CM1), ethanol (EM1), and water (WM1) for maceration. Additionally, two extracts were also prepared from its roots by maceration separately with ethanol (EM2) and water (WM2). One sample was prepared as a water infusion (WI), according to the procedure used in Turkish traditional medicine. The 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation scavenging activity tests showed that ethanol extracts had the strongest antioxidant activity: EM1 (IC50 – DPPH: 17.694 μg/mL; ABTS: 23.8 μg/mL) and EM2 (IC50 – DPPH: 20 μg/mL; ABTS: 21.5 μg/mL). The hexane extract, HM1, was the most cytotoxic (IC50<10 μg/mL against HepG2 and HUVEC) and EM2 strongly cytotoxic (IC50<10 μg/mL against HepG2 and IC50: 11.96 μg/mL against HUVEC). The extracts with demonstrated cytotoxic activities were further examined to check their insecticidal activity against adult female mosquito Aedes aegypti and first instar Ae. aegypti larvae. HM1 was the most effective (90±10 %), which was consistent with its cytotoxic activity. Because of the high antioxidant, cytotoxic, and insecticidal activities, we ran phytochemical analyses of the HM1, EM1, and EM2 extracts with GC-MS (for HM1) and LC-MS/MS (for EM1 and EM2). We also analysed the composition of the essential oil obtained from V. alliariifolia roots by micro-distillation in order to compare its content with HM1, which contains volatile compounds. Phytochemical analyses revealed that the major compound in HM1 was isovaleric acid (16 %) and in the essential oil 1,8-cineole (2.9 %). EM1 and EM2 contained 5-O-caffeoylquinic acid (chlorogenic acid), verbascoside (acteoside), and 3,5-dicaffeoylquinic acid as major components. In the light of our findings and available literature, we can conclude that V. alliariifolia has a good bioactive potential that could be used for different purposes, including the development of new agents for the treatment of various diseases. The difference in the content between the essential oil and HM1 was remarkable. It suggests that the variability observed in the activity of the samples was a result of composition and that, therefore, the aim of treatment should dictate which type of preparation is to be selected. An added value of our study is that it determined verbascoside and methylquercetin rutinoside for the first time in the Valeriana extracts.Valerijana (odoljen) česta je biljna vrsta koja se zbog svojih ljekovitih svojstava od davnina rabi u narodnoj medicini. U ovome se istraživanju utvrdio fitokemijski profil te antioksidacijsko, citotoksično i insekticidno djelovanje tradicionalne vrste koja se za liječenje rabi u Turskoj – Valeriana alliariifolia Adams. Za analizu je maceracijom pripremljeno šest ekstrakata njezina korijena pomoću heksana (HM1), kloroforma (CM1), etanola (EM1, EM2) i vode (WM1, WM2). Jedan je uzorak pripremljen infuzijom vodom (WI) prema tradicionalnom turskom receptu za ljekovite pripravke. Testovima antioksidacijskoga djelovanja pomoću 2,2-difenil-1-pikrilhidrazila (DPPH) i 2,2’-azino-bis(3-etilbenzotiazolin-6-sulfonične kiseline (ABTS) izdvojeni su sljedeći ekstrakti s najjačim antioksidacijskim djelovanjem: EM1 (IC50 – DPPH: 17,694 μg/mL; ABTS: 23,8 μg/mL) i EM2 (IC50 – DPPH: 20 μg/mL; ABTS: 21,5 μg/mL). Ekstrakt s heksanom, HM1, iskazao je najveću citotoksičnost (IC50<10 μg/mL protiv tumorskih stanica HepG2 i HUVEC), a EM2 snažnu citotoksičnost (IC50<10 μg/mL protiv HepG2 stanica te IC50 11,96 μg/mL protiv HUVEC stanica). Ekstrakte s najsnažnijim citotoksičnim djelovanjem također smo analizirali za insekticidno djelovanje protiv odraslih ženki komarca vrste Aedes aegypti te njihovih ličinki. U skladu sa svojom citotoksičnosti, HM1 se pokazao najdjelotvornijim (smrtnost 90±10 %). Zbog snažnog antioksidacijskog, citotoksičnog i insekticidnog djelovanja, napravili smo i fitokemijsku analizu ekstrakata HM1, EM1 i EM2 služeći se metodama GC-MS (za HM1) i LC-MS/MS (za EM1 i EM2). Također smo analizirali sastav esencijalnoga ulja dobivenoga mikrodestilacijom korijena V. alliariifolia kako bismo ga usporedili sa sastavom HM1, koji je sadržavao hlapljive sastojke. Fitokemijska je analiza pokazala da je glavni sastojak HM1 izovalerijanska kiselina (16 %), a esencijalnoga ulja 1,8-cineol (2,9 %). Glavni sastojci ekstrakata EM1 i EM2 bili su 5-O-kafeoilkvinska kiselina (klorogena kiselina), verbakozid (akteozid) i 3,5-dikafeoilkvinska kiselina. U svjetlu ovih rezultata i dostupne literature, možemo zaključiti da V. alliariifolia ima dobar bioaktivni potencijal, koji se može iskoristiti za različite svrhe poput razvoja novih tvari za liječenje bolesti. Razlika u sadržaju između esencijalnoga ulja i ekstrakta HM1 pokazala se golemom te upućuje na to da su razlike u aktivnosti između uzoraka rezultat sastava, zbog čega primjena/liječenje trebaju uvjetovati koja će se vrsta pripravka odabrati. Dodatna je vrijednost ovoga istraživanja što su se u ekstraktima valerijane prvi put otkrili verbaskozid i metilkvercetin rutinozid

Hysteretic Behavior of Proprotein Convertase 1/3 (PC1/3)

The proprotein convertases (PCs) are calcium-dependent proteases responsible for processing precursor proteins into their active forms in eukariotes. The PC1/3 is a pivotal enzyme of this family that participates in the proteolytic maturation of prohormones and neuropeptides inside the regulated secretory pathway. In this paper we demonstrate that mouse proprotein convertase 1/3 (mPC1/3) has a lag phase of activation by substrates that can be interpreted as a hysteretic behavior of the enzyme for their hydrolysis. This is an unprecedented observation in peptidases, but is frequent in regulatory enzymes with physiological relevance. The lag phase of mPC1/3 is dependent on substrate, calcium concentration and pH. This hysteretic behavior may have implications in the physiological processes in which PC1/3 participates and could be considered an additional control step in the peptide hormone maturation processes as for instance in the transformation of proinsulin to insulin