TET-2 up-regulation is associated with the anti-inflammatory action of Vicenin-2

Vicenin-2, a C-glycoside flavone that is present in many plant sources, exerts potent anti-inflammatory effects in a number of cell and animal models of inflammation. Ten-eleven translocation (TET)-2 has recently gained considerable attention due to the role it plays in regulating the inflammasome. We studied the ability of Vicenin-2 (V-2) to regulate a range of lipopolysaccharide (LPS) stimulated inflammatory activities in PMA-differentiated THP-1 cells and human primary mononuclear cells. We also investigated the action of V-2 on the secretion of NLRP3 inflammasome regulated cytokines (IL-1β and IL-18) by ELISA, and determined if V-2 can regulate the expression of NLRP3, IL-10, IL-1Ra and TET-2. The effect of V-2 on NF-κB signalling was investigated by fluorescence microscopy and gene reporter assay. Additionally, the effect of V-2 on LPS-induced phosphorylation of IKB-α was also investigated by Western blot analysis. V-2 down-regulated LPS-induced secretion of proinflammatory cytokines (TNF-α and IL-1β), in both THP-1 and primary mononuclear cells. V-2 also decreased the LPS-stimulated secretion of IL-18 in THP-1 cells. V-2 significantly down-regulated TNF-α induced NF-κB reporter activity in HEK293T transfected cells and attenuated IKB-α phosphorylation in THP-1 cells. V-2 treatment also induced enhanced nuclear staining of the p50 subunit and reduced p65 subunit of NF-κB. V-2 treatment alone increased the expression of anti-inflammatory cytokine, IL-10, and the regulator of the inflammasome; IL-1Ra, in the presence of LPS. V-2 also significantly decreased LPS-induced NLRP3 expression while concomitantly increasing TET-2 expression. This study demonstrates that the anti-inflammatory actions of V-2 are associated not only with increased IL-10 and IL-1Ra expression, but also with TET-2 up-regulation. Further work is required to establish if the effects of V-2 can be definitively linked to TET-2 activity and that these actions are mirrored in a range of relevant cell types

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Įsipareigojimų įvertinimas kooperatinėje organizacijoje Nigerijoje

Limited studies exist on the commitment of members to cooperative business organizations. This study assesses commitment in the cooperative organization and determines its relationship with members’ individual characteristics. Primary data collected covers information on affective, continuance and normative commitment of cooperative members, in addition to demographic characteristics. Analysis of the data shows that cooperative members are indifferent to affective, continuance and normative measures of commitment in cooperative organizations. Gender characteristics, level of education and years of membership are critical to obtaining commitment in cooperative organizations. Cooperative organizations are encouraged to consider the personal characteristics of members in a drive to elicit the desired level of commitment.Tyrimų, kuriuose įvertinamas narių įsipareigojimas kooperatinėms verslo organizacijoms, kiekis yra labai ribotas. Šis tyrimas įvertina narių įsipareigojimo kooperatinėms organizacijoms lygį ir nustato jo santykį su šių organizacijų narių individualiomis savybėmis. Pirminiai surinkti duomenys apima informaciją apie kooperatinių organizacijų narių emocinį, tęstinumo ir norminį įsipareigojimą ir demografines ypatybes. Duomenų analizė rodo, kad kooperatinės organizacijos nariai neabejingi šiose organizacijose vykstančioms afektinėms, tęstinumo ir norminėms įsipareigojimų priemonėms. Lyties ypatumai, išsilavinimo lygis ir narystės metai yra labai svarbūs norint, kad nariai būtų įsipareigoję kooperatinėms organizacijoms. Kooperatinės organizacijos yra skatinamos atsižvelgti į narių asmenines savybes, norint pasiekti norimą įsipareigojimų lygį

The Minority Question in Ife Politics, 1946–2014

The minority problem has been a major issue of interest at both the micro and national levels. Aside from the acclaimed Yoruba homogeneity and the notion of Ile-Ife as the cradle of Yoruba civilization, relationships between Ife indigenes and other communities in Ife Division (now in Osun State, Nigeria) have generated issues due to, and influenced by, political representation. Where allegations of marginalization have not been leveled, accommodation has been based on extraneous considerations, similar to the ways in which outright exclusion and/or extermination have been put forward. Not only have suspicion, feelings of outright rejection, and subtle antagonism characterized majority–minority relations in Ife Division/ Administrative Zone, they have also produced political-cum-administrative and territorial adjustments. As a microcosm of the Nigerian state, whose major challenge since attaining political independence has been the harmonization of interests among the various ethnic groups in the country, the Ife situation presents a peculiar example of the myths and realities of majority domination and minority resistance/response, or even a supposed minority attempt at domination. This study examines the nature of relationships between Ile-Ife and its surrounding communities, all of which are organized using a nomenclature that has been variously called Ife Division, District, Constituency, or Zone since 1946. It examines the claims or allegations of marginalization vis-à-vis efforts at integration and accommodation over a period of time with the aim of determining trends and/or changes or shifts, along with their underlying causes and implications. Given that political accommodation mostly goes beyond ethnic or sub-ethnic factors and defies majority–minority permutations, this study contends that building bridges across ethnic or sub-ethnic divides will enhance reciprocity and the eventual accommodation of the supposed minority

The Assessment of Commitment in the Cooperative Organization in Nigeria

Limited studies exist on the commitment of members to cooperative business organizations. This study assesses commitment in the cooperative organization and determines its relationship with members’ individual characteristics. Primary data collected covers information on affective, continuance and normative commitment of cooperative members, in addition to demographic characteristics. Analysis of the data shows that cooperative members are indifferent to affective, continuance and normative measures of commitment in cooperative organizations. Gender characteristics, level of education and years of membership are critical to obtaining commitment in cooperative organizations. Cooperative organizations are encouraged to consider the personal characteristics of members in a drive to elicit the desired level of commitment

Applications, Prospects and Challenges of Silicon Carbide Junction Field Effect Transistor (SIC JFET)

Properties of Silicon Carbide Junction Field Effect Transistor (SiC JFET) such as high switching speed, low forward voltage drop and high temperature operation have attracted the interest of power electronic researchers and technologists, who for many years developed devices based on Silicon (Si).  A number of power system Engineers have made efforts to develop more robust equipment including circuits or modules with higher power density. However, it was realized that several available power semiconductor devices were approaching theoretical limits offered by Si material with respect to capability to block high voltage, provide low on-state voltage drop and switch at high frequencies. This paper presents an overview of the current applications of SiC JFET in circuits such as inverters, rectifiers and amplifiers. Other areas of application reviewed include; usage of the SiC JFET in pulse signal circuits and boost converters. Efforts directed toward mitigating the observed increase in electromagnetic interference were also discussed. It also presented some areas for further research, such as having more applications of SiC JFET in harsh, high temperature environment. More work is needed with regards to SiC JFET drivers so as to ensure stable and reliable operation, and reduction in the prices of SiC JFETs through mass production by industries

Direct formation of thienopyridine-derived nitrosothiols - Just add nitrite!

Thienopyridines (ticlopidine, clopidogrel and prasugrel) are pro-drugs that require metabolism to exhibit a critical thiol group in the active form that binds to the P2Y"1"2 receptor to inhibit platelet activation and prevent thrombus formation in vivo. We investigated whether these thienopyridines participate in S-nitrosation (SNO) reactions that might exhibit direct anti-platelet behaviour. Optimum conditions for in vitro formation of thienopyridine-SNO formation were studied by crushing ticlopidine, clopidogrel or prasugrel into aqueous solution and adding sodium nitrite, or albumin-SNO. Ozone-based chemiluminescence techniques were utilised to specifically detect NO release from the SNO produced. Effect on agonist-induced platelet aggregation was monitored using light transmittance in a 96 well microplate assay. Pharmaceutical grade preparations of ticlopidine, clopidogrel and prasugrel were found to exhibit significant free thiol and formed SNO derivatives directly from anionic nitrite in water under laboratory conditions without the need for prior metabolism. Thienopyridine-SNO formation was dependent on pH, duration of mixing and nitrite concentration, with prasugrel-SNO being more favourably formed. The SNO moiety readily participated in trans-nitrosation reactions with albumin and plasma. Prasugrel-SNO showed significantly better inhibition of platelet aggregation compared with clopidogrel-SNO, however when compared on the basis of SNO concentration these were equally effective (IC"5"0=7.91+/-1.03 v/s 10.56+/-1.43@mM, ns). Thienopyridine-derived SNO is formed directly from the respective base drug without the need for prior in vivo metabolism and therefore may be an important additional contributor to the pharmacological effectiveness of thienopyridines not previously considered

The discovery of some promising putative binders of KRAS G12D receptor using computer-aided drug discovery approach

A prospective target for the therapy of solid tumors is KRAS G12D, the most prevalent oncogenic KRAS mutation. However, despite decades of research that focused on the identification of druggable compounds against this highly challenging therapeutic cancer target, no drug has been clinically approved for the treatment of KRAS G12D-driven cancers. Herein, we employed computational techniques such as molecular docking and molecular dynamics simulations to investigate small-molecule compounds with the potential to bind putatively with KRAS G12D. The docking screening portrayed three compounds (Quercetin, Psoralidin, and Resveratrol) as promising drug candidates for the receptor target due to their higher binding affinities when compared with a known noncovalent, potent, and selective KRAS G12D inhibitor (MRTX1133). The stability analysis after 100000 ps molecular dynamics simulation suggests Quercetin as a more stable compound when compared with the other simulated chemical entities, including the referenced inhibitor (MRTX1133). In spite of our research findings, it will be too early to conclude the drug candidates can be advanced to the clinic for use with KRAS G12D cancer patients without extensive preclinical and clinical studies