Evidence that phosphatidylinositol 3-kinase is involved in sperm-induced tyrosine kinase signaling in Xenopus egg fertilization

<p>Abstract</p> <p>Background</p> <p>Studies have examined the function of PI 3-kinase in the early developmental processes that operate in oocytes or early embryos of various species. However, the roles of egg-associated PI 3-kinase and Akt, especially in signal transduction at fertilization, are not well understood.</p> <p>Results</p> <p>Here we show that in <it>Xenopus </it>eggs, a potent inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), LY294002 inhibits sperm-induced activation of the tyrosine kinase Src and a transient increase in the intracellular concentration of Ca²⁺at fertilization. LY294002 also inhibits sperm-induced dephosphorylation of mitogen-activated protein kinase, breakdown of cyclin B2 and Mos, and first embryonic cleavage, all of which are events of Ca²⁺-dependent egg activation. In fertilized eggs, an 85-kDa subunit of PI 3-kinase (p85) undergoes a transient translocation to the low-density, detergent-insoluble membranes (membrane microdomains) where Src tyrosine kinase signaling is operating. However, the tyrosine phosphorylation of p85 in fertilized eggs is not as evident as that in H2O2-activated eggs, arguing against the possibility that PI 3-kinase is activated by Src phosphorylation. Nevertheless, sperm-induced activation of PI 3-kinase has been demonstrated by the finding that Akt, a serine/threonine-specific protein kinase, is phosphorylated at threonine-308. The threonine-phosphorylated Akt also localizes to the membrane microdomains of fertilized eggs. Application of bp(V), an inhibitor of PTEN that dephosphorylates PIP3, the enzymatic product of PI 3-kinase, promotes parthenogenetic activation of <it>Xenopus </it>eggs. In vitro kinase assays demonstrate that PIP3 activates Src in a dose-dependent manner.</p> <p>Conclusions</p> <p>These results suggest that PI 3-kinase is involved in sperm-induced egg activation via production of PIP3 that would act as a positive regulator of the Src signaling pathway in <it>Xenopus </it>fertilization.</p

1-Methyl-2,3-dihydro-1H-benzimidazole-2-selone

The title compound C8H8N2Se, is the product of the reaction of 2-chloro-1-methyl­benzimidazole with sodium hydro­selenide. The mol­ecule is almost planar (r.m.s. deviation = 0.041 Å) owing to the presence of the long chain of conjugated bonds (Se=C—NMe—C=C—C=C—C=C—NH). The C=Se bond length [1.838 (2) Å] corresponds well to those found in the close analogs and indicates its pronounced double-bond character. In the crystal, mol­ecules form helicoidal chains along the b axis by means of N—H⋯Se hydrogen bonds

rac-Ethyl 6-hy­droxy-6-methyl-3-oxo-4-phenyl-1,3,4,5,6,7-hexa­hydro­benzo[c][1,2]oxazole-5-carboxyl­ate

In the title compound, C17H19NO5, the cyclo­hexene ring is in a half-chair conformation and the isoxazole ring in an envelope conformation with the N atom as the flap. The C atoms in the 4- and 6-positions are of the same absolute configuration, whereas the C atom in the 5-position is of the opposite configuration, i.e. (4S*,5R*,6S*). The methyl fragment of the eth­oxy­carbonyl group at position 5 is disordered over two sets of sites in a 0.60:0.40 ratio. The crystal packing displays inter­molecular N—H⋯O and O—H⋯O hydrogen bonds

(7aR*,12bS*)-8,12b-Dihydro-7aH-indeno­[1′,2′:5,6][1,4]selenazino[2,3,4-ij]quinolin-13-ium hydrogen sulfate

In the title compound, C18H14NSe+·HSO4 −, the cyclo­pentene ring in the cation has an envelope conformation while the central six-membered 1,4-selenazine ring adopts a sofa conformation. The dihedral angle between the planes of the terminal benzene rings is 68.08 (11)°. In the crystal, the anions form chains along the c axis through O—H⋯O hydrogen bonds. Weak C—H⋯O and C—H⋯π hydrogen bonds, as well as attractive Se⋯Se [3.5608 (8) Å] inter­actions, further consolidate the crystal structure

1,3-Benzothia­zole-2(3H)-selone

The title compound, C7H5NSSe, is the product of the reaction of 2-chloro­benzothia­zole with sodium hydro­selenide. The mol­ecule is almost planar (r.m.s. deviation = 0.018 Å) owing to the presence of the long chain of conjugated bonds (Se=C—N—C=C—C=C—C=C). The geometrical parameters correspond well to those of the analog N-methyl­benzothia­zole-2(3H)-selone, demonstrating that the S atom does not take a significant role in the electron delocalization within the mol­ecule. In the crystal, mol­ecules form centrosymmetric dimers by means of inter­molecular N—H⋯Se hydrogen bonds. The dimers have a nonplanar ladder-like structure. Furthermore, the dimers are linked into ribbons propagating in [010] by weak attractive Se⋯S [3.7593 (4) Å] inter­actions

NATIONAL GEOINFORMATION SYSTEM OF NATURAL RESOURCES OF THE AZERBAIJAN REPUBLIC FOR ENVIRONMETNTAL PROTECTION

One of the main problems of natural and economic planning of the natural and anthropogenic geosystem is the detection of urgent characteristics of various types of geosystems through application of the complex of methods of modern mathematics such as, theory of information (information-statistical methods and etc.); theory of mathematic statics (methods of factoral, regressional, correlational, component and dispersional analysis etc.); theory of linear and matrix algebra (methods of linear programming, simplex methods and etc.); theory of distribution (methods of parameters estimation of universe etc.); theory of random functions (methods of definition of probability of events etc.); theory of graphs; theory of catastrophes etc

Constructing the National Identity Discourse in Citizenship Education Policy: The Case of Citizenship Education in England

The thesis examines the governmental construction of national identity through its citizenship education policy in England, the country with heightened tensions in diversity and identity re-construction aligning with its mandatory citizenship classes since 2002. Theoretically framing the study on the Foucauldian post-structuralism, the thesis utilises Foucauldian-influenced ‘What is the problem represented to be?’ (WPR) method by Bacchi that presents the government as a problem-producer. Conducting qualitative research methods, the study analyses the current National Curriculum in England with the explanatory and foundational state documents of Crick and Ajegbo Reports. The thesis identifies that the government primarily aims to re-construct the inclusive and integrative national identity based on the acknowledgement of multiple identities and a plurality of nations in the citizenship education curriculum in England. The study, however, also reveals that the English citizenship education policy implicitly presents a few assimilationist elements in the national identity discourse through exclusion and unrepresentativeness of the ethnic and racial identities, hierarchical establishment between native English and minorities, and the division of ‘whites’ and ‘non-whites’. Comparatively examining the documents, the thesis, therefore, concludes that the government has a powerful position in socially and politically re- constructing the discourses, concepts, and meanings over time

Alkol dışı yağlı karaciğer hastalığının fibrozisteki ilerleme hızı ve ilişkili faktörlerin saptanması

GİRİŞ: Non-alkolik yağlı karaciğer hastalığı (NAFLD) yetişkinlerin yaklaşık dörtte birinden fazlasını etkileyerek kronik karaciğer hastalığının dünya genelinde en sık nedeni haline gelmiştir. NAFLD sessiz, asemptomatik seyir göstermesine rağmen potansiyel olarak progressif hastalık olması nedeniyle erken teşhisi oldukça önemlidir. NAFLD'da karaciğerle ilişkili genel morbidite ve mortalitenin en önemli göstergesi ilerleyici karaciğer fibrozu gelişmesidir. Karaciğer biyopsisi invaziv işlem olup hastalığının evresini anlık olarak değerlendirmektedir, hastalığın takibinde anlık değerlendirmeden daha önemlisi hastalığın değişim hızının, ilerleme hızının önceden kestirilebilmesidir. Non-invaziv yöntemler tekrarlanabilir oldukları için hem tanı, hem hastaların takibinde kullanılabilirler. Karaciğer fibrozisini değerlendiren non-invaziv birçok skorlama sistemleri vardır ancak en yaygın kullanılanları Fib-4, APRI ve NAFLD-Fibrozis skorlarıdır. APRI diğerlerinden daha zayıf bir skorlama sistemi olarak görünmektedir. Fib-4 ve NAFLD-F skorunu karşılaştıran bazı çalışmalar, bu iki skor arasında fark bulmazken, bazı çalışmalarda seçilen cut-off değerine bağlı olarak Fib-4'ün invaziv ancak altın standart yöntem olan biyopsi ile uyumunu daha yüksek bulmuşlardır. Biz de çalışmamızda daha kolay hesaplanabilen, daha çok hastada verisi olan ve kendi veri tabanımızda biyopsi verileri olan NAFLD hastalarında yaptığımız değerlendirmede biyopsideki fibrozisle en fazla korelasyon gösteren Fib-4 skoru üzerinden hastalığın ilerleme hızını ön görebilecek bir prognostik indeks geliştirmeyi amaçladık. AMAÇ-YÖNTEM: Bu çalışmaya, Ocak 1996 tarihinden Ekim 2020 tarihine kadar Ege Üniversitesi Tıp Fakültesi Hastanesi Gastroenteroloji Bilim Dalı, Hepatoloji Polikliniğinde en az 1 yıl takip edilen alkol dışı karaciğer yağlanması tanısı konan, bazal verileri olan toplam 637 hasta çalışmaya alındı. Fib-4 skorunda yılda en az 0,4 puan ilerleme gösteren hastalar hızlı fibrozis ilerlemesi olan hastalar olarak kabul edildi. Hızlı fibrozis ilerlemesi ile ilişkili olabilecek bazal parametreler araştırıldı. İlişkili bulunan parametreler regresyon analizlerine alındı. Fib-4 skoru üzerinden hastalığın ilerleme hızını ön görebilecek bir prognostik indeks geliştirmek amaçlandı. BULGULAR: Hastaların 356'sı (% 55,9) kadın, 281'i (% 44,1) erkektir. Takip süresi: 5.9 ±4,7 yıl, median: 4,4 yıldır (1-23 yıl). Başvuru esnasında yaş: 51,6±11,5, median:53 yaş, x BMİ: 30,18±4,76 median:29,7 kg/m2 dir. Hastaların başvuru esnasında % 40,2'si kilolu, %47,7'si obez bireylerdir. Biyopsi verileri olan 161 NAFLD hastasında yaptığımız değerlendirmede APRI, Fib-4 ve NAFLD-fibrozis skorlarının biyopsideki fibrozisle korelasyonu araştırılmış ve en yüksek uyumun Fib-4'te görüldüğü hesaplanmıştır. Fib-4 skorunda yılda 0,4 puan ilerlemeyle ilişkili bulunan pekçok bazal parametre arasında AKŞ (OR: 1,0081, %95 CI: 1,0024 - 1,0139), potasyum düzeyi (OR: 0,2075, %95 CI: 0,0574 - 0,7503), ve trombosit sayısı (OR: 0,9832, %95 CI: 0,9765 - 0,9899) çok değişkenli lojistik regresyon analizinde bağımsız olarak ilişkili saptanmıştır. Regresyon analizleri sonrasında elde edilen prognostik indeks = 6,36769 + 0,008084×AKŞ (mg/dL) – 1,57261×Potasyum (mEq/L) - 0,01696×Platelet (x109 /μL) olarak saptanmış ve ROC analizi ile elde edilen cut-off değerinden (0,0453 puandan) yüksek olmanın Fib-4 skorunda yıllık 0,4 puan ilerlemesini ön görmedeki sensitivitesi %96,0, spesifisitesi %78,9 olarak hesaplanmıştır (AUC: 0,916). SONUÇ: Oluşturulan skor, takip sonunda ileri Fib-4, APRI ve NAFLD-F-skoruna sahip olmayı yüksek oranda öngörmektedir ancak oluşturulan bu prediktif indeksin karaciğer histolojisindeki progresyonla ilişkisi araştırılarak valide edilmesi gerekmektedir.INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) affects more than a quarter of adults, making it the most common cause of chronic liver disease worldwide. Although NAFLD has a silent and asymptomatic disease, early diagnosis is very important because it is a potentially progressive disease. The most important indicator of general liver-related morbidity and mortality in NAFLD is the degree of liver fibrosis. Liver biopsy is an invasive procedure and it evaluates the stage of the disease instantaneously. However, determining the rate of change in hepatic fibrosis is prognostically more important than the instantaneous assessment of fibrosis. Since noninvasive methods are reproducible, they can be used both in diagnosis and in the follow-up of patients. There are many non-invasive scoring systems that evaluate liver fibrosis, but the most commonly used are Fib-4, APRI and NAFLD-Fibrosis scores. APRI appears to be a weaker scoring system than others. While some studies comparing Fib-4 and NAFLD-F scores did not find a difference between these two scores, some found a higher agreement of Fib-4 with biopsy. In our study, we aimed to develop a prognostic index that can predict the rate of progression of the disease over the Fib-4 score, which is the most correlated with fibrosis in the biopsy in our evaluation of NAFLD patients, which can be calculated more easily, have data on more patients and have biopsy data in our database. AIMS ; METHODS: A total of 637 patients with baseline data and diagnosed with non alcoholic fatty liver disease, followed for at least 1 year in Ege University Medical Faculty Hospital Gastroenterology Department Hepatology Polyclinic from January 1996 to October 2020 were included in the study. Patients with a progression of at least 0,4 points per year in the Fib-4 score were considered as patients with rapid fibrosis progression. Basal parameters that may be associated with rapid fibrosis progression were investigated. The related parameters were included in the regression analysis. We aimed to develop a prognostic index that can predict the progression rate of the disease based on the Fib-4 score. RESULTS: Of the patients, 356 (55.9%) were female and 281 (44.1%) were male. Follow-up period: 5,9 ± 4,7 years, median: 4,4 years (1-23 years). Age at admission: 51,6±11,5, xii median:53 years, BMI: 30,18±4,76 median: 29,7 kg/m2. At the time of admission, 40,2% of the patients were overweight and 47,7% were obese. In our evaluation of 161 NAFLD patients with biopsy data, the correlation of APRI, Fib-4 and NAFLD-fibrosis scores with fibrosis in biopsy was investigated and it was calculated that the highest agreement was seen in Fib-4. Among the baseline parameters associated with an improvement of 0,4 points per year in the Fib-4 score, FAB (OR: 1,0081, 95% CI: 1,0024 – 1,0139), potassium level (OR: 0,2075, 95% CI: 0,0574 – 0,7503), and platelet count (OR: 0,9832, 95% CI: 0,9765 – 0,9899) were independently associated in multivariate logistic regression analysis. According to the multivariate logistic regression study, a prognostic index was developed (The prognostic index = 6.36769 + 0.008084×FPG (mg/dL) – 1.57261×Potassium (mEq/L) - 0.01696×Platelet (x109/L)). ROC analysis established a cut-off (>0,0453) level with 96,0% sensitivity and 78,9% specificity in predicting annual progression of 0,4 points in the Fiv-4 score (AUC=0,916). CONCLUSION: The generated score highly predicts to have advanced Fib-4, APRI and NAFLD-F-scores at the end of the follow-up, but this predictive index should be validated with the histological follow-up studies